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Ther. 247, 1046–1051 (1988).",{},{"id":24,"text":367,"url":24,"identifiers":368},"Beardsley, P. M., Scimeca, J. A. & Martin, B. R. Studies on the agonistic activity of delta 9-11-tetrahydrocannabinol in mice, dogs and rhesus monkeys and its interactions with delta 9-tetrahydrocannabinol. J. Pharmacol. Exp. Ther. 241, 521–526 (1987).",{},{"id":24,"text":370,"url":24,"identifiers":371},"Turner, S. E. et al. Molecular pharmacology of phytocannabinoids. Prog. Chem. Org. Nat. Prod. 103, 61–101 (2017).",{},{"id":24,"text":373,"url":24,"identifiers":374},"Mechoulam, R. et al. Chemical basis of hashish activity. Science 169, 611–612 (1970).",{"doi":375},"10.1126\u002Fscience.169.3945.611",{"id":24,"text":377,"url":24,"identifiers":378},"Devinsky, O. et al. Cannabidiol in patients with treatment-resistant epilepsy: an open-label interventional trial. Lancet Neurol. 15, 270–278 (2016).",{"doi":379},"10.1016\u002FS1474-4422(15)00379-8",{"id":24,"text":381,"url":24,"identifiers":382},"Devinsky, O. et al. Trial of cannabidiol for drug-resistant seizures in the Dravet syndrome. N. Engl. J. Med. 376, 2011–2020 (2017). One of the clinical trials that led to approval of botanical cannabidiol for the treatment of rare forms of paediatric epilepsy.",{"doi":383},"10.1056\u002FNEJMoa1611618",{"id":24,"text":385,"url":24,"identifiers":386},"Devane, W. A. et al. Determination and characterization of a cannabinoid receptor in rat brain. Mol. Pharmacol. 34, 605–613 (1988). The first evidence for the existence of a specific binding site for THC.",{},{"id":24,"text":388,"url":24,"identifiers":389},"Bisogno, T. et al. Cloning of the first sn1-DAG lipases points to the spatial and temporal regulation of endocannabinoid signaling in the brain. J. Cell Biol. 163, 463–468 (2003). Identification of the first endocannabinoid biosythetic enzymes.",{"doi":390},"10.1083\u002Fjcb.200305129",{"id":24,"text":392,"url":24,"identifiers":393},"Cravatt, B. F. et al. Molecular characterization of an enzyme that degrades neuromodulatory fatty-acid amides. Nature 384, 83–87 (1996). Identification of the first endocannabinoid-degrading enzyme.",{"doi":394},"10.1038\u002F384083a0",{"id":24,"text":396,"url":24,"identifiers":397},"Dinh, T. P. et al. Brain monoglyceride lipase participating in endocannabinoid inactivation. Proc. Natl Acad. Sci. USA 99, 10819–10824 (2002).",{"doi":398},"10.1073\u002Fpnas.152334899",{"id":24,"text":400,"url":24,"identifiers":401},"Okamoto, Y. et al. Molecular characterization of a phospholipase D generating anandamide and its congeners. J. Biol. Chem. 279, 5298–5305 (2004).",{"doi":402},"10.1074\u002Fjbc.M306642200",{"id":24,"text":404,"url":24,"identifiers":405},"Jung, K. M. et al. An amyloid beta42-dependent deficit in anandamide mobilization is associated with cognitive dysfunction in Alzheimer’s disease. Neurobiol. Aging 33, 1522–1532 (2012).",{"doi":406},"10.1016\u002Fj.neurobiolaging.2011.03.012",{"id":24,"text":408,"url":24,"identifiers":409},"Altamura, C. et al. Elevation of plasma 2-arachidonoylglycerol levels in Alzheimer’s disease patients as a potential protective mechanism against neurodegenerative decline. J. Alzheimers Dis. 46, 497–506 (2015).",{"doi":410},"10.3233\u002FJAD-142349",{"id":24,"text":412,"url":24,"identifiers":413},"Di Iorio et al. The endocannabinoid system: a putative role in neurodegenerative diseases. Int. J. High Risk Behav. Addict. 2, 100–106 (2013).",{"doi":414},"10.5812\u002Fijhrba.9222",{"id":24,"text":416,"url":24,"identifiers":417},"Aymerich, M. S. et al. Cannabinoid pharmacology\u002Ftherapeutics in chronic degenerative disorders affecting the central nervous system. Biochem. Pharmacol. 157, 67–84 (2018).",{"doi":418},"10.1016\u002Fj.bcp.2018.08.016",{"id":24,"text":420,"url":24,"identifiers":421},"Mulder, J. et al. Molecular reorganization of endocannabinoid signalling in Alzheimer’s disease. Brain 134, 1041–1060 (2011). The first molecular evidence that endocannabinoid signalling might be overactive in AD.",{"doi":422},"10.1093\u002Fbrain\u002Fawr046",{"id":24,"text":424,"url":24,"identifiers":425},"Celorrio, M. et al. Fatty acid amide hydrolase inhibition for the symptomatic relief of Parkinson’s disease. Brain Behav. Immun. 57, 94–105 (2016).",{"doi":426},"10.1016\u002Fj.bbi.2016.06.010",{"id":24,"text":428,"url":24,"identifiers":429},"D’Addario, C. et al. Epigenetic regulation of fatty acid amide hydrolase in Alzheimer disease. PLOS ONE 7, e39186 (2012).",{"doi":430},"10.1371\u002Fjournal.pone.0039186",{"id":24,"text":432,"url":24,"identifiers":433},"Bilsland, L. G. et al. Increasing cannabinoid levels by pharmacological and genetic manipulation delay disease progression in SOD1 mice. FASEB J. 20, 1003–1005 (2006).",{"doi":434},"10.1096\u002Ffj.05-4743fje",{"id":24,"text":436,"url":24,"identifiers":437},"Di Marzo, V. Targeting the endocannabinoid system: to enhance or reduce? Nat. Rev. Drug Discov. 7, 438–455 (2008).",{"doi":438},"10.1038\u002Fnrd2553",{"id":24,"text":440,"url":24,"identifiers":441},"Kawahara, H. et al. Inhibition of fatty acid amide hydrolase unmasks CB1 receptor and TRPV1 channel-mediated modulation of glutamatergic synaptic transmission in midbrain periaqueductal grey. Br. J. Pharmacol. 163, 1214–1222 (2011).",{"doi":442},"10.1111\u002Fj.1476-5381.2010.01157.x",{"id":24,"text":444,"url":24,"identifiers":445},"Benito, C. et al. beta-Amyloid exacerbates inflammation in astrocytes lacking fatty acid amide hydrolase through a mechanism involving PPAR-alpha, PPAR-gamma and TRPV1, but not CB(1) or CB(2) receptors. Br. J. Pharmacol. 166, 1474–1489 (2012).",{"doi":446},"10.1111\u002Fj.1476-5381.2012.01889.x",{"id":24,"text":448,"url":24,"identifiers":449},"Hansen, H. S. et al. GPR119 as a fat sensor. Trends. Pharmacol. Sci. 33, 374–381 (2012).",{"doi":450},"10.1016\u002Fj.tips.2012.03.014",{"id":24,"text":452,"url":24,"identifiers":453},"Luchicchi, A. et al. Effects of fatty acid amide hydrolase inhibition on neuronal responses to nicotine, cocaine and morphine in the nucleus accumbens shell and ventral tegmental area: involvement of PPAR-alpha nuclear receptors. Addict. Biol. 15, 277–288 (2010).",{"doi":454},"10.1111\u002Fj.1369-1600.2010.00222.x",{"id":24,"text":456,"url":24,"identifiers":457},"Blankman, J. L., Simon, G. M. & Cravatt, B. F. A comprehensive profile of brain enzymes that hydrolyze the endocannabinoid 2-arachidonoylglycerol. Chem. Biol. 14, 1347–1356 (2007).",{"doi":458},"10.1016\u002Fj.chembiol.2007.11.006",{"id":24,"text":460,"url":24,"identifiers":461},"Zygmunt, P. M. et al. Monoacylglycerols activate TRPV1–a link between phospholipase C and TRPV1. PLOS ONE 8, e81618 (2013).",{"doi":462},"10.1371\u002Fjournal.pone.0081618",{"id":24,"text":464,"url":24,"identifiers":465},"Kozak, K. R., Prusakiewicz, J. J. & Marnett, L. J. Oxidative metabolism of endocannabinoids by COX-2. Curr. Pharm. Des. 10, 659–667 (2004).",{"doi":466},"10.2174\u002F1381612043453081",{"id":24,"text":468,"url":24,"identifiers":469},"Valdeolivas, S. et al. The inhibition of 2-arachidonoyl-glycerol (2-AG) biosynthesis, rather than enhancing striatal damage, protects striatal neurons from malonate-induced death: a potential role of cyclooxygenase-2-dependent metabolism of 2-AG. Cell Death Dis. 4, e862 (2013).",{"doi":470},"10.1038\u002Fcddis.2013.387",{"id":24,"text":472,"url":24,"identifiers":473},"Liang, Y. et al. Identification and pharmacological characterization of the prostaglandin FP receptor and FP receptor variant complexes. Br. J. Pharmacol. 154, 1079–1093 (2008).",{"doi":474},"10.1038\u002Fbjp.2008.142",{"id":24,"text":476,"url":24,"identifiers":477},"Nakane, S. et al. 2-Arachidonoyl-sn-glycero-3-phosphate, an arachidonic acid-containing lysophosphatidic acid: occurrence and rapid enzymatic conversion to 2-arachidonoyl-sn-glycerol, a cannabinoid receptor ligand, in rat brain. Arch. Biochem. Biophys. 402, 51–58 (2002).",{"doi":478},"10.1016\u002FS0003-9861(02)00038-3",{"id":24,"text":480,"url":24,"identifiers":481},"Tsuboi, K. et al. Predominant expression of lysosomal N-acylethanolamine-hydrolyzing acid amidase in macrophages revealed by immunochemical studies. Biochim. Biophys. Acta 1771, 623–632 (2007).",{"doi":482},"10.1016\u002Fj.bbalip.2007.03.005",{"id":24,"text":484,"url":24,"identifiers":485},"Navia-Paldanius, D. et al. Increased tonic cannabinoid CB1R activity and brain region-specific desensitization of CB1R Gi\u002Fo signaling axis in mice with global genetic knockout of monoacylglycerol lipase. Eur. J. Pharm. Sci. 77, 180–188 (2015).",{"doi":486},"10.1016\u002Fj.ejps.2015.06.005",{"id":24,"text":488,"url":24,"identifiers":489},"Imperatore, R. et al. Genetic deletion of monoacylglycerol lipase leads to impaired cannabinoid receptor CB(1)R signaling and anxiety-like behavior. J. Neurochem. 135, 799–813 (2015).",{"doi":490},"10.1111\u002Fjnc.13267",{"id":24,"text":492,"url":24,"identifiers":493},"Nomura, D. K. et al. Monoacylglycerol lipase exerts dual control over endocannabinoid and fatty acid pathways to support prostate cancer. Chem. Biol. 18, 846–856 (2011).",{"doi":494},"10.1016\u002Fj.chembiol.2011.05.009",{"id":24,"text":496,"url":24,"identifiers":497},"Piro, J. R. et al. A dysregulated endocannabinoid-eicosanoid network supports pathogenesis in a mouse model of Alzheimer’s disease. Cell. Rep. 1, 617–623 (2012).",{"doi":498},"10.1016\u002Fj.celrep.2012.05.001",{"id":24,"text":500,"url":24,"identifiers":501},"Saghatelian, A. et al. A FAAH-regulated class of N-acyl taurines that activates TRP ion channels. Biochemistry 45, 9007–9015 (2006).",{"doi":502},"10.1021\u002Fbi0608008",{"id":24,"text":504,"url":24,"identifiers":505},"Verhoeckx, K. C. et al. Presence, formation and putative biological activities of N-acyl serotonins, a novel class of fatty-acid derived mediators, in the intestinal tract. Biochim. Biophys. Acta 1811, 578–586 (2011). Identification of N-acyl-serotonins, endocannabinoidome molecules with a dual mechanism of action.",{"doi":506},"10.1016\u002Fj.bbalip.2011.07.008",{"id":24,"text":508,"url":24,"identifiers":509},"Chu, C. J. et al. N-oleoyldopamine, a novel endogenous capsaicin-like lipid that produces hyperalgesia. J. Biol. Chem. 278, 13633–13639 (2003).",{"doi":510},"10.1074\u002Fjbc.M211231200",{"id":24,"text":512,"url":24,"identifiers":513},"Di Marzo, V. & Wang, J. (eds) The Endocannabinoidome: The World of Endocannabinoids and Related Mediators (Elsevier, 2015).",{"doi":514},"10.1016\u002FB978-0-12-420126-2.00018-3",{"id":24,"text":516,"url":24,"identifiers":517},"Morales, P., Goya, P. & Jagerovic, N. Emerging strategies targeting CB2 cannabinoid receptor: biased agonism and allosterism. Biochem. Pharmacol. 157, 8–17 (2018).",{"doi":518},"10.1016\u002Fj.bcp.2018.07.031",{"id":24,"text":520,"url":24,"identifiers":521},"Dopart, R. et al. Allosteric modulators of cannabinoid receptor 1: developing compounds for improved specificity. Drug Metab. Rev. 50, 3–13 (2018).",{"doi":522},"10.1080\u002F03602532.2018.1428342",{"id":24,"text":524,"url":24,"identifiers":525},"Bauer, M. et al. Identification and quantification of a new family of peptide endocannabinoids (Pepcans) showing negative allosteric modulation at CB1 receptors. J. Biol. Chem. 287, 36944–36967 (2012). Identification of the first endogenous peptidic allosteric modulators of cannabinoid receptors.",{"doi":526},"10.1074\u002Fjbc.M112.382481",{"id":24,"text":528,"url":24,"identifiers":529},"Pamplona, F. A. et al. Anti-inflammatory lipoxin A4 is an endogenous allosteric enhancer of CB1 cannabinoid receptor. Proc. Natl Acad. Sci. USA 109, 21134–21139 (2012).",{"doi":530},"10.1073\u002Fpnas.1202906109",{"id":24,"text":532,"url":24,"identifiers":533},"Vallee, M. et al. Pregnenolone can protect the brain from cannabis intoxication. Science 343, 94–98 (2014).",{"doi":534},"10.1126\u002Fscience.1243985",{"id":24,"text":536,"url":24,"identifiers":537},"Cristino, L., Imperatore, R. & Di Marzo, V. Techniques for the cellular and subcellular localization of endocannabinoid receptors and enzymes in the mammalian brain. Methods. Enzymol. 593, 61–98 (2017).",{"doi":538},"10.1016\u002Fbs.mie.2017.05.003",{"id":24,"text":540,"url":24,"identifiers":541},"Hu, S. S. & Mackie, K. Distribution of the endocannabinoid system in the central nervous system. Handb. Exp. Pharmacol. 231, 59–93 (2015).",{"doi":542},"10.1007\u002F978-3-319-20825-1_3",{"id":24,"text":544,"url":24,"identifiers":545},"Katona, I. & Freund, T. F. Endocannabinoid signaling as a synaptic circuit breaker in neurological disease. Nat. Med. 14, 923–930 (2008).",{"doi":546},"10.1038\u002Fnm.f.1869",{"id":24,"text":548,"url":24,"identifiers":549},"Matyas, F. et al. Identification of the sites of 2-arachidonoylglycerol synthesis and action imply retrograde endocannabinoid signaling at both GABAergic and glutamatergic synapses in the ventral tegmental area. Neuropharmacology 54, 95–107 (2008).",{"doi":550},"10.1016\u002Fj.neuropharm.2007.05.028",{"id":24,"text":552,"url":24,"identifiers":553},"Wilson, R. I. & Nicoll, R. A. Endogenous cannabinoids mediate retrograde signalling at hippocampal synapses. Nature 410, 588–592 (2001). The first evidence that CB1 and endocannabinoids act as retrograde neuromodulators of synaptic plasticity.",{"doi":554},"10.1038\u002F35069076",{"id":24,"text":556,"url":24,"identifiers":557},"Araque, A. et al. Synaptic functions of endocannabinoid signaling in health and disease. Neuropharmacology 124, 13–24 (2017).",{"doi":558},"10.1016\u002Fj.neuropharm.2017.06.017",{"id":24,"text":560,"url":24,"identifiers":561},"Marinelli, S. et al. The endocannabinoid 2-arachidonoylglycerol is responsible for the slow self-inhibition in neocortical interneurons. J. Neurosci. 28, 13532–13541 (2008).",{"doi":562},"10.1523\u002FJNEUROSCI.0847-08.2008",{"id":24,"text":564,"url":24,"identifiers":565},"Koch, M. et al. Hypothalamic POMC neurons promote cannabinoid-induced feeding. Nature 519, 45–50 (2015).",{"doi":566},"10.1038\u002Fnature14260",{"id":24,"text":568,"url":24,"identifiers":569},"Morello, G. et al. Orexin-A represses satiety-inducing POMC neurons and contributes to obesity via stimulation of endocannabinoid signaling. Proc. Natl Acad. Sci. USA 113, 4759–4764 (2016).",{"doi":570},"10.1073\u002Fpnas.1521304113",{"id":24,"text":572,"url":24,"identifiers":573},"Benard, G. et al. Mitochondrial CB(1) receptors regulate neuronal energy metabolism. Nat. Neurosci. 15, 558–564 (2012). Identification of putative mitochondrial CB1 receptors.",{"doi":574},"10.1038\u002Fnn.3053",{"id":24,"text":576,"url":24,"identifiers":577},"Hebert-Chatelain, E. et al. A cannabinoid link between mitochondria and memory. Nature 539, 555–559 (2016).",{"doi":578},"10.1038\u002Fnature20127",{"id":24,"text":580,"url":24,"identifiers":581},"Bosier, B. et al. Astroglial CB1 cannabinoid receptors regulate leptin signaling in mouse brain astrocytes. Mol. Metab. 2, 393–404 (2013).",{"doi":582},"10.1016\u002Fj.molmet.2013.08.001",{"id":24,"text":584,"url":24,"identifiers":585},"Robin, L. M. et al. Astroglial CB1 receptors determine synaptic D-serine availability to enable recognition memory. Neuron 98, 935–944.e5 (2018).",{"doi":586},"10.1016\u002Fj.neuron.2018.04.034",{"id":24,"text":588,"url":24,"identifiers":589},"Prenderville, J. A., Kelly, Á. M. & Downer, E. J. The role of cannabinoids in adult neurogenesis. Br. J. Pharmacol. 172, 3950–3963 (2015).",{"doi":590},"10.1111\u002Fbph.13186",{"id":24,"text":592,"url":24,"identifiers":593},"Cassano, T. et al. Cannabinoid receptor 2 signaling in neurodegenerative disorders: from pathogenesis to a promising therapeutic target. Front. Neurosci. 11, 30 (2017).",{"doi":594},"10.3389\u002Ffnins.2017.00030",{"id":24,"text":596,"url":24,"identifiers":597},"Palazuelos, J. et al. CB2 cannabinoid receptors promote neural progenitor cell proliferation via mTORC1 signaling. J. Biol. Chem. 287, 1198–1209 (2012).",{"doi":598},"10.1074\u002Fjbc.M111.291294",{"id":24,"text":600,"url":24,"identifiers":601},"Chung, Y. C. et al. CB2 receptor activation prevents glial-derived neurotoxic mediator production, BBB leakage and peripheral immune cell infiltration and rescues dopamine neurons in the MPTP model of Parkinson’s disease. Exp. Mol. Med. 48, e205 (2016).",{"doi":602},"10.1038\u002Femm.2015.100",{"id":24,"text":604,"url":24,"identifiers":605},"Xi, Z. X. et al. Brain cannabinoid CB(2) receptors modulate cocaine’s actions in mice. Nat. Neurosci. 14, 1160–1166 (2011).",{"doi":606},"10.1038\u002Fnn.2874",{"id":24,"text":608,"url":24,"identifiers":609},"Navarrete, F. et al. Role of CB2 cannabinoid receptors in the rewarding, reinforcing, and physical effects of nicotine. Neuropsychopharmacology 38, 2515–2524 (2013).",{"doi":610},"10.1038\u002Fnpp.2013.157",{"id":24,"text":612,"url":24,"identifiers":613},"Marchalant, Y. et al. Validating antibodies to the cannabinoid CB2 receptor: antibody sensitivity is not evidence of antibody specificity. J. Histochem. Cytochem. 62, 395–404 (2014).",{"doi":614},"10.1369\u002F0022155414530995",{"id":24,"text":616,"url":24,"identifiers":617},"Soethoudt, M. et al. Cannabinoid CB2 receptor ligand profiling reveals biased signalling and off-target activity. Nat. Commun. 8, 13958 (2017).",{"doi":618},"10.1038\u002Fncomms13958",{"id":24,"text":620,"url":24,"identifiers":621},"Stempel, A. V. et al. Cannabinoid type 2 receptors mediate a cell type-specific plasticity in the hippocampus. Neuron 90, 795–809 (2016). The first molecular study to suggest a mechanism of action for CB2 receptors in neurons.",{"doi":622},"10.1016\u002Fj.neuron.2016.03.034",{"id":24,"text":624,"url":24,"identifiers":625},"Cristino, L. et al. Immunohistochemical localization of cannabinoid type 1 and vanilloid transient receptor potential vanilloid type 1 receptors in the mouse brain. Neuroscience 139, 1405–1415 (2006).",{"doi":626},"10.1016\u002Fj.neuroscience.2006.02.074",{"id":24,"text":628,"url":24,"identifiers":629},"Cristino, L. et al. Immunohistochemical localization of anabolic and catabolic enzymes for anandamide and other putative endovanilloids in the hippocampus and cerebellar cortex of the mouse brain. Neuroscience 151, 955–968 (2008).",{"doi":630},"10.1016\u002Fj.neuroscience.2007.11.047",{"id":24,"text":632,"url":24,"identifiers":633},"Edwards, J. G. TRPV1 in the central nervous system: synaptic plasticity, function, and pharmacological implications. Prog. Drug Res. 68, 77–104 (2014).",{},{"id":24,"text":635,"url":24,"identifiers":636},"Sun, F. J. et al. Increased expression of TRPV1 in the cortex and hippocampus from patients with mesial temporal lobe epilepsy. J. Mol. Neurosci. 49, 182–193 (2013).",{"doi":637},"10.1007\u002Fs12031-012-9878-2",{"id":24,"text":639,"url":24,"identifiers":640},"Bhaskaran, M. D. & Smith, B. N. Cannabinoid-mediated inhibition of recurrent excitatory circuitry in the dentate gyrus in a mouse model of temporal lobe epilepsy. PLOS ONE 5, e10683 (2010).",{"doi":641},"10.1371\u002Fjournal.pone.0010683",{"id":24,"text":643,"url":24,"identifiers":644},"Chavez, A. E., Chiu, C. Q. & Castillo, P. E. TRPV1 activation by endogenous anandamide triggers postsynaptic long-term depression in dentate gyrus. Nat. Neurosci. 13, 1511–1518 (2010). Important evidence for a functional role of TRPV1 in neurons.",{"doi":645},"10.1038\u002Fnn.2684",{"id":24,"text":647,"url":24,"identifiers":648},"Marrone, M. C. et al. TRPV1 channels are critical brain inflammation detectors and neuropathic pain biomarkers in mice. Nat. Commun. 10, 15292 (2017).",{"doi":649},"10.1038\u002Fncomms15292",{"id":24,"text":651,"url":24,"identifiers":652},"Stampanoni Bassi, M. et al. Transient receptor potential vanilloid 1 modulates central inflammation in multiple sclerosis. Front. Neurol. 10, 30 (2019).",{"doi":653},"10.3389\u002Ffneur.2019.00030",{"id":24,"text":655,"url":24,"identifiers":656},"Villapol, S. Roles of peroxisome proliferator-activated receptor gamma on brain and peripheral inflammation. Cell Mol. Neurobiol. 38, 121–132 (2018).",{"doi":657},"10.1007\u002Fs10571-017-0554-5",{"id":24,"text":659,"url":24,"identifiers":660},"Blednov, Y. A. et al. Peroxisome proliferator-activated receptors alpha and gamma are linked with alcohol consumption in mice and withdrawal and dependence in humans. Alcohol Clin. Exp. Res. 39, 136–145 (2015).",{"doi":661},"10.1111\u002Facer.12610",{"id":24,"text":663,"url":24,"identifiers":664},"Donvito, G. et al. N-oleoyl-glycine reduces nicotine reward and withdrawal in mice. Neuropharmacology 148, 320–331 (2018). Identification of an endogenous nicotine anti-additive molecule.",{"doi":665},"10.1016\u002Fj.neuropharm.2018.03.020",{"id":24,"text":667,"url":24,"identifiers":668},"Laleh, P. et al. Oleoylethanolamide increases the expression of PPAR-alpha and reduces appetite and body weight in obese people: a clinical trial. Appetite 128, 44–49 (2018).",{"doi":669},"10.1016\u002Fj.appet.2018.05.129",{"id":24,"text":671,"url":24,"identifiers":672},"Quintanilla, R. A., Utreras, E. & Cabezas-Opazo, F. A. Role of PPAR gamma in the differentiation and function of neurons. PPAR Res. 2014, 768594 (2014).",{"doi":673},"10.1155\u002F2014\u002F768594",{"id":24,"text":675,"url":24,"identifiers":676},"Sylantyev, S. et al. Cannabinoid- and lysophosphatidylinositol-sensitive receptor GPR55 boosts neurotransmitter release at central synapses. Proc. Natl Acad. Sci. USA 110, 5193–5198 (2013).",{"doi":677},"10.1073\u002Fpnas.1211204110",{"id":24,"text":679,"url":24,"identifiers":680},"Kaplan, J. S. et al. Cannabidiol attenuates seizures and social deficits in a mouse model of Dravet syndrome. Proc. Natl Acad. Sci. USA 114, 11229–11234 (2017).",{"doi":681},"10.1073\u002Fpnas.1711351114",{"id":24,"text":683,"url":24,"identifiers":684},"McHugh, D. et al. siRNA knockdown of GPR18 receptors in BV-2 microglia attenuates N-arachidonoyl glycine-induced cell migration. J. Mol. Signal. 7, 10 (2012).",{"doi":685},"10.1186\u002F1750-2187-7-10",{"id":24,"text":687,"url":24,"identifiers":688},"Penumarti, A. & Abdel-Rahman, A. A. The novel endocannabinoid receptor GPR18 is expressed in the rostral ventrolateral medulla and exerts tonic restraining influence on blood pressure. J. Pharmacol. Exp. Ther. 349, 29–38 (2014).",{"doi":689},"10.1124\u002Fjpet.113.209213",{"id":24,"text":691,"url":24,"identifiers":692},"Sharkey, K. A. & Wiley, J. W. The role of the endocannabinoid system in the brain-gut axis. Gastroenterology 151, 252–266 (2016).",{"doi":693},"10.1053\u002Fj.gastro.2016.04.015",{"id":24,"text":695,"url":24,"identifiers":696},"Cani, P. D. et al. Endocannabinoids–at the crossroads between the gut microbiota and host metabolism. Nat. Rev. Endocrinol. 12, 133–143 (2016).",{"doi":697},"10.1038\u002Fnrendo.2015.211",{"id":24,"text":699,"url":24,"identifiers":700},"Muccioli, G. G. et al. The endocannabinoid system links gut microbiota to adipogenesis. Mol. Syst. Biol. 6, 392 (2010). One of the first studies to link the endocannabinoid system with the gut microbiota.",{"doi":701},"10.1038\u002Fmsb.2010.46",{"id":24,"text":703,"url":24,"identifiers":704},"Mehrpouya-Bahrami, P. et al. Blockade of CB1 cannabinoid receptor alters gut microbiota and attenuates inflammation and diet-induced obesity. Sci. Rep. 7, 15645 (2017).",{"doi":705},"10.1038\u002Fs41598-017-15154-6",{"id":24,"text":707,"url":24,"identifiers":708},"Guida, F. et al. Antibiotic-induced microbiota perturbation causes gut endocannabinoidome changes, hippocampal neuroglial reorganization and depression in mice. Brain Behav. Immun. 67, 230–245 (2018). Discovery of the potential role of intestinal N-acyl-serotonins in antibiotic-induced depression.",{"doi":709},"10.1016\u002Fj.bbi.2017.09.001",{"id":24,"text":711,"url":24,"identifiers":712},"Rousseaux, C. et al. Lactobacillus acidophilus modulates intestinal pain and induces opioid and cannabinoid receptors. Nat. Med. 13, 35–37 (2007). Identification of an important potential link between probiotic therapeutic effects and the endocannabinoid system.",{"doi":713},"10.1038\u002Fnm1521",{"id":24,"text":715,"url":24,"identifiers":716},"Geurts, L. et al. Adipose tissue NAPE-PLD controls fat mass development by altering the browning process and gut microbiota. Nat. Commun. 6, 6495 (2015).",{"doi":717},"10.1038\u002Fncomms7495",{"id":24,"text":719,"url":24,"identifiers":720},"Janakiraman, M. & Krishnamoorthy, G. Emerging role of diet and microbiota interactions in neuroinflammation. Front. Immunol. 9, 2067 (2018).",{"doi":721},"10.3389\u002Ffimmu.2018.02067",{"id":24,"text":723,"url":24,"identifiers":724},"Garcia-Arencibia, M. et al. Cannabinoid CB1 receptors are early downregulated followed by a further upregulation in the basal ganglia of mice with deletion of specific PARK genes. J. Neural Transm. Suppl. 73, 269–275 (2009).",{},{"id":24,"text":726,"url":24,"identifiers":727},"Walsh, S. et al. Loss of cannabinoid CB1 receptor expression in the 6-hydroxydopamine-induced nigrostriatal terminal lesion model of Parkinson’s disease in the rat. Brain Res. Bull. 81, 543–548 (2010).",{"doi":728},"10.1016\u002Fj.brainresbull.2010.01.009",{"id":24,"text":730,"url":24,"identifiers":731},"Rojo-Bustamante, E. et al. The expression of cannabinoid type 1 receptor and 2-arachidonoyl glycerol synthesizing\u002Fdegrading enzymes is altered in basal ganglia during the active phase of levodopa-induced dyskinesia. Neurobiol. Dis. 118, 64–75 (2018).",{"doi":732},"10.1016\u002Fj.nbd.2018.06.019",{"id":24,"text":734,"url":24,"identifiers":735},"Van Laere, K. et al. Regional changes in type 1 cannabinoid receptor availability in Parkinson’s disease in vivo. Neurobiol. Aging 33, 620.e1–620.e8 (2012).",{"doi":736},"10.1016\u002Fj.neurobiolaging.2011.02.009",{"id":24,"text":738,"url":24,"identifiers":739},"Navarrete, F. et al. Cannabinoid CB1 and CB2 receptors, and monoacylglycerol lipase gene expression alterations in the basal ganglia of patients with Parkinson’s disease. Neurotherapeutics 15, 459–469 (2018).",{"doi":740},"10.1007\u002Fs13311-018-0603-x",{"id":24,"text":742,"url":24,"identifiers":743},"Gomez-Galvez, Y. et al. Potential of the cannabinoid CB(2) receptor as a pharmacological target against inflammation in Parkinson’s disease. Prog. Neuropsychopharmacol. Biol. Psychiatry 64, 200–208 (2016).",{"doi":744},"10.1016\u002Fj.pnpbp.2015.03.017",{"id":24,"text":746,"url":24,"identifiers":747},"Morgese, M. G. et al. Anti-dyskinetic effects of cannabinoids in a rat model of Parkinson’s disease: role of CB(1) and TRPV1 receptors. Exp. Neurol. 208, 110–119 (2007).",{"doi":748},"10.1016\u002Fj.expneurol.2007.07.021",{"id":24,"text":750,"url":24,"identifiers":751},"Fox, S. H. et al. Stimulation of cannabinoid receptors reduces levodopa-induced dyskinesia in the MPTP-lesioned nonhuman primate model of Parkinson’s disease. Mov. Disord. 17, 1180–1187 (2002).",{"doi":752},"10.1002\u002Fmds.10289",{"id":24,"text":754,"url":24,"identifiers":755},"van der Stelt, M. et al. A role for endocannabinoids in the generation of parkinsonism and levodopa-induced dyskinesia in MPTP-lesioned non-human primate models of Parkinson’s disease. FASEB J. 19, 1140–1142 (2005).",{"doi":756},"10.1096\u002Ffj.04-3010fje",{"id":24,"text":758,"url":24,"identifiers":759},"Fernandez-Espejo, E. et al. Cannabinoid CB1 antagonists possess antiparkinsonian efficacy only in rats with very severe nigral lesion in experimental parkinsonism. Neurobiol. Dis. 18, 591–601 (2005).",{"doi":760},"10.1016\u002Fj.nbd.2004.10.015",{"id":24,"text":762,"url":24,"identifiers":763},"Cao, X. et al. Blockade of cannabinoid type 1 receptors augments the antiparkinsonian action of levodopa without affecting dyskinesias in 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine-treated rhesus monkeys. J. Pharmacol. Exp. Ther. 323, 318–326 (2007).",{"doi":764},"10.1124\u002Fjpet.107.125666",{"id":24,"text":766,"url":24,"identifiers":767},"Garcia-Arencibia, M. et al. Evaluation of the neuroprotective effect of cannabinoids in a rat model of Parkinson’s disease: importance of antioxidant and cannabinoid receptor-independent properties. Brain Res. 1134, 162–170 (2007).",{"doi":768},"10.1016\u002Fj.brainres.2006.11.063",{"id":24,"text":770,"url":24,"identifiers":771},"Shi, J. et al. AM1241 alleviates MPTP-induced Parkinson’s disease and promotes the regeneration of DA neurons in PD mice. Oncotarget 8, 67837–67850 (2017).",{"doi":772},"10.18632\u002Foncotarget.18871",{"id":24,"text":774,"url":24,"identifiers":775},"Pisani, A. et al. High endogenous cannabinoid levels in the cerebrospinal fluid of untreated Parkinson’s disease patients. Ann. Neurol. 57, 777–779 (2005). The first data from human studies on the potential dysregulation of endocannabinoids in PD.",{"doi":776},"10.1002\u002Fana.20462",{"id":24,"text":778,"url":24,"identifiers":779},"Gubellini, P. et al. Experimental parkinsonism alters endocannabinoid degradation: implications for striatal glutamatergic transmission. J. Neurosci. 22, 6900–6907 (2002).",{"doi":780},"10.1523\u002FJNEUROSCI.22-16-06900.2002",{"id":24,"text":782,"url":24,"identifiers":783},"Di Marzo, V. et al. Enhanced levels of endogenous cannabinoids in the globus pallidus are associated with a reduction in movement in an animal model of Parkinson’s disease. FASEB J. 14, 1432–1438 (2000). The first evidence for a role of endocannabinoids in PD.",{"doi":784},"10.1096\u002Ffasebj.14.10.1432",{"id":24,"text":786,"url":24,"identifiers":787},"Pisani, V. et al. Dynamic changes of anandamide in the cerebrospinal fluid of Parkinson’s disease patients. Mov. Disord. 25, 920–924 (2010).",{"doi":788},"10.1002\u002Fmds.23014",{"id":24,"text":790,"url":24,"identifiers":791},"Fernandez-Suarez, D. et al. Monoacylglycerol lipase inhibitor JZL184 is neuroprotective and alters glial cell phenotype in the chronic MPTP mouse model. Neurobiol. Aging 35, 2603–2616 (2014).",{"doi":792},"10.1016\u002Fj.neurobiolaging.2014.05.021",{"id":24,"text":794,"url":24,"identifiers":795},"Esposito, E. et al. Neuroprotective activities of palmitoylethanolamide in an animal model of Parkinson’s disease. PLOS ONE 7, e41880 (2012).",{"doi":796},"10.1371\u002Fjournal.pone.0041880",{"id":24,"text":798,"url":24,"identifiers":799},"Gonzalez-Aparicio, R. & Moratalla, R. Oleoylethanolamide reduces L-DOPA-induced dyskinesia via TRPV1 receptor in a mouse model of Parkinson s disease. Neurobiol. Dis. 62, 416–425 (2014).",{"doi":800},"10.1016\u002Fj.nbd.2013.10.008",{"id":24,"text":802,"url":24,"identifiers":803},"Lastres-Becker, I. et al. Cannabinoids provide neuroprotection against 6-hydroxydopamine toxicity in vivo and in vitro: relevance to Parkinson’s disease. Neurobiol. Dis. 19, 96–107 (2005).",{"doi":804},"10.1016\u002Fj.nbd.2004.11.009",{"id":24,"text":806,"url":24,"identifiers":807},"Garcia, C. et al. Symptom-relieving and neuroprotective effects of the phytocannabinoid delta(9)-THCV in animal models of Parkinson’s disease. Br. J. Pharmacol. 163, 1495–1506 (2011).",{"doi":808},"10.1111\u002Fj.1476-5381.2011.01278.x",{"id":24,"text":810,"url":24,"identifiers":811},"Chagas, M. H. et al. Effects of cannabidiol in the treatment of patients with Parkinson’s disease: an exploratory double-blind trial. J. Psychopharmacol. 28, 1088–1098 (2014).",{"doi":812},"10.1177\u002F0269881114550355",{"id":24,"text":814,"url":24,"identifiers":815},"Sieradzan, K. A. et al. Cannabinoids reduce levodopa-induced dyskinesia in Parkinson’s disease: a pilot study. Neurology 57, 2108–2111 (2001).",{"doi":816},"10.1212\u002FWNL.57.11.2108",{"id":24,"text":818,"url":24,"identifiers":819},"Brotini, S., S.C., Schievano, C. & Guidi, L. Ultra-micronized palmitoylethanolamide: an efficacious adjuvant therapy for Parkinson’s disease. CNS Neurol. Disord. Drug Targets 16, 705–713 (2017).",{"doi":820},"10.2174\u002F1871527316666170321124949",{"id":24,"text":822,"url":24,"identifiers":823},"Petrosino, S. & Di Marzo, V. The pharmacology of palmitoylethanolamide and first data on the therapeutic efficacy of some of its new formulations. Br. J. Pharmacol. 174, 1349–1365 (2017).",{"doi":824},"10.1111\u002Fbph.13580",{"id":24,"text":826,"url":24,"identifiers":827},"Karkkaine, E., Tanila, H. & Laitinen, J. T. Functional autoradiography shows unaltered cannabinoid CB1 receptor signalling in hippocampus and cortex of APP\u002FPS1 transgenic mice. CNS Neurol. Disord. Drug Targets 11, 1038–1044 (2012).",{"doi":828},"10.2174\u002F1871527311211080014",{"id":24,"text":830,"url":24,"identifiers":831},"Maccarrone, M. et al. Early alteration of distribution and activity of hippocampal type-1 cannabinoid receptor in Alzheimer’s disease-like mice overexpressing the human mutant amyloid precursor protein. Pharmacol. Res. 130, 366–373 (2018).",{"doi":832},"10.1016\u002Fj.phrs.2018.02.009",{"id":24,"text":834,"url":24,"identifiers":835},"Aso, E. et al. CB2 cannabinoid receptor agonist ameliorates Alzheimer-like phenotype in AbetaPP\u002FPS1 mice. J. Alzheimers Dis. 35, 847–858 (2013).",{"doi":836},"10.3233\u002FJAD-130137",{"id":24,"text":838,"url":24,"identifiers":839},"Ramirez, B. G. et al. Prevention of Alzheimer’s disease pathology by cannabinoids: neuroprotection mediated by blockade of microglial activation. J. Neurosci. 25, 1904–1913 (2005).",{"doi":840},"10.1523\u002FJNEUROSCI.4540-04.2005",{"id":24,"text":842,"url":24,"identifiers":843},"Martin-Moreno, A. M. et al. Cannabidiol and other cannabinoids reduce microglial activation in vitro and in vivo: relevance to Alzheimer’s disease. Mol. Pharmacol. 79, 964–973 (2011).",{"doi":844},"10.1124\u002Fmol.111.071290",{"id":24,"text":846,"url":24,"identifiers":847},"Westlake, T. M. et al. Cannabinoid receptor binding and messenger RNA expression in human brain: an in vitro receptor autoradiography and in situ hybridization histochemistry study of normal aged and Alzheimer’s brains. Neuroscience 63, 637–652 (1994).",{"doi":848},"10.1016\u002F0306-4522(94)90511-8",{"id":24,"text":850,"url":24,"identifiers":851},"Lee, J. H. et al. Intact cannabinoid CB1 receptors in the Alzheimer’s disease cortex. Neurochem. Int. 57, 985–989 (2010).",{"doi":852},"10.1016\u002Fj.neuint.2010.10.010",{"id":24,"text":854,"url":24,"identifiers":855},"Ahmad, R. et al. In vivo type 1 cannabinoid receptor availability in Alzheimer’s disease. Eur. Neuropsychopharmacol. 24, 242–250 (2014).",{"doi":856},"10.1016\u002Fj.euroneuro.2013.10.002",{"id":24,"text":858,"url":24,"identifiers":859},"Manuel, I. et al. Type-1 cannabinoid receptor activity during Alzheimer’s disease progression. J. Alzheimers Dis. 42, 761–766 (2014).",{"doi":860},"10.3233\u002FJAD-140492",{"id":24,"text":862,"url":24,"identifiers":863},"Esposito, G. et al. Opposing control of cannabinoid receptor stimulation on amyloid-beta-induced reactive gliosis: in vitro and in vivo evidence. J. Pharmacol. Exp. Ther. 322, 1144–1152 (2007).",{"doi":864},"10.1124\u002Fjpet.107.121566",{"id":24,"text":866,"url":24,"identifiers":867},"Lopez, A. et al. Cannabinoid CB2 receptors in the mouse brain: relevance for Alzheimer’s disease. J. Neuroinflammation 15, 158 (2018).",{"doi":868},"10.1186\u002Fs12974-018-1174-9",{"id":24,"text":870,"url":24,"identifiers":871},"Sheng, W. S. et al. Synthetic cannabinoid WIN55,212-2 inhibits generation of inflammatory mediators by IL-1beta-stimulated human astrocytes. Glia 49, 211–219 (2005).",{"doi":872},"10.1002\u002Fglia.20108",{"id":24,"text":874,"url":24,"identifiers":875},"Ehrhart, J. et al. Stimulation of cannabinoid receptor 2 (CB2) suppresses microglial activation. J. Neuroinflammation 2, 29 (2005).",{"doi":876},"10.1186\u002F1742-2094-2-29",{"id":24,"text":878,"url":24,"identifiers":879},"Walter, L. et al. Nonpsychotropic cannabinoid receptors regulate microglial cell migration. J. Neurosci. 23, 1398–1405 (2003).",{"doi":880},"10.1523\u002FJNEUROSCI.23-04-01398.2003",{"id":24,"text":882,"url":24,"identifiers":883},"Koppel, J. et al. CB2 receptor deficiency increases amyloid pathology and alters tau processing in a transgenic mouse model of Alzheimer’s disease. Mol. Med. 20, 29–36 (2014).",{"doi":884},"10.2119\u002Fmolmed.2013.00140.revised",{"id":24,"text":886,"url":24,"identifiers":887},"Benito, C. et al. Cannabinoid CB2 receptors and fatty acid amide hydrolase are selectively overexpressed in neuritic plaque-associated glia in Alzheimer’s disease brains. J. Neurosci. 23, 11136–11141 (2003). The first evidence that the endocannabinoid system is altered in post-mortem brains from patients with AD.",{"doi":888},"10.1523\u002FJNEUROSCI.23-35-11136.2003",{"id":24,"text":890,"url":24,"identifiers":891},"Vazquez, C. et al. Endocannabinoid regulation of amyloid-induced neuroinflammation. Neurobiol. Aging 36, 3008–3019 (2015).",{"doi":892},"10.1016\u002Fj.neurobiolaging.2015.08.003",{"id":24,"text":894,"url":24,"identifiers":895},"van der Stelt, M. et al. Endocannabinoids and beta-amyloid-induced neurotoxicity in vivo: effect of pharmacological elevation of endocannabinoid levels. Cell Mol. Life Sci. 63, 1410–1424 (2006).",{"doi":896},"10.1007\u002Fs00018-006-6037-3",{"id":24,"text":898,"url":24,"identifiers":899},"Chen, R. et al. Monoacylglycerol lipase is a therapeutic target for Alzheimer’s disease. Cell Rep. 2, 1329–1339 (2012).",{"doi":900},"10.1016\u002Fj.celrep.2012.09.030",{"id":24,"text":902,"url":24,"identifiers":903},"Zhang, J. & Chen, C. Alleviation of neuropathology by inhibition of monoacylglycerol lipase in APP transgenic mice lacking CB2 receptors. Mol. Neurobiol. 55, 4802–4810 (2018).",{"doi":904},"10.1007\u002Fs12035-017-0689-x",{"id":24,"text":906,"url":24,"identifiers":907},"Pihlaja, R. et al. Monoacylglycerol lipase inhibitor JZL184 reduces neuroinflammatory response in APdE9 mice and in adult mouse glial cells. J. Neuroinflammation 12, 81 (2015).",{"doi":908},"10.1186\u002Fs12974-015-0305-9",{"id":24,"text":910,"url":24,"identifiers":911},"D’Agostino, G. et al. Palmitoylethanolamide protects against the amyloid-beta25-35-induced learning and memory impairment in mice, an experimental model of Alzheimer disease. Neuropsychopharmacology 37, 1784–1792 (2012).",{"doi":912},"10.1038\u002Fnpp.2012.25",{"id":24,"text":914,"url":24,"identifiers":915},"Bronzuoli, M. R. et al. Palmitoylethanolamide dampens reactive astrogliosis and improves neuronal trophic support in a triple transgenic model of Alzheimer’s disease: in vitro and in vivo evidence. Oxid. Med. Cell. Longev. 2018, 4720532 (2018).",{"doi":916},"10.1155\u002F2018\u002F4720532",{"id":24,"text":918,"url":24,"identifiers":919},"Esposito, G. et al. The marijuana component cannabidiol inhibits beta-amyloid-induced tau protein hyperphosphorylation through Wnt\u002Fbeta-catenin pathway rescue in PC12 cells. J. Mol. Med. 84, 253–258 (2006).",{"doi":920},"10.1007\u002Fs00109-005-0025-1",{"id":24,"text":922,"url":24,"identifiers":923},"Cheng, D. et al. Long-term cannabidiol treatment prevents the development of social recognition memory deficits in Alzheimer’s disease transgenic mice. J. Alzheimers Dis. 42, 1383–1396 (2014).",{"doi":924},"10.3233\u002FJAD-140921",{"id":24,"text":926,"url":24,"identifiers":927},"Aso, E. et al. Cannabis-based medicine reduces multiple pathological processes in AbetaPP\u002FPS1 mice. J. Alzheimers Dis. 43, 977–991 (2015).",{"doi":928},"10.3233\u002FJAD-141014",{"id":24,"text":930,"url":24,"identifiers":931},"Passmore, M. J. The cannabinoid receptor agonist nabilone for the treatment of dementia-related agitation. Int. J. Geriatr. Psychiatry 23, 116–117 (2008).",{"doi":932},"10.1002\u002Fgps.1828",{"id":24,"text":934,"url":24,"identifiers":935},"van den Elsen, G. A. et al. Tetrahydrocannabinol for neuropsychiatric symptoms in dementia: a randomized controlled trial. Neurology 84, 2338–2346 (2015).",{"doi":936},"10.1212\u002FWNL.0000000000001675",{"id":24,"text":938,"url":24,"identifiers":939},"van den Elsen, G. A. H. et al. Tetrahydrocannabinol in behavioral disturbances in dementia: a crossover randomized controlled trial. Am. J. Geriatr. Psychiatry 23, 1214–1224 (2015).",{"doi":940},"10.1016\u002Fj.jagp.2015.07.011",{"id":24,"text":942,"url":24,"identifiers":943},"van den Elsen, G. A. et al. Effects of tetrahydrocannabinol on balance and gait in patients with dementia: a randomised controlled crossover trial. J. Psychopharmacol. 31, 184–191 (2017).",{"doi":944},"10.1177\u002F0269881116665357",{"id":24,"text":946,"url":24,"identifiers":947},"Denovan-Wright, E. M. & Robertson, H. A. Cannabinoid receptor messenger RNA levels decrease in a subset of neurons of the lateral striatum, cortex and hippocampus of transgenic Huntington’s disease mice. Neuroscience 98, 705–713 (2000).",{"doi":948},"10.1016\u002FS0306-4522(00)00157-3",{"id":24,"text":950,"url":24,"identifiers":951},"Lastres-Becker, I. et al. Loss of mRNA levels, binding and activation of GTP-binding proteins for cannabinoid CB1 receptors in the basal ganglia of a transgenic model of Huntington’s disease. Brain Res. 929, 236–242 (2002).",{"doi":952},"10.1016\u002FS0006-8993(01)03403-5",{"id":24,"text":954,"url":24,"identifiers":955},"Dowie, M. J. et al. Altered CB1 receptor and endocannabinoid levels precede motor symptom onset in a transgenic mouse model of Huntington’s disease. Neuroscience 163, 456–465 (2009).",{"doi":956},"10.1016\u002Fj.neuroscience.2009.06.014",{"id":24,"text":958,"url":24,"identifiers":959},"Glass, M., Faull, R. L. & Dragunow, M. Loss of cannabinoid receptors in the substantia nigra in Huntington’s disease. Neuroscience 56, 523–527 (1993). The first evidence for defective endocannabinoid signalling in post-mortem brains from patients with HD.",{"doi":960},"10.1016\u002F0306-4522(93)90352-G",{"id":24,"text":962,"url":24,"identifiers":963},"Monory, K. et al. Genetic dissection of behavioural and autonomic effects of delta(9)-tetrahydrocannabinol in mice. PLOS Biol. 5, e269 (2007).",{"doi":964},"10.1371\u002Fjournal.pbio.0050269",{"id":24,"text":966,"url":24,"identifiers":967},"Chiarlone, A. et al. A restricted population of CB1 cannabinoid receptors with neuroprotective activity. Proc. Natl Acad. Sci. USA 111, 8257–8262 (2014). Identification that CB1 receptors in only glutamatergic neurons have a neuroprotective role in HD.",{"doi":968},"10.1073\u002Fpnas.1400988111",{"id":24,"text":970,"url":24,"identifiers":971},"Ruiz-Calvo, A. et al. Pathway-specific control of striatal neuron vulnerability by corticostriatal cannabinoid CB1 receptors. Cereb. Cortex 28, 307–322 (2018).",{"doi":972},"10.1093\u002Fcercor\u002Fbhx285",{"id":24,"text":974,"url":24,"identifiers":975},"Mievis, S., Blum, D. & Ledent, C. Worsening of Huntington disease phenotype in CB1 receptor knockout mice. Neurobiol. Dis. 42, 524–529 (2011).",{"doi":976},"10.1016\u002Fj.nbd.2011.03.006",{"id":24,"text":978,"url":24,"identifiers":979},"Palazuelos, J. et al. Microglial CB2 cannabinoid receptors are neuroprotective in Huntington’s disease excitotoxicity. Brain 132, 3152–3164 (2009).",{"doi":980},"10.1093\u002Fbrain\u002Fawp239",{"id":24,"text":982,"url":24,"identifiers":983},"Bouchard, J. et al. Cannabinoid receptor 2 signaling in peripheral immune cells modulates disease onset and severity in mouse models of Huntington’s disease. J. Neurosci. 32, 18259–18268 (2012).",{"doi":984},"10.1523\u002FJNEUROSCI.4008-12.2012",{"id":24,"text":986,"url":24,"identifiers":987},"Sagredo, O. et al. Cannabinoid CB2 receptor agonists protect the striatum against malonate toxicity: relevance for Huntington’s disease. Glia 57, 1154–1167 (2009).",{"doi":988},"10.1002\u002Fglia.20838",{"id":24,"text":990,"url":24,"identifiers":991},"Pietropaolo, S. et al. Chronic cannabinoid receptor stimulation selectively prevents motor impairments in a mouse model of Huntington’s disease. Neuropharmacology 89, 368–374 (2015).",{"doi":992},"10.1016\u002Fj.neuropharm.2014.07.021",{"id":24,"text":994,"url":24,"identifiers":995},"Bisogno, T. et al. Symptom-related changes of endocannabinoid and palmitoylethanolamide levels in brain areas of R6\u002F2 mice, a transgenic model of Huntington’s disease. Neurochem. Int. 52, 307–313 (2008).",{"doi":996},"10.1016\u002Fj.neuint.2007.06.031",{"id":24,"text":998,"url":24,"identifiers":999},"Bari, M. et al. In vitro and in vivo models of Huntington’s disease show alterations in the endocannabinoid system. FEBS J. 280, 3376–3388 (2013).",{"doi":1000},"10.1111\u002Ffebs.12329",{"id":24,"text":1002,"url":24,"identifiers":1003},"Battista, N. et al. Severe deficiency of the fatty acid amide hydrolase (FAAH) activity segregates with the Huntington’s disease mutation in peripheral lymphocytes. Neurobiol. Dis. 27, 108–116 (2007).",{"doi":1004},"10.1016\u002Fj.nbd.2007.04.012",{"id":24,"text":1006,"url":24,"identifiers":1007},"Lastres-Becker, I. et al. Compounds acting at the endocannabinoid and\u002For endovanilloid systems reduce hyperkinesia in a rat model of Huntington’s disease. J. Neurochem. 84, 1097–1109 (2003).",{"doi":1008},"10.1046\u002Fj.1471-4159.2003.01595.x",{"id":24,"text":1010,"url":24,"identifiers":1011},"Sagredo, O. et al. Cannabidiol reduced the striatal atrophy caused 3-nitropropionic acid in vivo by mechanisms independent of the activation of cannabinoid, vanilloid TRPV1 and adenosine A2A receptors. Eur. J. Neurosci. 26, 843–851 (2007).",{"doi":1012},"10.1111\u002Fj.1460-9568.2007.05717.x",{"id":24,"text":1014,"url":24,"identifiers":1015},"Valdeolivas, S. et al. Neuroprotective properties of cannabigerol in Huntington’s disease: studies in R6\u002F2 mice and 3-nitropropionate-lesioned mice. Neurotherapeutics 12, 185–199 (2015).",{"doi":1016},"10.1007\u002Fs13311-014-0304-z",{"id":24,"text":1018,"url":24,"identifiers":1019},"Sagredo, O., Pazos, M. R., Valdeolivas, S. & Fernandez-Ruiz, J. Cannabinoids: novel medicines for the treatment of Huntington’s disease. Recent Pat. CNS Drug Discov. 7, 41–48 (2012).",{"doi":1020},"10.2174\u002F157488912798842278",{"id":24,"text":1022,"url":24,"identifiers":1023},"Lopez-Sendon Moreno, J. L. et al. A double-blind, randomized, cross-over, placebo-controlled, pilot trial with Sativex in Huntington’s disease. J. Neurol. 263, 1390–1400 (2016).",{"doi":1024},"10.1007\u002Fs00415-016-8145-9",{"id":24,"text":1026,"url":24,"identifiers":1027},"Saft, C. et al. Cannabinoids for treatment of dystonia in Huntington’s disease. J. Huntingt. Dis. 7, 167–173 (2018).",{"doi":1028},"10.3233\u002FJHD-170283",{"id":24,"text":1030,"url":24,"identifiers":1031},"Consroe, P. et al. Controlled clinical trial of cannabidiol in Huntington’s disease. Pharmacol. Biochem. Behav. 40, 701–708 (1991).",{"doi":1032},"10.1016\u002F0091-3057(91)90386-G",{"id":24,"text":1034,"url":24,"identifiers":1035},"Curtis, A. et al. A pilot study using nabilone for symptomatic treatment in Huntington’s disease. Mov. Disord. 24, 2254–2259 (2009).",{"doi":1036},"10.1002\u002Fmds.22809",{"id":24,"text":1038,"url":24,"identifiers":1039},"Muller-Vahl, K. R. et al. Treatment of Tourette’s syndrome with delta-9-tetrahydrocannabinol. Am. J. Psychiatry 156, 495 (1999). The first evidence that THC might have beneficial effect in Tourette syndrome.",{"doi":1040},"10.1176\u002Fajp.156.3.495",{"id":24,"text":1042,"url":24,"identifiers":1043},"Cabranes, A. et al. Decreased endocannabinoid levels in the brain and beneficial effects of agents activating cannabinoid and\u002For vanilloid receptors in a rat model of multiple sclerosis. Neurobiol. Dis. 20, 207–217 (2005).",{"doi":1044},"10.1016\u002Fj.nbd.2005.03.002",{"id":24,"text":1046,"url":24,"identifiers":1047},"Cabranes, A. et al. Changes in CB1 receptors in motor-related brain structures of chronic relapsing experimental allergic encephalomyelitis mice. Brain Res. 1107, 199–205 (2006).",{"doi":1048},"10.1016\u002Fj.brainres.2006.06.001",{"id":24,"text":1050,"url":24,"identifiers":1051},"Benito, C. et al. Cannabinoid CB1 and CB2 receptors and fatty acid amide hydrolase are specific markers of plaque cell subtypes in human multiple sclerosis. J. Neurosci. 27, 2396–2402 (2007).",{"doi":1052},"10.1523\u002FJNEUROSCI.4814-06.2007",{"id":24,"text":1054,"url":24,"identifiers":1055},"Loria, F. et al. Study of the regulation of the endocannabinoid system in a virus model of multiple sclerosis reveals a therapeutic effect of palmitoylethanolamide. Eur. J. Neurosci. 28, 633–641 (2008).",{"doi":1056},"10.1111\u002Fj.1460-9568.2008.06377.x",{"id":24,"text":1058,"url":24,"identifiers":1059},"Jean-Gilles, L. et al. Plasma endocannabinoid levels in multiple sclerosis. J. Neurol. Sci. 287, 212–215 (2009).",{"doi":1060},"10.1016\u002Fj.jns.2009.07.021",{"id":24,"text":1062,"url":24,"identifiers":1063},"Baker, D. et al. Cannabinoids control spasticity and tremor in a multiple sclerosis model. Nature 404, 84–87 (2000). The first study to demonstrate that CB1 receptors have a role in the control of MS spasticity.",{"doi":1064},"10.1038\u002F35003583",{"id":24,"text":1066,"url":24,"identifiers":1067},"Baker, D. et al. Endocannabinoids control spasticity in a multiple sclerosis model. FASEB J. 15, 300–302 (2001). The first study to suggest that protective brain and spinal cord endocannabinoids are produced in parallel with the appearance of spasticity in an MS model.",{"doi":1068},"10.1096\u002Ffj.00-0399fje",{"id":24,"text":1070,"url":24,"identifiers":1071},"Arevalo-Martin, A. et al. Therapeutic action of cannabinoids in a murine model of multiple sclerosis. J. Neurosci. 23, 2511–2516 (2003).",{"doi":1072},"10.1523\u002FJNEUROSCI.23-07-02511.2003",{"id":24,"text":1074,"url":24,"identifiers":1075},"Arevalo-Martin, A., Molina-Holgado, E. & Guaza, C. A. CB(1)\u002FCB(2) receptor agonist, WIN 55,212-2, exerts its therapeutic effect in a viral autoimmune model of multiple sclerosis by restoring self-tolerance to myelin. Neuropharmacology 63, 385–393 (2012).",{"doi":1076},"10.1016\u002Fj.neuropharm.2012.04.012",{"id":24,"text":1078,"url":24,"identifiers":1079},"Maresz, K. et al. Direct suppression of CNS autoimmune inflammation via the cannabinoid receptor CB1 on neurons and CB2 on autoreactive T cells. Nat. Med. 13, 492–497 (2007). The discovery of two different protective roles of CB1 and CB2 in a model of MS.",{"doi":1080},"10.1038\u002Fnm1561",{"id":24,"text":1082,"url":24,"identifiers":1083},"Sanchez Lopez, A. J. et al. Regulation of cannabinoid receptor gene expression and endocannabinoid levels in lymphocyte subsets by interferon-beta: a longitudinal study in multiple sclerosis patients. Clin. Exp. Immunol. 179, 119–127 (2015).",{"doi":1084},"10.1111\u002Fcei.12443",{"id":24,"text":1086,"url":24,"identifiers":1087},"Musella, A. et al. Pre- and postsynaptic type-1 cannabinoid receptors control the alterations of glutamate transmission in experimental autoimmune encephalomyelitis. Neuropharmacology 79, 567–572 (2014).",{"doi":1088},"10.1016\u002Fj.neuropharm.2014.01.007",{"id":24,"text":1090,"url":24,"identifiers":1091},"Centonze, D. et al. The endocannabinoid system is dysregulated in multiple sclerosis and in experimental autoimmune encephalomyelitis. Brain 130, 2543–2553 (2007). The discovery that endocannabinoid levels are altered in patients with MS.",{"doi":1092},"10.1093\u002Fbrain\u002Fawm160",{"id":24,"text":1094,"url":24,"identifiers":1095},"Di Filippo, M. et al. Abnormalities in the cerebrospinal fluid levels of endocannabinoids in multiple sclerosis. J. Neurol. Neurosurg. Psychiatry. 79, 1224–1229 (2008).",{"doi":1096},"10.1136\u002Fjnnp.2007.139071",{"id":24,"text":1098,"url":24,"identifiers":1099},"de Lago, E. et al. UCM707, an inhibitor of the anandamide uptake, behaves as a symptom control agent in models of Huntington’s disease and multiple sclerosis, but fails to delay\u002Farrest the progression of different motor-related disorders. Eur. Neuropsychopharmacol. 16, 7–18 (2006).",{"doi":1100},"10.1016\u002Fj.euroneuro.2005.06.001",{"id":24,"text":1102,"url":24,"identifiers":1103},"Loria, F. et al. An endocannabinoid tone limits excitotoxicity in vitro and in a model of multiple sclerosis. Neurobiol. Dis. 37, 166–176 (2010).",{"doi":1104},"10.1016\u002Fj.nbd.2009.09.020",{"id":24,"text":1106,"url":24,"identifiers":1107},"Pryce, G. et al. Control of experimental spasticity by targeting the degradation of endocannabinoids using selective fatty acid amide hydrolase inhibitors. Mult. Scler. 19, 1896–1904 (2013).",{"doi":1108},"10.1177\u002F1352458513485982",{"id":24,"text":1110,"url":24,"identifiers":1111},"Brindisi, M. et al. Development and pharmacological characterization of selective blockers of 2-arachidonoyl glycerol degradation with efficacy in rodent models of multiple sclerosis and pain. J. Med. Chem. 59, 2612–2632 (2016).",{"doi":1112},"10.1021\u002Facs.jmedchem.5b01812",{"id":24,"text":1114,"url":24,"identifiers":1115},"Wen, J. et al. Activation of CB2 receptor is required for the therapeutic effect of ABHD6 inhibition in experimental autoimmune encephalomyelitis. Neuropharmacology 99, 196–209 (2015).",{"doi":1116},"10.1016\u002Fj.neuropharm.2015.07.010",{"id":24,"text":1118,"url":24,"identifiers":1119},"Rahimi, A. et al. Interaction between the protective effects of cannabidiol and palmitoylethanolamide in experimental model of multiple sclerosis in C57BL\u002F6 mice. Neuroscience 290, 279–287 (2015).",{"doi":1120},"10.1016\u002Fj.neuroscience.2015.01.030",{"id":24,"text":1122,"url":24,"identifiers":1123},"Kozela, E. et al. Cannabidiol inhibits pathogenic T cells, decreases spinal microglial activation and ameliorates multiple sclerosis-like disease in C57BL\u002F6 mice. Br. J. Pharmacol. 163, 1507–1519 (2011).",{"doi":1124},"10.1111\u002Fj.1476-5381.2011.01379.x",{"id":24,"text":1126,"url":24,"identifiers":1127},"Giacoppo, S., Bramanti, P. & Mazzon, E. Sativex in the management of multiple sclerosis-related spasticity: an overview of the last decade of clinical evaluation. Mult. Scler. Relat. Disord. 17, 22–31 (2017).",{"doi":1128},"10.1016\u002Fj.msard.2017.06.015",{"id":24,"text":1130,"url":24,"identifiers":1131},"Mecha, M. et al. Cannabidiol provides long-lasting protection against the deleterious effects of inflammation in a viral model of multiple sclerosis: a role for A2A receptors. Neurobiol. Dis. 59, 141–150 (2013).",{"doi":1132},"10.1016\u002Fj.nbd.2013.06.016",{"id":24,"text":1134,"url":24,"identifiers":1135},"Hilliard, A. et al. Evaluation of the effects of sativex (THC BDS: CBD BDS) on inhibition of spasticity in a chronic relapsing experimental allergic autoimmune encephalomyelitis: a model of multiple sclerosis. ISRN Neurol. 2012, 802649 (2012).",{"doi":1136},"10.5402\u002F2012\u002F802649",{"id":24,"text":1138,"url":24,"identifiers":1139},"Markova, J. et al. Sativex® as add-on therapy vs. further optimized first-line ANTispastics (SAVANT) in resistant multiple sclerosis spasticity: a double-blind, placebo-controlled randomised clinical trial. Int. J. Neurosci. 129, 119–128 (2018).",{"doi":1140},"10.1080\u002F00207454.2018.1481066",{"id":24,"text":1142,"url":24,"identifiers":1143},"Koch, G. et al. Cannabis-based treatment induces polarity-reversing plasticity assessed by theta burst stimulation in humans. Brain Stimul. 2, 229–233 (2009).",{"doi":1144},"10.1016\u002Fj.brs.2009.03.001",{"id":24,"text":1146,"url":24,"identifiers":1147},"Carotenuto, A. et al. Upper motor neuron evaluation in multiple sclerosis patients treated with Sativex®. Acta Neurol. Scand. 135, 442–448 (2017).",{"doi":1148},"10.1111\u002Fane.12660",{"id":24,"text":1150,"url":24,"identifiers":1151},"Russo, M. et al. Sativex in the management of multiple sclerosis-related spasticity: role of the corticospinal modulation. Neural Plast. 2015, 656582 (2015).",{"doi":1152},"10.1155\u002F2015\u002F656582",{"id":24,"text":1154,"url":24,"identifiers":1155},"Turri, M. et al. Pain modulation after oromucosal cannabinoid spray (SATIVEX®) in patients with multiple sclerosis: a study with quantitative sensory testing and laser-evoked potentials. Medicines 5, 59 (2018).",{"doi":1156},"10.3390\u002Fmedicines5030059",{"id":24,"text":1158,"url":24,"identifiers":1159},"Messina, S. et al. Sativex in resistant multiple sclerosis spasticity: discontinuation study in a large population of Italian patients (SA.FE. study). PLOS ONE 12, e0180651 (2017).",{"doi":1160},"10.1371\u002Fjournal.pone.0180651",{"id":24,"text":1162,"url":24,"identifiers":1163},"Patti, F. et al. Efficacy and safety of cannabinoid oromucosal spray for multiple sclerosis spasticity. J. Neurol. Neurosurg. Psychiatry 87, 944–951 (2016).",{"doi":1164},"10.1136\u002Fjnnp-2015-312591",{"id":24,"text":1166,"url":24,"identifiers":1167},"Sorosina, M. et al. Clinical response to Nabiximols correlates with the downregulation of immune pathways in multiple sclerosis. Eur. J. Neurol. 25, 934–e70 (2018).",{"doi":1168},"10.1111\u002Fene.13623",{"id":24,"text":1170,"url":24,"identifiers":1171},"Orefice, N. S. et al. Oral palmitoylethanolamide treatment is associated with reduced cutaneous adverse effects of interferon-beta1a and circulating proinflammatory cytokines in relapsing-remitting multiple sclerosis. Neurotherapeutics 13, 428–438 (2016).",{"doi":1172},"10.1007\u002Fs13311-016-0420-z",{"id":24,"text":1174,"url":24,"identifiers":1175},"Moreno-Martet, M. et al. Changes in endocannabinoid receptors and enzymes in the spinal cord of SOD1(G93A) transgenic mice and evaluation of a Sativex®-like combination of phytocannabinoids: interest for future therapies in amyotrophic lateral sclerosis. CNS Neurosci. Ther. 20, 809–815 (2014).",{"doi":1176},"10.1111\u002Fcns.12262",{"id":24,"text":1178,"url":24,"identifiers":1179},"Zhao, P. et al. Altered presymptomatic AMPA and cannabinoid receptor trafficking in motor neurons of ALS model mice: implications for excitotoxicity. Eur. J. Neurosci. 27, 572–579 (2008).",{"doi":1180},"10.1111\u002Fj.1460-9568.2008.06041.x",{"id":24,"text":1182,"url":24,"identifiers":1183},"Pasquarelli, N. et al. Evaluation of monoacylglycerol lipase as a therapeutic target in a transgenic mouse model of ALS. Neuropharmacology 124, 157–169 (2017).",{"doi":1184},"10.1016\u002Fj.neuropharm.2017.03.037",{"id":24,"text":1186,"url":24,"identifiers":1187},"Shoemaker, J. L. et al. The CB2 cannabinoid agonist AM-1241 prolongs survival in a transgenic mouse model of amyotrophic lateral sclerosis when initiated at symptom onset. J. Neurochem. 101, 87–98 (2007).",{"doi":1188},"10.1111\u002Fj.1471-4159.2006.04346.x",{"id":24,"text":1190,"url":24,"identifiers":1191},"Espejo-Porras, F. et al. Changes in the endocannabinoid signaling system in CNS structures of TDP-43 transgenic mice: relevance for a neuroprotective therapy in TDP-43-related disorders. J. Neuroimmune Pharmacol. 10, 233–244 (2015).",{"doi":1192},"10.1007\u002Fs11481-015-9602-4",{"id":24,"text":1194,"url":24,"identifiers":1195},"Espejo-Porras, F., Fernandez-Ruiz, J. & de Lago, E. Analysis of endocannabinoid receptors and enzymes in the post-mortem motor cortex and spinal cord of amyotrophic lateral sclerosis patients. Amyotroph. Lateral Scler. Frontotemporal Degener. 19, 377–386 (2018).",{"doi":1196},"10.1080\u002F21678421.2018.1425454",{"id":24,"text":1198,"url":24,"identifiers":1199},"Witting, A. et al. Endocannabinoids accumulate in spinal cord of SOD1 G93A transgenic mice. J. Neurochem. 89, 1555–1557 (2004).",{"doi":1200},"10.1111\u002Fj.1471-4159.2004.02544.x",{"id":24,"text":1202,"url":24,"identifiers":1203},"Rajan, T. S. et al. Gingival stromal cells as an in vitro model: cannabidiol modulates genes linked with amyotrophic lateral sclerosis. J. Cell. Biochem. 118, 819–828 (2017).",{"doi":1204},"10.1002\u002Fjcb.25757",{"id":24,"text":1206,"url":24,"identifiers":1207},"Palma, E. et al. Acetylcholine receptors from human muscle as pharmacological targets for ALS therapy. Proc. Natl Acad. Sci. USA 113, 3060–3065 (2016).",{"doi":1208},"10.1073\u002Fpnas.1600251113",{"id":24,"text":1210,"url":24,"identifiers":1211},"Clemente, S. Amyotrophic lateral sclerosis treatment with ultramicronized palmitoylethanolamide: a case report. CNS Neurol. Disord. Drug Targets 11, 933–936 (2012). The first study to suggest a therapeutic effect of palmitoylethanolamide in ALS.",{"doi":1212},"10.2174\u002F1871527311201070933",{"id":24,"text":1214,"url":24,"identifiers":1215},"Donat, C. K. et al. Early increase of cannabinoid receptor density after experimental traumatic brain injury in the newborn piglet. Acta Neurobiol. Exp. 74, 197–210 (2014).",{"doi":1216},"10.55782\u002Fane-2014-1985",{"id":24,"text":1218,"url":24,"identifiers":1219},"Panikashvili, D. et al. CB1 cannabinoid receptors are involved in neuroprotection via NF-kappa B inhibition. J. Cereb. Blood Flow Metab. 25, 477–484 (2005).",{"doi":1220},"10.1038\u002Fsj.jcbfm.9600047",{"id":24,"text":1222,"url":24,"identifiers":1223},"Elliott, M. B. et al. Acute effects of a selective cannabinoid-2 receptor agonist on neuroinflammation in a model of traumatic brain injury. J. Neurotrauma 28, 973–981 (2011).",{"doi":1224},"10.1089\u002Fneu.2010.1672",{"id":24,"text":1226,"url":24,"identifiers":1227},"Amenta, P. S. et al. A cannabinoid type 2 receptor agonist attenuates blood-brain barrier damage and neurodegeneration in a murine model of traumatic brain injury. J. Neurosci. Res. 90, 2293–2305 (2012).",{"doi":1228},"10.1002\u002Fjnr.23114",{"id":24,"text":1230,"url":24,"identifiers":1231},"Panikashvili, D. et al. An endogenous cannabinoid (2-AG) is neuroprotective after brain injury. Nature 413, 527–531 (2001).",{"doi":1232},"10.1038\u002F35097089",{"id":24,"text":1234,"url":24,"identifiers":1235},"Panikashvili, D. et al. The endocannabinoid 2-AG protects the blood-brain barrier after closed head injury and inhibits mRNA expression of proinflammatory cytokines. Neurobiol. Dis. 22, 257–264 (2006). The first study to suggest a protective role for endocannabinoids in brain trauma.",{"doi":1236},"10.1016\u002Fj.nbd.2005.11.004",{"id":24,"text":1238,"url":24,"identifiers":1239},"Tchantchou, F. et al. The fatty acid amide hydrolase inhibitor PF-3845 promotes neuronal survival, attenuates inflammation and improves functional recovery in mice with traumatic brain injury. Neuropharmacology 85, 427–439 (2014).",{"doi":1240},"10.1016\u002Fj.neuropharm.2014.06.006",{"id":24,"text":1242,"url":24,"identifiers":1243},"Tchantchou, F. & Zhang, Y. Selective inhibition of alpha\u002Fbeta-hydrolase domain 6 attenuates neurodegeneration, alleviates blood brain barrier breakdown, and improves functional recovery in a mouse model of traumatic brain injury. J. Neurotrauma 30, 565–579 (2013).",{"doi":1244},"10.1089\u002Fneu.2012.2647",{"id":24,"text":1246,"url":24,"identifiers":1247},"Katz, P. S. et al. Endocannabinoid degradation inhibition improves neurobehavioral function, blood-brain barrier integrity, and neuroinflammation following mild traumatic brain injury. J. Neurotrauma 32, 297–306 (2015).",{"doi":1248},"10.1089\u002Fneu.2014.3508",{"id":24,"text":1250,"url":24,"identifiers":1251},"Mayeux, J. et al. Inhibition of endocannabinoid degradation improves outcomes from mild traumatic brain injury: a mechanistic role for synaptic hyperexcitability. J. Neurotrauma 34, 436–443 (2017).",{"doi":1252},"10.1089\u002Fneu.2016.4452",{"id":24,"text":1254,"url":24,"identifiers":1255},"Ahmad, A. et al. Administration of palmitoylethanolamide (PEA) protects the neurovascular unit and reduces secondary injury after traumatic brain injury in mice. Brain Behav. Immun. 26, 1310–1321 (2012).",{"doi":1256},"10.1016\u002Fj.bbi.2012.07.021",{"id":24,"text":1258,"url":24,"identifiers":1259},"Cohen-Yeshurun, A. et al. N-arachidonoyl-L-serine (AraS) possesses proneurogenic properties in vitro and in vivo after traumatic brain injury. J. Cereb. Blood Flow Metab. 33, 1242–1250 (2013).",{"doi":1260},"10.1038\u002Fjcbfm.2013.75",{"id":24,"text":1262,"url":24,"identifiers":1263},"Yang, D. X. et al. Inhibition of transient receptor potential vanilloid 1 attenuates blood–brain barrier disruption after traumatic brain injury in mice. J. Neurotrauma 36, 1279–1290 (2019).",{"doi":1264},"10.1089\u002Fneu.2018.5942",{"id":24,"text":1266,"url":24,"identifiers":1267},"Feigenbaum, J. J. et al. Nonpsychotropic cannabinoid acts as a functional N-methyl-D-aspartate receptor blocker. Proc. Natl Acad. Sci. USA 86, 9584–9587 (1989).",{"doi":1268},"10.1073\u002Fpnas.86.23.9584",{"id":24,"text":1270,"url":24,"identifiers":1271},"Maas, A. I. et al. Efficacy and safety of dexanabinol in severe traumatic brain injury: results of a phase III randomised, placebo-controlled, clinical trial. Lancet Neurol. 5, 38–45 (2006).",{"doi":1272},"10.1016\u002FS1474-4422(05)70253-2",{"id":24,"text":1274,"url":24,"identifiers":1275},"Chi, O. Z. et al. Effects of cannabinoid receptor agonist WIN 55,212-2 on blood-brain barrier disruption in focal cerebral ischemia in rats. Pharmacology 89, 333–338 (2012).",{"doi":1276},"10.1159\u002F000338755",{"id":24,"text":1278,"url":24,"identifiers":1279},"Mauler, F. et al. Neuroprotective and brain edema-reducing efficacy of the novel cannabinoid receptor agonist BAY 38-7271. Brain Res. 989, 99–111 (2003).",{"doi":1280},"10.1016\u002FS0006-8993(03)03376-6",{"id":24,"text":1282,"url":24,"identifiers":1283},"Hayakawa, K. et al. Delta9-tetrahydrocannabinol (delta9-THC) prevents cerebral infarction via hypothalamic-independent hypothermia. Life Sci. 80, 1466–1471 (2007).",{"doi":1284},"10.1016\u002Fj.lfs.2007.01.014",{"id":24,"text":1286,"url":24,"identifiers":1287},"Parmentier-Batteur, S. et al. Increased severity of stroke in CB1 cannabinoid receptor knock-out mice. J. Neurosci. 22, 9771–9775 (2002).",{"doi":1288},"10.1523\u002FJNEUROSCI.22-22-09771.2002",{"id":24,"text":1290,"url":24,"identifiers":1291},"Muthian, S. et al. Anandamide content is increased and CB1 cannabinoid receptor blockade is protective during transient, focal cerebral ischemia. Neuroscience 129, 743–750 (2004).",{"doi":1292},"10.1016\u002Fj.neuroscience.2004.08.044",{"id":24,"text":1294,"url":24,"identifiers":1295},"Zarruk, J. G. et al. Cannabinoid type 2 receptor activation downregulates stroke-induced classic and alternative brain macrophage\u002Fmicroglial activation concomitant to neuroprotection. Stroke 43, 211–219 (2012).",{"doi":1296},"10.1161\u002FSTROKEAHA.111.631044",{"id":24,"text":1298,"url":24,"identifiers":1299},"Zhang, M. et al. CB2 receptor activation attenuates microcirculatory dysfunction during cerebral ischemic\u002Freperfusion injury. Microvasc. Res. 78, 86–94 (2009).",{"doi":1300},"10.1016\u002Fj.mvr.2009.03.005",{"id":24,"text":1302,"url":24,"identifiers":1303},"Ward, S. J. et al. Surprising outcomes in cannabinoid CB1\u002FCB2 receptor double knockout mice in two models of ischemia. Life Sci. 195, 1–5 (2018).",{"doi":1304},"10.1016\u002Fj.lfs.2017.12.030",{"id":24,"text":1306,"url":24,"identifiers":1307},"Schomacher, M. et al. Endocannabinoids mediate neuroprotection after transient focal cerebral ischemia. Brain Res. 1240, 213–220 (2008).",{"doi":1308},"10.1016\u002Fj.brainres.2008.09.019",{"id":24,"text":1310,"url":24,"identifiers":1311},"Sun, Y. et al. Cannabinoid activation of PPAR alpha; a novel neuroprotective mechanism. Br. J. Pharmacol. 152, 734–743 (2007).",{"doi":1312},"10.1038\u002Fsj.bjp.0707478",{"id":24,"text":1314,"url":24,"identifiers":1315},"Yang, L. C. et al. Chronic oleoylethanolamide treatment improves spatial cognitive deficits through enhancing hippocampal neurogenesis after transient focal cerebral ischemia. Biochem. Pharmacol. 94, 270–281 (2015).",{"doi":1316},"10.1016\u002Fj.bcp.2015.02.012",{"id":24,"text":1318,"url":24,"identifiers":1319},"Schabitz, W. R. et al. Release of fatty acid amides in a patient with hemispheric stroke: a microdialysis study. Stroke 33, 2112–2114 (2002).",{"doi":1320},"10.1161\u002F01.STR.0000023491.63693.18",{"id":24,"text":1322,"url":24,"identifiers":1323},"Franklin, A. et al. Palmitoylethanolamide increases after focal cerebral ischemia and potentiates microglial cell motility. J. Neurosci. 23, 7767–7775 (2003).",{"doi":1324},"10.1523\u002FJNEUROSCI.23-21-07767.2003",{"id":24,"text":1326,"url":24,"identifiers":1327},"Naccarato, M. et al. Possible anandamide and palmitoylethanolamide involvement in human stroke. Lipids Health Dis. 9, 47 (2010).",{"doi":1328},"10.1186\u002F1476-511X-9-47",{"id":24,"text":1330,"url":24,"identifiers":1331},"Mishima, K. et al. Cannabidiol prevents cerebral infarction via a serotonergic 5-hydroxytryptamine1A receptor-dependent mechanism. Stroke 36, 1077–1082 (2005).",{"doi":1332},"10.1161\u002F01.STR.0000163083.59201.34",{"id":24,"text":1334,"url":24,"identifiers":1335},"Khaksar, S. & Bigdeli, M. R. Anti-excitotoxic effects of cannabidiol are partly mediated by enhancement of NCX2 and NCX3 expression in animal model of cerebral ischemia. Eur. J. Pharmacol. 794, 270–279 (2017).",{"doi":1336},"10.1016\u002Fj.ejphar.2016.11.011",{"id":24,"text":1338,"url":24,"identifiers":1339},"Alvarez, F. J. et al. Neuroprotective effects of the nonpsychoactive cannabinoid cannabidiol in hypoxic-ischemic newborn piglets. Pediatr. Res. 64, 653–658 (2008).",{"doi":1340},"10.1203\u002FPDR.0b013e318186e5dd",{"id":24,"text":1342,"url":24,"identifiers":1343},"Castillo, A. et al. The neuroprotective effect of cannabidiol in an in vitro model of newborn hypoxic-ischemic brain damage in mice is mediated by CB(2) and adenosine receptors. Neurobiol. Dis. 37, 434–440 (2010).",{"doi":1344},"10.1016\u002Fj.nbd.2009.10.023",{"id":24,"text":1346,"url":24,"identifiers":1347},"Lafuente, H. et al. Cannabidiol reduces brain damage and improves functional recovery after acute hypoxia-ischemia in newborn pigs. Pediatr. Res. 70, 272–277 (2011).",{"doi":1348},"10.1203\u002FPDR.0b013e3182276b11",{"id":24,"text":1350,"url":24,"identifiers":1351},"Pazos, M. R. et al. Cannabidiol administration after hypoxia-ischemia to newborn rats reduces long-term brain injury and restores neurobehavioral function. Neuropharmacology 63, 776–783 (2012).",{"doi":1352},"10.1016\u002Fj.neuropharm.2012.05.034",{"id":24,"text":1354,"url":24,"identifiers":1355},"Ceprian, M. et al. Cannabidiol reduces brain damage and improves functional recovery in a neonatal rat model of arterial ischemic stroke. Neuropharmacology 116, 151–159 (2017).",{"doi":1356},"10.1016\u002Fj.neuropharm.2016.12.017",{"id":24,"text":1358,"url":24,"identifiers":1359},"Marinelli, L. et al. A randomised controlled cross-over double-blind pilot study protocol on THC:CBD oromucosal spray efficacy as an add-on therapy for post-stroke spasticity. BMJ Open 7, e016843 (2017).",{"doi":1360},"10.1136\u002Fbmjopen-2017-016843",{"id":24,"text":1362,"url":24,"identifiers":1363},"Caltagirone, C. et al. Co-ultramicronized palmitoylethanolamide\u002Fluteolin in the treatment of cerebral ischemia: from rodent to man. Transl. Stroke Res. 7, 54–69 (2016).",{"doi":1364},"10.1007\u002Fs12975-015-0440-8",{"id":24,"text":1366,"url":24,"identifiers":1367},"Vinogradova, L. V. & van Rijn, C. M. Long-term disease-modifying effect of the endocannabinoid agonist WIN55,212-2 in a rat model of audiogenic epilepsy. Pharmacol. Rep. 67, 501–503 (2015).",{"doi":1368},"10.1016\u002Fj.pharep.2014.12.002",{"id":24,"text":1370,"url":24,"identifiers":1371},"Di Maio, R., Cannon, J. R. & Greenamyre, J. T. Post-status epilepticus treatment with the cannabinoid agonist WIN 55,212-2 prevents chronic epileptic hippocampal damage in rats. Neurobiol. Dis. 73, 356–365 (2015).",{"doi":1372},"10.1016\u002Fj.nbd.2014.10.018",{"id":24,"text":1374,"url":24,"identifiers":1375},"Wallace, M. J. et al. The endogenous cannabinoid system regulates seizure frequency and duration in a model of temporal lobe epilepsy. J. Pharmacol. Exp. Ther. 307, 129–137 (2003).",{"doi":1376},"10.1124\u002Fjpet.103.051920",{"id":24,"text":1378,"url":24,"identifiers":1379},"Vinogradova, L. V., Shatskova, A. B. & van Rijn, C. M. Pro-epileptic effects of the cannabinoid receptor antagonist SR141716 in a model of audiogenic epilepsy. Epilepsy Res. 96, 250–256 (2011).",{"doi":1380},"10.1016\u002Fj.eplepsyres.2011.06.007",{"id":24,"text":1382,"url":24,"identifiers":1383},"Echegoyen, J. et al. Single application of a CB1 receptor antagonist rapidly following head injury prevents long-term hyperexcitability in a rat model. Epilepsy Res. 85, 123–127 (2009).",{"doi":1384},"10.1016\u002Fj.eplepsyres.2009.02.019",{"id":24,"text":1386,"url":24,"identifiers":1387},"Wang, X. et al. CB1 receptor antagonism prevents long-term hyperexcitability after head injury by regulation of dynorphin-KOR system and mGluR5 in rat hippocampus. Brain Res. 1646, 174–181 (2016).",{"doi":1388},"10.1016\u002Fj.brainres.2016.05.055",{"id":24,"text":1390,"url":24,"identifiers":1391},"Feng, B. et al. Transient increase of interleukin-1beta after prolonged febrile seizures promotes adult epileptogenesis through long-lasting upregulating endocannabinoid signaling. Sci. Rep. 6, 21931 (2016).",{"doi":1392},"10.1038\u002Fsrep21931",{"id":24,"text":1394,"url":24,"identifiers":1395},"Wallace, M. J. et al. Assessment of the role of CB1 receptors in cannabinoid anticonvulsant effects. Eur. J. Pharmacol. 428, 51–57 (2001).",{"doi":1396},"10.1016\u002FS0014-2999(01)01243-2",{"id":24,"text":1398,"url":24,"identifiers":1399},"Luszczki, J. J. et al. Effects of WIN 55,212-2 mesylate on the anticonvulsant action of lamotrigine, oxcarbazepine, pregabalin and topiramate against maximal electroshock-induced seizures in mice. Eur. J. Pharmacol. 720, 247–254 (2013).",{"doi":1400},"10.1016\u002Fj.ejphar.2013.10.020",{"id":24,"text":1402,"url":24,"identifiers":1403},"Payandemehr, B. et al. Involvement of PPAR receptors in the anticonvulsant effects of a cannabinoid agonist, WIN 55,212-2. Prog. Neuropsychopharmacol. Biol. Psychiatry 57, 140–145 (2015).",{"doi":1404},"10.1016\u002Fj.pnpbp.2014.11.005",{"id":24,"text":1406,"url":24,"identifiers":1407},"Bahremand, A. et al. Involvement of nitrergic system in the anticonvulsant effect of the cannabinoid CB(1) agonist ACEA in the pentylenetetrazole-induced seizure in mice. Epilepsy Res. 84, 110–119 (2009).",{"doi":1408},"10.1016\u002Fj.eplepsyres.2009.01.003",{"id":24,"text":1410,"url":24,"identifiers":1411},"Marsicano, G. et al. CB1 cannabinoid receptors and on-demand defense against excitotoxicity. Science 302, 84–88 (2003). The first study to demonstrate the on-demand neuroprotective role of endocannabinoids and CB1 against excitotoxicity-induced neuronal damage.",{"doi":1412},"10.1126\u002Fscience.1088208",{"id":24,"text":1414,"url":24,"identifiers":1415},"Lerner, R. et al. Targeting brain and peripheral plasticity of the lipidome in acute kainic acid-induced epileptic seizures in mice via quantitative mass spectrometry. Biochim. Biophys. Acta Mol. Cell Biol. Lipids 1862, 255–267 (2017).",{"doi":1416},"10.1016\u002Fj.bbalip.2016.11.008",{"id":24,"text":1418,"url":24,"identifiers":1419},"Chen, K. et al. Long-term plasticity of endocannabinoid signaling induced by developmental febrile seizures. Neuron 39, 599–611 (2003).",{"doi":1420},"10.1016\u002FS0896-6273(03)00499-9",{"id":24,"text":1422,"url":24,"identifiers":1423},"Vilela, L. R. et al. Effects of cannabinoids and endocannabinoid hydrolysis inhibition on pentylenetetrazole-induced seizure and electroencephalographic activity in rats. Epilepsy Res. 104, 195–202 (2013).",{"doi":1424},"10.1016\u002Fj.eplepsyres.2012.11.006",{"id":24,"text":1426,"url":24,"identifiers":1427},"Shubina, L., Aliev, R. & Kitchigina, V. Attenuation of kainic acid-induced status epilepticus by inhibition of endocannabinoid transport and degradation in guinea pigs. Epilepsy Res. 111, 33–44 (2015).",{"doi":1428},"10.1016\u002Fj.eplepsyres.2015.01.003",{"id":24,"text":1430,"url":24,"identifiers":1431},"Manna, S. S. & Umathe, S. N. Involvement of transient receptor potential vanilloid type 1 channels in the pro-convulsant effect of anandamide in pentylenetetrazole-induced seizures. Epilepsy Res. 100, 113–124 (2012).",{"doi":1432},"10.1016\u002Fj.eplepsyres.2012.02.003",{"id":24,"text":1434,"url":24,"identifiers":1435},"Zareie, P. et al. Anticonvulsive effects of endocannabinoids; an investigation to determine the role of regulatory components of endocannabinoid metabolism in the pentylenetetrazol induced tonic- clonic seizures. Metab. Brain Dis. 33, 939–948 (2018).",{"doi":1436},"10.1007\u002Fs11011-018-0195-5",{"id":24,"text":1438,"url":24,"identifiers":1439},"Naydenov, A. V. et al. ABHD6 blockade exerts antiepileptic activity in PTZ-induced seizures and in spontaneous seizures in R6\u002F2 mice. Neuron 83, 361–371 (2014).",{"doi":1440},"10.1016\u002Fj.neuron.2014.06.030",{"id":24,"text":1442,"url":24,"identifiers":1443},"Griebel, G. et al. Selective blockade of the hydrolysis of the endocannabinoid 2-arachidonoylglycerol impairs learning and memory performance while producing antinociceptive activity in rodents. Sci. Rep. 5, 7642 (2015).",{"doi":1444},"10.1038\u002Fsrep07642",{"id":24,"text":1446,"url":24,"identifiers":1447},"Ma, L. et al. Disease-modifying effects of RHC80267 and JZL184 in a pilocarpine mouse model of temporal lobe epilepsy. CNS Neurosci. Ther. 20, 905–915 (2014).",{"doi":1448},"10.1111\u002Fcns.12302",{"id":24,"text":1450,"url":24,"identifiers":1451},"Shirazi, M. et al. Involvement of central TRPV1 receptors in pentylenetetrazole and amygdala-induced kindling in male rats. Neurol. Sci. 35, 1235–1241 (2014).",{"doi":1452},"10.1007\u002Fs10072-014-1689-5",{"id":24,"text":1454,"url":24,"identifiers":1455},"Aghaei, I. et al. Palmitoylethanolamide attenuates PTZ-induced seizures through CB1 and CB2 receptors. Epilepsy Res. 117, 23–28 (2015).",{"doi":1456},"10.1016\u002Fj.eplepsyres.2015.08.010",{"id":24,"text":1458,"url":24,"identifiers":1459},"Jones, N. A. et al. Cannabidiol displays antiepileptiform and antiseizure properties in vitro and in vivo. J. Pharmacol. Exp. Ther. 332, 569–577 (2010).",{"doi":1460},"10.1124\u002Fjpet.109.159145",{"id":24,"text":1462,"url":24,"identifiers":1463},"Jones, N. A. et al. Cannabidiol exerts anti-convulsant effects in animal models of temporal lobe and partial seizures. Seizure 21, 344–352 (2012).",{"doi":1464},"10.1016\u002Fj.seizure.2012.03.001",{"id":24,"text":1466,"url":24,"identifiers":1467},"Khan, A. A. et al. Cannabidiol exerts antiepileptic effects by restoring hippocampal interneuron functions in a temporal lobe epilepsy model. Br. J. Pharmacol. 175, 2097–2115 (2018).",{"doi":1468},"10.1111\u002Fbph.14202",{"id":24,"text":1470,"url":24,"identifiers":1471},"Hill, A. J. et al. Cannabidivarin is anticonvulsant in mouse and rat. Br. J. Pharmacol. 167, 1629–1642 (2012).",{"doi":1472},"10.1111\u002Fj.1476-5381.2012.02207.x",{"id":24,"text":1474,"url":24,"identifiers":1475},"Thiele, E. A. et al. Cannabidiol in patients with seizures associated with Lennox-Gastaut syndrome (GWPCARE4): a randomised, double-blind, placebo-controlled phase 3 trial. Lancet 391, 1085–1096 (2018). One of two controlled clinical studies that led to the approval of botanical cannabidiol against rare and untreatable forms of paediatric epilepsy.",{"doi":1476},"10.1016\u002FS0140-6736(18)30136-3",{"id":24,"text":1478,"url":24,"identifiers":1479},"Szaflarski, J. P. et al. Cannabidiol improves frequency and severity of seizures and reduces adverse events in an open-label add-on prospective study. Epilepsy Behav. 87, 131–136 (2018).",{"doi":1480},"10.1016\u002Fj.yebeh.2018.07.020",{"id":24,"text":1482,"url":24,"identifiers":1483},"Devinsky, O. et al. Open-label use of highly purified CBD (Epidiolex®) in patients with CDKL5 deficiency disorder and Aicardi, Dup15q, and Doose syndromes. Epilepsy Behav. 86, 131–137 (2018).",{"doi":1484},"10.1016\u002Fj.yebeh.2018.05.013",{"id":24,"text":1486,"url":24,"identifiers":1487},"Gofshteyn, J. S. Cannabidiol as a potential treatment for febrile infection-related epilepsy syndrome (FIRES) in the acute and chronic phases. J. Child. Neurol. 32, 35–40 (2017).",{"doi":1488},"10.1177\u002F0883073816669450",{"id":24,"text":1490,"url":24,"identifiers":1491},"Gaston, T. E. et al. Interactions between cannabidiol and commonly used antiepileptic drugs. Epilepsia 58, 1586–1592 (2017).",{"doi":1492},"10.1111\u002Fepi.13852",{"id":24,"text":1494,"url":24,"identifiers":1495},"De Jesus, M. L. et al. Opposite changes in cannabinoid CB1 and CB2 receptor expression in human gliomas. Neurochem. Int. 56, 829–833 (2010).",{"doi":1496},"10.1016\u002Fj.neuint.2010.03.007",{"id":24,"text":1498,"url":24,"identifiers":1499},"Wu, X. et al. Alteration of endocannabinoid system in human gliomas. J. Neurochem. 120, 842–849 (2012).",{"doi":1500},"10.1111\u002Fj.1471-4159.2011.07625.x",{"id":24,"text":1502,"url":24,"identifiers":1503},"Ellert-Miklaszewska, A., Ciechomska, I. & Kaminska, B. Cannabinoid signaling in glioma cells. Adv. Exp. Med. Biol. 986, 209–220 (2013).",{"doi":1504},"10.1007\u002F978-94-007-4719-7_11",{"id":24,"text":1506,"url":24,"identifiers":1507},"Galve-Roperh, I. et al. Anti-tumoral action of cannabinoids: involvement of sustained ceramide accumulation and extracellular signal-regulated kinase activation. Nat. Med. 6, 313–319 (2000). The first study to suggest that THC could be used in the treatment of glioblastoma.",{"doi":1508},"10.1038\u002F73171",{"id":24,"text":1510,"url":24,"identifiers":1511},"Blazquez, C. et al. Inhibition of tumor angiogenesis by cannabinoids. FASEB J. 17, 529–531 (2003).",{"doi":1512},"10.1096\u002Ffj.02-0795fje",{"id":24,"text":1514,"url":24,"identifiers":1515},"Gurley, S. N. et al. Mechanism of anti-glioma activity and in vivo efficacy of the cannabinoid ligand KM-233. J. Neurooncol. 110, 163–177 (2012).",{"doi":1516},"10.1007\u002Fs11060-012-0958-5",{"id":24,"text":1518,"url":24,"identifiers":1519},"Sanchez, C. et al. Inhibition of glioma growth in vivo by selective activation of the CB(2) cannabinoid receptor. Cancer Res. 61, 5784–5789 (2001).",{},{"id":24,"text":1521,"url":24,"identifiers":1522},"Aguado, T. et al. Cannabinoids induce glioma stem-like cell differentiation and inhibit gliomagenesis. J. Biol. Chem. 282, 6854–6862 (2007).",{"doi":1523},"10.1074\u002Fjbc.M608900200",{"id":24,"text":1525,"url":24,"identifiers":1526},"Ma, C. et al. Anti-carcinogenic activity of anandamide on human glioma in vitro and in vivo. Mol. Med. Rep. 13, 1558–1562 (2016).",{"doi":1527},"10.3892\u002Fmmr.2015.4721",{"id":24,"text":1529,"url":24,"identifiers":1530},"Stock, K. et al. Neural precursor cells induce cell death of high-grade astrocytomas through stimulation of TRPV1. Nat. Med. 18, 1232–1238 (2012). The discovery that endocannabinoid-like mediators acting at TRPV1 could have a role in the control of glioblastoma.",{"doi":1531},"10.1038\u002Fnm.2827",{"id":24,"text":1533,"url":24,"identifiers":1534},"Nabissi, M. et al. Post-transcriptional regulation of 5′-untranslated regions of human transient receptor potential vanilloid type-1 (TRPV-1) channels: role in the survival of glioma patients. Oncotarget 7, 81541–81554 (2016).",{"doi":1535},"10.18632\u002Foncotarget.13132",{"id":24,"text":1537,"url":24,"identifiers":1538},"Vaccani, A. et al. Cannabidiol inhibits human glioma cell migration through a cannabinoid receptor-independent mechanism. Br. J. Pharmacol. 144, 1032–1036 (2005).",{"doi":1539},"10.1038\u002Fsj.bjp.0706134",{"id":24,"text":1541,"url":24,"identifiers":1542},"Moreno, E. et al. Targeting CB2-GPR55 receptor heteromers modulates cancer cell signaling. J. Biol. Chem. 289, 21960–21972 (2014).",{"doi":1543},"10.1074\u002Fjbc.M114.561761",{"id":24,"text":1545,"url":24,"identifiers":1546},"Scott, K. A., Dalgleish, A. G. & Liu, W. M. The combination of cannabidiol and delta9-tetrahydrocannabinol enhances the anticancer effects of radiation in an orthotopic murine glioma model. Mol. Cancer. Ther. 13, 2955–2967 (2014).",{"doi":1547},"10.1158\u002F1535-7163.MCT-14-0402",{"id":24,"text":1549,"url":24,"identifiers":1550},"Torres, S. et al. A combined preclinical therapy of cannabinoids and temozolomide against glioma. Mol. Cancer. Ther. 10, 90–103 (2011).",{"doi":1551},"10.1158\u002F1535-7163.MCT-10-0688",{"id":24,"text":1553,"url":24,"identifiers":1554},"Nabissi, M. et al. Triggering of the TRPV2 channel by cannabidiol sensitizes glioblastoma cells to cytotoxic chemotherapeutic agents. Carcinogenesis 34, 48–57 (2013).",{"doi":1555},"10.1093\u002Fcarcin\u002Fbgs328",{"id":24,"text":1557,"url":24,"identifiers":1558},"Nabissi, M. et al. Cannabidiol stimulates Aml-1a-dependent glial differentiation and inhibits glioma stem-like cells proliferation by inducing autophagy in a TRPV2-dependent manner. Int. J. Cancer 137, 1855–1869 (2015).",{"doi":1559},"10.1002\u002Fijc.29573",{"id":24,"text":1561,"url":24,"identifiers":1562},"GW Pharmaceuticals. GW Pharmaceuticals achieves positive results in phase 2 proof of concept study in glioma. gwpharm https:\u002F\u002Fwww.gwpharm.co.uk\u002Fabout\u002Fnews\u002Fgw-pharmaceuticals-achieves-positive-results-phase-2-proof-concept-study-glioma (2017).",{},{"id":24,"text":1564,"url":24,"identifiers":1565},"US National Library of Medicine. Clinicaltrials.gov https:\u002F\u002Fclinicaltrials.gov\u002Fct2\u002Fshow\u002FNCT01654497 (2017).",{},{"id":24,"text":1567,"url":24,"identifiers":1568},"Chiurchiù, V. et al. Modulation of monocytes by bioactive lipid anandamide in multiple sclerosis involves distinct Toll-like receptors. Pharmacol. Res. 113, 313–319 (2016).",{"doi":1569},"10.1016\u002Fj.phrs.2016.09.003",{"id":24,"text":1571,"url":24,"identifiers":1572},"Franco, R. & Fernández-Suárez, D. Alternatively activated microglia and macrophages in the central nervous system. Prog. Neurobiol. 131, 65–86 (2015).",{"doi":1573},"10.1016\u002Fj.pneurobio.2015.05.003",{"id":24,"text":1575,"url":24,"identifiers":1576},"Muller-Vahl, K. R. Treatment of Tourette syndrome with cannabinoids. Behav. Neurol. 27, 119–124 (2013).",{"doi":1577},"10.1155\u002F2013\u002F294264",{"id":24,"text":1579,"url":24,"identifiers":1580},"Ruzic Zecevic, D. et al. Investigational cannabinoids in seizure disorders, what have we learned thus far? Expert Opin. Investig. Drugs 27, 535–541 (2018).",{"doi":1581},"10.1080\u002F13543784.2018.1482275",{"id":24,"text":1583,"url":24,"identifiers":1584},"US National Library of Medicine. Clinicaltrials.gov https:\u002F\u002Fclinicaltrials.gov\u002Fct2\u002Fshow\u002FNCT03202303 (2019).",{},{"id":24,"text":1586,"url":24,"identifiers":1587},"Ganley, O. H., Graessle, O. E. & Robinson, H. J. Anti-inflammatory activity on compounds obtained from egg yolk, peanut oil, and soybean lecithin. J. Lab. Clin. Med. 51, 709–714 (1958).",{},{"id":24,"text":1589,"url":24,"identifiers":1590},"Guida, F. et al. Palmitoylethanolamide induces microglia changes associated with increased migration and phagocytic activity: involvement of the CB2 receptor. Sci. Rep. 7, 375 (2017).",{"doi":1591},"10.1038\u002Fs41598-017-00342-1",{"id":24,"text":1593,"url":24,"identifiers":1594},"Chiurchiù, V. et al. Resolution of inflammation is altered in chronic heart failure and entails a dysfunctional responsiveness of T lymphocytes. FASEB J. 33, 909–916 (2019).",{"doi":1595},"10.1096\u002Ffj.201801017R",{"id":24,"text":1597,"url":24,"identifiers":1598},"Mestre, L. et al. Gut microbiota, cannabinoid system and neuroimmune interactions: new perspectives in multiple sclerosis. Biochem. Pharmacol 157, 51–66 (2018).",{"doi":1599},"10.1016\u002Fj.bcp.2018.08.037",{"id":24,"text":1601,"url":24,"identifiers":1602},"Russo, R. et al. Gut-brain axis: role of lipids in the regulation of inflammation, pain and CNS diseases. 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Future life expectancy in 35 industrialised countries: projections with a Bayesian model ensemble. Lancet 389, 1323–1335 (2017).",{"doi":1833},"10.1016\u002FS0140-6736(16)32381-9",{"id":24,"text":1835,"url":24,"identifiers":1836},"Prince, M. et al. World Alzheimer Report 2015: The Global Impact of Dementia: An Analysis of Prevalence, Incidence, Cost and Trends (Alzheimer’s Disease International, 2015).",{},{"id":24,"text":1838,"url":24,"identifiers":1839},"METACOHORTS Consortium. METACOHORTS for the study of vascular disease and its contribution to cognitive decline and neurodegeneration: an initiative of the Joint Programme for Neurodegenerative Disease Research. Alzheimers Dement. 12, 1235–1249 (2016).",{"doi":1840},"10.1016\u002Fj.jalz.2016.06.004",{"id":24,"text":1842,"url":24,"identifiers":1843},"de Laat, K. F. et al. Gait in elderly with cerebral small vessel disease. Stroke 41, 1652–1658 (2010).",{"doi":1844},"10.1161\u002FSTROKEAHA.110.583229",{"id":24,"text":1846,"url":24,"identifiers":1847},"Wardlaw, J. M. et al. Neuroimaging standards for research into small vessel disease and its contribution to ageing and neurodegeneration. Lancet Neurol. 12, 822–838 (2013).",{"doi":1848},"10.1016\u002FS1474-4422(13)70124-8",{"id":24,"text":1850,"url":24,"identifiers":1851},"Debette, S. & Markus, H. S. The clinical importance of white matter hyperintensities on brain magnetic resonance imaging: systematic review and meta-analysis. BMJ 341, c3666 (2010).",{"doi":1852},"10.1136\u002Fbmj.c3666",{"id":24,"text":1854,"url":24,"identifiers":1855},"van Agtmaal, M. J. M., Houben, A., Pouwer, F., Stehouwer, C. D. A. & Schram, M. T. Association of microvascular dysfunction with late-life depression: a systematic review and meta-analysis. JAMA Psychiatry 74, 729–739 (2017).",{"doi":1856},"10.1001\u002Fjamapsychiatry.2017.0984",{"id":24,"text":1858,"url":24,"identifiers":1859},"de Leeuw, F. E. et al. Prevalence of cerebral white matter lesions in elderly people: a population based magnetic resonance imaging study. The Rotterdam Scan Study. J. Neurol. Neurosurg. Psychiatry 70, 9–14 (2001).",{"doi":1860},"10.1136\u002Fjnnp.70.1.9",{"id":24,"text":1862,"url":24,"identifiers":1863},"Pantoni, L. Cerebral small vessel disease: from pathogenesis and clinical characteristics to therapeutic challenges. Lancet Neurol. 9, 689–701 (2010).",{"doi":1864},"10.1016\u002FS1474-4422(10)70104-6",{"id":24,"text":1866,"url":24,"identifiers":1867},"Cummings, J. L. Frontal-subcortical circuits and human behavior. Arch. Neurol. 50, 873–880 (1993).",{"doi":1868},"10.1001\u002Farchneur.1993.00540080076020",{"id":24,"text":1870,"url":24,"identifiers":1871},"Jokinen, H. et al. Longitudinal cognitive decline in subcortical ischemic vascular disease — the LADIS Study. Cerebrovasc. Dis. 27, 384–391 (2009).",{"doi":1872},"10.1159\u002F000207442",{"id":24,"text":1874,"url":24,"identifiers":1875},"Baezner, H. et al. Association of gait and balance disorders with age-related white matter changes: the LADIS study. Neurology 70, 935–942 (2008).",{"doi":1876},"10.1212\u002F01.wnl.0000305959.46197.e6",{"id":24,"text":1878,"url":24,"identifiers":1879},"Smith, E. E. et al. Early cerebral small vessel disease and brain volume, cognition, and gait. Ann. Neurol. 77, 251–261 (2015).",{"doi":1880},"10.1002\u002Fana.24320",{"id":24,"text":1882,"url":24,"identifiers":1883},"van der Holst, H. M. et al. Cerebral small vessel disease and incident parkinsonism: the RUN DMC study. Neurology 85, 1569–1577 (2015).",{"doi":1884},"10.1212\u002FWNL.0000000000002082",{"id":24,"text":1886,"url":24,"identifiers":1887},"Marin, R. S., Biedrzycki, R. C. & Firinciogullari, S. Reliability and validity of the Apathy Evaluation Scale. Psychiatry Res. 38, 143–162 (1991).",{"doi":1888},"10.1016\u002F0165-1781(91)90040-V",{"id":24,"text":1890,"url":24,"identifiers":1891},"Stanton, B. R. & Carson, A. Apathy: a practical guide for neurologists. Pract. Neurol. 16, 42–47 (2016).",{"doi":1892},"10.1136\u002Fpractneurol-2015-001232",{"id":24,"text":1894,"url":24,"identifiers":1895},"Hollocks, M. J. et al. Differential relationships between apathy and depression with white matter microstructural changes and functional outcomes. Brain 138, 3803–3815 (2015).",{"doi":1896},"10.1093\u002Fbrain\u002Fawv304",{"id":24,"text":1898,"url":24,"identifiers":1899},"van Uden, I. W. et al. White matter integrity and depressive symptoms in cerebral small vessel disease: the RUN DMC study. Am. J. Geriatr. Psychiatry 23, 525–535 (2015).",{"doi":1900},"10.1016\u002Fj.jagp.2014.07.002",{"id":24,"text":1902,"url":24,"identifiers":1903},"Edwards, J. D., Jacova, C., Sepehry, A. A., Pratt, B. & Benavente, O. R. A quantitative systematic review of domain-specific cognitive impairment in lacunar stroke. Neurology 80, 315–322 (2013).",{"doi":1904},"10.1212\u002FWNL.0b013e31827deb85",{"id":24,"text":1906,"url":24,"identifiers":1907},"Seo, S. W. et al. Clinical significance of microbleeds in subcortical vascular dementia. Stroke 38, 1949–1951 (2007).",{"doi":1908},"10.1161\u002FSTROKEAHA.106.477315",{"id":24,"text":1910,"url":24,"identifiers":1911},"Hillis, A. E. et al. Subcortical aphasia and neglect in acute stroke: the role of cortical hypoperfusion. Brain 125, 1094–1104 (2002).",{"doi":1912},"10.1093\u002Fbrain\u002Fawf113",{"id":24,"text":1914,"url":24,"identifiers":1915},"Hoffmann, M. & Chen, R. The spectrum of aphasia subtypes and etiology in subacute stroke. J. Stroke Cerebrovasc. Dis. 22, 1385–1392 (2013).",{"doi":1916},"10.1016\u002Fj.jstrokecerebrovasdis.2013.04.017",{"id":24,"text":1918,"url":24,"identifiers":1919},"Van Zandvoort, M. J., De Haan, E. H. & Kappelle, L. J. Chronic cognitive disturbances after a single supratentorial lacunar infarct. Neuropsychiatry Neuropsychol. Behav. Neurol. 14, 98–102 (2001).",{},{"id":24,"text":1921,"url":24,"identifiers":1922},"Vasquez, B. P. & Zakzanis, K. K. The neuropsychological profile of vascular cognitive impairment not demented: a meta-analysis. J. Neuropsychol. 9, 109–136 (2015).",{"doi":1923},"10.1111\u002Fjnp.12039",{"id":24,"text":1925,"url":24,"identifiers":1926},"Van der Werf, Y. D. et al. Deficits of memory, executive functioning and attention following infarction in the thalamus; a study of 22 cases with localised lesions. Neuropsychologia 41, 1330–1344 (2003).",{"doi":1927},"10.1016\u002FS0028-3932(03)00059-9",{"id":24,"text":1929,"url":24,"identifiers":1930},"Van Der Werf, Y. D. et al. Neuropsychological correlates of a right unilateral lacunar thalamic infarction. J. Neurol. Neurosurg. Psychiatry 66, 36–42 (1999).",{"doi":1931},"10.1136\u002Fjnnp.66.1.36",{"id":24,"text":1933,"url":24,"identifiers":1934},"Kooistra, C. A. & Heilman, K. M. Memory loss from a subcortical white matter infarct. J. Neurol. Neurosurg. Psychiatry 51, 866–869 (1988).",{"doi":1935},"10.1136\u002Fjnnp.51.6.866",{"id":24,"text":1937,"url":24,"identifiers":1938},"Tatemichi, T. K. et al. Confusion and memory loss from capsular genu infarction: a thalamocortical disconnection syndrome? Neurology 42, 1966–1979 (1992).",{"doi":1939},"10.1212\u002FWNL.42.10.1966",{"id":24,"text":1941,"url":24,"identifiers":1942},"van Uden, I. W. et al. White matter and hippocampal volume predict the risk of dementia in patients with cerebral small vessel disease: the RUN DMC study. J. Alzheimers Dis. 49, 863–873 (2016).",{"doi":1943},"10.3233\u002FJAD-150573",{"id":24,"text":1945,"url":24,"identifiers":1946},"Gouw, A. A. et al. Heterogeneity of small vessel disease: a systematic review of MRI and histopathology correlations. J. Neurol. Neurosurg. Psychiatry 82, 126–135 (2011).",{"doi":1947},"10.1136\u002Fjnnp.2009.204685",{"id":24,"text":1949,"url":24,"identifiers":1950},"Lammie, G. A., Brannan, F. & Wardlaw, J. M. Incomplete lacunar infarction (Type Ib lacunes). Acta Neuropathol. 96, 163–171 (1998).",{"doi":1951},"10.1007\u002Fs004010050877",{"id":24,"text":1953,"url":24,"identifiers":1954},"Shoamanesh, A., Kwok, C. S. & Benavente, O. Cerebral microbleeds: histopathological correlation of neuroimaging. Cerebrovasc Dis. 32, 528–534 (2011).",{"doi":1955},"10.1159\u002F000331466",{"id":24,"text":1957,"url":24,"identifiers":1958},"van Veluw, S. J., Biessels, G. J., Klijn, C. J. & Rozemuller, A. J. Heterogeneous histopathology of cortical microbleeds in cerebral amyloid angiopathy. Neurology 86, 867–871 (2016).",{"doi":1959},"10.1212\u002FWNL.0000000000002419",{"id":24,"text":1961,"url":24,"identifiers":1962},"Jessen, N. A., Munk, A. S., Lundgaard, I. & Nedergaard, M. The glymphatic system: a beginner’s guide. Neurochem. Res. 40, 2583–2599 (2015).",{"doi":1963},"10.1007\u002Fs11064-015-1581-6",{"id":24,"text":1965,"url":24,"identifiers":1966},"Joutel, A. & Chabriat, H. Pathogenesis of white matter changes in cerebral small vessel diseases: beyond vessel-intrinsic mechanisms. Clin. Sci. 131, 635–651 (2017).",{"doi":1967},"10.1042\u002FCS20160380",{"id":24,"text":1969,"url":24,"identifiers":1970},"Keith, J. et al. Collagenosis of the deep medullary veins: an underrecognized pathologic correlate of white matter hyperintensities and periventricular infarction? J. Neuropathol. Exp. Neurol. 76, 299–312 (2017).",{"doi":1971},"10.1093\u002Fjnen\u002Fnlx009",{"id":24,"text":1973,"url":24,"identifiers":1974},"Brown, W. R., Moody, D. M., Challa, V. R., Thore, C. R. & Anstrom, J. A. Venous collagenosis and arteriolar tortuosity in leukoaraiosis. J. Neurol. Sci. 203–204, 159–163 (2002).",{"doi":1975},"10.1016\u002FS0022-510X(02)00283-6",{"id":24,"text":1977,"url":24,"identifiers":1978},"Matsusue, E. et al. White matter changes in elderly people: MR-pathologic correlations. Magn. Reson. Med. Sci. 5, 99–104 (2006).",{"doi":1979},"10.2463\u002Fmrms.5.99",{"id":24,"text":1981,"url":24,"identifiers":1982},"Auriel, E. et al. Microinfarct disruption of white matter structure: a longitudinal diffusion tensor analysis. Neurology 83, 182–188 (2014).",{"doi":1983},"10.1212\u002FWNL.0000000000000579",{"id":24,"text":1985,"url":24,"identifiers":1986},"Maillard, P. et al. White matter hyperintensities and their penumbra lie along a continuum of injury in the aging brain. Stroke 45, 1721–1726 (2014).",{"doi":1987},"10.1161\u002FSTROKEAHA.113.004084",{"id":24,"text":1989,"url":24,"identifiers":1990},"Spilt, A. et al. Not all age-related white matter hyperintensities are the same: a magnetization transfer imaging study. AJNR Am. J. Neuroradiol. 27, 1964–1968 (2006).",{},{"id":24,"text":1992,"url":24,"identifiers":1993},"Tanabe, J. L. et al. Magnetization transfer ratio of white matter hyperintensities in subcortical ischemic vascular dementia. AJNR Am. J. Neuroradiol. 20, 839–844 (1999).",{},{"id":24,"text":1995,"url":24,"identifiers":1996},"Haller, S. et al. Do brain T2\u002FFLAIR white matter hyperintensities correspond to myelin loss in normal aging? A radiologic-neuropathologic correlation study. Acta Neuropathol. Commun. 1, 14 (2013).",{"doi":1997},"10.1186\u002F2051-5960-1-14",{"id":24,"text":1999,"url":24,"identifiers":2000},"Wardlaw, J. M., Valdes Hernandez, M. C. & Munoz-Maniega, S. What are white matter hyperintensities made of? Relevance to vascular cognitive impairment. J. Am. Heart Assoc. 4, 001140 (2015).",{"doi":2001},"10.1161\u002FJAHA.114.001140",{"id":24,"text":2003,"url":24,"identifiers":2004},"Soares, J. M., Marques, P., Alves, V. & Sousa, N. A hitchhiker’s guide to diffusion tensor imaging. Front. Neurosci. 7, 31 (2013).",{"doi":2005},"10.3389\u002Ffnins.2013.00031",{"id":24,"text":2007,"url":24,"identifiers":2008},"Bouvy, W. H. et al. Abnormalities of cerebral deep medullary veins on 7 Tesla MRI in amnestic mild cognitive impairment and early Alzheimer’s disease: a pilot study. J. Alzheimers Dis. 57, 705–710 (2017).",{"doi":2009},"10.3233\u002FJAD-160952",{"id":24,"text":2011,"url":24,"identifiers":2012},"van Dalen, J. W. et al. White matter hyperintensity volume and cerebral perfusion in older individuals with hypertension using arterial spin-labeling. AJNR Am. J. Neuroradiol. 37, 1824–1830 (2016).",{"doi":2013},"10.3174\u002Fajnr.A4828",{"id":24,"text":2015,"url":24,"identifiers":2016},"van Nieuwenhuizen, K. M., Hendrikse, J. & Klijn, C. J. M. New microbleed after blood-brain barrier leakage in intracerebral haemorrhage. BMJ Case Rep. \n                    https:\u002F\u002Fdoi.org\u002F10.1136\u002Fbcr-2016-218794\n                    \n                   (2017).",{"doi":2017},"10.1136\u002Fbcr-2016-218794",{"id":24,"text":2019,"url":24,"identifiers":2020},"Koch, S., McClendon, M. S. & Bhatia, R. Imaging evolution of acute lacunar infarction: leukoariosis or lacune? Neurology 77, 1091–1095 (2011).",{"doi":2021},"10.1212\u002FWNL.0b013e31822e1470",{"id":24,"text":2023,"url":24,"identifiers":2024},"van Veluw, S. J. et al. Evolution of DWI lesions in cerebral amyloid angiopathy: evidence for ischemia. Neurology 89, 2136–2142 (2017).",{"doi":2025},"10.1212\u002FWNL.0000000000004668",{"id":24,"text":2027,"url":24,"identifiers":2028},"Maillard, P. et al. White matter hyperintensity penumbra. Stroke 42, 1917–1922 (2011).",{"doi":2029},"10.1161\u002FSTROKEAHA.110.609768",{"id":24,"text":2031,"url":24,"identifiers":2032},"Maniega, S. M. et al. White matter hyperintensities and normal-appearing white matter integrity in the aging brain. Neurobiol. Aging 36, 909–918 (2015).",{"doi":2033},"10.1016\u002Fj.neurobiolaging.2014.07.048",{"id":24,"text":2035,"url":24,"identifiers":2036},"Reijmer, Y. D., Freeze, W. M., Leemans, A. & Biessels, G. J. The effect of lacunar infarcts on white matter tract integrity. Stroke 44, 2019–2021 (2013).",{"doi":2037},"10.1161\u002FSTROKEAHA.113.001321",{"id":24,"text":2039,"url":24,"identifiers":2040},"Hinman, J. D., Lee, M. D., Tung, S., Vinters, H. V. & Carmichael, S. T. Molecular disorganization of axons adjacent to human lacunar infarcts. Brain 138, 736–745 (2015).",{"doi":2041},"10.1093\u002Fbrain\u002Fawu398",{"id":24,"text":2043,"url":24,"identifiers":2044},"Lee, W. J., Lee, J. Y., Lim, J. S., Kwon, H. M. & Lee, Y. S. Transient isolated ocular motor abnormality related to perilesional edema of an acute medullary microbleed: A case report and review of the literatures. Clin. Neurol. Neurosurg. 138, 174–176 (2015).",{"doi":2045},"10.1016\u002Fj.clineuro.2015.08.029",{"id":24,"text":2047,"url":24,"identifiers":2048},"Lawrence, A. J. et al. Mechanisms of cognitive impairment in cerebral small vessel disease: multimodal MRI results from the St George’s cognition and neuroimaging in stroke (SCANS) study. PLoS ONE 8, e61014 (2013).",{"doi":2049},"10.1371\u002Fjournal.pone.0061014",{"id":24,"text":2051,"url":24,"identifiers":2052},"Pasi, M., van Uden, I. W., Tuladhar, A. M., de Leeuw, F. E. & Pantoni, L. White matter microstructural damage on diffusion tensor imaging in cerebral small vessel disease: clinical consequences. Stroke 47, 1679–1684 (2016).",{"doi":2053},"10.1161\u002FSTROKEAHA.115.012065",{"id":24,"text":2055,"url":24,"identifiers":2056},"Tuladhar, A. M. et al. White matter integrity in small vessel disease is related to cognition. Neuroimage Clin. 7, 518–524 (2015).",{"doi":2057},"10.1016\u002Fj.nicl.2015.02.003",{"id":24,"text":2059,"url":24,"identifiers":2060},"Baykara, E. et al. A novel imaging marker for small vessel disease based on skeletonization of white matter tracts and diffusion histograms. Ann. Neurol. 80, 581–592 (2016).",{"doi":2061},"10.1002\u002Fana.24758",{"id":24,"text":2063,"url":24,"identifiers":2064},"Williams, O. A. et al. Diffusion tensor image segmentation of the cerebrum provides a single measure of cerebral small vessel disease severity related to cognitive change. Neuroimage Clin. 16, 330–342 (2017).",{"doi":2065},"10.1016\u002Fj.nicl.2017.08.016",{"id":24,"text":2067,"url":24,"identifiers":2068},"Coban, H., Tung, S., Yoo, B., Vinters, H. V. & Hinman, J. D. Molecular disorganization of axons adjacent to human cortical microinfarcts. Front. Neurol. 8, 405 (2017).",{"doi":2069},"10.3389\u002Ffneur.2017.00405",{"id":24,"text":2071,"url":24,"identifiers":2072},"Shih, A. Y. et al. The smallest stroke: occlusion of one penetrating vessel leads to infarction and a cognitive deficit. Nat. Neurosci. 16, 55–63 (2013).",{"doi":2073},"10.1038\u002Fnn.3278",{"id":24,"text":2075,"url":24,"identifiers":2076},"Summers, P. M. et al. Functional deficits induced by cortical microinfarcts. J. Cereb. Blood Flow Metab. 37, 3599–3614 (2017).",{"doi":2077},"10.1177\u002F0271678X16685573",{"id":24,"text":2079,"url":24,"identifiers":2080},"Arvanitakis, Z., Leurgans, S. E., Barnes, L. L., Bennett, D. A. & Schneider, J. A. Microinfarct pathology, dementia, and cognitive systems. Stroke 42, 722–727 (2011).",{"doi":2081},"10.1161\u002FSTROKEAHA.110.595082",{"id":24,"text":2083,"url":24,"identifiers":2084},"van Veluw, S. J. et al. Detection, risk factors, and functional consequences of cerebral microinfarcts. Lancet Neurol. 16, 730–740 (2017).",{"doi":2085},"10.1016\u002FS1474-4422(17)30196-5",{"id":24,"text":2087,"url":24,"identifiers":2088},"Tullberg, M. et al. White matter lesions impair frontal lobe function regardless of their location. Neurology 63, 246–253 (2004).",{"doi":2089},"10.1212\u002F01.WNL.0000130530.55104.B5",{"id":24,"text":2091,"url":24,"identifiers":2092},"Dickie, D. A. et al. Progression of white matter disease and cortical thinning are not related in older community-dwelling subjects. Stroke 47, 410–416 (2016).",{"doi":2093},"10.1161\u002FSTROKEAHA.115.011229",{"id":24,"text":2095,"url":24,"identifiers":2096},"Lambert, C. et al. Characterising the grey matter correlates of leukoaraiosis in cerebral small vessel disease. Neuroimage Clin. 9, 194–205 (2015).",{"doi":2097},"10.1016\u002Fj.nicl.2015.07.002",{"id":24,"text":2099,"url":24,"identifiers":2100},"Tuladhar, A. M. et al. Relationship between white matter hyperintensities, cortical thickness, and cognition. Stroke 46, 425–432 (2015).",{"doi":2101},"10.1161\u002FSTROKEAHA.114.007146",{"id":24,"text":2103,"url":24,"identifiers":2104},"Lambert, C. et al. Longitudinal patterns of leukoaraiosis and brain atrophy in symptomatic small vessel disease. Brain 139, 1136–1151 (2016).",{"doi":2105},"10.1093\u002Fbrain\u002Faww009",{"id":24,"text":2107,"url":24,"identifiers":2108},"Duering, M. et al. Incident subcortical infarcts induce focal thinning in connected cortical regions. Neurology 79, 2025–2028 (2012).",{"doi":2109},"10.1212\u002FWNL.0b013e3182749f39",{"id":24,"text":2111,"url":24,"identifiers":2112},"Duering, M. et al. Acute infarcts cause focal thinning in remote cortex via degeneration of connecting fiber tracts. Neurology 84, 1685–1692 (2015).",{"doi":2113},"10.1212\u002FWNL.0000000000001502",{"id":24,"text":2115,"url":24,"identifiers":2116},"Jokinen, H. et al. Brain atrophy accelerates cognitive decline in cerebral small vessel disease: the LADIS study. Neurology 78, 1785–1792 (2012).",{"doi":2117},"10.1212\u002FWNL.0b013e3182583070",{"id":24,"text":2119,"url":24,"identifiers":2120},"Schmidt, R. et al. White matter lesion progression, brain atrophy, and cognitive decline: the Austrian stroke prevention study. Ann. Neurol. 58, 610–616 (2005).",{"doi":2121},"10.1002\u002Fana.20630",{"id":24,"text":2123,"url":24,"identifiers":2124},"Righart, R. et al. Impact of regional cortical and subcortical changes on processing speed in cerebral small vessel disease. Neuroimage Clin. 2, 854–861 (2013).",{"doi":2125},"10.1016\u002Fj.nicl.2013.06.006",{"id":24,"text":2127,"url":24,"identifiers":2128},"Kim, Y. J. et al. Gray and white matter changes linking cerebral small vessel disease to gait disturbances. Neurology 86, 1199–1207 (2016).",{"doi":2129},"10.1212\u002FWNL.0000000000002516",{"id":24,"text":2131,"url":24,"identifiers":2132},"Lawrence, A. J., Chung, A. W., Morris, R. G., Markus, H. S. & Barrick, T. R. Structural network efficiency is associated with cognitive impairment in small-vessel disease. Neurology 83, 304–311 (2014).",{"doi":2133},"10.1212\u002FWNL.0000000000000612",{"id":24,"text":2135,"url":24,"identifiers":2136},"Tuladhar, A. M. et al. Disruption of rich club organisation in cerebral small vessel disease. Hum. Brain Mapp. 38, 1751–1766 (2017).",{"doi":2137},"10.1002\u002Fhbm.23479",{"id":24,"text":2139,"url":24,"identifiers":2140},"Tuladhar, A. M. et al. Structural network connectivity and cognition in cerebral small vessel disease. Hum. Brain Mapp. 37, 300–310 (2016).",{"doi":2141},"10.1002\u002Fhbm.23032",{"id":24,"text":2143,"url":24,"identifiers":2144},"Tang, J. et al. Aberrant white matter networks mediate cognitive impairment in patients with silent lacunar infarcts in basal ganglia territory. J. Cereb. Blood Flow Metab. 35, 1426–1434 (2015).",{"doi":2145},"10.1038\u002Fjcbfm.2015.67",{"id":24,"text":2147,"url":24,"identifiers":2148},"van den Heuvel, M. P. & Sporns, O. Rich-club organization of the human connectome. J. Neurosci. 31, 15775–15786 (2011).",{"doi":2149},"10.1523\u002FJNEUROSCI.3539-11.2011",{"id":24,"text":2151,"url":24,"identifiers":2152},"van den Heuvel, M. P., Kahn, R. S., Goni, J. & Sporns, O. High-cost, high-capacity backbone for global brain communication. Proc. Natl Acad. Sci. USA 109, 11372–11377 (2012).",{"doi":2153},"10.1073\u002Fpnas.1203593109",{"id":24,"text":2155,"url":24,"identifiers":2156},"Reijmer, Y. D. et al. Structural network alterations and neurological dysfunction in cerebral amyloid angiopathy. Brain 138, 179–188 (2015).",{"doi":2157},"10.1093\u002Fbrain\u002Fawu316",{"id":24,"text":2159,"url":24,"identifiers":2160},"Xie, X., Shi, Y. & Zhang, J. Structural network connectivity impairment and depressive symptoms in cerebral small vessel disease. J. Affect. Disord. 220, 8–14 (2017).",{"doi":2161},"10.1016\u002Fj.jad.2017.05.039",{"id":24,"text":2163,"url":24,"identifiers":2164},"Tuladhar, A. M. et al. Structural network efficiency predicts conversion to dementia. Neurology 86, 1112–1119 (2016).",{"doi":2165},"10.1212\u002FWNL.0000000000002502",{"id":24,"text":2167,"url":24,"identifiers":2168},"Reijmer, Y. D. et al. Small vessel disease and cognitive impairment: the relevance of central network connections. Hum. Brain Mapp. 37, 2446–2454 (2016).",{"doi":2169},"10.1002\u002Fhbm.23186",{"id":24,"text":2171,"url":24,"identifiers":2172},"Fornito, A., Zalesky, A. & Breakspear, M. The connectomics of brain disorders. Nat. Rev. Neurosci. 16, 159–172 (2015).",{"doi":2173},"10.1038\u002Fnrn3901",{"id":24,"text":2175,"url":24,"identifiers":2176},"van den Heuvel, M. P. & Hulshoff Pol, H. E. Exploring the brain network: a review on resting-state fMRI functional connectivity. Eur. Neuropsychopharmacol 20, 519–534 (2010).",{"doi":2177},"10.1016\u002Fj.euroneuro.2010.03.008",{"id":24,"text":2179,"url":24,"identifiers":2180},"Spreng, R. N., Sepulcre, J., Turner, G. R., Stevens, W. D. & Schacter, D. L. Intrinsic architecture underlying the relations among the default, dorsal attention, and frontoparietal control networks of the human brain. J. Cogn. Neurosci. 25, 74–86 (2013).",{"doi":2181},"10.1162\u002Fjocn_a_00281",{"id":24,"text":2183,"url":24,"identifiers":2184},"Dey, A. K., Stamenova, V., Turner, G., Black, S. E. & Levine, B. Pathoconnectomics of cognitive impairment in small vessel disease: a systematic review. Alzheimers Dement. 12, 831–845 (2016).",{"doi":2185},"10.1016\u002Fj.jalz.2016.01.007",{"id":24,"text":2187,"url":24,"identifiers":2188},"Cheng, H. L. et al. Impairments in cognitive function and brain connectivity in severe asymptomatic carotid stenosis. Stroke 43, 2567–2573 (2012).",{"doi":2189},"10.1161\u002FSTROKEAHA.111.645614",{"id":24,"text":2191,"url":24,"identifiers":2192},"Schaefer, A. et al. Early small vessel disease affects frontoparietal and cerebellar hubs in close correlation with clinical symptoms — a resting-state fMRI study. J. Cereb. Blood Flow Metab. 34, 1091–1095 (2014).",{"doi":2193},"10.1038\u002Fjcbfm.2014.70",{"id":24,"text":2195,"url":24,"identifiers":2196},"Sun, Y. W. et al. Abnormal functional connectivity in patients with vascular cognitive impairment, no dementia: a resting-state functional magnetic resonance imaging study. Behav. Brain Res. 223, 388–394 (2011).",{"doi":2197},"10.1016\u002Fj.bbr.2011.05.006",{"id":24,"text":2199,"url":24,"identifiers":2200},"van Duinkerken, E. et al. Resting-state brain networks in type 1 diabetic patients with and without microangiopathy and their relation to cognitive functions and disease variables. Diabetes 61, 1814–1821 (2012).",{"doi":2201},"10.2337\u002Fdb11-1358",{"id":24,"text":2203,"url":24,"identifiers":2204},"Yi, L. et al. Structural and functional changes in subcortical vascular mild cognitive impairment: a combined voxel-based morphometry and resting-state fMRI study. PLoS ONE 7, e44758 (2012).",{"doi":2205},"10.1371\u002Fjournal.pone.0044758",{"id":24,"text":2207,"url":24,"identifiers":2208},"Zhou, Y., Yu, F. & Duong, T. Q. Alzheimer’s Disease Neuroimaging Initiative. White matter lesion load is associated with resting state functional MRI activity and amyloid PET but not FDG in mild cognitive impairment and early Alzheimer’s disease patients. J. Magn. Reson. Imag. 41, 102–109 (2015).",{"doi":2209},"10.1002\u002Fjmri.24550",{"id":24,"text":2211,"url":24,"identifiers":2212},"Nordahl, C. W. et al. White matter changes compromise prefrontal cortex function in healthy elderly individuals. J. Cogn. Neurosci. 18, 418–429 (2006).",{"doi":2213},"10.1162\u002Fjocn.2006.18.3.418",{"id":24,"text":2215,"url":24,"identifiers":2216},"Venkatraman, V. K. et al. Executive control function, brain activation and white matter hyperintensities in older adults. Neuroimage 49, 3436–3442 (2010).",{"doi":2217},"10.1016\u002Fj.neuroimage.2009.11.019",{"id":24,"text":2219,"url":24,"identifiers":2220},"Welker, K. M., De Jesus, R. O., Watson, R. E., Machulda, M. M. & Jack, C. R. Altered functional MR imaging language activation in elderly individuals with cerebral leukoaraiosis. Radiology 265, 222–232 (2012).",{"doi":2221},"10.1148\u002Fradiol.12112052",{"id":24,"text":2223,"url":24,"identifiers":2224},"Aizenstein, H. J. et al. fMRI correlates of white matter hyperintensities in late-life depression. Am. J. Psychiatry 168, 1075–1082 (2011).",{"doi":2225},"10.1176\u002Fappi.ajp.2011.10060853",{"id":24,"text":2227,"url":24,"identifiers":2228},"Liu, C. et al. Abnormal intrinsic brain activity patterns in patients with subcortical ischemic vascular dementia. PLoS ONE 9, e87880 (2014).",{"doi":2229},"10.1371\u002Fjournal.pone.0087880",{"id":24,"text":2231,"url":24,"identifiers":2232},"Mayda, A. B., Westphal, A., Carter, C. S. & DeCarli, C. Late life cognitive control deficits are accentuated by white matter disease burden. Brain 134, 1673–1683 (2011).",{"doi":2233},"10.1093\u002Fbrain\u002Fawr065",{"id":24,"text":2235,"url":24,"identifiers":2236},"Papma, J. M. et al. The influence of cerebral small vessel disease on default mode network deactivation in mild cognitive impairment. Neuroimage Clin. 2, 33–42 (2012).",{"doi":2237},"10.1016\u002Fj.nicl.2012.11.005",{"id":24,"text":2239,"url":24,"identifiers":2240},"Chen, Y. et al. Aberrant functional networks connectivity and structural atrophy in silent lacunar infarcts: relationship with cognitive impairments. J. Alzheimers Dis. 42, 841–850 (2014).",{"doi":2241},"10.3233\u002FJAD-140948",{"id":24,"text":2243,"url":24,"identifiers":2244},"Stern, Y. Cognitive reserve. Neuropsychologia 47, 2015–2028 (2009).",{"doi":2245},"10.1016\u002Fj.neuropsychologia.2009.03.004",{"id":24,"text":2247,"url":24,"identifiers":2248},"Brickman, A. M. et al. White matter hyperintensities and cognition: testing the reserve hypothesis. Neurobiol. Aging 32, 1588–1598 (2011).",{"doi":2249},"10.1016\u002Fj.neurobiolaging.2009.10.013",{"id":24,"text":2251,"url":24,"identifiers":2252},"Mortimer, J. A., Snowdon, D. A. & Markesbery, W. R. Head circumference, education and risk of dementia: findings from the Nun Study. J. Clin. Exp. Neuropsychol 25, 671–679 (2003).",{"doi":2253},"10.1076\u002Fjcen.25.5.671.14584",{"id":24,"text":2255,"url":24,"identifiers":2256},"Smith, E. E. et al. Magnetic resonance imaging white matter hyperintensities and brain volume in the prediction of mild cognitive impairment and dementia. Arch. Neurol. 65, 94–100 (2008).",{},{"id":24,"text":2258,"url":24,"identifiers":2259},"Pinter, D., Enzinger, C. & Fazekas, F. Cerebral small vessel disease, cognitive reserve and cognitive dysfunction. J. Neurol. 262, 2411–2419 (2015).",{"doi":2260},"10.1007\u002Fs00415-015-7776-6",{"id":24,"text":2262,"url":24,"identifiers":2263},"Barulli, D. & Stern, Y. Efficiency, capacity, compensation, maintenance, plasticity: emerging concepts in cognitive reserve. Trends Cogn. Sci. 17, 502–509 (2013).",{"doi":2264},"10.1016\u002Fj.tics.2013.08.012",{"id":24,"text":2266,"url":24,"identifiers":2267},"Stern, Y. What is cognitive reserve? Theory and research application of the reserve concept. J. Int. Neuropsychol Soc. 8, 448–460 (2002).",{"doi":2268},"10.1017\u002FS1355617702813248",{"id":24,"text":2270,"url":24,"identifiers":2271},"Dufouil, C., Alperovitch, A. & Tzourio, C. Influence of education on the relationship between white matter lesions and cognition. Neurology 60, 831–836 (2003).",{"doi":2272},"10.1212\u002F01.WNL.0000049456.33231.96",{"id":24,"text":2274,"url":24,"identifiers":2275},"Elbaz, A. et al. Motor function in the elderly: evidence for the reserve hypothesis. 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The balance between cognitive reserve and brain imaging biomarkers of cerebrovascular and Alzheimer’s diseases. Brain 134, 3687–3696 (2011).",{"doi":2292},"10.1093\u002Fbrain\u002Fawr259",{"id":24,"text":2294,"url":24,"identifiers":2295},"Jokinen, H. et al. Cognitive reserve moderates long-term cognitive and functional outcome in cerebral small vessel disease. J. Neurol. Neurosurg. Psychiatry 87, 1296–1302 (2016).",{"doi":2296},"10.1136\u002Fjnnp-2016-313914",{"id":24,"text":2298,"url":24,"identifiers":2299},"Park, D. C. & Reuter-Lorenz, P. The adaptive brain: aging and neurocognitive scaffolding. Annu. Rev. Psychol. 60, 173–196 (2009).",{"doi":2300},"10.1146\u002Fannurev.psych.59.103006.093656",{"id":24,"text":2302,"url":24,"identifiers":2303},"Steffener, J., Brickman, A. M., Rakitin, B. C., Gazes, Y. & Stern, Y. The impact of age-related changes on working memory functional activity. Brain Imag. 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Medial temporal lobe atrophy and white matter hyperintensities are associated with mild cognitive deficits in non-disabled elderly people: the LADIS study. J. Neurol. Neurosurg. Psychiatry 76, 1497–1500 (2005).",{"doi":2320},"10.1136\u002Fjnnp.2005.064998",{"id":24,"text":2322,"url":24,"identifiers":2323},"Koncz, R. & Sachdev, P. S. Are the brain’s vascular and Alzheimer pathologies additive or interactive? Curr. Opin. Psychiatry 31, 147–152 (2018).",{"doi":2324},"10.1097\u002FYCO.0000000000000395",{"id":24,"text":2326,"url":24,"identifiers":2327},"Roseborough, A., Ramirez, J., Black, S. E. & Edwards, J. D. Associations between amyloid beta and white matter hyperintensities: a systematic review. Alzheimers Dement 13, 1154–1167 (2017).",{"doi":2328},"10.1016\u002Fj.jalz.2017.01.026",{"id":24,"text":2330,"url":24,"identifiers":2331},"Oosterman, J. M., Oosterveld, S., Rikkert, M. G., Claassen, J. A. & Kessels, R. P. Medial temporal lobe atrophy relates to executive dysfunction in Alzheimer’s disease. Int. Psychogeriatr. 24, 1474–1482 (2012).",{"doi":2332},"10.1017\u002FS1041610212000506",{"id":24,"text":2334,"url":24,"identifiers":2335},"De Guio, F. et al. Reproducibility and variability of quantitative magnetic resonance imaging markers in cerebral small vessel disease. J. Cereb. Blood Flow Metab. 36, 1319–1337 (2016).",{"doi":2336},"10.1177\u002F0271678X16647396",{"id":24,"text":2338,"url":24,"identifiers":2339},"Goos, J. D. et al. Clinical relevance of improved microbleed detection by susceptibility-weighted magnetic resonance imaging. Stroke 42, 1894–1900 (2011).",{"doi":2340},"10.1161\u002FSTROKEAHA.110.599837",{"id":24,"text":2342,"url":24,"identifiers":2343},"Tryambake, D. et al. Intensive blood pressure lowering increases cerebral blood flow in older subjects with hypertension. Hypertension 61, 1309–1315 (2013).",{"doi":2344},"10.1161\u002FHYPERTENSIONAHA.112.200972",{"id":24,"text":2346,"url":24,"identifiers":2347},"Fleischer, V. et al. Graph theoretical framework of brain networks in multiple sclerosis: a review of concepts. Neuroscience \n                    https:\u002F\u002Fdoi.org\u002F10.1016\u002Fj.neuroscience.2017.10.033\n                    \n                   (2017).",{"doi":2348},"10.1016\u002Fj.neuroscience.2017.10.033",{"id":24,"text":2350,"url":24,"identifiers":2351},"Charidimou, A., Pantoni, L. & Love, S. The concept of sporadic cerebral small vessel disease: a road map on key definitions and current concepts. Int. J. Stroke 11, 6–18 (2016).",{"doi":2352},"10.1177\u002F1747493015607485",{"id":24,"text":2354,"url":24,"identifiers":2355},"Wardlaw, J. M., Smith, C. & Dichgans, M. Mechanisms of sporadic cerebral small vessel disease: insights from neuroimaging. 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Accuracy of the clinical diagnosis of corticobasal degeneration: a clinicopathologic study. Neurology 48, 119–125 (1997).",{"doi":2569},"10.1212\u002FWNL.48.1.119",{"id":24,"text":2571,"url":24,"identifiers":2572},"Togasaki, D. M. & Tanner, C. M. Epidemiologic aspects. Adv. Neurol. 82, 53–59 (2000).",{},{"id":24,"text":2574,"url":24,"identifiers":2575},"Winter, Y. et al. Incidence of Parkinson's disease and atypical parkinsonism: Russian population-based study. Mov. Disord. 25, 349–356 (2010).",{"doi":2576},"10.1002\u002Fmds.22966",{"id":24,"text":2578,"url":24,"identifiers":2579},"Rebeiz, J. J., Kolodny, E. H. & Richardson, E. P. Jr. Corticodentatonigral degeneration with neuronal achromasia. Arch. Neurol. 18, 20–33 (1968).",{"doi":2580},"10.1001\u002Farchneur.1968.00470310034003",{"id":24,"text":2582,"url":24,"identifiers":2583},"Gibb, W. R., Luthert, P. J. & Marsden, C. D. Corticobasal degeneration. Brain 112, 1171–1192 (1989).",{"doi":2584},"10.1093\u002Fbrain\u002F112.5.1171",{"id":24,"text":2586,"url":24,"identifiers":2587},"Bergeron, C., Davis, A. & Lang, A. E. Corticobasal ganglionic degeneration and progressive supranuclear palsy presenting with cognitive decline. Brain Pathol. 8, 355–365 (1998).",{"doi":2588},"10.1111\u002Fj.1750-3639.1998.tb00159.x",{"id":24,"text":2590,"url":24,"identifiers":2591},"Watts, R. L., Mirra, S. S. & Richarson, E. P. Jr in Movement Disorders III: Blue Books of Practical Neurology Vol. 13 (eds Marsden, C. D. & Fahn, S.) 282–299 (Butterworth–Heinemann, Oxford, 1994).",{},{"id":24,"text":2593,"url":24,"identifiers":2594},"Riley, D. E. & Lang, A. E. Corticobasal ganglionic degeneration (CBGD): further observations in six additional cases. Neurology 38, 360 (1988).",{"doi":2595},"10.1212\u002FWNL.38.7.1026",{"id":24,"text":2597,"url":24,"identifiers":2598},"Boeve, B. F. et al. Pathologic heterogeneity in clinically diagnosed corticobasal degeneration. Neurology 53, 795–800 (1999).",{"doi":2599},"10.1212\u002FWNL.53.4.795",{"id":24,"text":2601,"url":24,"identifiers":2602},"Riley, D. E. et al. Cortical–basal ganglionic degeneration. Neurology 40, 1203–1212 (1990).",{"doi":2603},"10.1212\u002FWNL.40.8.1203",{"id":24,"text":2605,"url":24,"identifiers":2606},"Bak, T. H. & Hodges, J. R. Corticobasal degeneration: clinical aspects. Handb. Clin. Neurol. 89, 509–521 (2008).",{"doi":2607},"10.1016\u002FS0072-9752(07)01247-X",{"id":24,"text":2609,"url":24,"identifiers":2610},"Lang, A. E., Riley, D. E. & Bergeron, C. in Neurodegenerative Diseases Ch. 49 (ed. Calne, D. B.) 877–894 (W. B. Saunders, Philadelphia, 1994).",{},{"id":24,"text":2612,"url":24,"identifiers":2613},"Grundke-Iqbal, I. et al. Microtubule-associated protein tau. A component of Alzheimer paired helical filaments. J. Biol. Chem. 261, 6084–6089 (1986).",{"doi":2614},"10.1016\u002FS0021-9258(17)38495-8",{"id":24,"text":2616,"url":24,"identifiers":2617},"Williams, D. R. et al. Characteristics of two distinct clinical phenotypes in pathologically proven progressive supranuclear palsy: Richardson's syndrome and PSP-parkinsonism. Brain 128, 1247–1258 (2005).",{"doi":2618},"10.1093\u002Fbrain\u002Fawh488",{"id":24,"text":2620,"url":24,"identifiers":2621},"Bergeron, C., Pollanen, M. S., Weyer, L., Black, S. E. & Lang, A. E. Unusual clinical presentations of cortical–basal ganglionic degeneration. Ann. Neurol. 40, 893–900 (1996).",{"doi":2622},"10.1002\u002Fana.410400611",{"id":24,"text":2624,"url":24,"identifiers":2625},"Murray, R. et al. Cognitive and motor assessment in autopsy-proven corticobasal degeneration. Neurology 68, 1274–1283 (2007).",{"doi":2626},"10.1212\u002F01.wnl.0000259519.78480.c3",{"id":24,"text":2628,"url":24,"identifiers":2629},"Ling, H. et al. Does corticobasal degeneration exist? A clinicopathological re-evaluation. Brain 133, 2045–2057 (2010).",{"doi":2630},"10.1093\u002Fbrain\u002Fawq123",{"id":24,"text":2632,"url":24,"identifiers":2633},"Schneider, J. A., Watts, R. L., Gearing, M., Brewer, R. P. & Mirra, S. S. Corticobasal degeneration: neuropathologic and clinical heterogeneity. Neurology 48, 959–969 (1997).",{"doi":2634},"10.1212\u002FWNL.48.4.959",{"id":24,"text":2636,"url":24,"identifiers":2637},"Grimes, D. A., Lang, A. E. & Bergeron, C. B. Dementia as the most common presentation of cortical-basal ganglionic degeneration. Neurology 53, 1969–1974 (1999).",{"doi":2638},"10.1212\u002FWNL.53.9.1969",{"id":24,"text":2640,"url":24,"identifiers":2641},"Kertesz, A., Martinez-Lage, P., Davidson, W. & Munoz, D. G. The corticobasal degeneration syndrome overlaps progressive aphasia and frontotemporal dementia. Neurology 55, 1368–1375 (2000).",{"doi":2642},"10.1212\u002FWNL.55.9.1368",{"id":24,"text":2644,"url":24,"identifiers":2645},"Gorno-Tempini, M. L., Murray, R. C., Rankin, K. P., Weiner, M. W. & Miller, B. L. Clinical, cognitive and anatomical evolution from nonfluent progressive aphasia to corticobasal syndrome: a case report. Neurocase 10, 426–436 (2004).",{"doi":2646},"10.1080\u002F13554790490894011",{"id":24,"text":2648,"url":24,"identifiers":2649},"Josephs, K. A. et al. Clinicopathological and imaging correlates of progressive aphasia and apraxia of speech. Brain 129, 1385–1398 (2006).",{"doi":2650},"10.1093\u002Fbrain\u002Fawl078",{"id":24,"text":2652,"url":24,"identifiers":2653},"Raggi, A. et al. The clinical overlap between the corticobasal degeneration syndrome and other diseases of the frontotemporal spectrum: three case reports. Behav. Neurol. 18, 159–164 (2007).",{"doi":2654},"10.1155\u002F2007\u002F218189",{"id":24,"text":2656,"url":24,"identifiers":2657},"Gibb, W. R., Luthert, P. J. & Marsden, C. D. Clinical and pathological features of corticobasal degeneration. Adv. Neurol. 53, 51–54 (1990).",{},{"id":24,"text":2659,"url":24,"identifiers":2660},"Wenning, G. K. et al. Natural history and survival of 14 patients with corticobasal degeneration confirmed at postmortem examination. J. Neurol. Neurosurg. Psychiatry 64, 184–189 (1998).",{"doi":2661},"10.1136\u002Fjnnp.64.2.184",{"id":24,"text":2663,"url":24,"identifiers":2664},"Litvan, I., Grimes, D. A. & Lang, A. E. Phenotypes and prognosis: clinicopathologic studies of corticobasal degeneration. Adv. Neurol. 82, 183–196 (2000).",{},{"id":24,"text":2666,"url":24,"identifiers":2667},"Kertesz, A., McMonagle, P., Blair, M., Davidson, W. & Munoz, D. G. The evolution and pathology of frontotemporal dementia. Brain 128, 1996–2005 (2005).",{"doi":2668},"10.1093\u002Fbrain\u002Fawh598",{"id":24,"text":2670,"url":24,"identifiers":2671},"Lang, A. E., Bergeron, C., Pollanen, M. S. & Ashby, P. Parietal Pick's disease mimicking cortical–basal ganglionic degeneration. Neurology 44, 1436–1440 (1994).",{"doi":2672},"10.1212\u002FWNL.44.8.1436",{"id":24,"text":2674,"url":24,"identifiers":2675},"Grimes, D. A., Bergeron, C. B. & Lang, A. E. Motor neuron disease-inclusion dementia presenting as cortical–basal ganglionic degeneration. Mov. Disord. 14, 674–680 (1999).",{"doi":2676},"10.1002\u002F1531-8257(199907)14:4\u003C674::AID-MDS1019>3.0.CO;2-X",{"id":24,"text":2678,"url":24,"identifiers":2679},"Horoupian, D. S. & Wasserstein, P. H. Alzheimer's disease pathology in motor cortex in dementia with Lewy bodies clinically mimicking corticobasal degeneration. Acta Neuropathol. 98, 317–322 (1999).",{"doi":2680},"10.1007\u002Fs004010051087",{"id":24,"text":2682,"url":24,"identifiers":2683},"Hu, W. T. et al. Alzheimer's disease and corticobasal degeneration presenting as corticobasal syndrome. Mov. Disord. 24, 1375–1379 (2009).",{"doi":2684},"10.1002\u002Fmds.22574",{"id":24,"text":2686,"url":24,"identifiers":2687},"Benussi, L. et al. Progranulin Leu271LeufsX10 is one of the most common FTLD and CBS associated mutations worldwide. Neurobiol. Dis. 33, 379–385 (2009).",{"doi":2688},"10.1016\u002Fj.nbd.2008.11.008",{"id":24,"text":2690,"url":24,"identifiers":2691},"Whitwell, J. L. et al. Imaging correlates of pathology in corticobasal syndrome. Neurology 75, 1879–1887 (2010).",{"doi":2692},"10.1212\u002FWNL.0b013e3181feb2e8",{"id":24,"text":2694,"url":24,"identifiers":2695},"Williams, D. R., Lees, A. J., Wherrett, J. R. & Steele, J. C. J. Clifford Richardson and 50 years of progressive supranuclear palsy. Neurology 70, 566–573 (2008).",{"doi":2696},"10.1212\u002F01.wnl.0000286938.39473.0e",{"id":24,"text":2698,"url":24,"identifiers":2699},"Steele, J. C., Richardson, J. C. & Olszewski, J. Progressive supranuclear palsy. A heterogeneous degeneration involving the brain stem, basal ganglia and cerebellum with vertical gaze and pseudobulbar palsy, nuchal dystonia and dementia. Arch. Neurol. 10, 333–359 (1964).",{"doi":2700},"10.1001\u002Farchneur.1964.00460160003001",{"id":24,"text":2702,"url":24,"identifiers":2703},"Tsuboi, Y. et al. Increased tau burden in the cortices of progressive supranuclear palsy presenting with corticobasal syndrome. Mov. Disord. 20, 982–988 (2005).",{"doi":2704},"10.1002\u002Fmds.20478",{"id":24,"text":2706,"url":24,"identifiers":2707},"Oide, T. et al. Progressive supranuclear palsy with asymmetric tau pathology presenting with unilateral limb dystonia. Acta Neuropathol. 104, 209–214 (2002).",{"doi":2708},"10.1007\u002Fs00401-002-0531-y",{"id":24,"text":2710,"url":24,"identifiers":2711},"Litvan, I. et al. Clinical features differentiating patients with postmortem confirmed progressive supranuclear palsy and corticobasal degeneration. J. Neurol. 246 (Suppl. 2), II1–II5 (1999).",{},{"id":24,"text":2713,"url":24,"identifiers":2714},"Dickson, D. W. Neuropathologic differentiation of progressive supranuclear palsy and corticobasal degeneration. J. Neurol. 246 (Suppl. 2), II6–II15 (1999).",{"doi":2715},"10.1007\u002FBF03161076",{"id":24,"text":2717,"url":24,"identifiers":2718},"Shiozawa, M. et al. Corticobasal degeneration: an autopsy case clinically diagnosed as progressive supranuclear palsy. Clin. Neuropathol. 19, 192–199 (2000).",{},{"id":24,"text":2720,"url":24,"identifiers":2721},"Hassan, A. et al. Symmetric corticobasal degeneration (S-CBD). Parkinsonism Relat. Disord. 16, 208–214 (2010).",{"doi":2722},"10.1016\u002Fj.parkreldis.2009.11.013",{"id":24,"text":2724,"url":24,"identifiers":2725},"Vidailhet, M. et al. Eye movements in parkinsonian syndromes. Ann. Neurol. 35, 420–426 (1994).",{"doi":2726},"10.1002\u002Fana.410350408",{"id":24,"text":2728,"url":24,"identifiers":2729},"Rivaud-Péchoux, S. et al. Longitudinal ocular motor study in corticobasal degeneration and progressive supranuclear palsy. Neurology 54, 1029–1032 (2000).",{"doi":2730},"10.1212\u002FWNL.54.5.1029",{"id":24,"text":2732,"url":24,"identifiers":2733},"Zadikoff, C. & Lang, A. E. Apraxia in movement disorders. Brain 128, 1480–1497 (2005).",{"doi":2734},"10.1093\u002Fbrain\u002Fawh560",{"id":24,"text":2736,"url":24,"identifiers":2737},"Houghton, D. J. & Litvan, I. Unraveling progressive supranuclear palsy: from the bedside back to the bench. Parkinsonism Relat. Disord. 13 (Suppl. 3), S341–S346 (2007).",{"doi":2738},"10.1016\u002FS1353-8020(08)70028-2",{"id":24,"text":2740,"url":24,"identifiers":2741},"Cummings, J. L. & Litvan, I. Neuropsychiatric aspects of corticobasal degeneration. Adv. Neurol. 82, 147–152 (2000).",{},{"id":24,"text":2743,"url":24,"identifiers":2744},"Josephs, K. A. et al. Voxel-based morphometry in autopsy proven PSP and CBD. Neurobiol. Aging 29, 280–289 (2008).",{"doi":2745},"10.1016\u002Fj.neurobiolaging.2006.09.019",{"id":24,"text":2747,"url":24,"identifiers":2748},"Neary, D. et al. Frontotemporal lobar degeneration: a consensus on clinical diagnostic criteria. Neurology 51, 1546–1554 (1998).",{"doi":2749},"10.1212\u002FWNL.51.6.1546",{"id":24,"text":2751,"url":24,"identifiers":2752},"Hodges, J. R. et al. Clinicopathological correlates in frontotemporal dementia. Ann. Neurol. 56, 399–406 (2004).",{"doi":2753},"10.1002\u002Fana.20203",{"id":24,"text":2755,"url":24,"identifiers":2756},"Forman, M. S. et al. Frontotemporal dementia: clinicopathological correlations. Ann. Neurol. 59, 952–962 (2006).",{"doi":2757},"10.1002\u002Fana.20873",{"id":24,"text":2759,"url":24,"identifiers":2760},"Whitwell, J. L. et al. MRI correlates of protein deposition and disease severity in postmortem frontotemporal lobar degeneration. Neurodegener. Dis. 6, 106–117 (2009).",{"doi":2761},"10.1159\u002F000209507",{"id":24,"text":2763,"url":24,"identifiers":2764},"Josephs, K. A. et al. Clinicopathologic analysis of frontotemporal and corticobasal degenerations and PSP. Neurology 66, 41–48 (2006).",{"doi":2765},"10.1212\u002F01.wnl.0000191307.69661.c3",{"id":24,"text":2767,"url":24,"identifiers":2768},"Grossman, M. et al. Longitudinal decline in autopsy-defined frontotemporal lobar degeneration. Neurology 70, 2036–2045 (2008).",{"doi":2769},"10.1212\u002F01.wnl.0000303816.25065.bc",{"id":24,"text":2771,"url":24,"identifiers":2772},"Mesulam, M. M. Primary progressive aphasia. Ann. Neurol. 49, 425–432 (2001).",{"doi":2773},"10.1002\u002Fana.91",{"id":24,"text":2775,"url":24,"identifiers":2776},"Knibb, J. A., Xuereb, J. H., Patterson, K. & Hodges, J. R. Clinical and pathological characterization of progressive aphasia. Ann. Neurol. 59, 156–165 (2006).",{"doi":2777},"10.1002\u002Fana.20700",{"id":24,"text":2779,"url":24,"identifiers":2780},"Grossman, M. Primary progressive aphasia: clinicopathological correlations. Nat. Rev. Neurol. 6, 88–97 (2010).",{"doi":2781},"10.1038\u002Fnrneurol.2009.216",{"id":24,"text":2783,"url":24,"identifiers":2784},"Josephs, K. A. et al. Frontotemporal lobar degeneration and ubiquitin immunohistochemistry. Neuropathol. Appl. Neurobiol. 30, 369–373 (2004).",{"doi":2785},"10.1111\u002Fj.1365-2990.2003.00545.x",{"id":24,"text":2787,"url":24,"identifiers":2788},"Benson, D. F., Davis, R. J. & Snyder, B. D. Posterior cortical atrophy. Arch. Neurol. 45, 789–793 (1988).",{"doi":2789},"10.1001\u002Farchneur.1988.00520310107024",{"id":24,"text":2791,"url":24,"identifiers":2792},"Renner, J. A. et al. Progressive posterior cortical dysfunction: a clinicopathologic series. Neurology 63, 1175–1180 (2004).",{"doi":2793},"10.1212\u002F01.WNL.0000140290.80962.BF",{"id":24,"text":2795,"url":24,"identifiers":2796},"Tang-Wai, D. F. et al. Clinical, genetic, and neuropathologic characteristics of posterior cortical atrophy. Neurology 63, 1168–1174 (2004).",{"doi":2797},"10.1212\u002F01.WNL.0000140289.18472.15",{"id":24,"text":2799,"url":24,"identifiers":2800},"Jellinger, K. A. et al. Four-repeat tauopathy clinically presenting as posterior cortical atrophy: atypical corticobasal degeneration? Acta Neuropathol. 121, 267–277 (2011).",{"doi":2801},"10.1007\u002Fs00401-010-0712-z",{"id":24,"text":2803,"url":24,"identifiers":2804},"Dickson, D. W. et al. Office of Rare Diseases neuropathologic criteria for corticobasal degeneration. J. Neuropathol. Exp. Neurol. 61, 935–946 (2002).",{"doi":2805},"10.1093\u002Fjnen\u002F61.11.935",{"id":24,"text":2807,"url":24,"identifiers":2808},"Fujino, Y., Delucia, M. W., Davies, P. & Dickson, D. W. Ballooned neurones in the limbic lobe are associated with Alzheimer type pathology and lack diagnostic specificity. Neuropathol. Appl. Neurobiol. 30, 676–682 (2004).",{"doi":2809},"10.1111\u002Fj.1365-2990.2004.00593.x",{"id":24,"text":2811,"url":24,"identifiers":2812},"Josephs, K. A. et al. Atypical progressive supranuclear palsy with corticospinal tract degeneration. J. Neuropathol. Exp. Neurol. 65, 396–405 (2006).",{"doi":2813},"10.1097\u002F01.jnen.0000218446.38158.61",{"id":24,"text":2815,"url":24,"identifiers":2816},"Dickson, D. W. in The Neuropathology of Dementia Ch. 11 (eds Esiri, M. M. et al.) 227–256 (Cambridge University Press, Cambridge, 2004).",{"doi":2817},"10.1017\u002FCBO9780511526886.012",{"id":24,"text":2819,"url":24,"identifiers":2820},"Komori, T. et al. Astrocytic plaques and tufts of abnormal fibers do not coexist in corticobasal degeneration and progressive supranuclear palsy. Acta Neuropathol. 96, 401–408 (1998).",{"doi":2821},"10.1007\u002Fs004010050911",{"id":24,"text":2823,"url":24,"identifiers":2824},"Feany, M. B. & Dickson, D. W. Widespread cytoskeletal pathology characterizes corticobasal degeneration. Am. J. Pathol. 146, 1388–1396 (1995).",{},{"id":24,"text":2826,"url":24,"identifiers":2827},"Yamada, T., McGeer, P. L. & McGeer, E. G. Appearance of paired nucleated, tau-positive glia in patients with progressive supranuclear palsy brain tissue. Neurosci. Lett. 135, 99–102 (1992).",{"doi":2828},"10.1016\u002F0304-3940(92)90145-W",{"id":24,"text":2830,"url":24,"identifiers":2831},"Arai, T. et al. Identification of amino-terminally cleaved tau fragments that distinguish progressive supranuclear palsy from corticobasal degeneration. Ann. Neurol. 55, 72–79 (2004).",{"doi":2832},"10.1002\u002Fana.10793",{"id":24,"text":2834,"url":24,"identifiers":2835},"Arai, T. et al. Intracellular processing of aggregated tau differs between corticobasal degeneration and progressive supranuclear palsy. Neuroreport 12, 935–938 (2001).",{"doi":2836},"10.1097\u002F00001756-200104170-00014",{"id":24,"text":2838,"url":24,"identifiers":2839},"Ishizawa, K. & Dickson, D. W. Microglial activation parallels system degeneration in progressive supranuclear palsy and corticobasal degeneration. J. Neuropathol. Exp. Neurol. 60, 647–657 (2001).",{"doi":2840},"10.1093\u002Fjnen\u002F60.6.647",{"id":24,"text":2842,"url":24,"identifiers":2843},"Gerhard, A. et al. In vivo imaging of microglial activation with [11C](R)-PK11195 PET in progressive supranuclear palsy. Mov. Disord. 21, 89–93 (2006).",{"doi":2844},"10.1002\u002Fmds.20668",{"id":24,"text":2846,"url":24,"identifiers":2847},"Bhaskar, K. et al. Regulation of tau pathology by the microglial fractalkine receptor. Neuron 68, 19–31 (2010).",{"doi":2848},"10.1016\u002Fj.neuron.2010.08.023",{"id":24,"text":2850,"url":24,"identifiers":2851},"Ittner, L. M. et al. Dendritic function of tau mediates amyloid-beta toxicity in Alzheimers's disease mouse models. Cell 142, 387–397 (2010).",{"doi":2852},"10.1016\u002Fj.cell.2010.06.036",{"id":24,"text":2854,"url":24,"identifiers":2855},"Hoover, B. R. et al. Tau mislocalization to dendritic spines mediates synaptic dysfunction independently of neurodegeneration. Neuron 68, 1067–1081 (2010).",{"doi":2856},"10.1016\u002Fj.neuron.2010.11.030",{"id":24,"text":2858,"url":24,"identifiers":2859},"Brunden, K. R. et al. Tau-directed drug discovery for Alzheimer's disease and related tauopathies: a focus on tau assembly inhibitors. Exp. Neurol. 223, 304–310 (2010).",{"doi":2860},"10.1016\u002Fj.expneurol.2009.08.031",{"id":24,"text":2862,"url":24,"identifiers":2863},"Wischik, C. M., Edwards, P. C., Lai, R. Y., Roth, M. & Harrington, C. R. Selective inhibition of Alzheimer disease-like tau aggregation by phenothiazines. Proc. Natl Acad. Sci. USA 93, 11213–11218 (1996).",{"doi":2864},"10.1073\u002Fpnas.93.20.11213",{"id":24,"text":2866,"url":24,"identifiers":2867},"Gong, C. X., Grundke-Iqbal, I. & Iqbal, K. Targeting tau protein in Alzheimer's disease. Drugs Aging 27, 351–365 (2010).",{"doi":2868},"10.2165\u002F11536110-000000000-00000",{"id":24,"text":2870,"url":24,"identifiers":2871},"Mandelkow, E. M. et al. Glycogen synthase kinase-3 and the Alzheimer-like state of microtubule-associated protein tau. FEBS Lett. 314, 315–321 (1992).",{"doi":2872},"10.1016\u002F0014-5793(92)81496-9",{"id":24,"text":2874,"url":24,"identifiers":2875},"Pérez, M., Hernandez, F., Lim, F., Diaz-Nido, J. & Avila, J. Chronic lithium treatment decreases mutant tau protein aggregation in a transgenic mouse model. J. Alzheimers Dis. 5, 301–308 (2003).",{"doi":2876},"10.3233\u002FJAD-2003-5405",{"id":24,"text":2878,"url":24,"identifiers":2879},"Noble, W. et al. Inhibition of glycogen synthase kinase-3 by lithium correlates with reduced tauopathy and degeneration in vivo. Proc. Natl Acad. Sci. USA 102, 6990–6995 (2005).",{"doi":2880},"10.1073\u002Fpnas.0500466102",{"id":24,"text":2882,"url":24,"identifiers":2883},"Nakashima, H. et al. Chronic lithium treatment decreases tau lesions by promoting ubiquitination in a mouse model of tauopathies. Acta Neuropathol. 110, 547–556 (2005).",{"doi":2884},"10.1007\u002Fs00401-005-1087-4",{"id":24,"text":2886,"url":24,"identifiers":2887},"Engel, T., Goñi-Oliver, P., Lucas, J. J., Avila, J. & Hernández, F. Chronic lithium administration to FTDP-17 tau and GSK-3β overexpressing mice prevents tau hyperphosphorylation and neurofibrillary tangle formation, but pre-formed neurofibrillary tangles do not revert. J. Neurochem. 99, 1445–1455 (2006).",{"doi":2888},"10.1111\u002Fj.1471-4159.2006.04139.x",{"id":24,"text":2890,"url":24,"identifiers":2891},"Caccamo, A., Oddo, S., Tran, L. X. & LaFerla, F. M. Lithium reduces tau phosphorylation but not Aβ or working memory deficits in a transgenic model with both plaques and tangles. Am. J. Pathol. 170, 1669–1675 (2007).",{"doi":2892},"10.2353\u002Fajpath.2007.061178",{"id":24,"text":2894,"url":24,"identifiers":2895},"Lee, V. M., Kenyon, T. K. & Trojanowski, J. Q. Transgenic animal models of tauopathies. Biochim. Biophys. Acta 1739, 251–259 (2005).",{"doi":2896},"10.1016\u002Fj.bbadis.2004.06.014",{"id":24,"text":2898,"url":24,"identifiers":2899},"Zhang, B. et al. Microtubule-binding drugs offset tau sequestration by stabilizing microtubules and reversing fast axonal transport deficits in a tauopathy model. Proc. Natl Acad. Sci. USA 102, 227–231 (2005).",{"doi":2900},"10.1073\u002Fpnas.0406361102",{"id":24,"text":2902,"url":24,"identifiers":2903},"Gozes, I. & Divinski, I. The femtomolar-acting NAP interacts with microtubules: novel aspects of astrocyte protection. J. Alzheimers Dis. 6, S37–S41 (2004).",{"doi":2904},"10.3233\u002FJAD-2004-6S605",{"id":24,"text":2906,"url":24,"identifiers":2907},"Matsuoka, Y. et al. Intranasal NAP administration reduces accumulation of amyloid peptide and tau hyperphosphorylation in a transgenic mouse model of Alzheimer's disease at early pathological stage. J. Mol. Neurosci. 31, 165–170 (2007).",{"doi":2908},"10.1385\u002FJMN\u002F31:02:165",{"id":24,"text":2910,"url":24,"identifiers":2911},"Matsuoka, Y. et al. A neuronal microtubule-interacting agent, NAPVSIPQ, reduces tau pathology and enhances cognitive function in a mouse model of Alzheimer's disease. J. Pharmacol. Exp. Ther. 325, 146–153 (2008).",{"doi":2912},"10.1124\u002Fjpet.107.130526",{"id":24,"text":2914,"url":24,"identifiers":2915},"Brunden, K. R. et al. Epothilone D improves microtubule density, axonal integrity, and cognition in a transgenic mouse model of tauopathy. J. Neurosci. 30, 13861–13866 (2010).",{"doi":2916},"10.1523\u002FJNEUROSCI.3059-10.2010",{"id":24,"text":2918,"url":24,"identifiers":2919},"Luo, W. et al. Roles of heat-shock protein 90 in maintaining and facilitating the neurodegenerative phenotype in tauopathies. Proc. Natl Acad. Sci. USA 104, 9511–9516 (2007).",{"doi":2920},"10.1073\u002Fpnas.0701055104",{"id":24,"text":2922,"url":24,"identifiers":2923},"Dickey, C. A. et al. The high-affinity HSP90–CHIP complex recognizes and selectively degrades phosphorylated tau client proteins. J. Clin. Invest. 117, 648–658 (2007).",{"doi":2924},"10.1172\u002FJCI29715",{"id":24,"text":2926,"url":24,"identifiers":2927},"Pickhardt, M. et al. Anthraquinones inhibit tau aggregation and dissolve Alzheimer's paired helical filaments in vitro and in cells. J. Biol. Chem. 280, 3628–3635 (2005).",{"doi":2928},"10.1074\u002Fjbc.M410984200",{"id":24,"text":2930,"url":24,"identifiers":2931},"Urakami, K. et al. A comparison of tau protein in cerebrospinal fluid between corticobasal degeneration and progressive supranuclear palsy. Neurosci. Lett. 259, 127–129 (1999).",{"doi":2932},"10.1016\u002FS0304-3940(98)00923-9",{"id":24,"text":2934,"url":24,"identifiers":2935},"Urakami, K. et al. Diagnostic significance of tau protein in cerebrospinal fluid from patients with corticobasal degeneration or progressive supranuclear palsy. J. Neurol. Sci. 183, 95–98 (2001).",{"doi":2936},"10.1016\u002FS0022-510X(00)00480-9",{"id":24,"text":2938,"url":24,"identifiers":2939},"Borroni, B. et al. Pattern of tau forms in CSF is altered in progressive supranuclear palsy. Neurobiol. Aging 30, 34–40 (2009).",{"doi":2940},"10.1016\u002Fj.neurobiolaging.2007.05.009",{"id":24,"text":2942,"url":24,"identifiers":2943},"Noguchi, M. et al. Decreased β-amyloid peptide42 in cerebrospinal fluid of patients with progressive supranuclear palsy and corticobasal degeneration. J. Neurol. Sci. 237, 61–65 (2005).",{"doi":2944},"10.1016\u002Fj.jns.2005.05.015",{"id":24,"text":2946,"url":24,"identifiers":2947},"Mitani, K. et al. Increased CSF tau protein in corticobasal degeneration. J. Neurol. 245, 44–46 (1998).",{"doi":2948},"10.1007\u002Fs004150050173",{"id":24,"text":2950,"url":24,"identifiers":2951},"Arai, H. et al. Cerebrospinal fluid tau levels in neurodegenerative diseases with distinct tau-related pathology. Biochem. Biophys. Res. Commun. 236, 262–264 (1997).",{"doi":2952},"10.1006\u002Fbbrc.1997.6908",{"id":24,"text":2954,"url":24,"identifiers":2955},"Portelius, E. et al. Characterization of tau in cerebrospinal fluid using mass spectrometry. J. Proteome Res. 7, 2114–2120 (2008).",{"doi":2956},"10.1021\u002Fpr7008669",{"id":24,"text":2958,"url":24,"identifiers":2959},"Guillozet-Bongaarts, A. L. et al. Phosphorylation and cleavage of tau in non-AD tauopathies. Acta Neuropathol. 113, 513–520 (2007).",{"doi":2960},"10.1007\u002Fs00401-007-0209-6",{"id":24,"text":2962,"url":24,"identifiers":2963},"Holmberg, B., Rosengren, L., Karlsson, J. E. & Johnels, B. Increased cerebrospinal fluid levels of neurofilament protein in progressive supranuclear palsy and multiple-system atrophy compared with Parkinson's disease. Mov. Disord. 13, 70–77 (1998).",{"doi":2964},"10.1002\u002Fmds.870130116",{"id":24,"text":2966,"url":24,"identifiers":2967},"Brettschneider, J. et al. Neurofilament heavy-chain NfHSMI35 in cerebrospinal fluid supports the differential diagnosis of parkinsonian syndromes. Mov. Disord. 21, 2224–2227 (2006).",{"doi":2968},"10.1002\u002Fmds.21124",{"id":24,"text":2970,"url":24,"identifiers":2971},"Müller, U. GWAS in PSP: results at disease-associated loci other than MAPT. Proc. CurePSP 2010 International Research Symposium (San Diego, CA, November 18, 2010).",{},{"id":24,"text":2973,"url":24,"identifiers":2974},"Sergeant, N., Wattez, A. & Delacourte, A. Neurofibrillary degeneration in progressive supranuclear palsy and corticobasal degeneration: tau pathologies with exclusively “exon 10” isoforms. J. Neurochem. 72, 1243–1249 (1999).",{"doi":2975},"10.1046\u002Fj.1471-4159.1999.0721243.x",{"id":24,"text":2977,"url":24,"identifiers":2978},"Delacourte, A., Sergeant, N., Wattez, A., Gauvreau, D. & Robitaille, Y. Vulnerable neuronal subsets in Alzheimer's and Pick's disease are distinguished by their tau isoform distribution and phosphorylation. Ann. Neurol. 43, 193–204 (1998).",{"doi":2979},"10.1002\u002Fana.410430209",{"id":24,"text":2981,"url":24,"identifiers":2982},"Hutton, M. Missense and splice site mutations in tau associated with FTDP-17: multiple pathogenic mechanisms. Neurology 56, S21–S25 (2001).",{"doi":2983},"10.1212\u002FWNL.56.suppl_4.S21",{"id":24,"text":2985,"url":24,"identifiers":2986},"Binder, L. I., Frankfurter, A. & Rebhun, L. I. The distribution of tau in the mammalian central nervous system. J. Cell. Biol. 101, 1371–1378 (1985).",{"doi":2987},"10.1083\u002Fjcb.101.4.1371",{"id":24,"text":2989,"url":24,"identifiers":2990},"LoPresti, P., Szuchet, S., Papasozomenos, S. C., Zinkowski, R. P. & Binder, L. I. Functional implications for the microtubule-associated protein tau: localization in oligodendrocytes. Proc. Natl Acad. Sci. USA 92, 10369–10373 (1995).",{"doi":2991},"10.1073\u002Fpnas.92.22.10369",{"id":24,"text":2993,"url":24,"identifiers":2994},"Witman, G. B., Cleveland, D. W., Weingarten, M. D. & Kirschner, M. W. Tubulin requires tau for growth onto microtubule initiating sites. Proc. Natl Acad. Sci. USA 73, 4070–4074 (1976).",{"doi":2995},"10.1073\u002Fpnas.73.11.4070",{"id":24,"text":2997,"url":24,"identifiers":2998},"Andreadis, A., Brown, W. M. & Kosik, K. S. Structure and novel exons of the human tau gene. Biochemistry 31, 10626–10633 (1992).",{"doi":2999},"10.1021\u002Fbi00158a027",{"id":24,"text":3001,"url":24,"identifiers":3002},"Goedert, M., Spillantini, M. G., Jakes, R., Rutherford, D. & Crowther, R. A. Multiple isoforms of human microtubule-associated protein tau: sequences and localization in neurofibrillary tangles of Alzheimer's disease. Neuron 3, 519–526 (1989).",{"doi":3003},"10.1016\u002F0896-6273(89)90210-9",{"id":24,"text":3005,"url":24,"identifiers":3006},"Baker, M. et al. Association of an extended haplotype in the tau gene with progressive supranuclear palsy. Hum. Mol. Genet. 8, 711–715 (1999).",{"doi":3007},"10.1093\u002Fhmg\u002F8.4.711",{"id":24,"text":3009,"url":24,"identifiers":3010},"Stefansson, H. et al. A common inversion under selection in Europeans. Nat. Genet. 37, 129–137 (2005).",{"doi":3011},"10.1038\u002Fng1508",{"id":24,"text":3013,"url":24,"identifiers":3014},"Conrad, C. et al. Genetic evidence for the involvement of tau in progressive supranuclear palsy. Ann. Neurol. 41, 277–281 (1997).",{"doi":3015},"10.1002\u002Fana.410410222",{"id":24,"text":3017,"url":24,"identifiers":3018},"Houlden, H. et al. Corticobasal degeneration and progressive supranuclear palsy share a common tau haplotype. Neurology 56, 1702–1706 (2001).",{"doi":3019},"10.1212\u002FWNL.56.12.1702",{"id":24,"text":3021,"url":24,"identifiers":3022},"Rademakers, R. et al. High-density SNP haplotyping suggests altered regulation of tau gene expression in progressive supranuclear palsy. Hum. Mol. Genet. 14, 3281–3292 (2005).",{"doi":3023},"10.1093\u002Fhmg\u002Fddi361",{"id":24,"text":3025,"url":24,"identifiers":3026},"Pittman, A. M. et al. Linkage disequilibrium fine mapping and haplotype association analysis of the tau gene in progressive supranuclear palsy and corticobasal degeneration. J. Med. Genet. 42, 837–846 (2005).",{"doi":3027},"10.1136\u002Fjmg.2005.031377",{"id":24,"text":3029,"url":24,"identifiers":3030},"Bugiani, O. et al. Frontotemporal dementia and corticobasal degeneration in a family with a P301S mutation in tau. J. Neuropathol. Exp. Neurol. 58, 667–677 (1999).",{"doi":3031},"10.1097\u002F00005072-199906000-00011",{"id":24,"text":3033,"url":24,"identifiers":3034},"Spillantini, M. G. et al. A novel tau mutation (N296N) in familial dementia with swollen achromatic neurons and corticobasal inclusion bodies. Ann. Neurol. 48, 939–943 (2000).",{"doi":3035},"10.1002\u002F1531-8249(200012)48:6\u003C939::AID-ANA17>3.0.CO;2-1",{"id":24,"text":3037,"url":24,"identifiers":3038},"Rossi, G. et al. The G389R mutation in the MAPT gene presenting as sporadic corticobasal syndrome. Mov. Disord. 23, 892–895 (2008).",{"doi":3039},"10.1002\u002Fmds.21970",{"id":24,"text":3041,"url":24,"identifiers":3042},"Rademakers, R., Cruts, M. & van Broeckhoven, C. The role of tau (MAPT) in frontotemporal dementia and related tauopathies. Hum. 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Alzheimers Dement. 12, 459–509 (2016).",{"doi":3167},"10.1016\u002Fj.jalz.2016.03.001",{"id":24,"text":3169,"url":24,"identifiers":3170},"Holtzman, D. M., Morris, J. C. & Goate, A. M. Alzheimer’s disease: the challenge of the second century. Sci. Transl Med. 3, 77sr71 (2011).",{},{"id":24,"text":3172,"url":24,"identifiers":3173},"St George-Hyslop, P. H. et al. The genetic defect causing familial Alzheimer’s disease maps on chromosome 21. Science 235, 885–890 (1987).",{"doi":3174},"10.1126\u002Fscience.2880399",{"id":24,"text":3176,"url":24,"identifiers":3177},"Sherrington, R. et al. Cloning of a gene bearing missense mutations in early-onset familial Alzheimer’s disease. Nature 375, 754–760 (1995).",{"doi":3178},"10.1038\u002F375754a0",{"id":24,"text":3180,"url":24,"identifiers":3181},"Goate, A. et al. Segregation of a missense mutation in the amyloid precursor protein gene with familial Alzheimer’s disease. Nature 349, 704–706 (1991).",{"doi":3182},"10.1038\u002F349704a0",{"id":24,"text":3184,"url":24,"identifiers":3185},"Levy, E. et al. Mutation of the Alzheimer’s disease amyloid gene in hereditary cerebral hemorrhage, Dutch type. Science 248, 1124–1126 (1990).",{"doi":3186},"10.1126\u002Fscience.2111584",{"id":24,"text":3188,"url":24,"identifiers":3189},"Levy-Lahad, E. et al. Candidate gene for the chromosome 1 familial Alzheimer’s disease locus. Science 269, 973–977 (1995).",{"doi":3190},"10.1126\u002Fscience.7638622",{"id":24,"text":3192,"url":24,"identifiers":3193},"Rogaev, E. I. et al. Familial Alzheimer’s disease in kindreds with missense mutations in a gene on chromosome 1 related to the Alzheimer’s disease type 3 gene. Nature 376, 775–778 (1995).",{"doi":3194},"10.1038\u002F376775a0",{"id":24,"text":3196,"url":24,"identifiers":3197},"Jonsson, T. et al. Variant of TREM2 associated with the risk of Alzheimer’s disease. N. Engl. J. Med. 368, 107–116 (2013).",{"doi":3198},"10.1056\u002FNEJMoa1211103",{"id":24,"text":3200,"url":24,"identifiers":3201},"Guerreiro, R. et al. TREM2 variants in Alzheimer’s disease. N. Engl. J. Med. 368, 117–127 (2013).",{"doi":3202},"10.1056\u002FNEJMoa1211851",{"id":24,"text":3204,"url":24,"identifiers":3205},"Sims, R. et al. Rare coding variants in PLCG2, ABI3, and TREM2 implicate microglial-mediated innate immunity in Alzheimer’s disease. Nat. Genet. 49, 1373–1384 (2017).",{"doi":3206},"10.1038\u002Fng.3916",{"id":24,"text":3208,"url":24,"identifiers":3209},"Hollingworth, P. et al. Common variants at ABCA7, MS4A6A\u002FMS4A4E, EPHA1, CD33 and CD2AP are associated with Alzheimer’s disease. Nat. Genet. 43, 429–435 (2011).",{"doi":3210},"10.1038\u002Fng.803",{"id":24,"text":3212,"url":24,"identifiers":3213},"Corder, E. H. et al. Gene dose of apolipoprotein E type 4 allele and the risk of Alzheimer’s disease in late onset families. Science 261, 921–923 (1993).",{"doi":3214},"10.1126\u002Fscience.8346443",{"id":24,"text":3216,"url":24,"identifiers":3217},"Strittmatter, W. J. et al. Apolipoprotein E: high-avidity binding to beta-amyloid and increased frequency of type 4 allele in late-onset familial Alzheimer disease. Proc. Natl Acad. Sci. USA 90, 1977–1981 (1993).",{"doi":3218},"10.1073\u002Fpnas.90.5.1977",{"id":24,"text":3220,"url":24,"identifiers":3221},"Song, W. et al. Alzheimer’s disease-associated TREM2 variants exhibit either decreased or increased ligand-dependent activation. Alzheimers Dement. 13, 381–387 (2017).",{"doi":3222},"10.1016\u002Fj.jalz.2016.07.004",{"id":24,"text":3224,"url":24,"identifiers":3225},"Benitez, B. A. et al. TREM2 is associated with the risk of Alzheimer’s disease in Spanish population. Neurobiol. Aging 34, 1711 (2013).",{"doi":3226},"10.1016\u002Fj.neurobiolaging.2012.12.018",{"id":24,"text":3228,"url":24,"identifiers":3229},"Ruiz, A. et al. Assessing the role of the TREM2 p. R47H variant as a risk factor for Alzheimer’s disease and frontotemporal dementia. Neurobiol. Aging 35, 444 (2014).",{"doi":3230},"10.1016\u002Fj.neurobiolaging.2014.06.016",{"id":24,"text":3232,"url":24,"identifiers":3233},"Slattery, C. F. et al. R47H TREM2 variant increases risk of typical early-onset Alzheimer’s disease but not of prion or frontotemporal dementia. Alzheimers Dement. 10, 602–608 (2014).",{"doi":3234},"10.1016\u002Fj.jalz.2014.05.1751",{"id":24,"text":3236,"url":24,"identifiers":3237},"Karch, C. M., Cruchaga, C. & Goate, A. M. Alzheimer’s disease genetics: from the bench to the clinic. Neuron 83, 11–26 (2014).",{"doi":3238},"10.1016\u002Fj.neuron.2014.05.041",{"id":24,"text":3240,"url":24,"identifiers":3241},"Bertram, L. et al. Genome-wide association analysis reveals putative Alzheimer’s disease susceptibility loci in addition to APOE. Am. J. Hum. Genet. 83, 623–632 (2008).",{"doi":3242},"10.1016\u002Fj.ajhg.2008.10.008",{"id":24,"text":3244,"url":24,"identifiers":3245},"Naj, A. C. et al. Common variants at MS4A4\u002FMS4A6E, CD2AP, CD33 and EPHA1 are associated with late-onset Alzheimer’s disease. Nat. Genet. 43, 436–441 (2011).",{"doi":3246},"10.1038\u002Fng.801",{"id":24,"text":3248,"url":24,"identifiers":3249},"Harold, D. et al. Genome-wide association study identifies variants at CLU and PICALM associated with Alzheimer’s disease. Nat. Genet. 41, 1088–1093 (2009).",{"doi":3250},"10.1038\u002Fng.440",{"id":24,"text":3252,"url":24,"identifiers":3253},"Lambert, J. C. et al. Genome-wide association study identifies variants at CLU and CR1 associated with Alzheimer’s disease. Nat. Genet. 41, 1094–1099 (2009).",{"doi":3254},"10.1038\u002Fng.439",{"id":24,"text":3256,"url":24,"identifiers":3257},"Seshadri, S. et al. Genome-wide analysis of genetic loci associated with Alzheimer disease. JAMA 303, 1832–1840 (2010).",{"doi":3258},"10.1001\u002Fjama.2010.574",{"id":24,"text":3260,"url":24,"identifiers":3261},"Lambert, J. C. et al. Meta-analysis of 74,046 individuals identifies 11 new susceptibility loci for Alzheimer’s disease. Nat. Genet. 45, 1452–1458 (2013).",{"doi":3262},"10.1038\u002Fng.2802",{"id":24,"text":3264,"url":24,"identifiers":3265},"Miyashita, A. et al. SORL1 is genetically associated with late-onset Alzheimer’s disease in Japanese, Koreans and Caucasians. PLoS ONE 8, e58618 (2013).",{"doi":3266},"10.1371\u002Fannotation\u002Ffcb56ea7-d32a-4e45-818d-39cef330c731",{"id":24,"text":3268,"url":24,"identifiers":3269},"Nissl, F. in Histologische und histopathologische Arbeiten über die Grosshirnrinde Vol. 1 (eds. Nissl, F., Alzheimer, A.) 315–494 (G. Fischer, Jena, Germany, 1904).",{},{"id":24,"text":3271,"url":24,"identifiers":3272},"Alzheimer, A. in Histologische und histopathologische Arbeiten über die Grosshirnrinde Vol. 3 (eds. Nissl, F., Alzheimer, A.) 401–562 (G. Fischer, Jena, Germany, 1910).",{},{"id":24,"text":3274,"url":24,"identifiers":3275},"Hortega, P. R. El tercer elemento de los centros nerviosos. III. Naturaleza probable de la microglía [Spanish]. Bol. Soc. Esp. Biol. 8, 108–115 (1919).",{},{"id":24,"text":3277,"url":24,"identifiers":3278},"Greter, M. & Merad, M. Regulation of microglia development and homeostasis. Glia 61, 121–127 (2013).",{"doi":3279},"10.1002\u002Fglia.22408",{"id":24,"text":3281,"url":24,"identifiers":3282},"Gomez Perdiguero, E., Schulz, C. & Geissmann, F. Development and homeostasis of “resident” myeloid cells: the case of the microglia. Glia 61, 112–120 (2013).",{"doi":3283},"10.1002\u002Fglia.22393",{"id":24,"text":3285,"url":24,"identifiers":3286},"Hong, S. et al. Complement and microglia mediate early synapse loss in Alzheimer mouse models. Science 352, 712–716 (2016).",{"doi":3287},"10.1126\u002Fscience.aad8373",{"id":24,"text":3289,"url":24,"identifiers":3290},"Paolicelli, R. C. et al. Synaptic pruning by microglia is necessary for normal brain development. Science 333, 1456–1458 (2011).",{"doi":3291},"10.1126\u002Fscience.1202529",{"id":24,"text":3293,"url":24,"identifiers":3294},"Schafer, D. P. et al. Microglia sculpt postnatal neural circuits in an activity and complement-dependent manner. Neuron 74, 691–705 (2012).",{"doi":3295},"10.1016\u002Fj.neuron.2012.03.026",{"id":24,"text":3297,"url":24,"identifiers":3298},"Lue, L. F., Kuo, Y. M., Beach, T. & Walker, D. G. Microglia activation and anti-inflammatory regulation in Alzheimer’s disease. Mol. Neurobiol. 41, 115–128 (2010).",{"doi":3299},"10.1007\u002Fs12035-010-8106-8",{"id":24,"text":3301,"url":24,"identifiers":3302},"Neumann, H., Kotter, M. R. & Franklin, R. J. Debris clearance by microglia: an essential link between degeneration and regeneration. Brain 132, 288–295 (2009).",{"doi":3303},"10.1093\u002Fbrain\u002Fawn109",{"id":24,"text":3305,"url":24,"identifiers":3306},"Butovsky, O. et al. Microglia activated by IL-4 or IFN-gamma differentially induce neurogenesis and oligodendrogenesis from adult stem\u002Fprogenitor cells. Mol. Cell. Neurosci. 31, 149–160 (2006).",{"doi":3307},"10.1016\u002Fj.mcn.2005.10.006",{"id":24,"text":3309,"url":24,"identifiers":3310},"Parkhurst, C. N. et al. Microglia promote learning-dependent synapse formation through brain-derived neurotrophic factor. Cell 155, 1596–1609 (2013).",{"doi":3311},"10.1016\u002Fj.cell.2013.11.030",{"id":24,"text":3313,"url":24,"identifiers":3314},"Keren-Shaul, H. et al. A unique microglia type associated with restricting development of Alzheimer’s disease. Cell 169, 1276–1290 (2017).",{"doi":3315},"10.1016\u002Fj.cell.2017.05.018",{"id":24,"text":3317,"url":24,"identifiers":3318},"Matcovitch-Natan, O. et al. Microglia development follows a stepwise program to regulate brain homeostasis. Science 353, aad8670 (2016).",{"doi":3319},"10.1126\u002Fscience.aad8670",{"id":24,"text":3321,"url":24,"identifiers":3322},"Mathys, H. et al. Temporal tracking of microglia activation in neurodegeneration at single-cell resolution. Cell Rep. 21, 366–380 (2017).",{"doi":3323},"10.1016\u002Fj.celrep.2017.09.039",{"id":24,"text":3325,"url":24,"identifiers":3326},"Chiu, I. M. et al. A neurodegeneration-specific gene-expression signature of acutely isolated microglia from an amyotrophic lateral sclerosis mouse model. Cell Rep. 4, 385–401 (2013).",{"doi":3327},"10.1016\u002Fj.celrep.2013.06.018",{"id":24,"text":3329,"url":24,"identifiers":3330},"Wang, Y. et al. TREM2 lipid sensing sustains the microglial response in an Alzheimer’s disease model. Cell 160, 1061–1071 (2015).",{"doi":3331},"10.1016\u002Fj.cell.2015.01.049",{"id":24,"text":3333,"url":24,"identifiers":3334},"Vincenti, J. E. et al. Defining the microglia response during the time course of chronic neurodegeneration. J. Virol. 90, 3003–3017 (2015).",{"doi":3335},"10.1128\u002FJVI.02613-15",{"id":24,"text":3337,"url":24,"identifiers":3338},"Alibhai, J. et al. Distribution of misfolded prion protein seeding activity alone does not predict regions of neurodegeneration. PLoS Biol. 14, e1002579 (2016).",{"doi":3339},"10.1371\u002Fjournal.pbio.1002579",{"id":24,"text":3341,"url":24,"identifiers":3342},"Gosselin, D. et al. An environment-dependent transcriptional network specifies human microglia identity. Science 356, eaal3222 (2017).",{"doi":3343},"10.1126\u002Fscience.aal3222",{"id":24,"text":3345,"url":24,"identifiers":3346},"Butovsky, O. et al. Identification of a unique TGF-beta-dependent molecular and functional signature in microglia. Nat. Neurosci. 17, 131–143 (2014).",{"doi":3347},"10.1038\u002Fnn.3599",{"id":24,"text":3349,"url":24,"identifiers":3350},"Ofengeim, D. et al. RIPK1 mediates a disease-associated microglial response in Alzheimer’s disease. Proc. Natl Acad. Sci. USA 114, E8788–E8797 (2017).",{"doi":3351},"10.1073\u002Fpnas.1714175114",{"id":24,"text":3353,"url":24,"identifiers":3354},"Deczkowska, A. et al. Disease-associated microglia: a universal immune sensor of neurodegeneration. Cell 173, 1073–1081 (2018).",{"doi":3355},"10.1016\u002Fj.cell.2018.05.003",{"id":24,"text":3357,"url":24,"identifiers":3358},"Kamphuis, W., Kooijman, L., Schetters, S., Orre, M. & Hol, E. M. Transcriptional profiling of CD11c-positive microglia accumulating around amyloid plaques in a mouse model for Alzheimer’s disease. Biochim. Biophys. Acta 1862, 1847–1860 (2016).",{"doi":3359},"10.1016\u002Fj.bbadis.2016.07.007",{"id":24,"text":3361,"url":24,"identifiers":3362},"Bouchon, A., Dietrich, J. & Colonna, M. Cutting edge: inflammatory responses can be triggered by TREM-1, a novel receptor expressed on neutrophils and monocytes. J. Immunol. 164, 4991–4995 (2000).",{"doi":3363},"10.4049\u002Fjimmunol.164.10.4991",{"id":24,"text":3365,"url":24,"identifiers":3366},"Cannon, J. P., O’Driscoll, M. & Litman, G. W. Specific lipid recognition is a general feature of CD300 and TREM molecules. Immunogenetics 64, 39–47 (2012).",{"doi":3367},"10.1007\u002Fs00251-011-0562-4",{"id":24,"text":3369,"url":24,"identifiers":3370},"Daws, M. R. et al. Pattern recognition by TREM-2: binding of anionic ligands. J. Immunol. 171, 594–599 (2003).",{"doi":3371},"10.4049\u002Fjimmunol.171.2.594",{"id":24,"text":3373,"url":24,"identifiers":3374},"Kawabori, M. et al. Triggering receptor expressed on myeloid cells 2 (TREM2) deficiency attenuates phagocytic activities of microglia and exacerbates ischemic damage in experimental stroke. J. Neurosci. 35, 3384–3396 (2015).",{"doi":3375},"10.1523\u002FJNEUROSCI.2620-14.2015",{"id":24,"text":3377,"url":24,"identifiers":3378},"Xing, J., Titus, A. R. & Humphrey, M. B. The TREM2-DAP12 signaling pathway in Nasu-Hakola disease: a molecular genetics perspective. Res. Rep. Biochem. 5, 89–100 (2015).",{},{"id":24,"text":3380,"url":24,"identifiers":3381},"Peng, Q. et al. TREM2- and DAP12-dependent activation of PI3K requires DAP10 and is inhibited by SHIP1. Sci. Signal. 3, ra38 (2010).",{"doi":3382},"10.1126\u002Fscisignal.2000500",{"id":24,"text":3384,"url":24,"identifiers":3385},"Ulland, T. K. et al. TREM2 maintains microglial metabolic fitness in Alzheimer’s disease. Cell 170, 649–663 (2017).",{"doi":3386},"10.1016\u002Fj.cell.2017.07.023",{"id":24,"text":3388,"url":24,"identifiers":3389},"Turnbull, I. R. et al. Cutting edge: TREM-2 attenuates macrophage activation. J. Immunol. 177, 3520–3524 (2006).",{"doi":3390},"10.4049\u002Fjimmunol.177.6.3520",{"id":24,"text":3392,"url":24,"identifiers":3393},"Piccio, L. et al. Blockade of TREM-2 exacerbates experimental autoimmune encephalomyelitis. Eur. J. Immunol. 37, 1290–1301 (2007).",{"doi":3394},"10.1002\u002Feji.200636837",{"id":24,"text":3396,"url":24,"identifiers":3397},"Wunderlich, P. et al. Sequential proteolytic processing of the triggering receptor expressed on myeloid cells-2 (TREM2) protein by ectodomain shedding and gamma-secretase-dependent intramembranous cleavage. J. Biol. Chem. 288, 33027–33036 (2013).",{"doi":3398},"10.1074\u002Fjbc.M113.517540",{"id":24,"text":3400,"url":24,"identifiers":3401},"Schlepckow, K. et al. An Alzheimer-associated TREM2 variant occurs at the ADAM cleavage site and affects shedding and phagocytic function. EMBO Mol. Med. 9, 1356–1365 (2017).",{"doi":3402},"10.15252\u002Femmm.201707672",{"id":24,"text":3404,"url":24,"identifiers":3405},"Thornton, P. et al. TREM2 shedding by cleavage at the H157-S158 bond is accelerated for the Alzheimer’s disease-associated H157Y variant. EMBO Mol. Med. 9, 1366–1378 (2017).",{"doi":3406},"10.15252\u002Femmm.201707673",{"id":24,"text":3408,"url":24,"identifiers":3409},"Feuerbach, D. et al. ADAM17 is the main sheddase for the generation of human triggering receptor expressed in myeloid cells (hTREM2) ectodomain and cleaves TREM2 after histidine 157. Preprint at https:\u002F\u002Fwww.biorxiv.org\u002Fcontent\u002Fearly\u002F2017\u002F05\u002F03\u002F133751 (2017).",{"doi":3410},"10.1016\u002Fj.neulet.2017.09.034",{"id":24,"text":3412,"url":24,"identifiers":3413},"Glebov, K., Wunderlich, P., Karaca, I. & Walter, J. Functional involvement of γ-secretase in signaling of the triggering receptor expressed on myeloid cells-2 (TREM2). J. Neuroinflammation 13, 17 (2016).",{"doi":3414},"10.1186\u002Fs12974-016-0479-9",{"id":24,"text":3416,"url":24,"identifiers":3417},"Paloneva, J. et al. Mutations in two genes encoding different subunits of a receptor signaling complex result in an identical disease phenotype. Am. J. Hum. Genet. 71, 656–662 (2002).",{"doi":3418},"10.1086\u002F342259",{"id":24,"text":3420,"url":24,"identifiers":3421},"Klunemann, H. H. et al. The genetic causes of basal ganglia calcification, dementia, and bone cysts: DAP12 and TREM2. Neurology 64, 1502–1507 (2005).",{"doi":3422},"10.1212\u002F01.WNL.0000160304.00003.CA",{"id":24,"text":3424,"url":24,"identifiers":3425},"Hakola, H. P. Neuropsychiatric and genetic aspects of a new hereditary disease characterized by progressive dementia and lipomembranous polycystic osteodysplasia. Acta Psychiatr. Scand. 232, 1–173 (1972).",{},{"id":24,"text":3427,"url":24,"identifiers":3428},"Cella, M. et al. Impaired differentiation of osteoclasts in TREM-2-deficient individuals. J. Exp. Med. 198, 645–651 (2003).",{"doi":3429},"10.1084\u002Fjem.20022220",{"id":24,"text":3431,"url":24,"identifiers":3432},"Poliani, P. L. et al. TREM2 sustains microglial expansion during aging and response to demyelination. J. Clin. Invest. 125, 2161–2170 (2015).",{"doi":3433},"10.1172\u002FJCI77983",{"id":24,"text":3435,"url":24,"identifiers":3436},"Otero, K. et al. Macrophage colony-stimulating factor induces the proliferation and survival of macrophages via a pathway involving DAP12 and beta-catenin. Nat. Immunol. 10, 734–743 (2009).",{"doi":3437},"10.1038\u002Fni.1744",{"id":24,"text":3439,"url":24,"identifiers":3440},"Zou, W., Reeve, J. L., Liu, Y., Teitelbaum, S. L. & Ross, F. P. DAP12 couples c-Fms activation to the osteoclast cytoskeleton by recruitment of Syk. Mol. Cell 31, 422–431 (2008).",{"doi":3441},"10.1016\u002Fj.molcel.2008.06.023",{"id":24,"text":3443,"url":24,"identifiers":3444},"Guerreiro, R. et al. Novel compound heterozygous mutation in TREM2 found in a Turkish frontotemporal dementia-like family. Neurobiol. Aging 34, 2890 (2013).",{"doi":3445},"10.1016\u002Fj.neurobiolaging.2013.06.005",{"id":24,"text":3447,"url":24,"identifiers":3448},"Jin, S. C. et al. TREM2 is associated with increased risk for Alzheimer’s disease in African Americans. Mol. Neurodegener. 10, 19 (2015).",{"doi":3449},"10.1186\u002Fs13024-015-0016-9",{"id":24,"text":3451,"url":24,"identifiers":3452},"Jiang, T. et al. A rare coding variant in TREM2 increases risk for Alzheimer’s disease in Han Chinese. Neurobiol. Aging 42, 217 (2016).",{"doi":3453},"10.1016\u002Fj.neurobiolaging.2016.02.029",{"id":24,"text":3455,"url":24,"identifiers":3456},"Huang, M. et al. Lack of genetic association between TREM2 and Alzheimer’s disease in East Asian population: a systematic review and meta-analysis. Am. J. Alzheimers Dis. Other Demen. 30, 541–546 (2015).",{"doi":3457},"10.1177\u002F1533317515577128",{"id":24,"text":3459,"url":24,"identifiers":3460},"Wang, Y. et al. TREM2-mediated early microglial response limits diffusion and toxicity of amyloid plaques. J. Exp. Med. 213, 667–675 (2016).",{"doi":3461},"10.1084\u002Fjem.20151948",{"id":24,"text":3463,"url":24,"identifiers":3464},"Mazaheri, F. et al. TREM2 deficiency impairs chemotaxis and microglial responses to neuronal injury. EMBO Rep. 18, 1186–1198 (2017).",{"doi":3465},"10.15252\u002Fembr.201743922",{"id":24,"text":3467,"url":24,"identifiers":3468},"Yuan, P. et al. TREM2 haplodeficiency in mice and humans impairs the microglia barrier function leading to decreased amyloid compaction and severe axonal dystrophy. Neuron 90, 724–739 (2016).",{"doi":3469},"10.1016\u002Fj.neuron.2016.05.003",{"id":24,"text":3471,"url":24,"identifiers":3472},"Mildner, A. et al. Distinct and non-redundant roles of microglia and myeloid subsets in mouse models of Alzheimer’s disease. J. Neurosci. 31, 11159–11171 (2011).",{"doi":3473},"10.1523\u002FJNEUROSCI.6209-10.2011",{"id":24,"text":3475,"url":24,"identifiers":3476},"Condello, C., Yuan, P., Schain, A. & Grutzendler, J. Microglia constitute a barrier that prevents neurotoxic protofibrillar Aβ42 hotspots around plaques. Nat. Commun. 6, 6176 (2015).",{"doi":3477},"10.1038\u002Fncomms7176",{"id":24,"text":3479,"url":24,"identifiers":3480},"Bradshaw, E. M. et al. CD33 Alzheimer’s disease locus: altered monocyte function and amyloid biology. Nat. Neurosci. 16, 848–850 (2013).",{"doi":3481},"10.1038\u002Fnn.3435",{"id":24,"text":3483,"url":24,"identifiers":3484},"Heneka, M. T. et al. NLRP3 is activated in Alzheimer’s disease and contributes to pathology in APP\u002FPS1 mice. Nature 493, 674–678 (2013).",{"doi":3485},"10.1038\u002Fnature11729",{"id":24,"text":3487,"url":24,"identifiers":3488},"Venegas, C. et al. Microglia-derived ASC specks cross-seed amyloid-beta in Alzheimer’s disease. Nature 552, 355–361 (2017).",{"doi":3489},"10.1038\u002Fnature25158",{"id":24,"text":3491,"url":24,"identifiers":3492},"Jay, T. R. et al. TREM2 deficiency eliminates TREM2+ inflammatory macrophages and ameliorates pathology in Alzheimer’s disease mouse models. J. Exp. Med. 212, 287–295 (2015).",{"doi":3493},"10.1084\u002Fjem.20142322",{"id":24,"text":3495,"url":24,"identifiers":3496},"Jay, T. R. et al. Disease progression-dependent effects of TREM2 deficiency in a mouse model of Alzheimer’s disease. J. Neurosci. 37, 637–647 (2017).",{"doi":3497},"10.1523\u002FJNEUROSCI.2110-16.2016",{"id":24,"text":3499,"url":24,"identifiers":3500},"Lee, C. Y. et al. Elevated TREM2 gene dosage reprograms microglia responsivity and ameliorates pathological phenotypes in Alzheimer’s disease models. Neuron 97, 1032–1048 (2018).",{"doi":3501},"10.1016\u002Fj.neuron.2018.02.002",{"id":24,"text":3503,"url":24,"identifiers":3504},"Carrasquillo, M. M. et al. A candidate regulatory variant at the TREM gene cluster associates with decreased Alzheimer’s disease risk and increased TREML1 and TREM2 brain gene expression. Alzheimers Dement. 13, 663–673 (2017).",{"doi":3505},"10.1016\u002Fj.jalz.2016.10.005",{"id":24,"text":3507,"url":24,"identifiers":3508},"Leyns, C. E. et al. TREM2 deficiency attenuates neuroinflammation and protects against neurodegeneration in a mouse model of tauopathy. Proc. Natl Acad. Sci. USA 114, 11524–11529 (2017).",{"doi":3509},"10.1073\u002Fpnas.1710311114",{"id":24,"text":3511,"url":24,"identifiers":3512},"Bemiller, S. M. et al. TREM2 deficiency exacerbates tau pathology through dysregulated kinase signaling in a mouse model of tauopathy. Mol. Neurodegener. 12, 74 (2017).",{"doi":3513},"10.1186\u002Fs13024-017-0216-6",{"id":24,"text":3515,"url":24,"identifiers":3516},"Kober, D. L. et al. Neurodegenerative disease mutations in TREM2 reveal a f unctional surface and distinct loss-of-function mechanisms. eLife 5, e20391 (2016).",{"doi":3517},"10.7554\u002FeLife.20391",{"id":24,"text":3519,"url":24,"identifiers":3520},"Sudom, A. et al. Molecular basis for the loss-of-function effects of the Alzheimer’s disease-associated R47H variant of the immune receptor TREM2. J. Biol. Chem. 293, 12634–12646 (2018).",{"doi":3521},"10.1074\u002Fjbc.RA118.002352",{"id":24,"text":3523,"url":24,"identifiers":3524},"Song, W. M. et al. Humanized TREM2 mice reveal microglia-intrinsic and -extrinsic effects of R47H polymorphism. J. Exp. Med. 215, 745–760 (2018).",{"doi":3525},"10.1084\u002Fjem.20171529",{"id":24,"text":3527,"url":24,"identifiers":3528},"Yeh, F. L., Wang, Y., Tom, I., Gonzalez, L. C. & Sheng, M. TREM2 binds to apolipoproteins, including APOE and CLU\u002FAPOJ, and thereby facilitates uptake of amyloid-beta by microglia. Neuron 91, 328–340 (2016).",{"doi":3529},"10.1016\u002Fj.neuron.2016.06.015",{"id":24,"text":3531,"url":24,"identifiers":3532},"Kleinberger, G. et al. TREM2 mutations implicated in neurodegeneration impair cell surface transport and phagocytosis. Sci. Transl Med. 6, 243ra286 (2014).",{"doi":3533},"10.1126\u002Fscitranslmed.3009093",{"id":24,"text":3535,"url":24,"identifiers":3536},"Ulrich, J. D., Ulland, T. K., Colonna, M. & Holtzman, D. M. Elucidating the role of TREM2 in Alzheimer’s disease. Neuron 94, 237–248 (2017).",{"doi":3537},"10.1016\u002Fj.neuron.2017.02.042",{"id":24,"text":3539,"url":24,"identifiers":3540},"Borroni, B. et al. Heterozygous TREM2 mutations in frontotemporal dementia. Neurobiol. Aging 35, 934 (2014).",{"doi":3541},"10.1016\u002Fj.neurobiolaging.2013.09.017",{"id":24,"text":3543,"url":24,"identifiers":3544},"Sirkis, D. W. et al. Rare TREM2 variants associated with Alzheimer’s disease display reduced cell surface expression. Acta Neuropathol. Commun. 4, 98 (2016).",{"doi":3545},"10.1186\u002Fs40478-016-0367-7",{"id":24,"text":3547,"url":24,"identifiers":3548},"Kleinberger, G. et al. The FTD-like syndrome causing TREM2 T66M mutation impairs microglia function, brain perfusion, and glucose metabolism. EMBO J. 36, 1837–1853 (2017).",{"doi":3549},"10.15252\u002Fembj.201796516",{"id":24,"text":3551,"url":24,"identifiers":3552},"Atagi, Y. et al. Apolipoprotein E is a ligand for triggering receptor expressed on myeloid cells 2 (TREM2). J. Biol. Chem. 290, 26043–26050 (2015).",{"doi":3553},"10.1074\u002Fjbc.M115.679043",{"id":24,"text":3555,"url":24,"identifiers":3556},"Bailey, C. C., DeVaux, L. B. & Farzan, M. The triggering receptor expressed on myeloid cells 2 binds apolipoprotein E. J. Biol. Chem. 290, 26033–26042 (2015).",{"doi":3557},"10.1074\u002Fjbc.M115.677286",{"id":24,"text":3559,"url":24,"identifiers":3560},"Jendresen, C., Arskog, V., Daws, M. R. & Nilsson, L. N. The Alzheimer’s disease risk factors apolipoprotein E and TREM2 are linked in a receptor signaling pathway. J. Neuroinflammation 14, 59 (2017).",{"doi":3561},"10.1186\u002Fs12974-017-0835-4",{"id":24,"text":3563,"url":24,"identifiers":3564},"Zhao, Y. et al. TREM2 is a receptor for beta-amyloid that mediates microglial function. Neuron 97, 1023–1031 (2018).",{"doi":3565},"10.1016\u002Fj.neuron.2018.01.031",{"id":24,"text":3567,"url":24,"identifiers":3568},"Lessard, C. B. et al. High affinity interactions and signal transduction between Aβ oligomers and TREM2. Preprint at https:\u002F\u002Fwww.biorxiv.org\u002Fcontent\u002Fearly\u002F2018\u002F02\u002F22\u002F269787 (2018).",{"doi":3569},"10.1101\u002F269787",{"id":24,"text":3571,"url":24,"identifiers":3572},"Zhong, L. et al. Soluble TREM2 induces inflammatory responses and enhances microglial survival. J. Exp. Med. 214, 597–607 (2017).",{"doi":3573},"10.1084\u002Fjem.20160844",{"id":24,"text":3575,"url":24,"identifiers":3576},"Wu, K. et al. TREM-2 promotes macrophage survival and lung disease after respiratory viral infection. J. Exp. Med. 212, 681–697 (2015).",{"doi":3577},"10.1084\u002Fjem.20141732",{"id":24,"text":3579,"url":24,"identifiers":3580},"Hsieh, C. L. et al. A role for TREM2 ligands in the phagocytosis of apoptotic neuronal cells by microglia. J. Neurochem. 109, 1144–1156 (2009).",{"doi":3581},"10.1111\u002Fj.1471-4159.2009.06042.x",{"id":24,"text":3583,"url":24,"identifiers":3584},"Zhong, L. et al. DAP12 stabilizes the C-terminal fragment of the triggering receptor expressed on myeloid cells-2 (TREM2) and protects against LPS-induced pro-inflammatory response. J. Biol. Chem. 290, 15866–15877 (2015).",{"doi":3585},"10.1074\u002Fjbc.M115.645986",{"id":24,"text":3587,"url":24,"identifiers":3588},"Ohrfelt, A. et al. Soluble TREM-2 in cerebrospinal fluid from patients with multiple sclerosis treated with natalizumab or mitoxantrone. Mult. Scler. 22, 1587–1595 (2016).",{"doi":3589},"10.1177\u002F1352458515624558",{"id":24,"text":3591,"url":24,"identifiers":3592},"Cooper-Knock, J. et al. A data-driven approach links microglia to pathology and prognosis in amyotrophic lateral sclerosis. Acta Neuropathol. Commun. 5, 23 (2017).",{"doi":3593},"10.1186\u002Fs40478-017-0424-x",{"id":24,"text":3595,"url":24,"identifiers":3596},"Suarez-Calvet, M. et al. sTREM2 cerebrospinal fluid levels are a potential biomarker for microglia activity in early-stage Alzheimer’s disease and associate with neuronal injury markers. EMBO Mol. Med. 8, 466–476 (2016).",{"doi":3597},"10.15252\u002Femmm.201506123",{"id":24,"text":3599,"url":24,"identifiers":3600},"Piccio, L. et al. Cerebrospinal fluid soluble TREM2 is higher in Alzheimer disease and associated with mutation status. Acta Neuropathol. 131, 925–933 (2016).",{"doi":3601},"10.1007\u002Fs00401-016-1533-5",{"id":24,"text":3603,"url":24,"identifiers":3604},"Heslegrave, A. et al. Increased cerebrospinal fluid soluble TREM2 concentration in Alzheimer’s disease. Mol. Neurodegener. 11, 3 (2016).",{"doi":3605},"10.1186\u002Fs13024-016-0071-x",{"id":24,"text":3607,"url":24,"identifiers":3608},"Suarez-Calvet, M. et al. Early changes in CSF sTREM2 in dominantly inherited Alzheimer’s disease occur after amyloid deposition and neuronal injury. Sci. Transl Med. 8, 369ra178 (2016).",{"doi":3609},"10.1126\u002Fscitranslmed.aag1767",{"id":24,"text":3611,"url":24,"identifiers":3612},"Henjum, K. et al. Cerebrospinal fluid soluble TREM2 in aging and Alzheimer’s disease. Alzheimers Res. Ther. 8, 17 (2016).",{"doi":3613},"10.1186\u002Fs13195-016-0182-1",{"id":24,"text":3615,"url":24,"identifiers":3616},"Voytyuk, I., De Strooper, B. & Chavez-Gutierrez, L. Modulation of γ- and β-secretases as early prevention against Alzheimer’s disease. Biol. Psychiatry 83, 320–327 (2018).",{"doi":3617},"10.1016\u002Fj.biopsych.2017.08.001",{"id":24,"text":3619,"url":24,"identifiers":3620},"van Dyck, C. H. Anti-amyloid-beta monoclonal antibodies for Alzheimer’s disease: pitfalls and promise. Biol. Psychiatry 83, 311–319 (2018).",{"doi":3621},"10.1016\u002Fj.biopsych.2017.08.010",{"id":24,"text":3623,"url":24,"identifiers":3624},"Strittmatter, S. M. Emerging mechanisms in Alzheimer’s disease and their therapeutic implications. Biol. Psychiatry 83, 298–299 (2018).",{"doi":3625},"10.1016\u002Fj.biopsych.2017.12.002",{"id":24,"text":3627,"url":24,"identifiers":3628},"Griciuc, A. et al. Alzheimer’s disease risk gene CD33 inhibits microglial uptake of amyloid beta. Neuron 78, 631–643 (2013).",{"doi":3629},"10.1016\u002Fj.neuron.2013.04.014",{"id":24,"text":3631,"url":24,"identifiers":3632},"Spangenberg, E. E. et al. Eliminating microglia in Alzheimer’s mice prevents neuronal loss without modulating amyloid-beta pathology. 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J. J. (Ed.) Neurology of the Newborn (Saunders, Philadelphia, 2001).",{},{"id":24,"text":3740,"url":24,"identifiers":3741},"Volpe, J. J. Brain injury in premature infants: a complex amalgam of destructive and developmental disturbances. Lancet Neurol. 8, 110–124 (2009).",{"doi":3742},"10.1016\u002FS1474-4422(08)70294-1",{"id":24,"text":3744,"url":24,"identifiers":3745},"Pleasure, D., Soulika, A., Singh, S. K., Gallo, V. & Bannerman, P. Inflammation in white matter: clinical and pathophysiological aspects. Ment. Retard. Dev. Disabil. Res. Rev. 12, 141–146 (2006).",{"doi":3746},"10.1002\u002Fmrdd.20100",{"id":24,"text":3748,"url":24,"identifiers":3749},"Deng, W., Pleasure, J. & Pleasure, D. Progress in periventricular leukomalacia. Arch. Neurol. 65, 1291–1295 (2008).",{"doi":3750},"10.1001\u002Farchneur.65.10.1291",{"id":24,"text":3752,"url":24,"identifiers":3753},"Inder, T. E.  et al. Periventricular white matter injury in the premature infant is followed by reduced cerebral cortical gray matter volume at term. Ann. Neurol. 46, 755–760 (1999).",{"doi":3754},"10.1002\u002F1531-8249(199911)46:5\u003C755::AID-ANA11>3.0.CO;2-0",{"id":24,"text":3756,"url":24,"identifiers":3757},"Inder, T. E., Wells, S. J., Mogridge, N. B., Spencer, C. & Volpe, J. J. Defining the nature of the cerebral abnormalities in the premature infant: a qualitative magnetic resonance imaging study. J. Pediatr. 143, 171–179 (2003).",{"doi":3758},"10.1067\u002FS0022-3476(03)00357-3",{"id":24,"text":3760,"url":24,"identifiers":3761},"Sizonenko, S. V.  et al. Selective cortical alteration after hypoxic-ischemic injury in the very immature rat brain. Pediatr. Res. 54, 263–269 (2003).",{"doi":3762},"10.1203\u002F01.PDR.0000072517.01207.87",{"id":24,"text":3764,"url":24,"identifiers":3765},"Nagae, L. M.  et al. Diffusion tensor imaging in children with periventricular leukomalacia: variability of injuries to white matter tracts. AJNR Am. J. Neuroradiol. 28, 1213–1222 (2007).",{"doi":3766},"10.3174\u002Fajnr.A0534",{"id":24,"text":3768,"url":24,"identifiers":3769},"Neil, J., Miller, J., Mukherjee, P. & Huppi, P. S. Diffusion tensor imaging of normal and injured developing human brain—a technical review. NMR Biomed. 15, 543–552 (2002).",{"doi":3770},"10.1002\u002Fnbm.784",{"id":24,"text":3772,"url":24,"identifiers":3773},"Larroque, B.  et al. Neurodevelopmental disabilities and special care of 5-year-old children born before 33 weeks of gestation (the EPIPAGE study): a longitudinal cohort study. Lancet 371, 813–820 (2008).",{"doi":3774},"10.1016\u002FS0140-6736(08)60380-3",{"id":24,"text":3776,"url":24,"identifiers":3777},"Banker, B. Q. & Larroche, J. C. Periventricular leukomalacia of infancy. A form of neonatal anoxic encephalopathy. Arch. Neurol. 7, 386–410 (1962).",{"doi":3778},"10.1001\u002Farchneur.1962.04210050022004",{"id":24,"text":3780,"url":24,"identifiers":3781},"Leviton, A. & Gilles, F. H. Acquired perinatal leukoencephalopathy. Ann. Neurol. 16, 1–8 (1984).",{"doi":3782},"10.1002\u002Fana.410160102",{"id":24,"text":3784,"url":24,"identifiers":3785},"Follett, P. L.  et al. Glutamate receptor-mediated oligodendrocyte toxicity in periventricular leukomalacia: a protective role for topiramate. J. Neurosci. 24, 4412–4420 (2004).",{"doi":3786},"10.1523\u002FJNEUROSCI.0477-04.2004",{"id":24,"text":3788,"url":24,"identifiers":3789},"Follett, P. L., Rosenberg, P. A., Volpe, J. J. & Jensen, F. E. NBQX attenuates excitotoxic injury in developing white matter. J. Neurosci. 20, 9235–9241 (2000).",{"doi":3790},"10.1523\u002FJNEUROSCI.20-24-09235.2000",{"id":24,"text":3792,"url":24,"identifiers":3793},"Jensen, F. E. Developmental factors regulating susceptibility to perinatal brain injury and seizures. Curr. Opin. Pediatr. 18, 628–633 (2006).",{"doi":3794},"10.1097\u002FMOP.0b013e328010c536",{"id":24,"text":3796,"url":24,"identifiers":3797},"Sizonenko, S. V., Kiss, J. Z., Inder, T., Gluckman, P. D. & Williams, C. E. Distinctive neuropathologic alterations in the deep layers of the parietal cortex after moderate ischemic-hypoxic injury in the P3 immature rat brain. Pediatr. Res. 57, 865–872 (2005).",{"doi":3798},"10.1203\u002F01.PDR.0000157673.36848.67",{"id":24,"text":3800,"url":24,"identifiers":3801},"Bemelmans, A. P.  et al. Lentiviral-mediated gene transfer of brain-derived neurotrophic factor is neuroprotective in a mouse model of neonatal excitotoxic challenge. J. Neurosci. Res. 83, 50–60 (2006).",{"doi":3802},"10.1002\u002Fjnr.20704",{"id":24,"text":3804,"url":24,"identifiers":3805},"Carpentier, P. A., Duncan, D. S. & Miller, S. D. Glial toll-like receptor signaling in central nervous system infection and autoimmunity. Brain Behav. Immun. 22, 140–147 (2008).",{"doi":3806},"10.1016\u002Fj.bbi.2007.08.011",{"id":24,"text":3808,"url":24,"identifiers":3809},"Coban, C.  et al. Pathological role of Toll-like receptor signaling in cerebral malaria. Int. Immunol. 19, 67–79 (2007).",{"doi":3810},"10.1093\u002Fintimm\u002Fdxl123",{"id":24,"text":3812,"url":24,"identifiers":3813},"Jung, D. Y.  et al. TLR4, but not TLR2, signals autoregulatory apoptosis of cultured microglia: a critical role of IFN-β as a decision maker. J. Immunol. 174, 6467–6476 (2005).",{"doi":3814},"10.4049\u002Fjimmunol.174.10.6467",{"id":24,"text":3816,"url":24,"identifiers":3817},"Lee, S. J. & Lee, S. Toll-like receptors and inflammation in the CNS. Curr. Drug Targets Inflamm. Allergy 1, 181–191 (2002).",{"doi":3818},"10.2174\u002F1568010023344698",{"id":24,"text":3820,"url":24,"identifiers":3821},"Jack, C. S.  et al. TLR signaling tailors innate immune responses in human microglia and astrocytes. J. Immunol. 175, 4320–4330 (2005).",{"doi":3822},"10.4049\u002Fjimmunol.175.7.4320",{"id":24,"text":3824,"url":24,"identifiers":3825},"Esen, N. & Kielian, T. Central role for MyD88 in the responses of microglia to pathogen-associated molecular patterns. J. Immunol. 176, 6802–6811 (2006).",{"doi":3826},"10.4049\u002Fjimmunol.176.11.6802",{"id":24,"text":3828,"url":24,"identifiers":3829},"Griffiths, M., Neal, J. W. & Gasque, P. Innate immunity and protective neuroinflammation: new emphasis on the role of neuroimmune regulatory proteins. Int. Rev. Neurobiol. 82, 29–55 (2007).",{"doi":3830},"10.1016\u002FS0074-7742(07)82002-2",{"id":24,"text":3832,"url":24,"identifiers":3833},"Nakanishi, K., Yoshimoto, T., Tsutsui, H. & Okamura, H. Interleukin-18 regulates both Th1 and Th2 responses. Annu. Rev. Immunol. 19, 423–474 (2001).",{"doi":3834},"10.1146\u002Fannurev.immunol.19.1.423",{"id":24,"text":3836,"url":24,"identifiers":3837},"Lehnardt, S.  et al. The toll-like receptor TLR4 is necessary for lipopolysaccharide-induced oligodendrocyte injury in the CNS. J. Neurosci. 22, 2478–2486 (2002).",{"doi":3838},"10.1523\u002FJNEUROSCI.22-07-02478.2002",{"id":24,"text":3840,"url":24,"identifiers":3841},"Coumans, A. B.  et al. Intracisternal application of endotoxin enhances the susceptibility to subsequent hypoxic-ischemic brain damage in neonatal rats. Pediatr. Res. 53, 770–775 (2003).",{"doi":3842},"10.1203\u002F01.PDR.0000059221.40073.82",{"id":24,"text":3844,"url":24,"identifiers":3845},"Volpe, J. J. Cerebral white matter injury of the premature infant—more common than you think. Pediatrics 112, 176–180 (2003).",{"doi":3846},"10.1542\u002Fpeds.112.1.176",{"id":24,"text":3848,"url":24,"identifiers":3849},"Vollmer, B.  et al. Predictors of long-term outcome in very preterm infants: gestational age versus neonatal cranial ultrasound. Pediatrics 112, 1108–1114 (2003).",{"doi":3850},"10.1542\u002Fpeds.112.5.1108",{"id":24,"text":3852,"url":24,"identifiers":3853},"Raff, M. C., Miller, R. H. & Noble, M. A glial progenitor cell that develops in vitro into an astrocyte or an oligodendrocyte depending on culture medium. Nature 303, 390–396 (1983).",{"doi":3854},"10.1038\u002F303390a0",{"id":24,"text":3856,"url":24,"identifiers":3857},"Pfeiffer, S. E., Warrington, A. E. & Bansal, R. The oligodendrocyte and its many cellular processes. Trends Cell Biol. 3, 191–197 (1993).",{"doi":3858},"10.1016\u002F0962-8924(93)90213-K",{"id":24,"text":3860,"url":24,"identifiers":3861},"Levine, J. M., Reynolds, R. & Fawcett, J. W. The oligodendrocyte precursor cell in health and disease. Trends Neurosci. 24, 39–47 (2001).",{"doi":3862},"10.1016\u002FS0166-2236(00)01691-X",{"id":24,"text":3864,"url":24,"identifiers":3865},"Deng, W. & Poretz, R. D. Oligodendroglia in developmental neurotoxicity. Neurotoxicology 24, 161–178 (2003).",{"doi":3866},"10.1016\u002FS0161-813X(02)00196-1",{"id":24,"text":3868,"url":24,"identifiers":3869},"Back, S. A.  et al. Late oligodendrocyte progenitors coincide with the developmental window of vulnerability for human perinatal white matter injury. J. Neurosci. 21, 1302–1312 (2001).",{"doi":3870},"10.1523\u002FJNEUROSCI.21-04-01302.2001",{"id":24,"text":3872,"url":24,"identifiers":3873},"Kinney, H. C. & Back, S. A. Human oligodendroglial development: relationship to periventricular leukomalacia. Semin. Pediatr. Neurol. 5, 180–189 (1998).",{"doi":3874},"10.1016\u002FS1071-9091(98)80033-8",{"id":24,"text":3876,"url":24,"identifiers":3877},"Sizonenko, S. V., Camm, E. J., Dayer, A. & Kiss, J. Z. Glial responses to neonatal hypoxic-ischemic injury in the rat cerebral cortex. Int. J. Dev. Neurosci. 26, 37–45 (2008).",{"doi":3878},"10.1016\u002Fj.ijdevneu.2007.08.014",{"id":24,"text":3880,"url":24,"identifiers":3881},"Juurlink, B. H. Response of glial cells to ischemia: roles of reactive oxygen species and glutathione. Neurosci. Biobehav. Rev. 21, 151–166 (1997).",{"doi":3882},"10.1016\u002FS0149-7634(96)00005-X",{"id":24,"text":3884,"url":24,"identifiers":3885},"Folkerth, R. D.  et al. Developmental lag in superoxide dismutases relative to other antioxidant enzymes in premyelinated human telencephalic white matter. J. Neuropathol. Exp. Neurol. 63, 990–999 (2004).",{"doi":3886},"10.1093\u002Fjnen\u002F63.9.990",{"id":24,"text":3888,"url":24,"identifiers":3889},"Li, J.  et al. Tumor necrosis factor alpha mediates lipopolysaccharide-induced microglial toxicity to developing oligodendrocytes when astrocytes are present. J. Neurosci. 28, 5321–5330 (2008).",{"doi":3890},"10.1523\u002FJNEUROSCI.3995-07.2008",{"id":24,"text":3892,"url":24,"identifiers":3893},"Oka, A., Belliveau, M. J., Rosenberg, P. A. & Volpe, J. J. Vulnerability of oligodendroglia to glutamate: pharmacology, mechanisms, and prevention. J. Neurosci. 13, 1441–1453 (1993).",{"doi":3894},"10.1523\u002FJNEUROSCI.13-04-01441.1993",{"id":24,"text":3896,"url":24,"identifiers":3897},"DeSilva, T. M., Kabakov, A. Y., Goldhoff, P. E., Volpe, J. J. & Rosenberg, P. A. Regulation of glutamate transport in developing rat oligodendrocytes. J. Neurosci. 29, 7898–7908 (2009).",{"doi":3898},"10.1523\u002FJNEUROSCI.6129-08.2009",{"id":24,"text":3900,"url":24,"identifiers":3901},"Back, S. A.  et al. Hypoxia-ischemia preferentially triggers glutamate depletion from oligodendroglia and axons in perinatal cerebral white matter. J. Cereb. Blood Flow Metab. 27, 334–347 (2007).",{"doi":3902},"10.1038\u002Fsj.jcbfm.9600344",{"id":24,"text":3904,"url":24,"identifiers":3905},"Desilva, T. M.  et al. The glutamate transporter EAAT2 is transiently expressed in developing human cerebral white matter. J. Comp. Neurol. 501, 879–890 (2007).",{"doi":3906},"10.1002\u002Fcne.21289",{"id":24,"text":3908,"url":24,"identifiers":3909},"Deng, W., Rosenberg, P. A., Volpe, J. J. & Jensen, F. E. Calcium-permeable AMPA\u002Fkainate receptors mediate toxicity and preconditioning by oxygen-glucose deprivation in oligodendrocyte precursors. Proc. Natl Acad. Sci. USA 100, 6801–6806 (2003).",{"doi":3910},"10.1073\u002Fpnas.1136624100",{"id":24,"text":3912,"url":24,"identifiers":3913},"Patneau, D. K., Wright, P. W., Winters, C., Mayer, M. L. & Gallo, V. Glial cells of the oligodendrocyte lineage express both kainate- and AMPA-preferring subtypes of glutamate receptor. Neuron 12, 357–371 (1994).",{"doi":3914},"10.1016\u002F0896-6273(94)90277-1",{"id":24,"text":3916,"url":24,"identifiers":3917},"Gallo, V. & Ghiani, C. A. Glutamate receptors in glia: new cells, new inputs and new functions. Trends Pharmacol. Sci. 21, 252–258 (2000).",{"doi":3918},"10.1016\u002FS0165-6147(00)01494-2",{"id":24,"text":3920,"url":24,"identifiers":3921},"Alberdi, E., Sanchez-Gomez, M. V., Marino, A. & Matute, C. Ca2+ influx through AMPA or kainate receptors alone is sufficient to initiate excitotoxicity in cultured oligodendrocytes. Neurobiol. Dis. 9, 234–243 (2002).",{"doi":3922},"10.1006\u002Fnbdi.2001.0457",{"id":24,"text":3924,"url":24,"identifiers":3925},"Sánchez-Gómez, M. V. & Matute, C. AMPA and kainate receptors each mediate excitotoxicity in oligodendroglial cultures. Neurobiol. Dis. 6, 475–485 (1999).",{"doi":3926},"10.1006\u002Fnbdi.1999.0264",{"id":24,"text":3928,"url":24,"identifiers":3929},"Karadottir, R., Cavelier, P., Bergersen, L. H. & Attwell, D. NMDA receptors are expressed in oligodendrocytes and activated in ischaemia. Nature 438, 1162–1166 (2005).",{"doi":3930},"10.1038\u002Fnature04302",{"id":24,"text":3932,"url":24,"identifiers":3933},"Salter, M. G. & Fern, R. NMDA receptors are expressed in developing oligodendrocyte processes and mediate injury. Nature 438, 1167–1171 (2005).",{"doi":3934},"10.1038\u002Fnature04301",{"id":24,"text":3936,"url":24,"identifiers":3937},"Micu, I.  et al. NMDA receptors mediate calcium accumulation in myelin during chemical ischaemia. Nature 439, 988–992 (2006).",{"doi":3938},"10.1038\u002Fnature04474",{"id":24,"text":3940,"url":24,"identifiers":3941},"Bergles, D. E., Roberts, J. D., Somogyi, P. & Jahr, C. E. Glutamatergic synapses on oligodendrocyte precursor cells in the hippocampus. Nature 405, 187–191 (2000).",{"doi":3942},"10.1038\u002F35012083",{"id":24,"text":3944,"url":24,"identifiers":3945},"Ge, W. P.  et al. Long-term potentiation of neuron–glia synapses mediated by Ca2+-permeable AMPA receptors. Science 312, 1533–1537 (2006).",{"doi":3946},"10.1126\u002Fscience.1124669",{"id":24,"text":3948,"url":24,"identifiers":3949},"Pende, M.  et al. Neurotransmitter- and growth factor-induced cAMP response element binding protein phosphorylation in glial cell progenitors: role of calcium ions, protein kinase C, and mitogen-activated protein kinase\u002Fribosomal S6 kinase pathway. J. Neurosci. 17, 1291–1301 (1997).",{"doi":3950},"10.1523\u002FJNEUROSCI.17-04-01291.1997",{"id":24,"text":3952,"url":24,"identifiers":3953},"Yuan, X., Eisen, A. M., McBain, C. J. & Gallo, V. A role for glutamate and its receptors in the regulation of oligodendrocyte development in cerebellar tissue slices. Development 125, 2901–2914 (1998).",{"doi":3954},"10.1242\u002Fdev.125.15.2901",{"id":24,"text":3956,"url":24,"identifiers":3957},"Kukley, M., Capetillo-Zarate, E. & Dietrich, D. Vesicular glutamate release from axons in white matter. Nat. Neurosci. 10, 311–320 (2007).",{"doi":3958},"10.1038\u002Fnn1850",{"id":24,"text":3960,"url":24,"identifiers":3961},"Ziskin, J. L., Nishiyama, A., Rubio, M., Fukaya, M. & Bergles, D. E. Vesicular release of glutamate from unmyelinated axons in white matter. Nat. Neurosci. 10, 321–330 (2007).",{"doi":3962},"10.1038\u002Fnn1854",{"id":24,"text":3964,"url":24,"identifiers":3965},"Lehnardt, S.  et al. Activation of innate immunity in the CNS triggers neurodegeneration through a Toll-like receptor 4-dependent pathway. Proc. Natl Acad. Sci. USA 100, 8514–8519 (2003).",{"doi":3966},"10.1073\u002Fpnas.1432609100",{"id":24,"text":3968,"url":24,"identifiers":3969},"Kauppinen, T. M. & Swanson, R. A. The role of poly(ADP-ribose) polymerase-1 in CNS disease. Neuroscience 145, 1267–1272 (2007).",{"doi":3970},"10.1016\u002Fj.neuroscience.2006.09.034",{"id":24,"text":3972,"url":24,"identifiers":3973},"Butovsky, O.  et al. Induction and blockage of oligodendrogenesis by differently activated microglia in an animal model of multiple sclerosis. J. Clin. Invest. 116, 905–915 (2006).",{"doi":3974},"10.1172\u002FJCI26836",{"id":24,"text":3976,"url":24,"identifiers":3977},"Kim, S. S.  et al. Inhibitory action of minocycline on lipopolysaccharide-induced release of nitric oxide and prostaglandin E2 in BV2 microglial cells. Arch. Pharm. Res. 27, 314–318 (2004).",{"doi":3978},"10.1007\u002FBF02980066",{"id":24,"text":3980,"url":24,"identifiers":3981},"Pitt, D., Nagelmeier, I. E., Wilson, H. C. & Raine, C. S. Glutamate uptake by oligodendrocytes: implications for excitotoxicity in multiple sclerosis. Neurology 61, 1113–1120 (2003).",{"doi":3982},"10.1212\u002F01.WNL.0000090564.88719.37",{"id":24,"text":3984,"url":24,"identifiers":3985},"Billiards, S. S.  et al. Development of microglia in the cerebral white matter of the human fetus and infant. J. Comp. Neurol. 497, 199–208 (2006).",{"doi":3986},"10.1002\u002Fcne.20991",{"id":24,"text":3988,"url":24,"identifiers":3989},"Takahashi, J. L., Giuliani, F., Power, C., Imai, Y. & Yong, V. W. Interleukin-1beta promotes oligodendrocyte death through glutamate excitotoxicity. Ann. Neurol. 53, 588–595 (2003).",{"doi":3990},"10.1002\u002Fana.10519",{"id":24,"text":3992,"url":24,"identifiers":3993},"Wender, R.  et al. Astrocytic glycogen influences axon function and survival during glucose deprivation in central white matter. J. Neurosci. 20, 6804–6810 (2000).",{"doi":3994},"10.1523\u002FJNEUROSCI.20-18-06804.2000",{"id":24,"text":3996,"url":24,"identifiers":3997},"McQuillen, P. S. & Ferriero, D. M. Perinatal subplate neuron injury: implications for cortical development and plasticity. Brain Pathol. 15, 250–260 (2005).",{"doi":3998},"10.1111\u002Fj.1750-3639.2005.tb00528.x",{"id":24,"text":4000,"url":24,"identifiers":4001},"Gressens, P. Mechanisms and disturbances of neuronal migration. Pediatr. Res. 48, 725–730 (2000).",{"doi":4002},"10.1203\u002F00006450-200012000-00004",{"id":24,"text":4004,"url":24,"identifiers":4005},"Kostovic, I. & Rakic, P. Developmental history of the transient subplate zone in the visual and somatosensory cortex of the macaque monkey and human brain. J. Comp. Neurol. 297, 441–470 (1990).",{"doi":4006},"10.1002\u002Fcne.902970309",{"id":24,"text":4008,"url":24,"identifiers":4009},"McQuillen, P. S., Sheldon, R. A., Shatz, C. J. & Ferriero, D. M. Selective vulnerability of subplate neurons after early neonatal hypoxia-ischemia. J. Neurosci. 23, 3308–3315 (2003).",{"doi":4010},"10.1523\u002FJNEUROSCI.23-08-03308.2003",{"id":24,"text":4012,"url":24,"identifiers":4013},"Hanganu, I. L., Kilb, W. & Luhmann, H. J. Functional synaptic projections onto subplate neurons in neonatal rat somatosensory cortex. J. Neurosci. 22, 7165–7176 (2002).",{"doi":4014},"10.1523\u002FJNEUROSCI.22-16-07165.2002",{"id":24,"text":4016,"url":24,"identifiers":4017},"Nguyen, V. & McQuillen, P. S. AMPA and metabotropic excitoxicity explain subplate neuron vulnerability. Neurobiol. Dis. 37, 195–207 (2010).",{"doi":4018},"10.1016\u002Fj.nbd.2009.10.002",{"id":24,"text":4020,"url":24,"identifiers":4021},"Weiss, J.  et al. Neonatal hypoxia suppresses oligodendrocyte Nogo-A and increases axonal sprouting in a rodent model for human prematurity. Exp. Neurol. 189, 141–149 (2004).",{"doi":4022},"10.1016\u002Fj.expneurol.2004.05.018",{"id":24,"text":4024,"url":24,"identifiers":4025},"Ligam, P.  et al. Thalamic damage in periventricular leukomalacia: novel pathologic observations relevant to cognitive deficits in survivors of prematurity. Pediatr. Res. 65, 524–529 (2009).",{"doi":4026},"10.1203\u002FPDR.0b013e3181998baf",{"id":24,"text":4028,"url":24,"identifiers":4029},"Pendlebury, S. T., Blamire, A. M., Lee, M. A., Styles, P. & Matthews, P. M. Axonal injury in the internal capsule correlates with motor impairment after stroke. Stroke 30, 956–962 (1999).",{"doi":4030},"10.1161\u002F01.STR.30.5.956",{"id":24,"text":4032,"url":24,"identifiers":4033},"Manning, S. M.  et al. NMDA receptor blockade with memantine attenuates white matter injury in a rat model of periventricular leukomalacia. J. Neurosci. 28, 6670–6678 (2008).",{"doi":4034},"10.1523\u002FJNEUROSCI.1702-08.2008",{"id":24,"text":4036,"url":24,"identifiers":4037},"Deng, W., Wang, H., Rosenberg, P. A., Volpe, J. J. & Jensen, F. E. Role of metabotropic glutamate receptors in oligodendrocyte excitotoxicity and oxidative stress. Proc. Natl Acad. Sci. USA 101, 7751–7756 (2004).",{"doi":4038},"10.1073\u002Fpnas.0307850101",{"id":24,"text":4040,"url":24,"identifiers":4041},"Keller, M.  et al. Erythropoietin is neuroprotective against NMDA-receptor-mediated excitotoxic brain injury in newborn mice. Neurobiol. Dis. 24, 357–366 (2006).",{"doi":4042},"10.1016\u002Fj.nbd.2006.07.007",{"id":24,"text":4044,"url":24,"identifiers":4045},"Sakanaka, M.  et al. In vivo evidence that erythropoietin protects neurons from ischemic damage. Proc. Natl Acad. Sci. USA 95, 4635–4640 (1998).",{"doi":4046},"10.1073\u002Fpnas.95.8.4635",{"id":24,"text":4048,"url":24,"identifiers":4049},"Kumral, A.  et al. Neuroprotective effect of erythropoietin on hypoxic-ischemic brain injury in neonatal rats. Biol. Neonate 83, 224–228 (2003).",{"doi":4050},"10.1159\u002F000068926",{"id":24,"text":4052,"url":24,"identifiers":4053},"Sola, A., Rogido, M., Lee, B. H., Genetta, T. & Wen, T. C. Erythropoietin after focal cerebral ischemia activates the Janus kinase-signal transducer and activator of transcription signaling pathway and improves brain injury in postnatal day 7 rats. Pediatr. Res. 57, 481–487 (2005).",{"doi":4054},"10.1203\u002F01.PDR.0000155760.88664.06",{"id":24,"text":4056,"url":24,"identifiers":4057},"Chang, Y. S.  et al. Erythropoietin improves functional and histological outcome in neonatal stroke. Pediatr. Res. 58, 106–111 (2005).",{"doi":4058},"10.1203\u002F01.PDR.0000163616.89767.69",{"id":24,"text":4060,"url":24,"identifiers":4061},"Yatsiv, I.  et al. Erythropoietin is neuroprotective, improves functional recovery, and reduces neuronal apoptosis and inflammation in a rodent model of experimental closed head injury. FASEB J. 19, 1701–1703 (2005).",{"doi":4062},"10.1096\u002Ffj.05-3907fje",{"id":24,"text":4064,"url":24,"identifiers":4065},"Arvin, K. L.  et al. Minocycline markedly protects the neonatal brain against hypoxic-ischemic injury. Ann. Neurol. 52, 54–61 (2002).",{"doi":4066},"10.1002\u002Fana.10242",{"id":24,"text":4068,"url":24,"identifiers":4069},"Amin, A. R.  et al. A novel mechanism of action of tetracyclines: effects on nitric oxide synthases. Proc. Natl Acad. Sci. USA 93, 14014–14019 (1996).",{"doi":4070},"10.1073\u002Fpnas.93.24.14014",{"id":24,"text":4072,"url":24,"identifiers":4073},"Brundula, V., Rewcastle, N. B., Metz, L. M., Bernard, C. C. & Yong, V. W. Targeting leukocyte MMPs and transmigration: minocycline as a potential therapy for multiple sclerosis. Brain 125, 1297–1308 (2002).",{"doi":4074},"10.1093\u002Fbrain\u002Fawf133",{"id":24,"text":4076,"url":24,"identifiers":4077},"Chen, M.  et al. Minocycline inhibits caspase-1 and caspase-3 expression and delays mortality in a transgenic mouse model of Huntington disease. Nat. Med. 6, 797–801 (2000).",{"doi":4078},"10.1038\u002F77528",{"id":24,"text":4080,"url":24,"identifiers":4081},"Diguet, E.  et al. Neuroprotective agents for clinical trials in Parkinson's disease: a systematic assessment. Neurology 62, 158 (2004).",{"doi":4082},"10.1212\u002FWNL.62.1.158",{"id":24,"text":4084,"url":24,"identifiers":4085},"Du, Y.  et al. Minocycline prevents nigrostriatal dopaminergic neurodegeneration in the MPTP model of Parkinson's disease. Proc. Natl Acad. Sci. USA 98, 14669–14674 (2001).",{"doi":4086},"10.1073\u002Fpnas.251341998",{"id":24,"text":4088,"url":24,"identifiers":4089},"Kriz, J., Nguyen, M. D. & Julien, J. P. Minocycline slows disease progression in a mouse model of amyotrophic lateral sclerosis. Neurobiol. Dis. 10, 268–278 (2002).",{"doi":4090},"10.1006\u002Fnbdi.2002.0487",{"id":24,"text":4092,"url":24,"identifiers":4093},"Lee, S. M.  et al. Minocycline reduces cell death and improves functional recovery after traumatic spinal cord injury in the rat. J. Neurotrauma 20, 1017–1027 (2003).",{"doi":4094},"10.1089\u002F089771503770195867",{"id":24,"text":4096,"url":24,"identifiers":4097},"Tikka, T. M.  et al. Minocycline prevents neurotoxicity induced by cerebrospinal fluid from patients with motor neurone disease. Brain 125, 722–731 (2002).",{"doi":4098},"10.1093\u002Fbrain\u002Fawf068",{"id":24,"text":4100,"url":24,"identifiers":4101},"Teng, Y. D.  et al. Minocycline inhibits contusion-triggered mitochondrial cytochrome c release and mitigates functional deficits after spinal cord injury. Proc. Natl Acad. Sci. USA 101, 3071–3076 (2004).",{"doi":4102},"10.1073\u002Fpnas.0306239101",{"id":24,"text":4104,"url":24,"identifiers":4105},"Fan, L. W.  et al. Minocycline reduces lipopolysaccharide-induced neurological dysfunction and brain injury in the neonatal rat. J. Neurosci. Res. 82, 71–82 (2005).",{"doi":4106},"10.1002\u002Fjnr.20623",{"id":24,"text":4108,"url":24,"identifiers":4109},"Cai, Z., Lin, S., Fan, L. W., Pang, Y. & Rhodes, P. G. Minocycline alleviates hypoxic-ischemic injury to developing oligodendrocytes in the neonatal rat brain. Neuroscience 137, 425–435 (2006).",{"doi":4110},"10.1016\u002Fj.neuroscience.2005.09.023",{"id":24,"text":4112,"url":24,"identifiers":4113},"Zhang, K. & Sejnowski, T. J. A universal scaling law between gray matter and white matter of cerebral cortex. Proc. Natl Acad. Sci. USA 97, 5621–5626 (2000).",{"doi":4114},"10.1073\u002Fpnas.090504197",{"id":24,"text":4116,"url":24,"identifiers":4117},"Olney, J. W., Ikonomidou, C., Mosinger, J. L. & Frierdich, G. MK-801 prevents hypobaric-ischemic neuronal degeneration in infant rat brain. J. Neurosci. 9, 1701–1704 (1989).",{"doi":4118},"10.1523\u002FJNEUROSCI.09-05-01701.1989",{"id":24,"text":4120,"url":24,"identifiers":4121},"Rothman, S. M. & Olney, J. W. Glutamate and the pathophysiology of hypoxic–ischemic brain damage. Ann. Neurol. 19, 105–111 (1986).",{"doi":4122},"10.1002\u002Fana.410190202",{"id":24,"text":4124,"url":24,"identifiers":4125},"Lipton, S. A. & Rosenberg, P. A. Excitatory amino acids as a final common pathway for neurologic disorders. N. Engl. J. Med. 330, 613–622 (1994).",{"doi":4126},"10.1056\u002FNEJM199403033300907",{"id":24,"text":4128,"url":24,"identifiers":4129},"Choi, D. W. & Rothman, S. M. The role of glutamate neurotoxicity in hypoxic-ischemic neuronal death. Annu. Rev. Neurosci. 13, 171–182 (1990).",{"doi":4130},"10.1146\u002Fannurev.ne.13.030190.001131",{"id":24,"text":4132,"url":24,"identifiers":4133},"Choi, D. W. Excitotoxic cell death. J. Neurobiol. 23, 1261–1276 (1992).",{"doi":4134},"10.1002\u002Fneu.480230915",{"id":24,"text":4136,"url":24,"identifiers":4137},"Yoshioka, A., Bacskai, B. & Pleasure, D. Pathophysiology of oligodendroglial excitotoxicity. J. Neurosci. Res. 46, 427–437 (1996).",{"doi":4138},"10.1002\u002F(SICI)1097-4547(19961115)46:4\u003C427::AID-JNR4>3.0.CO;2-I",{"id":24,"text":4140,"url":24,"identifiers":4141},"Yoshioka, A.  et al. Non-N-methyl-D-aspartate glutamate receptors mediate oxygen–glucose deprivation-induced oligodendroglial injury. Brain Res. 854, 207–215 (2000).",{"doi":4142},"10.1016\u002FS0006-8993(99)02359-8",{"id":24,"text":4144,"url":24,"identifiers":4145},"Itoh, T.  et al. AMPA glutamate receptor-mediated calcium signaling is transiently enhanced during development of oligodendrocytes. J. Neurochem. 81, 390–402 (2002).",{"doi":4146},"10.1046\u002Fj.1471-4159.2002.00866.x",{"id":24,"text":4148,"url":24,"identifiers":4149},"Itoh, T.  et al. Diminished calcium homeostasis and increased susceptibility to excitotoxicity of JS 3\u002F16 progenitor cells after differentiation to oligodendroglia. Glia 31, 165–180 (2000).",{"doi":4150},"10.1002\u002F1098-1136(200008)31:2\u003C165::AID-GLIA80>3.0.CO;2-#",{"id":24,"text":4152,"url":24,"identifiers":4153},"Matute, C., Sanchéz-Goméz, M. V., Martinez-Millán, L. & Miledi, R. Glutamate receptor-mediated toxicity in optic nerve oligodendrocytes. Proc. Natl Acad. Sci. USA 94, 8830–8835 (1997).",{"doi":4154},"10.1073\u002Fpnas.94.16.8830",{"id":24,"text":4156,"url":24,"identifiers":4157},"McDonald, J. W., Althomsons, S. P., Hyrc, K. L., Choi, D. W. & Goldberg, M. P. Oligodendrocytes from forebrain are highly vulnerable to AMPA\u002Fkainate receptor-mediated excitotoxicity. Nat. Med. 4, 291–297 (1998).",{"doi":4158},"10.1038\u002Fnm0398-291",{"id":24,"text":4160,"url":24,"identifiers":4161},"Fern, R. & Moller, T. Rapid ischemic cell death in immature oligodendrocytes: a fatal glutamate release feedback loop. J. Neurosci. 20, 34–42 (2000).",{"doi":4162},"10.1523\u002FJNEUROSCI.20-01-00034.2000",{"id":24,"text":4164,"url":24,"identifiers":4165},"Baumann, N. & Pham-Dinh, D. Biology of oligodendrocyte and myelin in the mammalian central nervous system. Physiol. Rev. 81, 871–927 (2001).",{"doi":4166},"10.1152\u002Fphysrev.2001.81.2.871",{"id":24,"text":4168,"url":24,"identifiers":4169},"Haynes, R. L.  et al. Oxidative and nitrative injury in periventricular leukomalacia: a review. Brain Pathol. 15, 225–233 (2005).",{"doi":4170},"10.1111\u002Fj.1750-3639.2005.tb00525.x",{"id":24,"text":4172,"url":24,"identifiers":4173},"Haynes, R. L.  et al. Nitrosative and oxidative injury to premyelinating oligodendrocytes in periventricular leukomalacia. J. Neuropathol. Exp. Neurol. 62, 441–450 (2003).",{"doi":4174},"10.1093\u002Fjnen\u002F62.5.441",{"id":24,"text":4176,"url":24,"identifiers":4177},"Dommergues, M. A., Plaisant, F., Verney, C. & Gressens, P. Early microglial activation following neonatal excitotoxic brain damage in mice: a potential target for neuroprotection. Neuroscience 121, 619–628 (2003).",{"doi":4178},"10.1016\u002FS0306-4522(03)00558-X",{"id":24,"text":4180,"url":24,"identifiers":4181},"Noda, M., Nakanishi, H., Nabekura, J. & Akaike, N. AMPA-kainate subtypes of glutamate receptor in rat cerebral microglia. J. Neurosci. 20, 251–258 (2000).",{"doi":4182},"10.1523\u002FJNEUROSCI.20-01-00251.2000",{"id":24,"text":4184,"url":24,"identifiers":4185},"Ivacko, J. A., Sun, R. & Silverstein, F. S. Hypoxic-ischemic brain injury induces an acute microglial reaction in perinatal rats. Pediatr. Res. 39, 39–47 (1996).",{"doi":4186},"10.1203\u002F00006450-199601000-00006",{"id":24,"text":4188,"url":24,"identifiers":4189},"Silverstein, F. S.  et al. Cytokines and perinatal brain injury. Neurochem. Int. 30, 375–383 (1997).",{"doi":4190},"10.1016\u002FS0197-0186(96)00072-1",{"id":24,"text":4192,"url":24,"identifiers":4193},"Debillon, T.  et al. Patterns of cerebral inflammatory response in a rabbit model of intrauterine infection-mediated brain lesion. Brain Res. Dev. Brain Res. 145, 39–48 (2003).",{"doi":4194},"10.1016\u002FS0165-3806(03)00193-7",{"id":24,"text":4196,"url":24,"identifiers":4197},"Debillon, T.  et al. Effect of maternal antibiotic treatment on fetal periventricular white matter cell death in a rabbit intrauterine infection model. Acta Paediatr. 92, 81–86 (2003).",{"doi":4198},"10.1111\u002Fj.1651-2227.2003.tb00474.x",{"id":24,"text":4200,"url":24,"identifiers":4201},"Saliba, E. & Henrot, A. Inflammatory mediators and neonatal brain damage. Biol. Neonate 79, 224–227 (2001).",{"doi":4202},"10.1159\u002F000047096",{"id":24,"text":4204,"url":24,"identifiers":4205},"Park, S. Y., Billiar, T. R. & Seol, D. W. Hypoxia inhibition of apoptosis induced by tumor necrosis factor-related apoptosis-inducing ligand (TRAIL). Biochem. Biophys. Res. Commun. 291, 150–153 (2002).",{"doi":4206},"10.1006\u002Fbbrc.2002.6421",{"id":24,"text":4208,"url":24,"identifiers":4209},"Pang, Y., Cai, Z. & Rhodes, P. G. Disturbance of oligodendrocyte development, hypomyelination and white matter injury in the neonatal rat brain after intracerebral injection of lipopolysaccharide. Brain Res. Dev. Brain Res. 140, 205–214 (2003).",{"doi":4210},"10.1016\u002FS0165-3806(02)00606-5",{"id":24,"text":4212,"url":24,"identifiers":4213},"Hermann, G. E., Rogers, R. C., Bresnahan, J. C. & Beattie, M. S. Tumor necrosis factor-alpha induces cFOS and strongly potentiates glutamate-mediated cell death in the rat spinal cord. Neurobiol. Dis. 8, 590–599 (2001).",{"doi":4214},"10.1006\u002Fnbdi.2001.0414",{"id":24,"text":4216,"url":24,"identifiers":4217},"Barger, S. W. & Basile, A. S. Activation of microglia by secreted amyloid precursor protein evokes release of glutamate by cystine exchange and attenuates synaptic function. J. Neurochem. 76, 846–854 (2001).",{"doi":4218},"10.1046\u002Fj.1471-4159.2001.00075.x",{"id":24,"text":4220,"url":24,"identifiers":4221},"Golde, S., Chandran, S., Brown, G. C. & Compston, A. Different pathways for iNOS-mediated toxicity in vitro dependent on neuronal maturation and NMDA receptor expression. J. Neurochem. 82, 269–282 (2002).",{"doi":4222},"10.1046\u002Fj.1471-4159.2002.00973.x",{"id":24,"text":4224,"url":24,"identifiers":4225},"Murphy, S. Production of nitric oxide by glial cells: regulation and potential roles in the CNS. Glia 29, 1–13 (2000).",{"doi":4226},"10.1002\u002F(SICI)1098-1136(20000101)29:1\u003C1::AID-GLIA1>3.0.CO;2-N",{"id":24,"text":4228,"url":24,"identifiers":4229},"Bernardo, A., Greco, A., Levi, G. & Minghetti, L. 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Neuropathic pain: redefinition and a grading system for clinical and research purposes. Neurology 70, 1630–1635 (2008).",{"doi":4383},"10.1212\u002F01.wnl.0000282763.29778.59",{"id":24,"text":4385,"url":24,"identifiers":4386},"Attal, N., Lanteri-Minet, M., Laurent, B., Fermanian, J. & Bouhassira, D. The specific disease burden of neuropathic pain: results of a French nationwide survey. Pain 152, 2836–2843 (2011).",{"doi":4387},"10.1016\u002Fj.pain.2011.09.014",{"id":24,"text":4389,"url":24,"identifiers":4390},"Bouhassira, D., Lantéri-Minet, M., Attal, N., Laurent, B. & Touboul, C. Prevalence of chronic pain with neuropathic characteristics in the general population. Pain 136, 380–387 (2008).",{"doi":4391},"10.1016\u002Fj.pain.2007.08.013",{"id":24,"text":4393,"url":24,"identifiers":4394},"Attal, N.  et al. Neuropathic pain: are there distinct subtypes depending on the aetiology or anatomical lesion? Pain 138, 343–353 (2008).",{"doi":4395},"10.1016\u002Fj.pain.2008.01.006",{"id":24,"text":4397,"url":24,"identifiers":4398},"Attal, N.  et al. Assessing symptom profiles in neuropathic pain clinical trials: can it improve outcome? Eur. J. Pain 15, 441–443 (2011).",{"doi":4399},"10.1016\u002Fj.ejpain.2011.03.005",{"id":24,"text":4401,"url":24,"identifiers":4402},"Baron, R., Förster, M. & Binder, A. Subgrouping of patients with neuropathic pain according to pain-related sensory abnormalities: a first step to a stratified treatment approach. Lancet Neurol. 11, 999–1005 (2012).",{"doi":4403},"10.1016\u002FS1474-4422(12)70189-8",{"id":24,"text":4405,"url":24,"identifiers":4406},"Garcia-Larrea, L. Objective pain diagnostics: clinical neurophysiology. Neurophysiol. Clin. 42, 187–197 (2012).",{"doi":4407},"10.1016\u002Fj.neucli.2012.03.001",{"id":24,"text":4409,"url":24,"identifiers":4410},"Hansson, P. Difficulties in stratifying neuropathic pain by mechanisms. Eur. J. Pain 7, 353–357 (2003).",{"doi":4411},"10.1016\u002FS1090-3801(03)00051-X",{"id":24,"text":4413,"url":24,"identifiers":4414},"Backonja, M. M.  et al. Quantitative sensory testing in measurement of neuropathic pain phenomena and other sensory abnormalities. Clin. J. Pain 25, 641–647 (2009).",{"doi":4415},"10.1097\u002FAJP.0b013e3181a68c7e",{"id":24,"text":4417,"url":24,"identifiers":4418},"Maier, C.  et al. Quantitative sensory testing in the German Research Network on Neuropathic Pain (DFNS): somatosensory abnormalities in 1236 patients with different neuropathic pain syndromes. Pain 150, 439–450 (2010).",{"doi":4419},"10.1016\u002Fj.pain.2010.05.002",{"id":24,"text":4421,"url":24,"identifiers":4422},"Krumova, E. K., Geber, C., Westermann, A. & Maier, C. Neuropathic pain: is quantitative sensory testing helpful? Curr. Diab. Rep. 12, 393–402 (2012).",{"doi":4423},"10.1007\u002Fs11892-012-0282-7",{"id":24,"text":4425,"url":24,"identifiers":4426},"Tesfaye, S.  et al. Diabetic neuropathies: update on definitions, diagnostic criteria, estimation of severity, and treatments. Diabetes Care 33, 2285–2293 (2010).",{"doi":4427},"10.2337\u002Fdc10-1303",{"id":24,"text":4429,"url":24,"identifiers":4430},"Cruccu, G.  et al. EFNS guidelines on neuropathic pain assessment: revised 2009. Eur. J. Neurol. 17, 1010–1018 (2010).",{"doi":4431},"10.1111\u002Fj.1468-1331.2010.02969.x",{"id":24,"text":4433,"url":24,"identifiers":4434},"Shy, M. E.  et al. Quantitative sensory testing: report of the Therapeutics and Technology Assessment Subcommittee of the American Academy of Neurology. Neurology 25, 898–904 (2003).",{"doi":4435},"10.1212\u002F01.WNL.0000058546.16985.11",{"id":24,"text":4437,"url":24,"identifiers":4438},"Ochoa, J. L. & Verdugo, R. J. Neuropathic pain syndrome displayed by malingerers. J. Neuropsychiatry Clin. Neurosci. 22, 278–286 (2010).",{"doi":4439},"10.1176\u002Fjnp.2010.22.3.278",{"id":24,"text":4441,"url":24,"identifiers":4442},"Cruccu, G.  et al. Recommendations for the clinical use of somatosensory-evoked potentials. Clin. Neurophysiol. 119, 1705–1719 (2008).",{"doi":4443},"10.1016\u002Fj.clinph.2008.03.016",{"id":24,"text":4445,"url":24,"identifiers":4446},"Cruccu, G.  et al. AAN–EFNS guidelines on trigeminal neuralgia management. Eur. J. Neurol. 15, 1013–1028 (2008).",{"doi":4447},"10.1111\u002Fj.1468-1331.2008.02185.x",{"id":24,"text":4449,"url":24,"identifiers":4450},"Garcia-Larrea, L.  et al. Laser-evoked potential abnormalities in central pain patients: the influence of spontaneous and provoked pain. Brain 125, 2766–2781 (2002).",{"doi":4451},"10.1093\u002Fbrain\u002Fawf275",{"id":24,"text":4453,"url":24,"identifiers":4454},"Truini, A.  et al. Mechanisms of pain in distal symmetric polyneuropathy: a combined clinical and neurophysiological study. Pain 150, 516–521 (2010).",{"doi":4455},"10.1016\u002Fj.pain.2010.06.006",{"id":24,"text":4457,"url":24,"identifiers":4458},"Truini, A.  et al. Differential involvement of A-delta and A-beta fibres in neuropathic pain related to carpal tunnel syndrome. Pain 145, 105–109 (2009).",{"doi":4459},"10.1016\u002Fj.pain.2009.05.023",{"id":24,"text":4461,"url":24,"identifiers":4462},"Truini, A.  et al. Mechanisms of pain in multiple sclerosis: a combined clinical and neurophysiological study. Pain 153, 2048–2054 (2012).",{"doi":4463},"10.1016\u002Fj.pain.2012.05.024",{"id":24,"text":4465,"url":24,"identifiers":4466},"Truini, A.  et al. Pathophysiology of pain in postherpetic neuralgia: a clinical and neurophysiological study. Pain 140, 405–410 (2008).",{"doi":4467},"10.1016\u002Fj.pain.2008.08.018",{"id":24,"text":4469,"url":24,"identifiers":4470},"Leandri, M.  et al. Measurement of skin temperature after infrared laser stimulation. Neurophysiol. Clin. 36, 207–218 (2006).",{"doi":4471},"10.1016\u002Fj.neucli.2006.08.004",{"id":24,"text":4473,"url":24,"identifiers":4474},"Treede, R. D., Meyer, R. A., Raja, S. N. & Campbell, J. N. Evidence for two different heat transduction mechanisms in nociceptive primary afferents innervating monkey skin. J. Physiol. 15, 747–758 (1995).",{"doi":4475},"10.1113\u002Fjphysiol.1995.sp020619",{"id":24,"text":4477,"url":24,"identifiers":4478},"Perchet, C.  et al. Do we activate specifically somatosensory thin fibres with the concentric planar electrode? A scalp and intracranial EEG study. Pain 153, 1244–1252 (2012).",{"doi":4479},"10.1016\u002Fj.pain.2012.03.004",{"id":24,"text":4481,"url":24,"identifiers":4482},"De Tommaso, M.  et al. A comparative study of cortical responses evoked by transcutaneous electrical vs CO2 laser stimulation. Clin. Neurophysiol. 122, 2482–2487 (2011).",{"doi":4483},"10.1016\u002Fj.clinph.2011.05.006",{"id":24,"text":4485,"url":24,"identifiers":4486},"Jørum, E. & Schmelz, M. Chapter 29. Microneurography in the assessment of neuropathic pain. Handb. Clin. Neurol. 81, 427–438 (2006).",{"doi":4487},"10.1016\u002FS0072-9752(06)80033-3",{"id":24,"text":4489,"url":24,"identifiers":4490},"Serra, J. Re-emerging microneurography. J. Physiol. 15, 295–296 (2009).",{"doi":4491},"10.1113\u002Fjphysiol.2008.167858",{"id":24,"text":4493,"url":24,"identifiers":4494},"Lauria, G.  et al. European Federation of Neurological Societies\u002FPeripheral Nerve Society Guideline on the use of skin biopsy in the diagnosis of small fiber neuropathy. Report of a joint task force of the European Federation of Neurological Societies and the Peripheral Nerve Society. Eur. J. Neurol. 17, 903–912 (2010).",{"doi":4495},"10.1111\u002Fj.1468-1331.2010.03023.x",{"id":24,"text":4497,"url":24,"identifiers":4498},"Vickova-Moravcova, E., Bednarik, J., Belobradkova, J. & Sommer, C. Small-fibre involvement in diabetic patients with neuropathic foot pain. Diabet. Med. 25, 692–699 (2008).",{"doi":4499},"10.1111\u002Fj.1464-5491.2008.02446.x",{"id":24,"text":4501,"url":24,"identifiers":4502},"Pan, C. L.  et al. Cutaneous innervation in Guillain–Barré syndrome: pathology and clinical correlations. Brain 126, 386–397 (2003).",{"doi":4503},"10.1093\u002Fbrain\u002Fawg039",{"id":24,"text":4505,"url":24,"identifiers":4506},"Ragé, M.  et al. The time course of CO2 laser-evoked responses and of skin nerve fibre markers after topical capsaicin in human volunteers. Clin. Neurophysiol. 121, 1256–1266 (2010).",{"doi":4507},"10.1016\u002Fj.clinph.2010.02.159",{"id":24,"text":4509,"url":24,"identifiers":4510},"Marchettini, P. The burning case of neuropathic pain wording. Pain 114, 313–314 (2005).",{"doi":4511},"10.1016\u002Fj.pain.2005.01.016",{"id":24,"text":4513,"url":24,"identifiers":4514},"Bouhassira, D.  et al. Comparison of pain syndromes associated with nervous or somatic lesions and development of a new neuropathic pain diagnostic questionnaire (DN4). Pain 114, 29–36 (2005).",{"doi":4515},"10.1016\u002Fj.pain.2004.12.010",{"id":24,"text":4517,"url":24,"identifiers":4518},"Tasker, R. R., Organ, L. W. & Hawrylyshyn, P. Deafferentation and causalgia. Res. Publ. Assoc. Res. Nerv. Ment. Dis. 58, 305–329 (1980).",{},{"id":24,"text":4520,"url":24,"identifiers":4521},"Djouhri, L., Koutsikou, S., Fang, X., McMullan, S. & Lawson, S. N. Spontaneous pain, both neuropathic and inflammatory, is related to frequency of spontaneous firing in intact C-fiber nociceptors. J. Neurosci. 26, 1281–1292 (2006).",{"doi":4522},"10.1523\u002FJNEUROSCI.3388-05.2006",{"id":24,"text":4524,"url":24,"identifiers":4525},"Costigan, M., Scholz, J. & Woolf, C. J. Neuropathic pain: a maladaptive response of the nervous system to damage. Annu. Rev. Neurosci. 32, 1–32 (2009).",{"doi":4526},"10.1146\u002Fannurev.neuro.051508.135531",{"id":24,"text":4528,"url":24,"identifiers":4529},"Han, H. C., Lee, D. H. & Chung J. M. Characteristics of ectopic discharges in a rat neuropathic pain model. Pain 84, 253–261 (2000).",{"doi":4530},"10.1016\u002FS0304-3959(99)00219-5",{"id":24,"text":4532,"url":24,"identifiers":4533},"Ørstavik, K.  et al. Abnormal function of C-fibers in patients with diabetic neuropathy. J. Neurosci. 26, 11287–11294 (2006).",{"doi":4534},"10.1523\u002FJNEUROSCI.2659-06.2006",{"id":24,"text":4536,"url":24,"identifiers":4537},"Cline, M. A., Ochoa, J. & Torebjörk, H. E. Chronic hyperalgesia and skin warming caused by sensitized C nociceptors. Brain 112, 621–647 (1989).",{"doi":4538},"10.1093\u002Fbrain\u002F112.3.621",{"id":24,"text":4540,"url":24,"identifiers":4541},"Kleggetveit, I. P.  et al. High spontaneous activity of C-nociceptors in painful polyneuropathy. Pain 153, 2040–2047 (2012).",{"doi":4542},"10.1016\u002Fj.pain.2012.05.017",{"id":24,"text":4544,"url":24,"identifiers":4545},"Serra, J. Microneurography: towards a biomarker of spontaneous pain. Pain 153, 1989–1990 (2012).",{"doi":4546},"10.1016\u002Fj.pain.2012.07.008",{"id":24,"text":4548,"url":24,"identifiers":4549},"Ochoa, J. L. Intraneural microstimulation in humans. Neurosci. Lett. 19, 162–167 (2010).",{"doi":4550},"10.1016\u002Fj.neulet.2009.10.007",{"id":24,"text":4552,"url":24,"identifiers":4553},"Casanova-Molla, J., Grau-Junyent, J. M., Morales, M. & Valls-Solé, J. On the relationship between nociceptive evoked potentials and intraepidermal nerve fiber density in painful sensory polyneuropathies. Pain 152, 410–418 (2011).",{"doi":4554},"10.1016\u002Fj.pain.2010.11.012",{"id":24,"text":4556,"url":24,"identifiers":4557},"Lauria, G.  et al. Axonal swellings predict the degeneration of epidermal nerve fibers in painful neuropathies. Neurology 61, 631–636 (2003).",{"doi":4558},"10.1212\u002F01.WNL.0000070781.92512.A4",{"id":24,"text":4560,"url":24,"identifiers":4561},"Amir, R., Kocsis, J. D. & Devor, M. Multiple interacting sites of ectopic spike electrogenesis in primary sensory neurons. J. Neurosci. 25, 2576–2585 (2005).",{"doi":4562},"10.1523\u002FJNEUROSCI.4118-04.2005",{"id":24,"text":4564,"url":24,"identifiers":4565},"Wu, G.  et al. Degeneration of myelinated efferent fibers induces spontaneous activity in uninjured C-fiber afferents. J. Neurosci. 22, 7746–7753 (2002).",{"doi":4566},"10.1523\u002FJNEUROSCI.22-17-07746.2002",{"id":24,"text":4568,"url":24,"identifiers":4569},"Zimmermann, M. Pathobiology of neuropathic pain. Eur. J. Pharmacol. 429, 23–37 (2001).",{"doi":4570},"10.1016\u002FS0014-2999(01)01303-6",{"id":24,"text":4572,"url":24,"identifiers":4573},"Bostock, H., Campero, M., Serra, J. & Ochoa, J. L. Temperature-dependent double spikes in C-nociceptors of neuropathic pain patients. Brain 128, 2154–2163 (2005).",{"doi":4574},"10.1093\u002Fbrain\u002Fawh552",{"id":24,"text":4576,"url":24,"identifiers":4577},"Campbell, J. N. & Meyer, R. A. Mechanisms of neuropathic pain. Neuron 52, 77–92 (2006).",{"doi":4578},"10.1016\u002Fj.neuron.2006.09.021",{"id":24,"text":4580,"url":24,"identifiers":4581},"Fields, H. L., Rowbotham, M. & Baron, R. Postherpetic neuralgia: irritable nociceptors and deafferentation. Neurobiol. Dis. 5, 209–227 (1998).",{"doi":4582},"10.1006\u002Fnbdi.1998.0204",{"id":24,"text":4584,"url":24,"identifiers":4585},"Craner, M. J., Klein, J. P., Renganathan, M., Black, J. A. & Waxman, S. G. Changes of sodium channel expression in experimental painful diabetic neuropathy. Ann. Neurol. 52, 786–792 (2002).",{"doi":4586},"10.1002\u002Fana.10364",{"id":24,"text":4588,"url":24,"identifiers":4589},"Devor, M. Sodium channels and mechanisms of neuropathic pain. J. Pain 7 (Suppl. 1), S3–S12 (2006).",{"doi":4590},"10.1016\u002Fj.jpain.2005.09.006",{"id":24,"text":4592,"url":24,"identifiers":4593},"Sommer, C. Painful neuropathies. Curr. Opin. Neurol. 16, 623–628 (2003).",{"doi":4594},"10.1097\u002F00019052-200310000-00009",{"id":24,"text":4596,"url":24,"identifiers":4597},"Choi, J. S.  et al. Paroxysmal extreme pain disorder: a molecular lesion of peripheral neurons. Nat. Rev. Neurol. 7, 51–55 (2011).",{"doi":4598},"10.1038\u002Fnrneurol.2010.162",{"id":24,"text":4600,"url":24,"identifiers":4601},"Hoeijmakers, J. G., Faber, C. G., Lauria, G., Merkies, I. S. & Waxman, S. G. Small-fibre neuropathies—advances in diagnosis, pathophysiology and management. Nat. Rev. Neurol. 29, 369–379 (2012).",{"doi":4602},"10.1038\u002Fnrneurol.2012.97",{"id":24,"text":4604,"url":24,"identifiers":4605},"Gold, M. S.  et al. Redistribution of NaV1.8 in uninjured axons enables neuropathic pain. J. Neurosci. 23, 158–166 (2003).",{"doi":4606},"10.1523\u002FJNEUROSCI.23-01-00158.2003",{"id":24,"text":4608,"url":24,"identifiers":4609},"Rowbotham, M. C., Davies, P. S. & Fields, H. L. Topical lidocaine gel relieves postherpetic neuralgia. Ann. Neurol. 37, 246–253 (1995).",{"doi":4610},"10.1002\u002Fana.410370216",{"id":24,"text":4612,"url":24,"identifiers":4613},"Rowbotham, M. C., Davies, P. S., Verkempinck, C. & Galer, B. S. Lidocaine patch: double-blind controlled study of a new treatment method for post-herpetic neuralgia. Pain 65, 39–44 (1996).",{"doi":4614},"10.1016\u002F0304-3959(95)00146-8",{"id":24,"text":4616,"url":24,"identifiers":4617},"Devor, M., Govrin-Lippmann, R. & Angelides, K. Na+ channel immunolocalization in peripheral mammalian axons and changes following nerve injury and neuroma formation. J. Neurosci. 13, 1976–1992 (1993).",{"doi":4618},"10.1523\u002FJNEUROSCI.13-05-01976.1993",{"id":24,"text":4620,"url":24,"identifiers":4621},"Yasuda, H.  et al. Diabetic neuropathy and nerve regeneration. Prog. Neurobiol. 69, 229–285 (2003).",{"doi":4622},"10.1016\u002FS0301-0082(03)00034-0",{"id":24,"text":4624,"url":24,"identifiers":4625},"Brown, T. H., Chapman, P. F., Kairiss, E. W. & Keenan, C. L. Long-term synaptic potentiation. Science 4, 724–728 (1988).",{"doi":4626},"10.1126\u002Fscience.2903551",{"id":24,"text":4628,"url":24,"identifiers":4629},"Okuno, H.  et al. Inverse synaptic tagging of inactive synapses via dynamic interaction of Arc\u002FArg3.1 with CaMKIIβ. Cell 149, 886–898 (2012).",{"doi":4630},"10.1016\u002Fj.cell.2012.02.062",{"id":24,"text":4632,"url":24,"identifiers":4633},"Wang, J. H., Ko, G. Y., Kelly, P. T. Cellular and molecular bases of memory: synaptic and neuronal plasticity. J. Clin. Neurophysiol. 14, 264–293 (1997).",{"doi":4634},"10.1097\u002F00004691-199707000-00002",{"id":24,"text":4636,"url":24,"identifiers":4637},"Kurvers, H.  et al. Partial peripheral neuropathy and denervation induced adrenoceptor supersensitivity. Functional studies in an experimental model. J. Acta Orthop. Belg. 64, 64–70 (1998).",{},{"id":24,"text":4639,"url":24,"identifiers":4640},"Fitzek, S.  et al. Mechanisms and predictors of chronic facial pain in lateral medullary infarction. Ann. Neurol. 49, 493–500 (2001).",{"doi":4641},"10.1002\u002Fana.99",{"id":24,"text":4643,"url":24,"identifiers":4644},"Defrin, R., Ohry, A., Blumen, N. & Urca, G. Characterization of chronic pain and somatosensory function in spinal cord injury subjects. Pain 89, 253–263 (2001).",{"doi":4645},"10.1016\u002FS0304-3959(00)00369-9",{"id":24,"text":4647,"url":24,"identifiers":4648},"Hains, B. C., Saab, C. Y. & Waxman, S. G. Changes in electrophysiological properties and sodium channel Nav1.3 expression in thalamic neurons after spinal cord injury. Brain 128, 2359–2371 (2005).",{"doi":4649},"10.1093\u002Fbrain\u002Fawh623",{"id":24,"text":4651,"url":24,"identifiers":4652},"Magnin, M., Morel, A. & Jeanmonod, D. Toward a unified theory of positive symptoms. Neurophysiol. Clin. 35, 154–161 (2005).",{"doi":4653},"10.1016\u002Fj.neucli.2005.12.002",{"id":24,"text":4655,"url":24,"identifiers":4656},"Waxman, S. G. & Hains, B. C. Fire and phantoms after spinal cord injury: Na+ channels and central pain. Trends Neurosci. 29, 207–215 (2006).",{"doi":4657},"10.1016\u002Fj.tins.2006.02.003",{"id":24,"text":4659,"url":24,"identifiers":4660},"Whitt, J. L., Masri, R., Pulimood, N. S. & Keller, A. Pathological activity in mediodorsal thalamus of rats with spinal cord injury pain. J. Neurosci. 33, 3915–3926 (2013).",{"doi":4661},"10.1523\u002FJNEUROSCI.2639-12.2013",{"id":24,"text":4663,"url":24,"identifiers":4664},"Sang, C. N., Gracely, R. H., Max, M. B. & Bennett, G. J. Capsaicin-evoked mechanical allodynia and hyperalgesia cross nerve territories. Evidence for a central mechanism. Anesthesiology 85, 491–496 (1996).",{"doi":4665},"10.1097\u002F00000542-199609000-00007",{"id":24,"text":4667,"url":24,"identifiers":4668},"Zanette, G., Cacciatori, C. & Tamburin, S. Central sensitization in carpal tunnel syndrome with extraterritorial spread of sensory symptoms. Pain 148, 227–236 (2010).",{"doi":4669},"10.1016\u002Fj.pain.2009.10.025",{"id":24,"text":4671,"url":24,"identifiers":4672},"Baron, R. Neuropathic pain—a clinical perspective. Nat. Clin. Pract. Neurol. 2, 95–106 (2006).",{"doi":4673},"10.1038\u002Fncpneuro0113",{"id":24,"text":4675,"url":24,"identifiers":4676},"Ochoa, J., Fowler, T. J. & Gilliatt, R. W. Anatomical changes in peripheral nerves compressed by a pneumatic tourniquet. J. Anat. 113, 433–455 (1972).",{},{"id":24,"text":4678,"url":24,"identifiers":4679},"Cruccu, G.  et al. Trigeminal neuralgia and pain related to multiple sclerosis. Pain 143, 186–191 (2009).",{"doi":4680},"10.1016\u002Fj.pain.2008.12.026",{"id":24,"text":4682,"url":24,"identifiers":4683},"Gass, A.  et al. Trigeminal neuralgia in patients with multiple sclerosis: lesion localization with magnetic resonance imaging. Neurology 49, 1142–1144 (1997).",{"doi":4684},"10.1212\u002FWNL.49.4.1142",{"id":24,"text":4686,"url":24,"identifiers":4687},"Love, S. & Coakham, H. B. Trigeminal neuralgia: pathology and pathogenesis. Brain 124, 2347–2360 (2001).",{"doi":4688},"10.1093\u002Fbrain\u002F124.12.2347",{"id":24,"text":4690,"url":24,"identifiers":4691},"Burchiel, K. J. Ectopic impulse generation in focally demyelinated trigeminal nerve. Exp. Neurol. 69, 423–429 (1980).",{"doi":4692},"10.1016\u002F0014-4886(80)90225-3",{"id":24,"text":4694,"url":24,"identifiers":4695},"Burchiel, K. J. Abnormal impulse generation in focally demyelinated trigeminal roots. J. Neurosurg. 53, 674–683 (1980).",{"doi":4696},"10.3171\u002Fjns.1980.53.5.0674",{"id":24,"text":4698,"url":24,"identifiers":4699},"Kuroki, A. & Møller, A. R. Facial nerve demyelination and vascular compression are both needed to induce facial hyperactivity: a study in rats. Acta Neurochir. (Wien) 126, 149–157 (1994).",{"doi":4700},"10.1007\u002FBF01476426",{"id":24,"text":4702,"url":24,"identifiers":4703},"Valls-Solé, J. Electrodiagnostic studies of the facial nerve in peripheral facial palsy and hemifacial spasm. Muscle Nerve 36, 14–20 (2007).",{"doi":4704},"10.1002\u002Fmus.20770",{"id":24,"text":4706,"url":24,"identifiers":4707},"Valls-Solé, J. Facial palsy, postparalytic facial syndrome, and hemifacial spasm. Mov. Disord. 17 (Suppl. 2), S49–S52 (2002).",{"doi":4708},"10.1002\u002Fmds.10059",{"id":24,"text":4710,"url":24,"identifiers":4711},"Daniele, C. A. & MacDermott, A. B. Low-threshold primary afferent drive onto GABAergic interneurons in the superficial dorsal horn of the mouse. J. Neurosci. 29, 686–695 (2009).",{"doi":4712},"10.1523\u002FJNEUROSCI.5120-08.2009",{"id":24,"text":4714,"url":24,"identifiers":4715},"Liu, X., Eschenfelder, S., Blenk, K. H., Jänig, W. & Häbler, H. Spontaneous activity of axotomized afferent neurons after L5 spinal nerve injury in rats. Pain 84, 309–318 (2000).",{"doi":4716},"10.1016\u002FS0304-3959(99)00211-0",{"id":24,"text":4718,"url":24,"identifiers":4719},"Wallace, V. C., Cottrell, D. F., Brophy, P. J. & Fleetwood-Walker, S. M. Focal lysolecithin-induced demyelination of peripheral afferents results in neuropathic pain behavior that is attenuated by cannabinoids. J. Neurosci. 15, 3221–3233 (2003).",{"doi":4720},"10.1523\u002FJNEUROSCI.23-08-03221.2003",{"id":24,"text":4722,"url":24,"identifiers":4723},"Zhu, Y. F. & Henry, J. L. Excitability of Aβ sensory neurons is altered in an animal model of peripheral neuropathy. BMC Neurosci. 13, 15 (2012).",{"doi":4724},"10.1186\u002F1471-2202-13-15",{"id":24,"text":4726,"url":24,"identifiers":4727},"Zhu, Y. L., Xie, Z. L., Wu, Y. W., Duan, W. R. & Xie, Y. K. Early demyelination of primary A-fibers induces a rapid-onset of neuropathic pain in rat. Neuroscience 200, 186–198 (2012).",{"doi":4728},"10.1016\u002Fj.neuroscience.2011.10.037",{"id":24,"text":4730,"url":24,"identifiers":4731},"Amir, R. & Devor, M. Functional cross-excitation between afferent A- and C-neurons in dorsal root ganglia. Neuroscience 95, 189–195 (2000).",{"doi":4732},"10.1016\u002FS0306-4522(99)00388-7",{"id":24,"text":4734,"url":24,"identifiers":4735},"Cervero, F. & Laird, J. M. Mechanisms of allodynia: interactions between sensitive mechanoreceptors and nociceptors. Neuroreport 31, 526–528 (1996).",{"doi":4736},"10.1097\u002F00001756-199601310-00036",{"id":24,"text":4738,"url":24,"identifiers":4739},"Craig, A. D. Pain mechanisms: labeled lines versus convergence in central processing. Annu. Rev. Neurosci. 26, 1–30 (2003).",{"doi":4740},"10.1146\u002Fannurev.neuro.26.041002.131022",{"id":24,"text":4742,"url":24,"identifiers":4743},"Aichaoui, F., Mertens, P. & Sindou, M. Dorsal root entry zone lesioning for pain after brachial plexus avulsion: results with special emphasis on differential effects on the paroxysmal versus the continuous components. A prospective study in a 29-patient consecutive series. Pain 152, 1923–1930 (2011).",{"doi":4744},"10.1016\u002Fj.pain.2011.03.037",{"id":24,"text":4746,"url":24,"identifiers":4747},"Ali, M.  et al. Differential efficacy of electric motor cortex stimulation and lesioning of the dorsal root entry zone for continuous vs paroxysmal pain after brachial plexus avulsion. Neurosurgery 68, 1252–1257 (2011).",{"doi":4748},"10.1227\u002FNEU.0b013e31820c04a9",{"id":24,"text":4750,"url":24,"identifiers":4751},"Sindou, M. Surgery in the DREZ for refractory neuropathic pain after spinal cord\u002Fcauda equina injury. World Neurosurg. 75, 447–448 (2011).",{"doi":4752},"10.1016\u002Fj.wneu.2011.01.034",{"id":24,"text":4754,"url":24,"identifiers":4755},"Koroschetz, J.  et al. Fibromyalgia and neuropathic pain—differences and similarities. A comparison of 3057 patients with diabetic painful neuropathy and fibromyalgia. BMC Neurol. 25, 55 (2011).",{"doi":4756},"10.1186\u002F1471-2377-11-55",{"id":24,"text":4758,"url":24,"identifiers":4759},"Devor, M. in Wall and Melzack's Textbook of Pain (eds McMahon, S. B. & Koltzenburg, M.) 905–927 (Elsevier, 2006).",{"doi":4760},"10.1016\u002FB0-443-07287-6\u002F50063-1",{"id":24,"text":4762,"url":24,"identifiers":4763},"Devor, M. Ectopic discharge in Aβ afferents as a source of neuropathic pain. Exp. Brain Res. 196, 115–128 (2009).",{"doi":4764},"10.1007\u002Fs00221-009-1724-6",{"id":24,"text":4766,"url":24,"identifiers":4767},"Campbell, J. N., Raja, S. N., Meyer, R. A. & Mackinnon, S. E. Myelinated afferents signal the hyperalgesia associated with nerve injury. Pain 32, 89–94 (1988).",{"doi":4768},"10.1016\u002F0304-3959(88)90027-9",{"id":24,"text":4770,"url":24,"identifiers":4771},"Lindblom, U. & Verrillo, R. T. Sensory functions in chronic neuralgia. J. Neurol. Neurosurg. Psychiatry 42, 422–435 (1979).",{"doi":4772},"10.1136\u002Fjnnp.42.5.422",{"id":24,"text":4774,"url":24,"identifiers":4775},"Landerholm, Å. H. & Hansson, P. T. Mechanisms of dynamic mechanical allodynia and dysesthesia in patients with peripheral and central neuropathic pain. Eur. J. Pain 15, 498–503 (2011).",{"doi":4776},"10.1016\u002Fj.ejpain.2010.10.003",{"id":24,"text":4778,"url":24,"identifiers":4779},"Koltzenburg, M., Torebjork, H. E. & Wahren, L. K. Nociceptor modulated central sensitization causes mechanical hyperalgesia in acute chemogenic and chronic neuropathic pain. Brain 117, 579–591 (1994).",{"doi":4780},"10.1093\u002Fbrain\u002F117.3.579",{"id":24,"text":4782,"url":24,"identifiers":4783},"Liu, C. N.  et al. Tactile allodynia in the absence of C-fiber activation: altered firing properties of DRG neurons following spinal nerve injury. Pain 85, 503–521 (2000).",{"doi":4784},"10.1016\u002FS0304-3959(00)00251-7",{"id":24,"text":4786,"url":24,"identifiers":4787},"Michaelis, M., Blenk, K. H., Jänig. W. & Vogel, C. Development of spontaneous activity and mechanosensitivity in axotomized afferent nerve fibers during the first hours after nerve transection in rats. J. Neurophysiol. 74, 1020–1027 (1995).",{"doi":4788},"10.1152\u002Fjn.1995.74.3.1020",{"id":24,"text":4790,"url":24,"identifiers":4791},"Tal, M., Kim, J., Back, S. K., Na, H. S. & Devor, M. in Proceedings of the 11th World Congress on Pain (eds Flor, H.  et al.) 119–130 (IASP Press, 2006).",{},{"id":24,"text":4793,"url":24,"identifiers":4794},"Sandkuhler, J. Learning and memory in pain pathways. Pain 88, 113–118 (2000).",{"doi":4795},"10.1016\u002FS0304-3959(00)00424-3",{"id":24,"text":4797,"url":24,"identifiers":4798},"Malcangio, M., Ramer, M. S., Jones, M. G. & McMahon, S. B. Abnormal substance P release from the spinal cord following injury to primary sensory neurons. Eur. J. Neurosci. 12, 397–399 (2000).",{"doi":4799},"10.1046\u002Fj.1460-9568.2000.00946.x",{"id":24,"text":4801,"url":24,"identifiers":4802},"Michael, G. J., Averill, S., Shortland, P. J., Yan, Q. & Priestley, J. V. Axotomy results in major changes in BDNF expression by dorsal root ganglion cells: BDNF expression in large trkB and trkC cells, in pericellular baskets, and in projections to deep dorsal horn and dorsal column nuclei. Eur. J. Neurosci. 11, 3539–3551 (1999).",{"doi":4803},"10.1046\u002Fj.1460-9568.1999.00767.x",{"id":24,"text":4805,"url":24,"identifiers":4806},"Schaible, H. G., Hope, P. J., Lang, C. W. & Duggan, A. W. Calcitonin gene-related peptide causes intraspinal spreading of substance P released by peripheral stimulation. Eur. J. Neurosci. 4, 750–757 (1992).",{"doi":4807},"10.1111\u002Fj.1460-9568.1992.tb00184.x",{"id":24,"text":4809,"url":24,"identifiers":4810},"Miraucourt, L. S., Moisset, X. & Voisin, D. L. Glycine inhibitory dysfunction induces a selectively dynamic, morphine-resistant, and neurokinin 1 receptor- independent mechanical allodynia. J. Neurosci. 29, 2519–2527 (2009).",{"doi":4811},"10.1523\u002FJNEUROSCI.3923-08.2009",{"id":24,"text":4813,"url":24,"identifiers":4814},"Neumann, S., Braz, J. M., Skinner, K., Llewellyn-Smith, I. J. & Basbaum, A. I. Innocuous, not noxious, input activates PKCγ interneurons of the spinal dorsal horn via myelinated afferent fibers. J. Neurosci. 28, 7936–7944 (2008).",{"doi":4815},"10.1523\u002FJNEUROSCI.1259-08.2008",{"id":24,"text":4817,"url":24,"identifiers":4818},"Woolf, C. J., Shortland, P., Coggeshall, R. E. Peripheral nerve injury triggers central sprouting of myelinated afferents. Nature 355, 75–78 (1992).",{"doi":4819},"10.1038\u002F355075a0",{"id":24,"text":4821,"url":24,"identifiers":4822},"Watkins, L. R. & Maier, S. F. Beyond neurons: evidence that immune and glial cells contribute to pathological pain states. Physiol. Rev. 82, 981–1011 (2002).",{"doi":4823},"10.1152\u002Fphysrev.00011.2002",{"id":24,"text":4825,"url":24,"identifiers":4826},"De Koninck, Y. Altered chloride homeostasis in neurological disorders: a new target. Curr. Opin. Pharmacol. 7, 93–99 (2007).",{"doi":4827},"10.1016\u002Fj.coph.2006.11.005",{"id":24,"text":4829,"url":24,"identifiers":4830},"Coull, J. A.  et al. Trans-synaptic shift in anion gradient in spinal lamina I neurons as a mechanism of neuropathic pain. Nature 424, 938–942 (2003).",{"doi":4831},"10.1038\u002Fnature01868",{"id":24,"text":4833,"url":24,"identifiers":4834},"Coull, J. A.  et al. BDNF from microglia causes the shift in neuronal anion gradient underlying neuropathic pain. Nature 438, 1017–1021 (2005).",{"doi":4835},"10.1038\u002Fnature04223",{"id":24,"text":4837,"url":24,"identifiers":4838},"Price, D. D., Bennett, G. J. & Rafii, A. Psychophysical observations on patients with neuropathic pain relieved by a sympathetic block. Pain 36, 273–288 (1989).",{"doi":4839},"10.1016\u002F0304-3959(89)90086-9",{"id":24,"text":4841,"url":24,"identifiers":4842},"Samuelsson, M., Leffler, A. S. & Hansson, P. Dynamic mechanical allodynia: on the relationship between temporo-spatial stimulus parameters and evoked pain in patients with peripheral neuropathy. Pain 115, 264–272 (2005).",{"doi":4843},"10.1016\u002Fj.pain.2005.03.001",{"id":24,"text":4845,"url":24,"identifiers":4846},"Torebjork, H. E., Lundberg, L. E. & LaMotte, R. H. Central changes in processing of mechanoreceptive input in capsaicin-induced secondary hyperalgesia in humans. J. Physiol. 448, 765–780 (1992).",{"doi":4847},"10.1113\u002Fjphysiol.1992.sp019069",{"id":24,"text":4849,"url":24,"identifiers":4850},"Garcia-Larrea, L. & Mauguière, F. Electrophysiological assessment of nociception in normals and patients: the use of nociceptive spinal reflexes. Electroencephal. Clin. Neurophysiol. Suppl. 41, 102–118 (1990).",{},{"id":24,"text":4852,"url":24,"identifiers":4853},"Le Bars, D., Dickenson, A. H. & Besson, J. M. Diffuse noxious inhibitory controls (DNIC). II. Lack of effect on non-convergent neurones, supraspinal involvement and theoretical implications. Pain 6, 305–327 (1979).",{"doi":4854},"10.1016\u002F0304-3959(79)90050-2",{"id":24,"text":4856,"url":24,"identifiers":4857},"Tuveson, B., Leffler, A. S. & Hansson, P. Heterotopic noxious conditioning stimulation (HNCS) reduced the intensity of spontaneous pain, but not of allodynia in painful peripheral neuropathy. Eur. J. Pain 11, 452–462 (2007).",{"doi":4858},"10.1016\u002Fj.ejpain.2006.06.007",{"id":24,"text":4860,"url":24,"identifiers":4861},"Truini, A.  et al. Peripheral nociceptor sensitization mediates allodynia in patients with distal symmetric polyneuropathy. J. Neurol. 260, 761–766 (2013).",{"doi":4862},"10.1007\u002Fs00415-012-6698-9",{"id":24,"text":4864,"url":24,"identifiers":4865},"Mendell, J. R. & Sahenk, Z. Clinical practice. Painful sensory neuropathy. N. Engl. J. Med. 348, 1243–1255 (2003).",{"doi":4866},"10.1056\u002FNEJMcp022282",{"id":24,"text":4868,"url":24,"identifiers":4869},"Cole, J.  et al. Unmyelinated tactile afferents underpin detection of low-force monofilaments. Muscle Nerve 34, 105–107 (2006).",{"doi":4870},"10.1002\u002Fmus.20534",{"id":24,"text":4872,"url":24,"identifiers":4873},"Koltzenburg, M. & Scadding, J. Neuropathic pain. Curr. Opin. Neurol. 14, 641–647 (2001).",{"doi":4874},"10.1097\u002F00019052-200110000-00014",{"id":24,"text":4876,"url":24,"identifiers":4877},"Ochoa, J. L., Campero, M., Serra, J. & Bostock, H. Hyperexcitable polymodal and insensitive nociceptors in painful human neuropathy. Muscle Nerve 32, 459–472 (2005).",{"doi":4878},"10.1002\u002Fmus.20367",{"id":24,"text":4880,"url":24,"identifiers":4881},"Lu, Y., Zheng, J., Xiong, L., Zimmermann, M. & Yang, J. Spinal cord injury-induced attenuation of GABAergic inhibition in spinal dorsal horn circuits is associated with down-regulation of the chloride transporter KCC2 in rat. J. Physiol. 586, 5701–5715 (2008).",{"doi":4882},"10.1113\u002Fjphysiol.2008.152348",{"id":24,"text":4884,"url":24,"identifiers":4885},"Nesic, O.  et al. Transcriptional profiling of spinal cord injury-induced central neuropathic pain. J. Neurochem. 95, 998–1014 (2005).",{"doi":4886},"10.1111\u002Fj.1471-4159.2005.03462.x",{"id":24,"text":4888,"url":24,"identifiers":4889},"Yu, C. G. & Yezierski, R. P. Activation of the ERK1\u002F2 signaling cascade by excitotoxic spinal cord injury. Brain Res. Mol. Brain Res. 138, 244–255 (2005).",{"doi":4890},"10.1016\u002Fj.molbrainres.2005.04.013",{"id":24,"text":4892,"url":24,"identifiers":4893},"Albe-Fessard, D. & Lombard, M. C. in Advances in Pain Research and Therapy (eds Bonica, J. J.  et al.) 691–700 (Raven Press, 1983).",{},{"id":24,"text":4895,"url":24,"identifiers":4896},"Banati, R. B. Brain plasticity and microglia: is transsynaptic glial activation in the thalamus after limb denervation linked to cortical plasticity and central sensitisation? J. Physiol. Paris 96, 289–299 (2000).",{"doi":4897},"10.1016\u002FS0928-4257(02)00018-9",{"id":24,"text":4899,"url":24,"identifiers":4900},"Wasserman, J. K. & Koeberle, P. D. Development and characterization of a hemorrhagic rat model of central post-stroke pain. Neuroscience 161, 173–183 (2009).",{"doi":4901},"10.1016\u002Fj.neuroscience.2009.03.042",{"id":24,"text":4903,"url":24,"identifiers":4904},"Kim, H. Y., Wang, J. & Gwak, Y. S. Gracile neurons contribute to the maintenance of neuropathic pain in peripheral and central neuropathic models. J. Neurotrauma 29, 2587–2592 (2012).",{"doi":4905},"10.1089\u002Fneu.2012.2396",{"id":24,"text":4907,"url":24,"identifiers":4908},"Ralston, H. J. 3rd. Pain and the primate thalamus. Prog. Brain Res. 149, 1–10 (2005).",{"doi":4909},"10.1016\u002FS0079-6123(05)49001-9",{"id":24,"text":4911,"url":24,"identifiers":4912},"Hirato, M.  et al. Pathophysiology of central (thalamic) pain: combined change of sensory thalamus with cerebral cortex around central sulcus. Stereotact. Funct. Neurosurg. 62, 300–303 (1994).",{"doi":4913},"10.1159\u002F000098636",{"id":24,"text":4915,"url":24,"identifiers":4916},"Rinaldi, P. C., Young, R. F., Albe-Fessard, D. & Chodakiewitz, J. Spontaneous neuronal hyperactivity in the medial and intralaminar thalamic nuclei of patients with deafferentation pain. J. Neurosurg. 74, 415–421 (1991).",{"doi":4917},"10.3171\u002Fjns.1991.74.3.0415",{"id":24,"text":4919,"url":24,"identifiers":4920},"Cesaro, P.  et al. Central pain and thalamic hyperactivity: a single photon emission computerized tomographic study. Pain 47, 329–336 (1991).",{"doi":4921},"10.1016\u002F0304-3959(91)90224-L",{"id":24,"text":4923,"url":24,"identifiers":4924},"Peyron, R.  et al. An fMRI study of cortical representation of mechanical allodynia in patients with neuropathic pain. Neurology 63, 1838–1846 (2004).",{"doi":4925},"10.1212\u002F01.WNL.0000144177.61125.85",{"id":24,"text":4927,"url":24,"identifiers":4928},"Masri, R.  et al. Zona incerta: a role in central pain. J. Neurophysiol. 102, 181–191 (2009).",{"doi":4929},"10.1152\u002Fjn.00152.2009",{"id":24,"text":4931,"url":24,"identifiers":4932},"Cesaro, P.  et al. Organization of the median and intralaminar nuclei of the thalamus: hypotheses on their role in the onset of certain central pain. Rev. Neurol. 142, 297–302 (1986).",{},{"id":24,"text":4934,"url":24,"identifiers":4935},"Schweinhardt, P.  et al. An fMRI study of cerebral processing of brush-evoked allodynia in neuropathic pain patients. Neuroimage 32, 256–265 (2006).",{"doi":4936},"10.1016\u002Fj.neuroimage.2006.03.024",{"id":24,"text":4938,"url":24,"identifiers":4939},"Apkarian, A. V., Hodge, C. J. Primate spinothalamic pathways: I. A quantitative study of the cells of origin of the spinothalamic pathway. J. Comp. Neurol. 288, 447–473 (1989).",{"doi":4940},"10.1002\u002Fcne.902880307",{"id":24,"text":4942,"url":24,"identifiers":4943},"Casey, K. L.  et al. Psychophysical and cerebral responses to heat stimulation in patients with central pain, painless central sensory loss, and in healthy persons. Pain 153, 331–341 (2012).",{"doi":4944},"10.1016\u002Fj.pain.2011.10.029",{"id":24,"text":4946,"url":24,"identifiers":4947},"Baron, R., Tölle, T. R., Gockel, U., Brosz, M. & Freynhagen, R. A cross-sectional cohort survey in 2100 patients with painful diabetic neuropathy and postherpetic neuralgia: differences in demographic data and sensory symptoms. Pain 146, 34–40 (2009).",{"doi":4948},"10.1016\u002Fj.pain.2009.06.001",{"id":24,"text":4950,"url":24,"identifiers":4951},"Finnerup, N. B. & Jensen, T. S. Mechanisms of disease: mechanism-based classification of neuropathic pain—a critical analysis. Nat. Clin. Pract. 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M. D., Lockwood, A. H., Hwo, S. Y. & Kirschner, M. W. A protein factor essential for microtubule assembly. Proc. Natl Acad. Sci. USA 72, 1858–1862 (1975).",{"doi":5097},"10.1073\u002Fpnas.72.5.1858",{"id":24,"text":5099,"url":24,"identifiers":5100},"Grundke-Iqbal, I. et al. Abnormal phosphorylation of the microtubule-associated protein τ (tau) in Alzheimer cytoskeletal pathology. Proc. Natl Acad. Sci. USA 83, 4913–4917 (1986).",{"doi":5101},"10.1073\u002Fpnas.83.13.4913",{"id":24,"text":5103,"url":24,"identifiers":5104},"Tomlinson, B. E., Blessed, G. & Roth, M. Observations on the brains of demented old people. J. Neurol. Sci. 11, 205–242 (1970).",{"doi":5105},"10.1016\u002F0022-510X(70)90063-8",{"id":24,"text":5107,"url":24,"identifiers":5108},"Iqbal, K. et al. Protein changes in senile dementia. Brain Res. 77, 337–343 (1974).",{"doi":5109},"10.1016\u002F0006-8993(74)90798-7",{"id":24,"text":2612,"url":24,"identifiers":5111},{"doi":2614},{"id":24,"text":5113,"url":24,"identifiers":5114},"Iqbal, K. et al. Defective brain microtubule assembly in Alzheimer's disease. Lancet 2, 421–426 (1986).",{"doi":5115},"10.1016\u002FS0140-6736(86)92134-3",{"id":24,"text":5117,"url":24,"identifiers":5118},"Goedert, M., Spillantini, M. G., Potier, M. C., Ulrich, J. & Crowther, R. A. Cloning and sequencing of the cDNA encoding an isoform of microtubule-associated protein tau containing four tandem repeats: differential expression of tau protein mRNAs in human brain. EMBO J. 8, 393–399 (1989).",{"doi":5119},"10.1002\u002Fj.1460-2075.1989.tb03390.x",{"id":24,"text":5121,"url":24,"identifiers":5122},"Drubin, D. G. & Kirschner, M. W. Tau protein function in living cells. J. Cell Biol. 103, 2739–2746 (1986).",{"doi":5123},"10.1083\u002Fjcb.103.6.2739",{"id":24,"text":5125,"url":24,"identifiers":5126},"Lee, G. et al. Phosphorylation of tau by fyn: implications for Alzheimer's disease. J. Neurosci. 24, 2304–2312 (2004).",{"doi":5127},"10.1523\u002FJNEUROSCI.4162-03.2004",{"id":24,"text":5129,"url":24,"identifiers":5130},"Roberson, E. D. et al. Amyloid-β\u002FFyn-induced synaptic, network, and cognitive impairments depend on tau levels in multiple mouse models of Alzheimer's disease. J. Neurosci. 31, 700–711 (2011).",{"doi":5131},"10.1523\u002FJNEUROSCI.4152-10.2011",{"id":24,"text":5133,"url":24,"identifiers":5134},"Lindwall, G. & Cole, R. D. Phosphorylation affects the ability of tau protein to promote microtubule assembly. J. Biol. Chem. 259, 5301–5305 (1984).",{"doi":5135},"10.1016\u002FS0021-9258(17)42989-9",{"id":24,"text":5137,"url":24,"identifiers":5138},"Alonso, A. C., Zaidi, T., Grundke-Iqbal, I. & Iqbal, K. Role of abnormally phosphorylated tau in the breakdown of microtubules in Alzheimer disease. Proc. Natl Acad. Sci. USA 91, 5562–5566 (1994).",{"doi":5139},"10.1073\u002Fpnas.91.12.5562",{"id":24,"text":5141,"url":24,"identifiers":5142},"Iqbal, K. & Tellez-Nagel, I. Isolation of neurons and glial cells from normal and pathological human brains. Brain Res. 45, 296–301 (1972).",{"doi":5143},"10.1016\u002F0006-8993(72)90241-7",{"id":24,"text":5145,"url":24,"identifiers":5146},"Cleveland, D. W., Hwo, S. Y. & Kirschner, M. W. Purification of tau, a microtubule-associated protein that induces assembly of microtubules from purified tubulin. J. Mol. Biol. 116, 207–225 (1977).",{"doi":5147},"10.1016\u002F0022-2836(77)90213-3",{"id":24,"text":5149,"url":24,"identifiers":5150},"Grundke-Iqbal, I., Johnson, A. B., Wisniewski, H. M., Terry, R. D. & Iqbal, K. Evidence that Alzheimer neurofibrillary tangles originate from neurotubules. Lancet 1, 578–580 (1979).",{"doi":5151},"10.1016\u002FS0140-6736(79)91006-7",{"id":24,"text":5153,"url":24,"identifiers":5154},"Grundke-Iqbal, I., Johnson, A. B., Terry, R. D., Wisniewski, H. M. & Iqbal, K. Alzheimer neurofibrillary tangles: antiserum and immunohistological staining. Ann. Neurol. 6, 532–537 (1979).",{"doi":5155},"10.1002\u002Fana.410060612",{"id":24,"text":5157,"url":24,"identifiers":5158},"Iqbal, K., Zaidi, T., Thompson, C. H., Merz, P. A. & Wisniewski, H. M. Alzheimer paired helical filaments: bulk isolation, solubility, and protein composition. Acta Neuropathol. 62, 167–177 (1984).",{"doi":5159},"10.1007\u002FBF00691849",{"id":24,"text":5161,"url":24,"identifiers":5162},"Grundke-Iqbal, I., Iqbal, K., Tung, Y. C. & Wisniewski, H. M. Alzheimer paired helical filaments: immunochemical identification of polypeptides. Acta Neuropathol. 62, 259–267 (1984).",{"doi":5163},"10.1007\u002FBF00687607",{"id":24,"text":5165,"url":24,"identifiers":5166},"Wang, G. P., Grundke-Iqbal, I., Kascsak, R. J., Iqbal, K. & Wisniewski, H. M. Alzheimer neurofibrillary tangles: monoclonal antibodies to inherent antigen(s). Acta Neuropathol. 62, 268–275 (1984).",{"doi":5167},"10.1007\u002FBF00687608",{"id":24,"text":5169,"url":24,"identifiers":5170},"Mehta, P. D., Thal, L., Wisniewski, H. M., Grundke-Iqbal, I. & Iqbal, K. Paired helical filament antigen in CSF. Lancet 2, 35 (1985).",{"doi":5171},"10.1016\u002FS0140-6736(85)90074-1",{"id":24,"text":5173,"url":24,"identifiers":5174},"Braak, H., Braak, E., Grundke-Iqbal, I. & Iqbal, K. Occurrence of neuropil threads in the senile human brain and in Alzheimer's disease: a third location of paired helical filaments outside of neurofibrillary tangles and neuritic plaques. Neurosci. Lett. 65, 351–355 (1986).",{"doi":5175},"10.1016\u002F0304-3940(86)90288-0",{"id":24,"text":5177,"url":24,"identifiers":5178},"Bancher, C. et al. Accumulation of abnormally phosphorylated tau precedes the formation of neurofibrillary tangles in Alzheimer's disease. Brain Res. 477, 90–99 (1989).",{"doi":5179},"10.1016\u002F0006-8993(89)91396-6",{"id":24,"text":5181,"url":24,"identifiers":5182},"Braak, H. & Braak, E. Neuropathological stageing of Alzheimer-related changes. Acta Neuropathol. 82, 239–259 (1991).",{"doi":5183},"10.1007\u002FBF00308809",{"id":24,"text":5185,"url":24,"identifiers":5186},"Lee, G., Cowan, N. & Kirschner, M. The primary structure and heterogeneity of tau protein from mouse brain. Science 239, 285–288 (1988).",{"doi":5187},"10.1126\u002Fscience.3122323",{"id":24,"text":5189,"url":24,"identifiers":5190},"Himmler, A., Drechsel, D., Kirschner, M. W. & Martin, D. W. Jr. Tau consists of a set of proteins with repeated C-terminal microtubule-binding domains and variable N-terminal domains. Mol. Cell. Biol. 9, 1381–1388 (1989).",{"doi":5191},"10.1128\u002FMCB.9.4.1381",{"id":24,"text":5193,"url":24,"identifiers":5194},"Kosik, K. S., Crandall, J. E., Mufson, E. J. & Neve, R. L. Tau in situ hybridization in normal and Alzheimer brain: localization in the somatodendritic compartment. Ann. Neurol. 26, 352–261 (1989).",{"doi":5195},"10.1002\u002Fana.410260308",{"id":24,"text":5197,"url":24,"identifiers":5198},"Novak, M., Kabat, J. & Wischik, C. M. Molecular characterization of the minimal protease resistant tau unit of the Alzheimer's disease paired helical filament. EMBO J. 12, 365–370 (1993).",{"doi":5199},"10.1002\u002Fj.1460-2075.1993.tb05665.x",{"id":24,"text":5201,"url":24,"identifiers":5202},"Zilka, N. et al. Truncated tau from sporadic Alzheimer's disease suffices to drive neurofibrillary degeneration in vivo. FEBS Lett. 580, 3582–3588 (2006).",{"doi":5203},"10.1016\u002Fj.febslet.2006.05.029",{"id":24,"text":5205,"url":24,"identifiers":5206},"Hasegawa, M. et al. Protein sequence and mass spectrometric analyses of tau in the Alzheimer's disease brain. J. Biol. Chem. 267, 17047–17054 (1992).",{"doi":5207},"10.1016\u002FS0021-9258(18)41890-X",{"id":24,"text":5209,"url":24,"identifiers":5210},"Hanger, D. P., Betts, J. C., Loviny, T. L., Blackstock, W. P. & Anderton, B. H. New phosphorylation sites identified in hyperphosphorylated tau (paired helical filament-tau) from Alzheimer's disease brain using nanoelectrospray mass spectrometry. J. Neurochem. 71, 2465–2476 (1998).",{"doi":5211},"10.1046\u002Fj.1471-4159.1998.71062465.x",{"id":24,"text":5213,"url":24,"identifiers":5214},"Gong, C. X., Singh, T. J., Grundke-Iqbal, I. & Iqbal, K. Phosphoprotein phosphatase activities in Alzheimer disease brain. J. Neurochem. 61, 921–927 (1993).",{"doi":5215},"10.1111\u002Fj.1471-4159.1993.tb03603.x",{"id":24,"text":5217,"url":24,"identifiers":5218},"Gong, C. X., Grundke-Iqbal, I. & Iqbal, K. Dephosphorylation of Alzheimer's disease abnormally phosphorylated tau by protein phosphatase-2A. Neuroscience 61, 765–772 (1994).",{"doi":5219},"10.1016\u002F0306-4522(94)90400-6",{"id":24,"text":5221,"url":24,"identifiers":5222},"Gong, C. X. et al. Phosphatase activity toward abnormally phosphorylated tau: decrease in Alzheimer disease brain. J. Neurochem. 65, 732–738 (1995).",{"doi":5223},"10.1046\u002Fj.1471-4159.1995.65020732.x",{"id":24,"text":5225,"url":24,"identifiers":5226},"Tanimukai, H., Grundke-Iqbal, I. & Iqbal, K. Up-regulation of inhibitors of protein phosphatase-2A in Alzheimer's disease. Am. J. Pathol. 166, 1761–1771 (2005).",{"doi":5227},"10.1016\u002FS0002-9440(10)62486-8",{"id":24,"text":5229,"url":24,"identifiers":5230},"Tsujio, I. et al. Inhibitors of protein phosphatase-2A from human brain structures, immunocytological localization and activities towards dephosphorylation of the Alzheimer type hyperphosphorylated tau. FEBS Lett. 579, 363–372 (2005).",{"doi":5231},"10.1016\u002Fj.febslet.2004.11.097",{"id":24,"text":5233,"url":24,"identifiers":5234},"Bolognin, S. et al. An experimental rat model of sporadic Alzheimer's disease and rescue of cognitive impairment with a neurotrophic peptide. Acta Neuropathol. 123, 133–151 (2012).",{"doi":5235},"10.1007\u002Fs00401-011-0908-x",{"id":24,"text":5237,"url":24,"identifiers":5238},"Basurto-Islas, G., Grundke-Iqbal, I., Tung, Y. C., Liu, F. & Iqbal, K. Activation of asparaginyl endopeptidase leads to Tau hyperphosphorylation in Alzheimer disease. J. Biol. Chem. 288, 17495–17507 (2013).",{"doi":5239},"10.1074\u002Fjbc.M112.446070",{"id":24,"text":5241,"url":24,"identifiers":5242},"Wang, X. et al. Alzheimer disease and amyotrophic lateral sclerosis: an etiopathogenic connection. Acta Neuropathol. 127, 243–256 (2014).",{"doi":5243},"10.1007\u002Fs00401-013-1175-9",{"id":24,"text":5245,"url":24,"identifiers":5246},"Arif, M., Kazim, S. F., Grundke-Iqbal, I., Garruto, R. M. & Iqbal, K. Tau pathology involves protein phosphatase 2A in parkinsonism–dementia of Guam. Proc. Natl Acad. Sci. USA 111, 1144–1149 (2014).",{"doi":5247},"10.1073\u002Fpnas.1322614111",{"id":24,"text":5249,"url":24,"identifiers":5250},"Khatoon, S., Grundke-Iqbal, I. & Iqbal, K. Brain levels of microtubule-associated protein tau are elevated in Alzheimer's disease: a radioimmuno-slot-blot assay for nanograms of the protein. J. Neurochem. 59, 750–753 (1992).",{"doi":5251},"10.1111\u002Fj.1471-4159.1992.tb09432.x",{"id":24,"text":5253,"url":24,"identifiers":5254},"Vandermeeren, M. et al. Detection of tau proteins in normal and Alzheimer's disease cerebrospinal fluid with a sensitive sandwich enzyme-linked immunosorbent assay. J. Neurochem. 61, 1828–1834 (1993).",{"doi":5255},"10.1111\u002Fj.1471-4159.1993.tb09823.x",{"id":24,"text":5257,"url":24,"identifiers":5258},"Kopke, E. et al. Microtubule-associated protein tau. Abnormal phosphorylation of a non-paired helical filament pool in Alzheimer disease. J. Biol. Chem. 268, 24374–24384 (1993).",{"doi":5259},"10.1016\u002FS0021-9258(20)80536-5",{"id":24,"text":5261,"url":24,"identifiers":5262},"Mandelkow, E., von Bergen, M., Biernat, J. & Mandelkow, E. M. Structural principles of tau and the paired helical filaments of Alzheimer's disease. Brain Pathol. 17, 83–90 (2007).",{"doi":5263},"10.1111\u002Fj.1750-3639.2007.00053.x",{"id":24,"text":5265,"url":24,"identifiers":5266},"Alonso, A., Zaidi, T., Novak, M., Grundke-Iqbal, I. & Iqbal, K. Hyperphosphorylation induces self-assembly of tau into tangles of paired helical filaments\u002Fstraight filaments. Proc. Natl Acad. Sci. USA 98, 6923–6928 (2001).",{"doi":5267},"10.1073\u002Fpnas.121119298",{"id":24,"text":5269,"url":24,"identifiers":5270},"Alonso, A. D., Mederlyova, A., Novak, M., Grundke-Iqbal, I. & Iqbal, K. Promotion of hyperphosphorylation by frontotemporal dementia tau mutations. J. Biol. Chem. 279, 34873–34881 (2004).",{"doi":5271},"10.1074\u002Fjbc.M405131200",{"id":24,"text":5273,"url":24,"identifiers":5274},"Alonso, A. C., Grundke-Iqbal, I. & Iqbal, K. Alzheimer's disease hyperphosphorylated tau sequesters normal tau into tangles of filaments and disassembles microtubules. Nat. Med. 2, 783–787 (1996).",{"doi":5275},"10.1038\u002Fnm0796-783",{"id":24,"text":5277,"url":24,"identifiers":5278},"Clavaguera, F. et al. Transmission and spreading of tauopathy in transgenic mouse brain. Nat. Cell Biol. 11, 909–913 (2009).",{"doi":5279},"10.1038\u002Fncb1901",{"id":24,"text":5281,"url":24,"identifiers":5282},"Clavaguera, F. et al. Brain homogenates from human tauopathies induce tau inclusions in mouse brain. Proc. Natl Acad. Sci. USA 110, 9535–9540 (2013).",{"doi":5283},"10.1073\u002Fpnas.1301175110",{"id":24,"text":5285,"url":24,"identifiers":5286},"Asuni, A. A., Boutajangout, A., Quartermain, D. & Sigurdsson, E. M. Immunotherapy targeting pathological tau conformers in a tangle mouse model reduces brain pathology with associated functional improvements. J. Neurosci. 27, 9115–9129 (2007).",{"doi":5287},"10.1523\u002FJNEUROSCI.2361-07.2007",{"id":24,"text":5289,"url":24,"identifiers":5290},"Encouraging results of AXON's tau vaccine advance Alzheimer's therapy. AXON Neuroscience [online] , (2015).",{},{"id":24,"text":5292,"url":24,"identifiers":5293},"Hutton, M. et al. Association of missense and 5′-splice-site mutations in tau with the inherited dementia FTDP-17. Nature 393, 702–705 (1998).",{"doi":5294},"10.1038\u002F31508",{"id":24,"text":5296,"url":24,"identifiers":5297},"Spillantini, M. G. et al. Mutation in the tau gene in familial multiple system tauopathy with presenile dementia. Proc. Natl Acad. Sci. USA 95, 7737–7741 (1998).",{"doi":5298},"10.1073\u002Fpnas.95.13.7737",{"id":24,"text":5300,"url":24,"identifiers":5301},"Poorkaj, P. et al. Tau is a candidate gene for chromosome 17 frontotemporal dementia. Ann. Neurol. 43, 815–825 (1998).",{"doi":5302},"10.1002\u002Fana.410430617",{"id":24,"text":5304,"url":24,"identifiers":5305},"Ghetti, B. et al. Invited review: frontotemporal dementia caused by microtubule-associated protein tau gene (MAPT) mutations: a chameleon for neuropathology and neuroimaging. Neuropathol. Appl. Neurobiol. 41, 24–46 (2015).",{"doi":5306},"10.1111\u002Fnan.12213",{"id":24,"text":5308,"url":24,"identifiers":5309},"Lu, M. & Kosik, K. S. Competition for microtubule-binding with dual expression of tau missense and splice isoforms. Mol. Biol. Cell 12, 171–184 (2001).",{"doi":5310},"10.1091\u002Fmbc.12.1.171",{"id":24,"text":5312,"url":24,"identifiers":5313},"Sengupta, A., Grundke-Iqbal, I. & Iqbal, K. Regulation of phosphorylation of tau by protein kinases in rat brain. Neurochem. Res. 31, 1473–1480 (2006).",{"doi":5314},"10.1007\u002Fs11064-006-9205-9",{"id":24,"text":5316,"url":24,"identifiers":5317},"Ishihara, T. et al. Age-dependent emergence and progression of a tauopathy in transgenic mice overexpressing the shortest human tau isoform. Neuron 24, 751–762 (1999).",{"doi":5318},"10.1016\u002FS0896-6273(00)81127-7",{"id":24,"text":5320,"url":24,"identifiers":5321},"Götz, J., Chen, F., van Dorpe, J. & Nitsch, R. M. Formation of neurofibrillary tangles in P301l tau transgenic mice induced by Aβ42 fibrils. Science 293, 1491–1495 (2001).",{"doi":5322},"10.1126\u002Fscience.1062097",{"id":24,"text":5324,"url":24,"identifiers":5325},"Lewis, J. et al. Enhanced neurofibrillary degeneration in transgenic mice expressing mutant tau and APP. Science 293, 1487–1491 (2001).",{"doi":5326},"10.1126\u002Fscience.1058189",{"id":24,"text":5328,"url":24,"identifiers":5329},"Rapoport, M., Dawson, H. N., Binder, L. I., Vitek, M. P. & Ferreira, A. Tau is essential to β-amyloid-induced neurotoxicity. Proc. Natl Acad. Sci. USA 99, 6364–6369 (2002).",{"doi":5330},"10.1073\u002Fpnas.092136199",{"id":24,"text":5332,"url":24,"identifiers":5333},"Iqbal, K. et al. Subgroups of Alzheimer's disease based on cerebrospinal fluid molecular markers. Ann. Neurol. 58, 748–757 (2005).",{"doi":5334},"10.1002\u002Fana.20639",{"id":24,"text":5336,"url":24,"identifiers":5337},"Maruyama, M. et al. Imaging of tau pathology in a tauopathy mouse model and in Alzheimer patients compared to normal controls. Neuron 79, 1094–1108 (2013).",{"doi":5338},"10.1016\u002Fj.neuron.2013.07.037",{"id":24,"text":5340,"url":24,"identifiers":5341},"Fodero-Tavoletti, M. T. et al. 18F-THK523: a novel in vivo tau imaging ligand for Alzheimer's disease. Brain 134, 1089–1100 (2011).",{"doi":5342},"10.1093\u002Fbrain\u002Fawr038",{"id":24,"text":5344,"url":24,"identifiers":5345},"Okamura, N. et al. Novel 18F-labeled arylquinoline derivatives for noninvasive imaging of tau pathology in Alzheimer disease. J. Nucl. Med. 54, 1420–1427 (2013).",{"doi":5346},"10.2967\u002Fjnumed.112.117341",{"id":24,"text":5348,"url":24,"identifiers":5349},"Chien, D. T. et al. Early clinical PET imaging results with the novel PHF-tau radioligand [F-18]-T807. J. Alzheimers Dis. 34, 457–468 (2013).",{"doi":5350},"10.3233\u002FJAD-122059",{"id":24,"text":5352,"url":24,"identifiers":5353},"Chien, D. T. et al. Early clinical PET imaging results with the novel PHF-tau radioligand [F18]-T808. J. Alzheimers Dis. 38, 171–184 (2014).",{"doi":5354},"10.3233\u002FJAD-130098",{"id":24,"text":5356,"url":24,"identifiers":5357},"Ksiezak-Reding, H., Liu, W. K. & Yen, S. H. Phosphate analysis and dephosphorylation of modified tau associated with paired helical filaments. Brain Res. 597, 209–219 (1992).",{"doi":5358},"10.1016\u002F0006-8993(92)91476-U",{"id":24,"text":5360,"url":24,"identifiers":5361},"Morishima-Kawashima, M. et al. Proline-directed and non-proline-directed phosphorylation of PHF-tau. J. Biol. Chem. 270, 823–829 (1995).",{"doi":5362},"10.1074\u002Fjbc.270.2.823",{"id":24,"text":5364,"url":24,"identifiers":5365},"Mori, H., Kondo, J. & Ihara, Y. Ubiquitin is a component of paired helical filaments in Alzheimer's disease. Science 235, 1641–1644 (1987).",{"doi":5366},"10.1126\u002Fscience.3029875",{"id":24,"text":5368,"url":24,"identifiers":5369},"Perry, G., Friedman, R., Shaw, G. & Chau, V. Ubiquitin is detected in neurofibrillary tangles and senile plaque neurites of Alzheimer disease brains. Proc. Natl Acad. Sci. USA 84, 3033–3036 (1987).",{"doi":5370},"10.1073\u002Fpnas.84.9.3033",{"id":24,"text":5372,"url":24,"identifiers":5373},"Grundke-Iqbal, I. et al. Microtubule-associated polypeptides tau are altered in Alzheimer paired helical filaments. Brain Res. 464, 43–52 (1988).",{},{"id":24,"text":5375,"url":24,"identifiers":5376},"Cripps, D. et al. Alzheimer disease-specific conformation of hyperphosphorylated paired helical filament-Tau is polyubiquitinated through Lys-48, Lys-11, and Lys-6 ubiquitin conjugation. J. Biol. Chem. 281, 10825–10838 (2006).",{"doi":5377},"10.1074\u002Fjbc.M512786200",{"id":24,"text":5379,"url":24,"identifiers":5380},"Wischik, C. M. et al. Structural characterization of the core of the paired helical filament of Alzheimer disease. Proc. Natl Acad. Sci. USA 85, 4884–4888 (1988).",{"doi":5381},"10.1073\u002Fpnas.85.13.4884",{"id":24,"text":5383,"url":24,"identifiers":5384},"Gamblin, T. C. et al. Caspase cleavage of tau: linking amyloid and neurofibrillary tangles in Alzheimer's disease. Proc. Natl Acad. Sci. USA 100, 10032–10037 (2003).",{"doi":5385},"10.1073\u002Fpnas.1630428100",{"id":24,"text":5387,"url":24,"identifiers":5388},"Zhang, Z. et al. Cleavage of tau by asparagine endopeptidase mediates the neurofibrillary pathology in Alzheimer's disease. Nat. Med. 20, 1254–1262 (2014).",{"doi":5389},"10.1038\u002Fnm.3700",{"id":24,"text":5391,"url":24,"identifiers":5392},"Ledesma, M. D., Bonay, P., Colaco, C. & Avila, J. Analysis of microtubule-associated protein tau glycation in paired helical filaments. J. Biol. Chem. 269, 21614–21619 (1994).",{"doi":5393},"10.1016\u002FS0021-9258(17)31849-5",{"id":24,"text":5395,"url":24,"identifiers":5396},"Smith, M. A. et al. Advanced Maillard reaction end products are associated with Alzheimer disease pathology. Proc. Natl Acad. Sci. USA 91, 5710–5714 (1994).",{"doi":5397},"10.1073\u002Fpnas.91.12.5710",{"id":24,"text":5399,"url":24,"identifiers":5400},"Wang, J. Z., Grundke-Iqbal, I. & Iqbal, K. Glycosylation of microtubule-associated protein tau: an abnormal posttranslational modification in Alzheimer's disease. Nat. Med. 2, 871–875 (1996).",{"doi":5401},"10.1038\u002Fnm0896-871",{"id":24,"text":5403,"url":24,"identifiers":5404},"Liu, F., Iqbal, K., Grundke-Iqbal, I., Hart, G. W. & Gong, C. X. O-GlcNAcylation regulates phosphorylation of tau: a mechanism involved in Alzheimer's disease. Proc. Natl Acad. Sci. USA 101, 10804–10809 (2004).",{"doi":5405},"10.1073\u002Fpnas.0400348101",{"id":24,"text":5407,"url":24,"identifiers":5408},"Reynolds, M. R. et al. Tau nitration occurs at tyrosine 29 in the fibrillar lesions of Alzheimer's disease and other tauopathies. J. Neurosci. 26, 10636–10645 (2006).",{"doi":5409},"10.1523\u002FJNEUROSCI.2143-06.2006",{"id":24,"text":5411,"url":24,"identifiers":5412},"Odetti, P. et al. Lipoperoxidation is selectively involved in progressive supranuclear palsy. J. Neuropathol. Exp. Neurol. 59, 393–397 (2000).",{"doi":5413},"10.1093\u002Fjnen\u002F59.5.393",{"id":24,"text":5415,"url":24,"identifiers":5416},"Dorval, V. & Fraser, P. E. Small ubiquitin-like modifier (SUMO) modification of natively unfolded proteins tau and α-synuclein. J. Biol. Chem. 281, 9919–9924 (2006).",{"doi":5417},"10.1074\u002Fjbc.M510127200",{"id":24,"text":5419,"url":24,"identifiers":5420},"Min, S. W. et al. Acetylation of tau inhibits its degradation and contributes to tauopathy. Neuron 67, 953–966 (2010).",{"doi":5421},"10.1016\u002Fj.neuron.2010.08.044",{"id":24,"text":5423,"url":24,"identifiers":5424},"Cohen, T. J. et al. The acetylation of tau inhibits its function and promotes pathological tau aggregation. Nat. Commun. 2, 252 (2011).",{"doi":5425},"10.1038\u002Fncomms1255",{"id":24,"text":5427,"url":24,"identifiers":5428},"Min, S. W. et al. Critical role of acetylation in tau-mediated neurodegeneration and cognitive deficits. Nat. Med. 21, 1154–1162 (2015).",{"doi":5429},"10.1038\u002Fnm.3951",{"id":24,"text":5431,"url":24,"identifiers":5432},"Wang, J. Z., Grundke-Iqbal, I. & Iqbal, K. Restoration of biological activity of Alzheimer abnormally phosphorylated tau by dephosphorylation with protein phosphatase-2A, -2B and -1. Brain Res. Mol. Brain Res. 38, 200–208 (1996).",{"doi":5433},"10.1016\u002F0169-328X(95)00316-K",{"id":24,"text":5435,"url":24,"identifiers":5436},"Alonso, A. D., Grundke-Iqbal, I., Barra, H. S. & Iqbal, K. Abnormal phosphorylation of tau and the mechanism of Alzheimer neurofibrillary degeneration: sequestration of microtubule-associated proteins 1 and 2 and the disassembly of microtubules by the abnormal tau. Proc. Natl Acad. Sci. USA 94, 298–303 (1997).",{"doi":5437},"10.1073\u002Fpnas.94.1.298",{"id":24,"text":5439,"url":24,"identifiers":5440},"Alonso, A. D. et al. Interaction of tau isoforms with Alzheimer's disease abnormally hyperphosphorylated tau and in vitro phosphorylation into the disease-like protein. J. Biol. Chem. 276, 37967–37973 (2001).",{"doi":5441},"10.1074\u002Fjbc.M006497200",{"id":24,"text":5443,"url":24,"identifiers":5444},"Wang, J. Z., Grundke-Iqbal, I. & Iqbal, K. Kinases and phosphatases and tau sites involved in Alzheimer neurofibrillary degeneration. Eur. J. Neurosci. 25, 59–68 (2007).",{"doi":5445},"10.1111\u002Fj.1460-9568.2006.05226.x",{"id":24,"text":5447,"url":24,"identifiers":5448},"Pérez, M., Valpuesta, J. M., Medina, M., Montejo de Garcini, E. & Avila, J. Polymerization of tau into filaments in the presence of heparin: the minimal sequence required for tau–tau interaction. J. Neurochem. 67, 1183–1190 (1996).",{"doi":5449},"10.1046\u002Fj.1471-4159.1996.67031183.x",{"id":24,"text":5451,"url":24,"identifiers":5452},"Kontsekova, E., Zilka, N., Kovacech, B., Novak, P. & Novak, M. First-in-man tau vaccine targeting structural determinants essential for pathological tau–tau interaction reduces tau oligomerisation and neurofibrillary degeneration in an Alzheimer's disease model. Alzheimers Res. Ther. 6, 44 (2014).",{"doi":5453},"10.1186\u002Falzrt278",{"id":24,"text":5455,"url":24,"identifiers":5456},"Arnold, C. S. et al. The microtubule-associated protein tau is extensively modified with O-linked N-acetylglucosamine. J. Biol. Chem. 271, 28741–28744 (1996).",{"doi":5457},"10.1074\u002Fjbc.271.46.28741",{"id":24,"text":5459,"url":24,"identifiers":5460},"Yuzwa, S. A. et al. Mapping O-GlcNAc modification sites on tau and generation of a site-specific O-GlcNAc tau antibody. Amino Acids 40, 857–868 (2011).",{"doi":5461},"10.1007\u002Fs00726-010-0705-1",{"id":24,"text":5463,"url":24,"identifiers":5464},"Liu, F. et al. Reduced O-GlcNAcylation links lower brain glucose metabolism and tau pathology in Alzheimer's disease. Brain 132, 1820–1832 (2009).",{"doi":5465},"10.1093\u002Fbrain\u002Fawp099",{"id":24,"text":5467,"url":24,"identifiers":5468},"Gong, C. X., Liu, F., Grundke-Iqbal, I. & Iqbal, K. Impaired brain glucose metabolism leads to Alzheimer neurofibrillary degeneration through a decrease in tau O-GlcNAcylation. J. Alzheimers Dis. 9, 1–12 (2006).",{"doi":5469},"10.3233\u002FJAD-2006-9101",{"id":24,"text":5471,"url":24,"identifiers":5472},"Liu, Y., Liu, F., Grundke-Iqbal, I., Iqbal, K. & Gong, C. X. Brain glucose transporters, O-GlcNAcylation and phosphorylation of tau in diabetes and Alzheimer's disease. J. Neurochem. 111, 242–249 (2009).",{"doi":5473},"10.1111\u002Fj.1471-4159.2009.06320.x",{"id":24,"text":5475,"url":24,"identifiers":5476},"Ishiguro, K. et al. Tau protein kinase I converts normal tau protein into A68-like component of paired helical filaments. J. Biol. Chem. 267, 10897–10901 (1992).",{"doi":5477},"10.1016\u002FS0021-9258(19)50102-8",{"id":24,"text":5479,"url":24,"identifiers":5480},"Arioka, M. et al. Tau protein kinase II is involved in the regulation of the normal phosphorylation state of tau protein. J. Neurochem. 60, 461–468 (1993).",{"doi":5481},"10.1111\u002Fj.1471-4159.1993.tb03173.x",{"id":24,"text":5483,"url":24,"identifiers":5484},"Liu, F. et al. Overexpression of Dyrk1A contributes to neurofibrillary degeneration in Down syndrome. FASEB J. 22, 3224–3233 (2008).",{"doi":5485},"10.1096\u002Ffj.07-104539",{"id":24,"text":5487,"url":24,"identifiers":5488},"Woods, Y. L. et al. The kinase DYRK phosphorylates protein-synthesis initiation factor eIF2Bε at Ser539 and the microtubule-associated protein tau at Thr212: potential role for DYRK as a glycogen synthase kinase 3-priming kinase. Biochem. J. 355, 609–615 (2001).",{"doi":5489},"10.1042\u002Fbj3550609",{"id":24,"text":5491,"url":24,"identifiers":5492},"Baudier, J. & Cole, R. D. Interactions between the microtubule-associated tau proteins and S100b regulate tau phosphorylation by the Ca2+\u002Fcalmodulin-dependent protein kinase II. J. Biol. Chem. 263, 5876–5883 (1988).",{"doi":5493},"10.1016\u002FS0021-9258(18)60647-7",{"id":24,"text":5495,"url":24,"identifiers":5496},"Ledesma, M. D., Correas, I., Avila, J. & Díaz-Nido, J. Implication of brain cdc2 and MAP2 kinases in the phosphorylation of tau protein in Alzheimer's disease. FEBS Lett. 308, 218–224 (1992).",{"doi":5497},"10.1016\u002F0014-5793(92)81278-T",{"id":24,"text":5499,"url":24,"identifiers":5500},"Singh, T. J., Grundke-Iqbal, I. & Iqbal, K. Differential phosphorylation of human tau isoforms containing three repeats by several protein kinases. Arch. Biochem. Biophys. 328, 43–50 (1996).",{"doi":5501},"10.1006\u002Fabbi.1996.0140",{"id":24,"text":5503,"url":24,"identifiers":5504},"Singh, T. J., Zaidi, T., Grundke-Iqbal, I. & Iqbal, K. Non-proline-dependent protein kinases phosphorylate several sites found in tau from Alzheimer disease brain. Mol. Cell. Biochem. 154, 143–151 (1996).",{"doi":5505},"10.1007\u002FBF00226782",{"id":24,"text":5507,"url":24,"identifiers":5508},"Drewes, G., Ebneth, A., Preuss, U., Mandelkow, E. M. & Mandelkow, E. MARK, a novel family of protein kinases that phosphorylate microtubule-associated proteins and trigger microtubule disruption. Cell 89, 297–308 (1997).",{"doi":5509},"10.1016\u002FS0092-8674(00)80208-1",{"id":24,"text":5511,"url":24,"identifiers":5512},"Sironi, J. J. et al. Ser-262 in human recombinant tau protein is a markedly more favorable site for phosphorylation by CaMKII than PKA or PhK. FEBS Lett. 436, 471–475 (1998).",{"doi":5513},"10.1016\u002FS0014-5793(98)01185-5",{"id":24,"text":5515,"url":24,"identifiers":5516},"Singh, T. J., Haque, N., Grundke-Iqbal, I. & Iqbal, K. Rapid Alzheimer-like phosphorylation of tau by the synergistic actions of non-proline-dependent protein kinases and GSK-3. FEBS Lett. 358, 267–272 (1995).",{"doi":5517},"10.1016\u002F0014-5793(94)01445-7",{"id":24,"text":5519,"url":24,"identifiers":5520},"Singh, T. J., Zaidi, T., Grundke-Iqbal, I. & Iqbal, K. Modulation of GSK-3-catalyzed phosphorylation of microtubule-associated protein tau by non-proline-dependent protein kinases. FEBS Lett. 358, 4–8 (1995).",{"doi":5521},"10.1016\u002F0014-5793(94)01383-C",{"id":24,"text":5523,"url":24,"identifiers":5524},"Sengupta, A. et al. Phosphorylation of tau at both Thr 231 and Ser 262 is required for maximal inhibition of its binding to microtubules. Arch. Biochem. Biophys. 357, 299–309 (1998).",{"doi":5525},"10.1006\u002Fabbi.1998.0813",{"id":24,"text":5527,"url":24,"identifiers":5528},"Sengupta, A., Wu, Q., Grundke-Iqbal, I., Iqbal, K. & Singh, T. J. Potentiation of GSK-3-catalyzed Alzheimer-like phosphorylation of human tau by cdk5. Mol. Cell. Biochem. 167, 99–105 (1997).",{"doi":5529},"10.1023\u002FA:1006883924775",{"id":24,"text":5531,"url":24,"identifiers":5532},"Liu, F. et al. PKA modulates GSK-3β- and cdk5-catalyzed phosphorylation of tau in site- and kinase-specific manners. FEBS Lett. 580, 6269–6274 (2006).",{"doi":5533},"10.1016\u002Fj.febslet.2006.10.033",{"id":24,"text":5535,"url":24,"identifiers":5536},"Yamaguchi, H. et al. Preferential labeling of Alzheimer neurofibrillary tangles with antisera for tau protein kinase (TPK) I\u002Fglycogen synthase kinase-3 beta and cyclin-dependent kinase 5, a component of TPK II. Acta Neuropathol. 92, 232–241 (1996).",{"doi":5537},"10.1007\u002Fs004010050513",{"id":24,"text":5539,"url":24,"identifiers":5540},"Pei, J. J. et al. Accumulation of cyclin-dependent kinase 5 (cdk5) in neurons with early stages of Alzheimer's disease neurofibrillary degeneration. Brain Res. 797, 267–277 (1998).",{"doi":5541},"10.1016\u002FS0006-8993(98)00296-0",{"id":24,"text":5543,"url":24,"identifiers":5544},"Pei, J. J. et al. Distribution of active glycogen synthase kinase 3beta (GSK-3beta) in brains staged for Alzheimer disease neurofibrillary changes. J. Neuropathol. Exp. Neurol. 58, 1010–1019 (1999).",{"doi":5545},"10.1097\u002F00005072-199909000-00011",{"id":24,"text":5547,"url":24,"identifiers":5548},"Pei, J. J. et al. Localization of active forms of C-jun kinase (JNK) and p38 kinase in Alzheimer's disease brains at different stages of neurofibrillary degeneration. J. Alzheimers Dis. 3, 41–48 (2001).",{"doi":5549},"10.3233\u002FJAD-2001-3107",{"id":24,"text":5551,"url":24,"identifiers":5552},"Jin, N. et al. Truncation and activation of dual specificity tyrosine phosphorylation-regulated kinase 1A by calpain I: a molecular mechanism linked to tau pathology in Alzheimer disease. J. Biol. Chem. 290, 15219–15237 (2015).",{"doi":5553},"10.1074\u002Fjbc.M115.645507",{"id":24,"text":5555,"url":24,"identifiers":5556},"Jin, N. et al. Truncation and activation of GSK-3β by calpain I: a molecular mechanism links to tau hyperphosphorylation in Alzheimer's disease. Sci. Rep. 5, 8187 (2015).",{"doi":5557},"10.1038\u002Fsrep08187",{"id":24,"text":5559,"url":24,"identifiers":5560},"Gong, C. X. et al. Phosphorylation of microtubule-associated protein tau is regulated by protein phosphatase 2A in mammalian brain. Implications for neurofibrillary degeneration in Alzheimer's disease. J. Biol. Chem. 275, 5535–5544 (2000).",{"doi":5561},"10.1074\u002Fjbc.275.8.5535",{"id":24,"text":5563,"url":24,"identifiers":5564},"Bennecib, M., Gong, C. X., Grundke-Iqbal, I. & Iqbal, K. Role of protein phosphatase-2A and -1 in the regulation of GSK-3, cdk5 and cdc2 and the phosphorylation of tau in rat forebrain. FEBS Lett. 485, 87–93 (2000).",{"doi":5565},"10.1016\u002FS0014-5793(00)02203-1",{"id":24,"text":5567,"url":24,"identifiers":5568},"Liu, F., Grundke-Iqbal, I., Iqbal, K. & Gong, C. X. Contributions of protein phosphatases PP1, PP2A, PP2B and PP5 to the regulation of tau phosphorylation. Eur. J. Neurosci. 22, 1942–1950 (2005).",{"doi":5569},"10.1111\u002Fj.1460-9568.2005.04391.x",{"id":24,"text":5571,"url":24,"identifiers":5572},"Iqbal, K. et al. Tau pathology in Alzheimer disease and other tauopathies. Biochim. Biophys. Acta 1739, 198–210 (2005).",{"doi":5573},"10.1016\u002Fj.bbadis.2004.09.008",{"id":24,"text":5575,"url":24,"identifiers":5576},"Sengupta, A., Novak, M., Grundke-Iqbal, I. & Iqbal, K. Regulation of phosphorylation of tau by cyclin-dependent kinase 5 and glycogen synthase kinase-3 at substrate level. FEBS Lett. 580, 5925–5933 (2006).",{"doi":5577},"10.1016\u002Fj.febslet.2006.09.060",{"id":24,"text":5579,"url":24,"identifiers":5580},"Qian, W. & Liu, F. Regulation of alternative splicing of tau exon 10. Neurosci. Bull. 30, 367–377 (2014).",{"doi":5581},"10.1007\u002Fs12264-013-1411-2",{"id":24,"text":5583,"url":24,"identifiers":5584},"Virshup, D. M. Protein phosphatase 2A: a panoply of enzymes. Curr. Opin. Cell Biol. 12, 180–185 (2000).",{"doi":5585},"10.1016\u002FS0955-0674(99)00074-5",{"id":24,"text":5587,"url":24,"identifiers":5588},"McCright, B., Brothman, A. R. & Virshup, D. M. Assignment of human protein phosphatase 2A regulatory subunit genes B56α, B56β, B56γ, B56δ, and B56ε (PPP2R5A–PPP2R5E), highly expressed in muscle and brain, to chromosome regions 1q41, 11q12, 3p21, 6p21.1, and 7p11.2 → p12. Genomics 36, 168–170 (1996).",{"doi":5589},"10.1006\u002Fgeno.1996.0438",{"id":24,"text":5591,"url":24,"identifiers":5592},"McCright, B. & Virshup, D. M. Identification of a new family of protein phosphatase 2A regulatory subunits. J. Biol. Chem. 270, 26123–26128 (1995).",{"doi":5593},"10.1074\u002Fjbc.270.44.26123",{"id":24,"text":5595,"url":24,"identifiers":5596},"Chen, J., Martin, B. L. & Brautigan, D. L. Regulation of protein serine–threonine phosphatase type-2A by tyrosine phosphorylation. Science 257, 1261–1264 (1992).",{"doi":5597},"10.1126\u002Fscience.1325671",{"id":24,"text":5599,"url":24,"identifiers":5600},"Lee, J. & Stock, J. Protein phosphatase 2A catalytic subunit is methyl-esterified at its carboxyl terminus by a novel methyltransferase. J. Biol. Chem. 268, 19192–19195 (1993).",{"doi":5601},"10.1016\u002FS0021-9258(19)36497-X",{"id":24,"text":5603,"url":24,"identifiers":5604},"Lee, J., Chen, Y., Tolstykh, T. & Stock, J. A specific protein carboxyl methylesterase that demethylates phosphoprotein phosphatase 2A in bovine brain. Proc. Natl Acad. Sci. USA 93, 6043–6047 (1996).",{"doi":5605},"10.1073\u002Fpnas.93.12.6043",{"id":24,"text":5607,"url":24,"identifiers":5608},"Tolstykh, T., Lee, J., Vafai, S. & Stock, J. B. Carboxyl methylation regulates phosphoprotein phosphatase 2A by controlling the association of regulatory B subunits. EMBO J. 19, 5682–5691 (2000).",{"doi":5609},"10.1093\u002Femboj\u002F19.21.5682",{"id":24,"text":5611,"url":24,"identifiers":5612},"Wu, J. et al. Carboxyl methylation of the phosphoprotein phosphatase 2A catalytic subunit promotes its functional association with regulatory subunits in vivo. EMBO J. 19, 5672–5681 (2000).",{"doi":5613},"10.1093\u002Femboj\u002F19.21.5672",{"id":24,"text":5615,"url":24,"identifiers":5616},"Longin, S. et al. Selection of protein phosphatase 2A regulatory subunits is mediated by the C terminus of the catalytic subunit. J. Biol. Chem. 282, 26971–26980 (2007).",{"doi":5617},"10.1074\u002Fjbc.M704059200",{"id":24,"text":5619,"url":24,"identifiers":5620},"Li, M., Lyon, M. K. & Garcea, R. L. In vitro phosphorylation of the polyomavirus major capsid protein VP1 on serine 66 by casein kinase II. J. Biol. Chem. 270, 26006–26011 (1995).",{"doi":5621},"10.1074\u002Fjbc.270.43.26006",{"id":24,"text":5623,"url":24,"identifiers":5624},"Li, M., Makkinje, A. & Damuni, Z. Molecular identification of I1PP2A, a novel potent heat-stable inhibitor protein of protein phosphatase 2A. Biochemistry 35, 6998–7002 (1996).",{"doi":5625},"10.1021\u002Fbi960581y",{"id":24,"text":5627,"url":24,"identifiers":5628},"Li, M., Makkinje, A. & Damuni, Z. The myeloid leukemia-associated protein SET is a potent inhibitor of protein phosphatase 2A. J. Biol. Chem. 271, 11059–11062 (1996).",{"doi":5629},"10.1074\u002Fjbc.271.19.11059",{"id":24,"text":5631,"url":24,"identifiers":5632},"Campion, D. et al. Early-onset autosomal dominant Alzheimer disease: prevalence, genetic heterogeneity, and mutation spectrum. Am. J. Hum. Genet. 65, 664–670 (1999).",{"doi":5633},"10.1086\u002F302553",{"id":24,"text":5635,"url":24,"identifiers":5636},"Corder, E. H. et al. Gene dose of apolipoprotein E type 4 allele and the risk of Alzheimer's disease in late onset families. Science 261, 921–923 (1993).",{"doi":3214},{"id":24,"text":5638,"url":24,"identifiers":5639},"Guerreiro, R. et al. TREM2 variants in Alzheimer's disease. N. Engl. J. Med. 368, 117–127 (2013).",{"doi":3202},{"id":24,"text":5641,"url":24,"identifiers":5642},"Jonsson, T. et al. Variant of TREM2 associated with the risk of Alzheimer's disease. N. Engl. J. Med. 368, 107–116 (2013).",{"doi":3198},{"id":24,"text":5644,"url":24,"identifiers":5645},"Halfon, S., Patel, S., Vega, F., Zurawski, S. & Zurawski, G. Autocatalytic activation of human legumain at aspartic acid residues. FEBS Lett. 438, 114–118 (1998).",{"doi":5646},"10.1016\u002FS0014-5793(98)01281-2",{"id":24,"text":5648,"url":24,"identifiers":5649},"Li, D. N., Matthews, S. P., Antoniou, A. N., Mazzeo, D. & Watts, C. Multistep autoactivation of asparaginyl endopeptidase in vitro and in vivo. J. Biol. Chem. 278, 38980–38990 (2003).",{"doi":5650},"10.1074\u002Fjbc.M305930200",{"id":24,"text":5652,"url":24,"identifiers":5653},"Liu, Z. et al. Neuroprotective actions of PIKE-L by inhibition of SET proteolytic degradation by asparagine endopeptidase. Mol. Cell 29, 665–678 (2008).",{"doi":5654},"10.1016\u002Fj.molcel.2008.02.017",{"id":24,"text":5656,"url":24,"identifiers":5657},"Arnaud, L. et al. Mechanism of inhibition of PP2A activity and abnormal hyperphosphorylation of tau by I2PP2A\u002FSET. FEBS Lett. 585, 2653–2659 (2011).",{"doi":5658},"10.1016\u002Fj.febslet.2011.07.020",{"id":24,"text":5660,"url":24,"identifiers":5661},"Lee, V. M., Goedert, M. & Trojanowski, J. Q. Neurodegenerative tauopathies. Annu. Rev. Neurosci. 24, 1121–1159 (2001).",{"doi":5662},"10.1146\u002Fannurev.neuro.24.1.1121",{"id":24,"text":5664,"url":24,"identifiers":5665},"Murch, S. J., Cox, P. A. & Banack, S. A. A mechanism for slow release of biomagnified cyanobacterial neurotoxins and neurodegenerative disease in Guam. Proc. Natl Acad. Sci. USA 101, 12228–12231 (2004).",{"doi":5666},"10.1073\u002Fpnas.0404926101",{"id":24,"text":5668,"url":24,"identifiers":5669},"Pablo, J. et al. Cyanobacterial neurotoxin BMAA in ALS and Alzheimer's disease. Acta Neurol. Scand. 120, 216–225 (2009).",{"doi":5670},"10.1111\u002Fj.1600-0404.2008.01150.x",{"id":24,"text":5672,"url":24,"identifiers":5673},"Liang, Z. et al. Decrease of protein phosphatase 2A and its association with accumulation and hyperphosphorylation of tau in Down syndrome. J. Alzheimers Dis. 13, 295–302 (2008).",{"doi":5674},"10.3233\u002FJAD-2008-13307",{"id":24,"text":5676,"url":24,"identifiers":5677},"Iqbal, K., Zaidi, T., Bancher, C. & Grundke-Iqbal, I. Alzheimer paired helical filaments. Restoration of the biological activity by dephosphorylation. FEBS Lett. 349, 104–108 (1994).",{"doi":5678},"10.1016\u002F0014-5793(94)00650-4",{"id":24,"text":5680,"url":24,"identifiers":5681},"Alonso, A. D., Li, B., Grundke-Iqbal, I. & Iqbal, K. Polymerization of hyperphosphorylated tau into filaments eliminates its inhibitory activity. Proc. Natl Acad. Sci. USA 23, 8864–8869 (2006).",{"doi":5682},"10.1073\u002Fpnas.0603214103",{"id":24,"text":5684,"url":24,"identifiers":5685},"Takeda, S. et al. Neuronal uptake and propagation of a rare phosphorylated high-molecular-weight tau derived from Alzheimer's disease brain. Nat. Commun. 6, 8490 (2015).",{"doi":5686},"10.1038\u002Fncomms9490",{"id":24,"text":5688,"url":24,"identifiers":5689},"Sanders, D. W. et al. Distinct tau prion strains propagate in cells and mice and define different tauopathies. Neuron 82, 1271–1288 (2014).",{"doi":5690},"10.1016\u002Fj.neuron.2014.04.047",{"id":24,"text":5692,"url":24,"identifiers":5693},"Khan, U. A. et al. Molecular drivers and cortical spread of lateral entorhinal cortex dysfunction in preclinical Alzheimer's disease. Nat. Neurosci. 17, 304–311 (2014).",{"doi":5694},"10.1038\u002Fnn.3606",{"id":24,"text":5696,"url":24,"identifiers":5697},"de Calignon, A. et al. Propagation of tau pathology in a model of early Alzheimer's disease. Neuron 73, 685–697 (2012).",{"doi":5698},"10.1016\u002Fj.neuron.2011.11.033",{"id":24,"text":5700,"url":24,"identifiers":5701},"Liu, L. et al. Trans-synaptic spread of tau pathology in vivo. PLoS ONE 7, e31302 (2012).",{"doi":5702},"10.1371\u002Fjournal.pone.0031302",{"id":24,"text":5704,"url":24,"identifiers":5705},"Asai, H. et al. Depletion of microglia and inhibition of exosome synthesis halt tau propagation. Nat. Neurosci. 18, 1584–1593 (2015).",{"doi":5706},"10.1038\u002Fnn.4132",{"id":24,"text":5708,"url":24,"identifiers":5709},"Reiman, E. M. et al. Alzheimer's Prevention Initiative: a plan to accelerate the evaluation of presymptomatic treatments. J. Alzheimers Dis. 26 (Suppl. 3), 321–329 (2011).",{"doi":5710},"10.3233\u002FJAD-2011-0059",{"id":24,"text":5712,"url":24,"identifiers":5713},"Moulder, K. L. et al. Dominantly Inherited Alzheimer Network: facilitating research and clinical trials. Alzheimers Res. Ther. 5, 48 (2013).",{"doi":5714},"10.1186\u002Falzrt213",{"id":24,"text":5716,"url":24,"identifiers":5717},"US National Library of Medicine. ClinicalTrials.gov [online] , (2015).",{},{"id":24,"text":5719,"url":24,"identifiers":5720},"Lovestone, S. et al. A Phase II trial of tideglusib in Alzheimer's disease. J. Alzheimers Dis. 45, 75–88 (2015).",{"doi":5721},"10.3233\u002FJAD-141959",{"id":24,"text":5723,"url":24,"identifiers":5724},"Forlenza, O. V., De-Paula, V. J. & Diniz, B. S. Neuroprotective effects of lithium: implications for the treatment of Alzheimer's disease and related neurodegenerative disorders. ACS Chem. Neurosci. 5, 443–450 (2014).",{"doi":5725},"10.1021\u002Fcn5000309",{"id":24,"text":5727,"url":24,"identifiers":5728},"Tariot, P. N. et al. Chronic divalproex sodium to attenuate agitation and clinical progression of Alzheimer disease. Arch. Gen. Psychiatry 68, 853–861 (2011).",{"doi":5729},"10.1001\u002Farchgenpsychiatry.2011.72",{"id":24,"text":5731,"url":24,"identifiers":5732},"Basurto-Islas, G. et al. Therapeutic benefits of a component of coffee in a rat model of Alzheimer's disease. Neurobiol. Aging 35, 2701–2712 (2014).",{"doi":5733},"10.1016\u002Fj.neurobiolaging.2014.06.012",{"id":24,"text":5735,"url":24,"identifiers":5736},"Kickstein, E. et al. Biguanide metformin acts on tau phosphorylation via mTOR\u002Fprotein phosphatase 2A (PP2A) signaling. Proc. Natl Acad. Sci. USA 107, 21830–21835 (2010).",{"doi":5737},"10.1073\u002Fpnas.0912793107",{"id":24,"text":5739,"url":24,"identifiers":5740},"van Eersel, J. et al. Sodium selenate mitigates tau pathology, neurodegeneration, and functional deficits in Alzheimer's disease models. Proc. Natl Acad. Sci. USA 107, 13888–13893 (2010).",{"doi":5741},"10.1073\u002Fpnas.1009038107",{"id":24,"text":5743,"url":24,"identifiers":5744},"Yuzwa, S. A. et al. A potent mechanism-inspired O-GlcNAcase inhibitor that blocks phosphorylation of tau in vivo. Nat. Chem. Biol. 4, 483–490 (2008).",{"doi":5745},"10.1038\u002Fnchembio.96",{"id":24,"text":5747,"url":24,"identifiers":5748},"Petrucelli, L. et al. CHIP and Hsp70 regulate tau ubiquitination, degradation and aggregation. Hum. Mol. Genet. 13, 703–714 (2004).",{"doi":5749},"10.1093\u002Fhmg\u002Fddh083",{"id":24,"text":2922,"url":24,"identifiers":5751},{"doi":2924},{"id":24,"text":5753,"url":24,"identifiers":5754},"Shibuya, Y. et al. Acyl-coenzyme A:cholesterol acyltransferase 1 blockage enhances autophagy in the neurons of triple transgenic Alzheimer's disease mouse and reduces human P301L-tau content at the presymptomatic stage. Neurobiol. Aging 36, 2248–2259 (2015).",{"doi":5755},"10.1016\u002Fj.neurobiolaging.2015.04.002",{"id":24,"text":5757,"url":24,"identifiers":5758},"Harrington, C. R. et al. Cellular models of aggregation-dependent template-directed proteolysis to characterize tau aggregation inhibitors for treatment of Alzheimer disease. J. Biol. Chem. 290, 10862–10875 (2015).",{"doi":5759},"10.1074\u002Fjbc.M114.616029",{"id":24,"text":5761,"url":24,"identifiers":5762},"Hochgrafe, K. et al. Preventive methylene blue treatment preserves cognition in mice expressing full-length pro-aggregant human Tau. Acta Neuropathol. Commun. 3, 25 (2015).",{"doi":5763},"10.1186\u002Fs40478-015-0204-4",{"id":24,"text":5765,"url":24,"identifiers":5766},"Wischik, C. M., Harrington, C. R. & Storey, J. M. Tau-aggregation inhibitor therapy for Alzheimer's disease. Biochem. Pharmacol. 88, 529–539 (2014).",{"doi":5767},"10.1016\u002Fj.bcp.2013.12.008",{"id":24,"text":5769,"url":24,"identifiers":5770},"US National Library of Medicine. ClinicalTrials.gov [online] , (2014).",{},{"id":24,"text":5769,"url":24,"identifiers":5772},{},{"id":24,"text":5716,"url":24,"identifiers":5774},{},{"id":24,"text":5776,"url":24,"identifiers":5777},"Congdon, E. E., Gu, J., Sait, H. B. & Sigurdsson, E. M. Antibody uptake into neurons occurs primarily via clathrin-dependent Fcγ receptor endocytosis and is a prerequisite for acute tau protein clearance. J. Biol. Chem. 288, 35452–35465 (2013).",{"doi":5778},"10.1074\u002Fjbc.M113.491001",{"id":24,"text":5780,"url":24,"identifiers":5781},"Chai, X. et al. Passive immunization with anti-Tau antibodies in two transgenic models: reduction of Tau pathology and delay of disease progression. J. Biol. Chem. 286, 34457–34467 (2011).",{"doi":5782},"10.1074\u002Fjbc.M111.229633",{"id":24,"text":5784,"url":24,"identifiers":5785},"Yanamandra, K. et al. Anti-tau antibodies that block tau aggregate seeding in vitro markedly decrease pathology and improve cognition in vivo. Neuron 80, 402–414 (2013).",{"doi":5786},"10.1016\u002Fj.neuron.2013.07.046",{"id":24,"text":5788,"url":24,"identifiers":5789},"Castillo-Carranza, D. L. et al. Passive immunization with Tau oligomer monoclonal antibody reverses tauopathy phenotypes without affecting hyperphosphorylated neurofibrillary tangles. J. Neurosci. 34, 4260–4272 (2014).",{"doi":5790},"10.1523\u002FJNEUROSCI.3192-13.2014",{"id":24,"text":5792,"url":24,"identifiers":5793},"Dai, C. L. et al. Passive immunization targeting the N-terminal projection domain of tau decreases tau pathology and improves cognition in a transgenic mouse model of Alzheimer disease and tauopathies. J. Neural Transm. (Vienna) 122, 607–617 (2015).",{"doi":5794},"10.1007\u002Fs00702-014-1315-y",{"id":24,"text":5796,"url":24,"identifiers":5797},"Funk, K. E., Mirbaha, H., Jiang, H., Holtzman, D. M. & Diamond, M. I. Distinct therapeutic mechanisms of Tau antibodies: promoting microglial clearance versus blocking neuronal uptake. J. Biol. Chem. 290, 21652–21662 (2015).",{"doi":5798},"10.1074\u002Fjbc.M115.657924",{"id":24,"text":5800,"url":24,"identifiers":5801},"Pedersen, J. T. & Sigurdsson, E. M. Tau immunotherapy for Alzheimer's disease. Trends Mol. Med. 21, 394–402 (2015).",{"doi":5802},"10.1016\u002Fj.molmed.2015.03.003",{"id":24,"text":2898,"url":24,"identifiers":5804},{"doi":2900},{"id":24,"text":5806,"url":24,"identifiers":5807},"Gozes, I., Schirer, Y., Idan-Feldman, A., David, M. & Furman-Assaf, S. NAP alpha-aminoisobutyric acid (IsoNAP). J. Mol. Neurosci. 52, 1–9 (2014).",{"doi":5808},"10.1007\u002Fs12031-013-0103-8",{"id":24,"text":5810,"url":24,"identifiers":5811},"Li, B. et al. Failure of neuronal maturation in Alzheimer disease dentate gyrus. J. Neuropathol. Exp. Neurol. 67, 78–84 (2008).",{"doi":5812},"10.1097\u002Fnen.0b013e318160c5db",{"id":24,"text":5814,"url":24,"identifiers":5815},"Kazim, S. F. et al. Disease modifying effect of chronic oral treatment with a neurotrophic peptidergic compound in a triple transgenic mouse model of Alzheimer's disease. Neurobiol. Dis. 71, 110–130 (2014).",{"doi":5816},"10.1016\u002Fj.nbd.2014.07.001",{"id":24,"text":5818,"url":24,"identifiers":5819},"Blanchard, J. et al. Pharmacologic reversal of neurogenic and neuroplastic abnormalities and cognitive impairments without affecting Aβ and tau pathologies in 3xTg-AD mice. Acta Neuropathol. 120, 605–621 (2010).",{"doi":5820},"10.1007\u002Fs00401-010-0734-6",{"id":24,"text":5822,"url":24,"identifiers":5823},"Chohan, M. O. et al. Enhancement of dentate gyrus neurogenesis, dendritic and synaptic plasticity and memory by a neurotrophic peptide. Neurobiol. Aging 32, 1420–1434 (2011).",{"doi":5824},"10.1016\u002Fj.neurobiolaging.2009.08.008",{"id":24,"text":5826,"url":24,"identifiers":5827},"Bolognin, S., Buffelli, M., Puolivali, J. & Iqbal, K. Rescue of cognitive-aging by administration of a neurogenic and\u002For neurotrophic compound. Neurobiol. Aging 35, 2134–2146 (2014).",{"doi":5828},"10.1016\u002Fj.neurobiolaging.2014.02.017",{"id":24,"text":5830,"url":24,"identifiers":5831},"Rosenmann, H. et al. Tauopathy-like abnormalities and neurologic deficits in mice immunized with neuronal tau protein. Arch. Neurol. 63, 1459–1467 (2006).",{"doi":5832},"10.1001\u002Farchneur.63.10.1459",{"id":24,"text":5834,"url":24,"identifiers":5835},"Brion, J. P., Couck, A. M., Passareiro, E. & Flament-Durand, J. Neurofibrillary tangles of Alzheimer's disease: an immunohistochemical study. J. Submicrosc. Cytol. 17, 89–96 (1985).",{},{"id":24,"text":5837,"url":24,"identifiers":5838},"Delacourte, A. & Defossez, A. Alzheimer's disease: Tau proteins, the promoting factors of microtubule assembly, are major components of paired helical filaments. J. Neurol. Sci. 76, 173–186 (1986).",{"doi":5839},"10.1016\u002F0022-510X(86)90167-X",{"id":24,"text":5841,"url":24,"identifiers":5842},"Ihara, Y., Nukina, N., Miura, R. & Ogawara, M. Phosphorylated tau protein is integrated into paired helical filaments in Alzheimer's disease. J. Biochem. 99, 1807–1810 (1986).",{"doi":5843},"10.1093\u002Foxfordjournals.jbchem.a135662",{"id":24,"text":5845,"url":24,"identifiers":5846},"Kosik, K. S., Joachim, C. L. & Selkoe, D. J. Microtubule-associated protein tau (τ) is a major antigenic component of paired helical filaments in Alzheimer disease. Proc. Natl Acad. Sci. USA 83, 4044–4048 (1986).",{"doi":5847},"10.1073\u002Fpnas.83.11.4044",{"id":24,"text":5849,"url":24,"identifiers":5850},"Spillantini, M. G. et al. Familial multiple system tauopathy with presenile dementia: a disease with abundant neuronal and glial tau filaments. Proc. Natl Acad. Sci. USA 94, 4113–4118 (1997).",{"doi":5851},"10.1073\u002Fpnas.94.8.4113",{"id":24,"text":5853,"url":24,"identifiers":5854},"Hong, M. et al. Mutation-specific functional impairments in distinct tau isoforms of hereditary FTDP-17. Science 282, 1914–1917 (1998).",{"doi":5855},"10.1126\u002Fscience.282.5395.1914",{"id":24,"text":5857,"url":24,"identifiers":5858},"Maeda, S. et al. Increased levels of granular tau oligomers: an early sign of brain aging and Alzheimer's disease. Neurosci. Res. 54, 197–201 (2006).",{"doi":5859},"10.1016\u002Fj.neures.2005.11.009",{"id":24,"text":5861,"url":24,"identifiers":5862},"Maeda, S. et al. Granular tau oligomers as intermediates of tau filaments. Biochemistry 46, 3856–3861 (2007).",{"doi":5863},"10.1021\u002Fbi061359o",{"id":24,"text":5865,"url":24,"identifiers":5866},"Shi, J. et al. Increased dosage of Dyrk1A alters alternative splicing factor (ASF)-regulated alternative splicing of tau in Down syndrome. J. Biol. Chem. 283, 28660–28669 (2008).",{"doi":5867},"10.1074\u002Fjbc.M802645200",{"id":24,"text":5869,"url":24,"identifiers":5870},"Chen, Y. et al. Intranasal insulin prevents anesthesia-induced hyperphosphorylation of tau in 3xTg-AD mice. Front. 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M. E. & Bartholdi, D. Degeneration and regeneration of axons in the lesioned spinal cord. Physiol. Rev. 76, 319–370 (1996).",{"doi":5973},"10.1152\u002Fphysrev.1996.76.2.319",{"id":24,"text":5975,"url":24,"identifiers":5976},"Raineteau, O. & Schwab, M. E. Plasticity of motor systems after incomplete spinal cord injury. Nat. Rev. Neurosci. 2, 263–273 (2001).",{"doi":5977},"10.1038\u002F35067570",{"id":24,"text":5979,"url":24,"identifiers":5980},"Deumens, R., Koopmans, G. C. & Joosten, E. A. Regeneration of descending axon tracts after spinal cord injury. Prog. Neurobiol. 77, 57–89 (2005).",{"doi":5981},"10.1016\u002Fj.pneurobio.2005.10.004",{"id":24,"text":5983,"url":24,"identifiers":5984},"Dietz, V. & Curt, A. Neurological aspects of spinal-cord repair: promises and challenges. Lancet Neurol. 5, 688–694 (2006).",{"doi":5985},"10.1016\u002FS1474-4422(06)70522-1",{"id":24,"text":5987,"url":24,"identifiers":5988},"Raisman, G. A promising therapeutic approach to spinal cord repair. J. R. Soc. Med. 96, 259–261 (2003).",{"doi":5989},"10.1177\u002F014107680309600601",{"id":24,"text":5991,"url":24,"identifiers":5992},"Barnett, S. C. & Chang, L. Olfactory ensheathing cells and CNS repair: going solo or in need of a friend? Trends Neurosci. 27, 54–60 (2004).",{"doi":5993},"10.1016\u002Fj.tins.2003.10.011",{"id":24,"text":5995,"url":24,"identifiers":5996},"Li, Y., Field, P. M. & Raisman, G. Repair of adult rat corticospinal tract by transplants of olfactory ensheathing cells. Science 277, 2000–2002 (1997).",{"doi":5997},"10.1126\u002Fscience.277.5334.2000",{"id":24,"text":5999,"url":24,"identifiers":6000},"Ramón-Cueto, A., Cordero, M. I., Santos-Benito, F. F. & Avila, J. Functional recovery of paraplegic rats and motor axon regeneration in their spinal cords by olfactory ensheathing glia. Neuron 25, 425–435 (2000).",{"doi":6001},"10.1016\u002FS0896-6273(00)80905-8",{"id":24,"text":6003,"url":24,"identifiers":6004},"Mackay-Sim, A.  et al. Autologous olfactory ensheathing cell transplantation in human paraplegia: a 3-year clinical trial. Brain 131, 2376–2386 (2008).",{"doi":6005},"10.1093\u002Fbrain\u002Fawn173",{"id":24,"text":6007,"url":24,"identifiers":6008},"Curt, A. & Dietz, V. Controversial treatments for spinal-cord injuries. Lancet 365, 841 (2005).",{"doi":6009},"10.1016\u002FS0140-6736(05)71031-X",{"id":24,"text":6011,"url":24,"identifiers":6012},"Dobkin, B. H., Curt, A. & Guest, J. Cellular transplants in China: observational study from the largest human experiment in chronic spinal cord injury. Neurorehabil. Neural Repair 20, 5–13 (2006).",{"doi":6013},"10.1177\u002F1545968305284675",{"id":24,"text":6015,"url":24,"identifiers":6016},"Dietz, V. Ready for human spinal cord repair? Brain 131, 2240–2242 (2008).",{"doi":6017},"10.1093\u002Fbrain\u002Fawn185",{"id":24,"text":6019,"url":24,"identifiers":6020},"Houle, J. D. & Tessler, A. Repair of chronic spinal cord injury. Exp. Neurol. 182, 247–260 (2003).",{"doi":6021},"10.1016\u002FS0014-4886(03)00029-3",{"id":24,"text":6023,"url":24,"identifiers":6024},"Ye, J. H. & Houle, J. D. Treatment of the chronically injured spinal cord with neurotrophic factors can promote axonal regeneration from supraspinal neurons. Exp. Neurol. 143, 70–81 (1997).",{"doi":6025},"10.1006\u002Fexnr.1996.6353",{"id":24,"text":6027,"url":24,"identifiers":6028},"Karimi-Abdolrezaee, S., Eftekharpour, E., Wang, J., Morshead, C. M. & Fehlings, M. G. Delayed transplantation of adult neural precursor cells promotes remyelination and functional neurological recovery after spinal cord injury. J. Neurosci. 26, 3377–3389 (2006).",{"doi":6029},"10.1523\u002FJNEUROSCI.4184-05.2006",{"id":24,"text":6031,"url":24,"identifiers":6032},"Nomura, H.  et al. Delayed implantation of intramedullary chitosan channels containing nerve grafts promotes extensive axonal regeneration after spinal cord injury. Neurosurgery 63, 127–141 (2008).",{"doi":6033},"10.1227\u002F01.NEU.0000335080.47352.31",{"id":24,"text":6035,"url":24,"identifiers":6036},"Klapka, N.  et al. Suppression of fibrous scarring in spinal cord injury of rat promotes long-distance regeneration of corticospinal tract axons, rescue of primary motoneurons in somatosensory cortex and significant functional recovery. Eur. J. Neurosci. 22, 3047–3058 (2005).",{"doi":6037},"10.1111\u002Fj.1460-9568.2005.04495.x",{"id":24,"text":6039,"url":24,"identifiers":6040},"Guest, J. D., Hiester, E. D. & Bunge, R. P. Demyelination and Schwann cell responses adjacent to injury epicenter cavities following chronic human spinal cord injury. Exp. Neurol. 192, 384–393 (2005).",{"doi":6041},"10.1016\u002Fj.expneurol.2004.11.033",{"id":24,"text":6043,"url":24,"identifiers":6044},"Dietz, V., Grillner, S., Trepp, A., Hubli, M. & Bolliger, M. Changes in spinal reflex and locomotor activity after a complete spinal cord injury: a common mechanism? Brain 132, 2196–2205 (2009).",{"doi":6045},"10.1093\u002Fbrain\u002Fawp124",{"id":24,"text":6047,"url":24,"identifiers":6048},"Dietz, V. & Müller, R. Degradation of neuronal function following a spinal cord injury: mechanisms and countermeasures. Brain 127, 2221–2231 (2004).",{"doi":6049},"10.1093\u002Fbrain\u002Fawh255",{"id":24,"text":6051,"url":24,"identifiers":6052},"Curt, A., Alkadhi, H., Crelier, G. R., Boendermaker, S. H., Hepp-Reymond, M. C. & Kollias, S. S. Changes of non-affected upper limb cortical representation in paraplegic patients as assessed by fMRI. Brain 125, 2567–2578 (2002).",{"doi":6053},"10.1093\u002Fbrain\u002Fawf250",{"id":24,"text":6055,"url":24,"identifiers":6056},"Halder, P.  et al. Preserved aspects of cortical foot control in paraplegia. Neuroimage 31, 692–698 (2006).",{"doi":6057},"10.1016\u002Fj.neuroimage.2005.12.018",{"id":24,"text":6059,"url":24,"identifiers":6060},"Hotz-Boendermaker, S.  et al. Preservation of motor programs in paraplegics as demonstrated by attempted and imagined foot movements. Neuroimage 39, 383–394 (2008).",{"doi":6061},"10.1016\u002Fj.neuroimage.2007.07.065",{"id":24,"text":6063,"url":24,"identifiers":6064},"Dietz, V., Colombo, G., Jensen, L. & Baumgartner, L. Locomotor capacity of spinal cord in paraplegic patients. Ann. Neurol. 37, 574–582 (1995).",{"doi":6065},"10.1002\u002Fana.410370506",{"id":24,"text":6067,"url":24,"identifiers":6068},"Dietz, V., Müller, R. & Colombo, G. Locomotor activity in spinal man: significance of afferent input from joint and load receptors. Brain 125, 2626–2634 (2002).",{"doi":6069},"10.1093\u002Fbrain\u002Fawf273",{"id":24,"text":6071,"url":24,"identifiers":6072},"Dobkin, B. H., Harkema, S., Requejo, P. & Edgerton, V. R. Modulation of locomotor-like EMG activity in subjects with complete and incomplete spinal cord injury. J. Neurol. Rehab. 9, 183–190 (1995).",{},{"id":24,"text":6074,"url":24,"identifiers":6075},"Harkema, S. J.  et al. Human lumbosacral spinal cord interprets loading during stepping. J. Neurophysiol. 77, 797–811 (1997).",{"doi":6076},"10.1152\u002Fjn.1997.77.2.797",{"id":24,"text":6078,"url":24,"identifiers":6079},"Andersson, O. & Grillner, S. Peripheral control of the cat's step cycle. II. Entrainment of the central pattern generators for locomotion by sinusoidal hip movements during “fictive locomotion”. Acta Physiol. Scand. 118, 229–239 (1983).",{"doi":6080},"10.1111\u002Fj.1748-1716.1983.tb07267.x",{"id":24,"text":6082,"url":24,"identifiers":6083},"Duysens, J. & Pearson, K. G. Inhibition of flexor burst generation by loading ankle extensor muscles in walking cats. Brain Res. 187, 321–332 (1980).",{"doi":6084},"10.1016\u002F0006-8993(80)90206-1",{"id":24,"text":6086,"url":24,"identifiers":6087},"Pearson, K. G. Proprioceptive regulation of locomotion. Curr. Opin. Neurobiol. 5, 786–791 (1995).",{"doi":6088},"10.1016\u002F0959-4388(95)80107-3",{"id":24,"text":6090,"url":24,"identifiers":6091},"Andersen, O. K., Finnerup, N. B., Spaich, E. G., Jensen, T. S. & Arendt-Nielsen, L. Expansion of nociceptive withdrawal reflex receptive fields in spinal cord injured humans. Clin. Neurophysiol. 115, 2798–2810 (2004).",{"doi":6092},"10.1016\u002Fj.clinph.2004.07.003",{"id":24,"text":6094,"url":24,"identifiers":6095},"Hornby, T. G., Rymer, W. Z., Benz, E. N. & Schmit, B. D. Windup of flexion reflexes in chronic human spinal cord injury: a marker for neuronal plateau potentials? J. Neurophysiol. 89, 416–426 (2003).",{"doi":6096},"10.1152\u002Fjn.00979.2001",{"id":24,"text":6098,"url":24,"identifiers":6099},"Conway, B. A. & Knikou, M. The action of plantar pressure on flexion reflex pathways in the isolated human spinal cord. Clin. Neurophysiol. 119, 892–896 (2008).",{"doi":6100},"10.1016\u002Fj.clinph.2007.12.015",{"id":24,"text":6102,"url":24,"identifiers":6103},"Schmit, B. D., McKenna-Cole, A. & Rymer, W. Z. Flexor reflexes in chronic spinal cord injury triggered by imposed ankle rotation. Muscle Nerve 23, 793–803 (2000).",{"doi":6104},"10.1002\u002F(SICI)1097-4598(200005)23:5\u003C793::AID-MUS18>3.0.CO;2-T",{"id":24,"text":6106,"url":24,"identifiers":6107},"Hiersemenzel, L. P., Curt, A. & Dietz, V. From spinal shock to spasticity: neuronal adaptations to a spinal cord injury. Neurology 54, 1574–1582 (2000).",{"doi":6108},"10.1212\u002FWNL.54.8.1574",{"id":24,"text":6110,"url":24,"identifiers":6111},"Lavrov, I.  et al. Plasticity of spinal cord reflexes after a complete transection in adult rats: relationship to stepping ability. J. Neurophysiol. 96, 1699–1710 (2006).",{"doi":6112},"10.1152\u002Fjn.00325.2006",{"id":24,"text":6114,"url":24,"identifiers":6115},"Valero-Cabré, A., Forés, J. & Navarro, X. Reorganization of reflex responses mediated by different afferent sensory fibers after spinal cord transection. J. Neurophysiol. 91, 2838–2848 (2004).",{"doi":6116},"10.1152\u002Fjn.01177.2003",{"id":24,"text":6118,"url":24,"identifiers":6119},"Jankowska, E., Jukes, M. G., Lund, S. & Lundberg, A. The effect of DOPA on the spinal cord. 6. Half-centre organization of interneurones transmitting effects from the flexor reflex afferents. Acta Physiol. Scand. 70, 389–402 (1967).",{"doi":6120},"10.1111\u002Fj.1748-1716.1967.tb03637.x",{"id":24,"text":6122,"url":24,"identifiers":6123},"Forssberg, H. & Grillner, S. The locomotion of the acute spinal cat injected with clonidine i.v. Brain Res. 50, 184–186 (1973).",{"doi":6124},"10.1016\u002F0006-8993(73)90606-9",{"id":24,"text":6126,"url":24,"identifiers":6127},"Grillner, S. & Zangger, P. On the central generation of locomotion in the low spinal cat. Exp. Brain Res. 34, 241–261 (1979).",{"doi":6128},"10.1007\u002FBF00235671",{"id":24,"text":6130,"url":24,"identifiers":6131},"Jones, C. A. & Yang, J. F. Reflex behavior during walking in incomplete spinal-cord-injured subjects. Exp. Neurol. 128, 239–248 (1994).",{"doi":6132},"10.1006\u002Fexnr.1994.1133",{"id":24,"text":6134,"url":24,"identifiers":6135},"Dietz, V., Quintern, J. & Berger, W. Electrophysiological studies of gait in spasticity and rigidity. Evidence that altered mechanical properties of muscle contribute to hypertonia. Brain 104, 431–449 (1981).",{"doi":6136},"10.1093\u002Fbrain\u002F104.3.431",{"id":24,"text":6138,"url":24,"identifiers":6139},"O'Dwyer, N. J., Ada, L. & Neilson, P. D. Spasticity and muscle contracture following stroke. Brain 119, 1737–1749 (1996).",{"doi":6140},"10.1093\u002Fbrain\u002F119.5.1737",{"id":24,"text":6142,"url":24,"identifiers":6143},"Ibrahim, I. K., Berger, W., Trippel, M. & Dietz, V. Stretch-induced electromyographic activity and torque in spastic elbow muscles. Brain 116, 971–989 (1993).",{"doi":6144},"10.1093\u002Fbrain\u002F116.4.971",{"id":24,"text":6146,"url":24,"identifiers":6147},"Lieber, R. L. & Fridén, J. Spasticity causes a fundamental rearrangement of muscle−joint interaction. Muscle Nerve 25, 265–270 (2002).",{"doi":6148},"10.1002\u002Fmus.10036",{"id":24,"text":6150,"url":24,"identifiers":6151},"Dietz, V. & Sinkjaer, T. Spastic movement disorder: impaired reflex function and altered muscle mechanics. Lancet Neurol. 6, 725–733 (2007).",{"doi":6152},"10.1016\u002FS1474-4422(07)70193-X",{"id":24,"text":6154,"url":24,"identifiers":6155},"Bennett, D. J., Sanelli, L., Cooke, C. L., Harvey, P. J. & Gorassini, M. A. Spastic long-lasting reflexes in the awake rat after sacral spinal cord injury. J. Neurophysiol. 91, 2247–2258 (2004).",{"doi":6156},"10.1152\u002Fjn.00946.2003",{"id":24,"text":6158,"url":24,"identifiers":6159},"Li, X., Murray, K., Harvey, P. J., Ballou, E. W. & Bennett, D. J. Serotonin facilitates a persistent calcium current in motoneurons of rats with and without chronic spinal cord injury. J. Neurophysiol. 97, 1236–1246 (2007).",{"doi":6160},"10.1152\u002Fjn.00995.2006",{"id":24,"text":6162,"url":24,"identifiers":6163},"Li, Y., Gorassini, M. A. & Bennett, D. J. Role of persistent sodium and calcium currents in motoneuron firing and spasticity in chronic spinal rats. J. Neurophysiol. 91, 767–783 (2004).",{"doi":6164},"10.1152\u002Fjn.00788.2003",{"id":24,"text":6166,"url":24,"identifiers":6167},"Kitzman, P. Alteration in axial motoneuronal morphology in the spinal cord injured spastic rat. Exp. Neurol. 192, 100–108 (2005).",{"doi":6168},"10.1016\u002Fj.expneurol.2004.10.021",{"id":24,"text":6170,"url":24,"identifiers":6171},"Kitzman, P. Changes in vesicular glutamate transporter 2, vesicular GABA transporter and vesicular acetylcholine transporter labeling of sacrocaudal motoneurons in the spastic rat. Exp. Neurol. 197, 407–419 (2006).",{"doi":6172},"10.1016\u002Fj.expneurol.2005.10.005",{"id":24,"text":6174,"url":24,"identifiers":6175},"Kakinohana, O.  et al. Development of GABA-sensitive spasticity and rigidity in rats after transient spinal cord ischemia: a qualitative and quantitative electrophysiological and histopathological study. Neuroscience 141, 1569–1583 (2006).",{"doi":6176},"10.1016\u002Fj.neuroscience.2006.04.083",{"id":24,"text":6178,"url":24,"identifiers":6179},"Hultborn, H. Changes in neuronal properties and spinal reflexes during development of spasticity following spinal cord lesions and stroke: studies in animal models and patients. J. Rehabil. Med. 35, 46–55 (2003).",{"doi":6180},"10.1080\u002F16501960310010142",{"id":24,"text":6182,"url":24,"identifiers":6183},"Müller, R. & Dietz, V. Neuronal function in chronic spinal cord injury: divergence between locomotor and flexion- and H-reflex activity. Clin. Neurophysiol. 117, 1499–1507 (2006).",{"doi":6184},"10.1016\u002Fj.clinph.2006.03.022",{"id":24,"text":6186,"url":24,"identifiers":6187},"Valero-Cabré, A. & Navarro, X. Changes in crossed spinal reflexes after peripheral nerve injury and repair. J. Neurophysiol. 87, 1763–1771 (2002).",{"doi":6188},"10.1152\u002Fjn.00305.2001",{"id":24,"text":6190,"url":24,"identifiers":6191},"de Leon, R. D., Hodgson, J. A., Roy, R. R. & Edgerton, V. R. Locomotor capacity attributable to step training versus spontaneous recovery after spinalization in adult cats. J. Neurophysiol. 79, 1329–1340 (1998).",{"doi":6192},"10.1152\u002Fjn.1998.79.3.1329",{"id":24,"text":6194,"url":24,"identifiers":6195},"Edgerton, V. R., de Leon, R. D., Tillakaratne, N., Recktenwald, M. R., Hodgson, J. A. & Roy, R. R. Use-dependent plasticity in spinal stepping and standing. Adv. Neurol. 72, 233–247 (1997).",{},{"id":24,"text":6197,"url":24,"identifiers":6198},"Hains, B. C., Willis, W. D. & Hulsebosch, C. E. Temporal plasticity of dorsal horn somatosensory neurons after acute and chronic spinal cord hemisection in rat. Brain Res. 970, 238–241 (2003).",{"doi":6199},"10.1016\u002FS0006-8993(03)02347-3",{"id":24,"text":6201,"url":24,"identifiers":6202},"García-Alías, G., Barkhuysen, S., Buckle, M. & Fawcett, J. W. Chondroitinase ABC treatment opens a window of opportunity for task-specific rehabilitation. Nat. Neurosci. 12, 1145–1151 (2009).",{"doi":6203},"10.1038\u002Fnn.2377",{"id":24,"text":6194,"url":24,"identifiers":6205},{},{"id":24,"text":6207,"url":24,"identifiers":6208},"Dietz, V. Proprioception and locomotor disorders. Nat. Rev. Neurosci. 3, 781–790 (2002).",{"doi":6209},"10.1038\u002Fnrn939",{"id":24,"text":6211,"url":24,"identifiers":6212},"Maier, I. C.  et al. Differential effects of anti-Nogo-A antibody treatment and treadmill training in rats with incomplete spinal cord injury. Brain 132, 1426–1440 (2009).",{"doi":6213},"10.1093\u002Fbrain\u002Fawp085",{"id":24,"text":6215,"url":24,"identifiers":6216},"Dietz, V. Human neuronal control of automatic functional movements: interaction between central programs and afferent input. Physiol. Rev. 72, 33–69 (1992).",{"doi":6217},"10.1152\u002Fphysrev.1992.72.1.33",{"id":24,"text":6219,"url":24,"identifiers":6220},"Burns, A. S., Lemay, M. A. & Tessler, A. Abnormal spontaneous potentials in distal muscles in animal models of spinal cord injury. Muscle Nerve 31, 46–51 (2005).",{"doi":6221},"10.1002\u002Fmus.20229",{"id":24,"text":6223,"url":24,"identifiers":6224},"Ginsberg, S. D. & Martin, L. J. Axonal transection in adult rat brain induces transsynaptic apoptosis and persistent atrophy of target neurons. J. Neurotrauma 19, 99–109 (2002).",{"doi":6225},"10.1089\u002F089771502753460277",{"id":24,"text":6227,"url":24,"identifiers":6228},"Wu, Y. P. & Ling, E. A. Transsynaptic changes of neurons and associated microglial reaction in the spinal cord of rats following middle cerebral artery occlusion. Neurosci. Lett. 256, 41–44 (1998).",{"doi":6229},"10.1016\u002FS0304-3940(98)00750-2",{"id":24,"text":6231,"url":24,"identifiers":6232},"Aisen, M. L., Brown, W. & Rubin, M. Electrophysiologic changes in lumbar spinal cord after cervical cord injury. Neurology 42, 623–626 (1992).",{"doi":6233},"10.1212\u002FWNL.42.3.623",{"id":24,"text":6235,"url":24,"identifiers":6236},"Chang, C. W. Evident transsynaptic degeneration of motor neurons after spinal cord injury: a study of neuromuscular jitter by axonal microstimulation. Am. J. Phys. Med. Rehabil. 77, 118–121 (1998).",{"doi":6237},"10.1097\u002F00002060-199803000-00006",{"id":24,"text":6239,"url":24,"identifiers":6240},"Lin, C. S., Macefield, V. G., Elam, M., Wallin, B. G., Engel, S. & Kiernan, M. C. Axonal changes in spinal cord injured patients distal to the site of injury. Brain 130, 985–994 (2007).",{"doi":6241},"10.1093\u002Fbrain\u002Fawl339",{"id":24,"text":6243,"url":24,"identifiers":6244},"Nyboer, V. J. & Johnson, H. E. Electromyographic findings in lower extremities of patients with traumatic quadriplegia. Arch. Phys. Med. Rehabil. 52, 256–259 (1971).",{},{"id":24,"text":6246,"url":24,"identifiers":6247},"Hara, Y., Akaboshi, K., Masakado, Y. & Chino, N. Physiologic decrease of single thenar motor units in the F-response in stroke patients. Arch. Phys. Med. Rehabil. 81, 418–423 (2000).",{"doi":6248},"10.1053\u002Fmr.2000.3872",{"id":24,"text":6250,"url":24,"identifiers":6251},"Lukacs, M., Vecsei, L. & Beniczky, S. Changes in muscle fiber density following a stroke. Clin. Neurophysiol. 120, 1539–1542 (2009).",{"doi":6252},"10.1016\u002Fj.clinph.2009.06.001",{"id":24,"text":6254,"url":24,"identifiers":6255},"Hansen, N. L.  et al. Reduction of common synaptic drive to ankle dorsiflexor motoneurons during walking in patients with spinal cord lesion. J. Neurophysiol. 94, 934–942 (2005).",{"doi":6256},"10.1152\u002Fjn.00082.2005",{"id":24,"text":6258,"url":24,"identifiers":6259},"Grillner, S.  et al. Neural networks that co-ordinate locomotion and body orientation in lamprey. Trends Neurosci. 18, 270–279 (1995).",{"doi":6260},"10.1016\u002F0166-2236(95)80008-P",{"id":24,"text":6262,"url":24,"identifiers":6263},"DeAngelis, G. C., Ohzawa, I. & Freeman, R. D. Receptive-field dynamics in the central visual pathways. Trends Neurosci. 18, 451–458 (1995).",{"doi":6264},"10.1016\u002F0166-2236(95)94496-R",{"id":24,"text":6266,"url":24,"identifiers":6267},"Tillakaratne, N. J.  et al. Use-dependent modulation of inhibitory capacity in the feline lumbar spinal cord. J. Neurosci. 22, 3130–3143 (2002).",{"doi":6268},"10.1523\u002FJNEUROSCI.22-08-03130.2002",{"id":24,"text":6270,"url":24,"identifiers":6271},"Ichiyama, R. M., Broman, J., Edgerton, V. R. & Havton, L. A. Ultrastructural synaptic features differ between alpha- and gamma-motoneurons innervating the tibialis anterior muscle in the rat. J. Comp. Neurol. 499, 306–315 (2006).",{"doi":6272},"10.1002\u002Fcne.21110",{"id":24,"text":6274,"url":24,"identifiers":6275},"de Leon, R. D., Tamaki, H., Hodgson, J. A., Roy, R. R. & Edgerton, V. R. Hindlimb locomotor and postural training modulates glycinergic inhibition in the spinal cord of the adult spinal cat. J. Neurophysiol. 82, 359–369 (1999).",{"doi":6276},"10.1152\u002Fjn.1999.82.1.359",{"id":24,"text":6278,"url":24,"identifiers":6279},"Wirz, M.  et al. Effectiveness of automated locomotor training in patients with chronic incomplete spinal cord injury: a multicenter trial. Arch. Phys. Med. Rehabil. 86, 672–680 (2005).",{"doi":6280},"10.1016\u002Fj.apmr.2004.08.004",{"id":24,"text":6282,"url":24,"identifiers":6283},"Courtine, G.  et al. Recovery of supraspinal control of stepping via indirect propriospinal relay connections after spinal cord injury. Nat. Med. 14, 69–74 (2008).",{"doi":6284},"10.1038\u002Fnm1682",{"id":24,"text":6286,"url":24,"identifiers":6287},"Courtine, G.  et al. Transformation of nonfunctional spinal circuits into functional states after the loss of brain input. Nat. Neurosci. 12, 1333–1342 (2009).",{"doi":6288},"10.1038\u002Fnn.2401",{"id":24,"text":6290,"url":24,"identifiers":6291},"Milanov, I. G. Flexor reflex for assessment of common interneurone activity in spasticity. Electromyogr. Clin. Neurophysiol. 32, 621–629 (1992).",{},{"id":24,"text":6293,"url":24,"identifiers":6294},"Dietz, V. Do human bipeds use quadrupedal coordination? Trends Neurosci. 25, 462–467 (2002).",{"doi":6295},"10.1016\u002FS0166-2236(02)02229-4",{"id":24,"text":6297,"url":24,"identifiers":6298},"Dietz, V., Fouad, K. & Bastiaanse, C. M. Neuronal coordination of arm and leg movements during human locomotion. Eur. J. Neurosci. 14, 1906–1914 (2001).",{"doi":6299},"10.1046\u002Fj.0953-816x.2001.01813.x",{"id":24,"text":6301,"url":24,"identifiers":6302},"Michel, J., van Hedel, H. J. & Dietz, V. Obstacle stepping involves spinal anticipatory activity associated with quadrupedal limb coordination. Eur. J. Neurosci. 27, 1867–1875 (2008).",{"doi":6303},"10.1111\u002Fj.1460-9568.2008.06145.x",{"id":24,"text":6305,"url":24,"identifiers":6306},"Zehr, E. P., Hesketh, K. L. & Chua, R. Differential regulation of cutaneous and H-reflexes during leg cycling in humans. J. Neurophysiol. 85, 1178–1184 (2001).",{"doi":6307},"10.1152\u002Fjn.2001.85.3.1178",{"id":24,"text":6309,"url":24,"identifiers":6310},"Zehr, E. P. & Kido, A. Neural control of rhythmic, cyclical human arm movement: task dependency, nerve specificity and phase modulation of cutaneous reflexes. J. 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C. Propensity-score matching in the cardiovascular surgery literature from 2004 to 2006: a systematic review and suggestions for improvement. J. Thorac. Cardiovasc. Surg. 134, 1128–1135 (2007).",{"doi":6665},"10.1016\u002Fj.jtcvs.2007.07.021",{"id":24,"text":6667,"url":24,"identifiers":6668},"Stenestrand, U., Wallentin, L. & Swedish Register of Cardiac Intensive Care (RIKS-HIA). Early statin treatment following acute myocardial infarction and 1-year survival. JAMA 285, 430–436 (2001).",{"doi":6669},"10.1001\u002Fjama.285.4.430",{"id":24,"text":6671,"url":24,"identifiers":6672},"Gum, P. A., Thamilarasan, M., Watanabe, J., Blackstone, E. H. & Lauer, M. S. Aspirin use and all-cause mortality among patients being evaluated for known or suspected coronary artery disease: a propensity analysis. JAMA 286, 1187–1194 (2001).",{"doi":6673},"10.1001\u002Fjama.286.10.1187",{"id":24,"text":6675,"url":24,"identifiers":6676},"Kern, L. M. et al. Association between screening for osteoporosis and the incidence of hip fracture. Ann. Intern. Med. 142, 173–181 (2005).",{"doi":6677},"10.7326\u002F0003-4819-142-3-200502010-00007",{"id":24,"text":6679,"url":24,"identifiers":6680},"Schneeweiss, S. et al. High-dimensional propensity score adjustment in studies of treatment effects using health care claims data. Epidemiology. 20, 512–522 (2009).",{"doi":6681},"10.1097\u002FEDE.0b013e3181a663cc",{"id":24,"text":6683,"url":24,"identifiers":6684},"Rosenbaum, P. R. Discussing hidden bias in observational studies. Ann. Intern. Med. 115, 901–905 (1991).",{"doi":6685},"10.7326\u002F0003-4819-115-11-901",{"id":24,"text":6687,"url":24,"identifiers":6688},"Lin, D. Y., Psaty, B. M. & Krommal, R. A. Assessing the sensitivity of regression results to unmeasured confounders in observational studies. Biometrics 54, 948–963 (1998).",{"doi":6689},"10.2307\u002F2533848",{"id":24,"text":6691,"url":24,"identifiers":6692},"Karim, M. E. et al. Marginal structural Cox models for estimating the association between β-interferon exposure and disease progression in a multiple sclerosis cohort. Am. J. Epidemiol. 180, 160–171 (2014).",{"doi":6693},"10.1093\u002Faje\u002Fkwu125",{"id":24,"text":6695,"url":24,"identifiers":6696},"Westreich, D., Cole, S. R., Schisterman, E. F. & Platt, R. W. A simulation study of finite-sample properties of marginal structural Cox proportional hazards models. Stat. Med. 31, 2098–2109 (2012).",{"doi":6697},"10.1002\u002Fsim.5317",{"id":24,"text":6699,"url":24,"identifiers":6700},"Havercroft, W. G. & Didelez, V. Simulating from marginal structural models with time-dependent confounding. Stat. Med. 31, 4190–4206 (2012).",{"doi":6701},"10.1002\u002Fsim.5472",{"id":24,"text":6703,"url":24,"identifiers":6704},"Debray, T., Moons, K. G., Ahmed, I., Koffijberg, H. & Riley, R. D. A framework for developing, implementing, and evaluating clinical prediction models in an individual participant data meta-analysis. Stat. Med. 32, 3158–3180 (2013).",{"doi":6705},"10.1002\u002Fsim.5732",{"id":24,"text":6707,"url":24,"identifiers":6708},"Ahmed, I., Debray, T. P., Moons, K. G. & Riley, R. D. Developing and validating risk prediction models in an individual participant data meta-analysis. BMC Med. Res. Methodol. 14, 3 (2014).",{"doi":6709},"10.1186\u002F1471-2288-14-3",{"id":24,"text":6711,"url":24,"identifiers":6712},"Zhao, L., Tian, L., Cai, T., Claggett, B. & Wei, L. J. Effectively selecting a target population for a future comparative study. J. Am. Stat. Assoc. 108, 527–539 (2013).",{"doi":6713},"10.1080\u002F01621459.2013.770705",{"id":24,"text":6715,"url":24,"identifiers":6716},"Verde, P. E., Ohmann, C., Morbach, S. & Icks, A. Bayesian evidence synthesis for exploring generalizability of treatment effects: a case study of combining randomized and non-randomized results in diabetes. Stat. Med. 35, 1654–1675 (2016).",{"doi":6717},"10.1002\u002Fsim.6809",{"id":24,"text":6719,"url":24,"identifiers":6720},"Scott, I. A. & Attia, J. Cautionary tales in the interpretation of observational studies of effects of clinical interventions. Intern. Med. J. http:\u002F\u002Fdx.doi.org\u002F10.1111\u002Fimj.13167 (2016). This article proposes criteria for identifying high quality observational studies.",{"doi":6721},"10.1111\u002Fimj.13167",{"id":24,"text":6723,"url":24,"identifiers":6724},"Arts, D. G., De Keizer, N. F. & Scheffer, G. J. Defining and improving data quality in medical registries: a literature review, case study, and generic framework. J. Am. Med. Inform. Assoc. 9, 600–611 (2002).",{"doi":6725},"10.1197\u002Fjamia.M1087",{"id":24,"text":6727,"url":24,"identifiers":6728},"Christiansen, D. H., Hosking, J. D., Dannenberg, A. L. & Williams, O. D. Computer-assisted data collection in multicenter epidemiologic research. The Atherosclerosis Risk Communities Study. Control. Clin. Trials 11, 101–115 (1990).",{"doi":6729},"10.1016\u002F0197-2456(90)90004-L",{"id":24,"text":6731,"url":24,"identifiers":6732},"Weiskopf, N. G. & Weng, C. Methods and dimensions of electronic health record data quality assessment: enabling reuse for clinical research. J. Am. Med. Inform. Assoc. 20, 144–151 (2013).",{"doi":6733},"10.1136\u002Famiajnl-2011-000681",{"id":24,"text":6735,"url":24,"identifiers":6736},"Goudar, S. et al. Data quality monitoring and performance metrics of a prospective, population-based observational study of maternal and newborn health in low resource settings. Reprod. Health 12 (Suppl. 2), S2 (2015).",{"doi":6737},"10.1186\u002F1742-4755-12-S2-S2",{"id":24,"text":6739,"url":24,"identifiers":6740},"Kalincik, T. et al. Data quality evaluation for observational multiple sclerosis registries. Mult. Scler. http:\u002F\u002Fdx.doi.org\u002F10.1177\u002F1352458516662728 (2016).",{"doi":6741},"10.1177\u002F1352458516662728",{"id":24,"text":6743,"url":24,"identifiers":6744},"Tintore, M. et al. Defining high, medium and low impact prognostic factors for developing multiple sclerosis. Brain 138, 1863–1874 (2015). The largest single-centre prospective study evaluating prognostic factors in patients with clinically isolated syndrome suggestive of MS.",{"doi":6745},"10.1093\u002Fbrain\u002Fawv105",{"id":24,"text":6747,"url":24,"identifiers":6748},"Jokubaitis, V. G. et al. Predictors of disability worsening in clinically isolated syndrome. Ann. Clin. Transl Neurol. 2, 479–491 (2015).",{"doi":6749},"10.1002\u002Facn3.187",{"id":24,"text":6751,"url":24,"identifiers":6752},"Marrie, R. A. et al. Recommendations for observational studies of comorbidity in multiple sclerosis. Neurology 86, 1446–1453 (2016).",{"doi":6753},"10.1212\u002FWNL.0000000000002474",{"id":24,"text":6755,"url":24,"identifiers":6756},"Trojano, M. et al. Real-life impact of early interferonβ therapy in relapsing multiple sclerosis. Ann. Neurol. 66, 513–520 (2009).",{"doi":6757},"10.1002\u002Fana.21757",{"id":24,"text":6759,"url":24,"identifiers":6760},"Río, J. et al. Defining the response to interferon-beta in relapsing-remitting multiple sclerosis patients. Ann. Neurol. 59, 344–352 (2006).",{"doi":6761},"10.1002\u002Fana.20740",{"id":24,"text":6763,"url":24,"identifiers":6764},"Río, J. et al. Measures in the first year of therapy predict the response to interferon beta in MS. Mult. Scler. 15, 848–853 (2009).",{"doi":6765},"10.1177\u002F1352458509104591",{"id":24,"text":6767,"url":24,"identifiers":6768},"Bermel, R. A. et al. Predictors of long-term outcome in multiple sclerosis patients treated with interferon β. Ann. Neurol. 73, 95–103 (2013).",{"doi":6769},"10.1002\u002Fana.23758",{"id":24,"text":6771,"url":24,"identifiers":6772},"Jokubaitis, V. G. et al. Predictors of long-term disability accrual in relapse-onset multiple sclerosis. Ann. Neurol. 80, 89–100 (2016).",{"doi":6773},"10.1002\u002Fana.24682",{"id":24,"text":6775,"url":24,"identifiers":6776},"Horakova, D. et al. Early predictors of non-response to interferon in multiple sclerosis. Acta Neurol. Scand. 126, 390–397 (2012).",{"doi":6777},"10.1111\u002Fj.1600-0404.2012.01662.x",{"id":24,"text":6779,"url":24,"identifiers":6780},"Uher, T. et al. Combining clinical and MRI predictors enhances prediction of 12-year disability in multiple sclerosis. Mult. Scler. http:\u002F\u002Fdx.doi.org\u002F10.1177\u002F1352458516642314 (2016).",{"doi":6781},"10.1177\u002F1352458516642314",{"id":24,"text":6783,"url":24,"identifiers":6784},"Uher, T. et al. Early magnetic resonance imaging predictors of clinical progression after 48 months in clinically isolated syndrome patients treated with intramuscular interferon β-1a. Eur. J. Neurol. 22, 1113–1123 (2015).",{"doi":6785},"10.1111\u002Fene.12716",{"id":24,"text":6787,"url":24,"identifiers":6788},"Río, J. et al. Evaluating the response to glatiramer acetate in relapsing-remitting multiple sclerosis (RRMS) patients. Mult. Scler. 20, 1602–1608 (2014).",{"doi":6789},"10.1177\u002F1352458514527863",{"id":24,"text":6791,"url":24,"identifiers":6792},"Sormani, M. P. et al. Scoring treatment response in patients with relapsing multiple sclerosis. Mult. Scler. 19, 605–612 (2013).",{"doi":6793},"10.1177\u002F1352458512460605",{"id":24,"text":6795,"url":24,"identifiers":6796},"Prosperini, L. et al. Interferon beta failure predicted by EMA criteria or isolated MRI activity in multiple sclerosis. Mult. Scler. 20, 566–576 (2014).",{"doi":6797},"10.1177\u002F1352458513502399",{"id":24,"text":6799,"url":24,"identifiers":6800},"Dobson, R., Rudick, R. A., Turner, B., Schmierer, K. & Giovannoni, G. Assessing treatment response to interferon-β: is there a role for MRI? Neurology 82, 248–254 (2014).",{"doi":6801},"10.1212\u002FWNL.0000000000000036",{"id":24,"text":6803,"url":24,"identifiers":6804},"Sormani, M. P. et al. Assessing response to interferon-β in a multicenter dataset of patients with MS. Neurology 87, 134–140 (2016). The largest study assessing MRI criteria for predicting IFN-β treatment non-response in real-world studies.",{"doi":6805},"10.1212\u002FWNL.0000000000002830",{"id":24,"text":6807,"url":24,"identifiers":6808},"Rio, J. et al. Clinical markers of long-term disability in RRMS patients treated with interferon beta [poster]. Mult. Scler. 20 (Suppl. 1), P285 (2014).",{},{"id":24,"text":6810,"url":24,"identifiers":6811},"Río, J. et al. Relationship between MRI lesion activity and response to IFN-beta in relapsing-remitting multiple sclerosis patients. Mult. Scler. 14, 479–484 (2008).",{"doi":6812},"10.1177\u002F1352458507085555",{"id":24,"text":6814,"url":24,"identifiers":6815},"Altay, E. E. et al. Reliability of classifying multiple sclerosis disease activity using magnetic resonance imaging in a multiple sclerosis clinic. JAMA Neurol. 70, 338–344 (2013).",{"doi":6816},"10.1001\u002F2013.jamaneurol.211",{"id":24,"text":6818,"url":24,"identifiers":6819},"Wattjes, M. P. et al. Evidence-based guidelines: MAGNIMS consensus guidelines on the use of MRI in multiple sclerosis — establishing disease prognosis and monitoring patients. Nat. Rev. Neurol. 11, 597–606 (2015).",{},{"id":24,"text":6821,"url":24,"identifiers":6822},"Rudick, R. A., Lee, J. C., Simon, J., Ransohoff, R. M. & Fisher, E. Defining interferon beta response status in multiple sclerosis patients. Ann. Neurol. 56, 548–555 (2004).",{"doi":6823},"10.1002\u002Fana.20224",{"id":24,"text":6825,"url":24,"identifiers":6826},"Bevan, C. J. & Cree, B. A. Disease activity free status: a new end point for a new era in multiple sclerosis clinical research? JAMA Neurol. 71, 269–270 (2014).",{"doi":6827},"10.1001\u002Fjamaneurol.2013.5486",{"id":24,"text":6829,"url":24,"identifiers":6830},"Kappos, L. et al. Inclusion of brain volume loss in a revised measure of 'no evidence of disease activity' (NEDA-4) in relapsing–remitting multiple sclerosis. Mult. Scler. 22, 1297–1305 (2016).",{"doi":6831},"10.1177\u002F1352458515616701",{"id":24,"text":6833,"url":24,"identifiers":6834},"Sormani, M. P., Arnold, D. L. & De Stefano, N. Treatment effect on brain atrophy correlates with treatment effect on disability in multiple sclerosis. Ann. Neurol. 75, 43–49 (2014).",{"doi":6835},"10.1002\u002Fana.24018",{"id":24,"text":6837,"url":24,"identifiers":6838},"Stangel, M., Penner, I., Kallmann, B. A., Lukas, C. & Kieseier, B. C. Towards the implementation of 'no evidence of disease activity' in multiple sclerosis treatment: the multiple sclerosis decision model. Ther. Adv. Neurol. Disord. 8, 3–13 (2015).",{"doi":6839},"10.1177\u002F1756285614560733",{"id":24,"text":6841,"url":24,"identifiers":6842},"Kuhle, J. et al. Fingolimod and CSF neurofilament light chain levels in relapsing–remitting multiple sclerosis. Neurology 84, 1639–1643 (2015).",{"doi":6843},"10.1212\u002FWNL.0000000000001491",{"id":24,"text":6845,"url":24,"identifiers":6846},"Rotstein, D. L., Healy, B. C., Malik, M. T., Chitnis, T. & Weiner, H. L. Evaluation of no evidence of disease activity in a 7-year longitudinal multiple sclerosis cohort. JAMA Neurol. 72, 152–158 (2015).",{"doi":6847},"10.1001\u002Fjamaneurol.2014.3537",{"id":24,"text":6849,"url":24,"identifiers":6850},"Jacobs, L. D. et al. Intramuscular interferon beta-1a therapy initiated during a first demyelinating event in multiple sclerosis. CHAMPS Study Group. N. Engl. J. Med. 343, 898–904 (2000).",{"doi":6851},"10.1056\u002FNEJM200009283431301",{"id":24,"text":6853,"url":24,"identifiers":6854},"Comi, G. et al. Effect of early interferon treatment on conversion to definite multiple sclerosis: a randomised study. Lancet 357, 1576–1582 (2001).",{"doi":6855},"10.1016\u002FS0140-6736(00)04725-5",{"id":24,"text":6857,"url":24,"identifiers":6858},"Kappos, L. et al. Long-term subcutaneous interferon beta-1a therapy in patients with relapsing-remitting MS. Neurology 67, 944–953 (2006).",{"doi":6859},"10.1212\u002F01.wnl.0000237994.95410.ce",{"id":24,"text":6861,"url":24,"identifiers":6862},"Polman, C. et al. Subgroups of the BENEFIT study: risk of developing MS and treatment effect of interferon beta-1b. J. Neurol. 255, 480–487 (2008).",{"doi":6863},"10.1007\u002Fs00415-007-0733-2",{"id":24,"text":6865,"url":24,"identifiers":6866},"Comi, G. et al. Effect of glatiramer acetate on conversion to clinically definite multiple sclerosis in patients with clinically isolated syndrome (PreCISe study): a randomised, double-blind, placebo-controlled trial. Lancet 374, 1503–1511 (2009).",{"doi":6867},"10.1016\u002FS0140-6736(09)61259-9",{"id":24,"text":6869,"url":24,"identifiers":6870},"Kappos, L. et al. Long-term effect of early treatment with interferon beta-1b after a first clinical event suggestive of multiple sclerosis: 5-year active treatment extension of the phase 3 BENEFIT trial. Lancet Neurol. 8, 987–997 (2009).",{"doi":6871},"10.1016\u002FS1474-4422(09)70237-6",{"id":24,"text":6873,"url":24,"identifiers":6874},"Kinkel, P. R. et al. Association between immediate initiation of intramuscular interferon beta-1a at the time of a clinically isolated syndrome and long-term outcomes: a 10-year follow-up of the Controlled High-Risk Avonex Multiple Sclerosis Prevention Study in Neurological Surveillance. Arch. Neurol. 69, 183–190 (2012).",{"doi":6875},"10.1001\u002Farchneurol.2011.1426",{"id":24,"text":6877,"url":24,"identifiers":6878},"Miller, A. E. et al. Oral teriflunomide for patients with a first clinical episode suggestive of multiple sclerosis (TOPIC): a randomised, double-blind, placebo-controlled, phase 3 trial. Lancet Neurol. 13, 977–986 (2014).",{"doi":6879},"10.1016\u002FS1474-4422(14)70191-7",{"id":24,"text":6881,"url":24,"identifiers":6882},"Boster, A. et al. Disease activity in the first year predicts longer-term clinical outcomes in the pooled population of the phase III FREEDOMS and FREEDOMS II studies [poster]. Neurology 84 (14 Suppl.), P7.239 (2015).",{"doi":6883},"10.1212\u002FWNL.84.14_supplement.P7.239",{"id":24,"text":6885,"url":24,"identifiers":6886},"Giovannoni, G. et al. Is it time to target no evident disease activity (NEDA) in multiple sclerosis? Mult. Scler. Relat. Disord. 4, 329–333 (2015).",{"doi":6887},"10.1016\u002Fj.msard.2015.04.006",{"id":24,"text":6889,"url":24,"identifiers":6890},"Filippini, G. et al. Immunomodulators and immunosuppressants for multiple sclerosis: a network meta-analysis. Cochrane Database Syst. Rev. 6, CD008933 (2013).",{},{"id":24,"text":6892,"url":24,"identifiers":6893},"Kalincik, T. et al. Comparative effectiveness of glatiramer acetate and interferon beta formulations in relapsing-remitting multiple sclerosis. Mult. Scler. 21, 1159–1171 (2015).",{"doi":6894},"10.1177\u002F1352458514559865",{"id":24,"text":6896,"url":24,"identifiers":6897},"Sekhon, J. Multivariate and propensity score matching software with automated balance optimization: the matching package for R. J. Stat. Software 42, 7 (2011).",{"doi":6898},"10.18637\u002Fjss.v042.i07",{"id":24,"text":6900,"url":24,"identifiers":6901},"Spelman, T. et al. Comparative efficacy of first-line natalizumab versus IFNβ or glatiramer acetate in relapsing-remitting MS. Neurol. Clin. Pract. 6, 102–115 (2016).",{"doi":6902},"10.1212\u002FCPJ.0000000000000227",{"id":24,"text":6904,"url":24,"identifiers":6905},"Rassen, J. A. et al. One-to-many propensity score matching in cohort studies. Pharmacoepidemiol. Drug Saf. 21 (Suppl. 2), 69–80 (2012).",{"doi":6906},"10.1002\u002Fpds.3263",{"id":24,"text":6908,"url":24,"identifiers":6909},"Winkelmann, A., Loebermann, M., Reisinger, E. C., Hartung, H. P. & Zettl, U. K. Disease-modifying therapies and infectious risks in multiple sclerosis. Nat. Rev. Neurol. 12, 217–233 (2016).",{"doi":6910},"10.1038\u002Fnrneurol.2016.21",{"id":24,"text":6912,"url":24,"identifiers":6913},"Lublin, F. D., Baier, M. & Cutter, G. Effect of relapses on development of residual deficit in multiple sclerosis. Neurology 61, 1528–1532 (2003).",{"doi":6914},"10.1212\u002F01.WNL.0000096175.39831.21",{"id":24,"text":6916,"url":24,"identifiers":6917},"Hirst, C. et al. Contribution of relapses to disability in multiple sclerosis. J. Neurol. 255, 280–287 (2008).",{"doi":6918},"10.1007\u002Fs00415-008-0743-8",{"id":24,"text":6920,"url":24,"identifiers":6921},"Stewart, T. et al. Contribution of different relapse phenotypes to disability in multiple sclerosis. Mult. Scler. http:\u002F\u002Fdx.doi.org\u002F10.1177\u002F1352458516643392 (2016).",{"doi":6922},"10.1177\u002F1352458516643392",{"id":24,"text":6924,"url":24,"identifiers":6925},"Khatri, B. et al. Comparison of fingolimod with interferon beta-1a in relapsing-remitting multiple sclerosis: a randomised extension of the TRANSFORMS study. Lancet Neurol. 10, 520–529 (2011).",{"doi":6926},"10.1016\u002FS1474-4422(11)70099-0",{"id":24,"text":6928,"url":24,"identifiers":6929},"Coles, A. J. et al. Alemtuzumab for patients with relapsing multiple sclerosis after disease-modifying therapy: a randomised controlled phase 3 trial. Lancet 380, 1829–1839 (2012).",{"doi":6930},"10.1016\u002FS0140-6736(12)61768-1",{"id":24,"text":6932,"url":24,"identifiers":6933},"Spelman, T. et al. Comparative efficacy of switching to natalizumab in active multiple sclerosis. Ann. Clin. Transl Neurol. 2, 373–387 (2015).",{"doi":6934},"10.1002\u002Facn3.180",{"id":24,"text":6936,"url":24,"identifiers":6937},"He, A. et al. Comparison of switch to fingolimod or interferon beta\u002Fglatiramer acetate in active multiple sclerosis. JAMA Neurol. 72, 405–413 (2015).",{"doi":6938},"10.1001\u002Fjamaneurol.2014.4147",{"id":24,"text":6940,"url":24,"identifiers":6941},"Schoenfeld, D. Chi-squared goodness-of-fit tests for the proportional hazards regression model. Biometrika 67, 145–153 (1980).",{"doi":6942},"10.1093\u002Fbiomet\u002F67.1.145",{"id":24,"text":6944,"url":24,"identifiers":6945},"Kalincik, T. et al. Switch to natalizumab versus fingolimod in active relapsing-remitting multiple sclerosis. Ann. Neurol. 77, 425–435 (2015). The first comparative study evaluating the effectiveness of natalizumab and fingolimod after first-line treatment failure.",{"doi":6946},"10.1002\u002Fana.24339",{"id":24,"text":6948,"url":24,"identifiers":6949},"Baroncini, D. et al. Natalizumab versus fingolimod in patients with relapsing-remitting multiple sclerosis non-responding to first-line injectable therapies. Mult. Scler. 22, 1315–1326 (2016).",{"doi":6950},"10.1177\u002F1352458516650736",{"id":24,"text":6952,"url":24,"identifiers":6953},"Barbin, L. et al. Comparative efficacy of fingolimod versus natalizumab: a French multicenter observational study. Neurology 86, 771–778 (2016).",{"doi":6954},"10.1212\u002FWNL.0000000000002395",{"id":24,"text":6956,"url":24,"identifiers":6957},"Koch-Henriksen, N., Magyari, M., Sellebjerg, F. & Soelberg Sorensen, P. A comparison of multiple sclerosis clinical disease activity between patients treated with natalizumab and fingolimod. Mult. Scler. http:\u002F\u002Fdx.doi.org\u002F10.1177\u002F1352458516643393 (2016).",{"doi":6958},"10.1177\u002F1352458516643393",{"id":24,"text":6960,"url":24,"identifiers":6961},"Spelman, T. et al. Risk of early relapse following the switch from injectables to oral agents for multiple sclerosis. Eur. J. Neurol. 23, 729–736 (2016).",{"doi":6962},"10.1111\u002Fene.12929",{"id":24,"text":6964,"url":24,"identifiers":6965},"Bloomgren, G. et al. Risk of natalizumab-associated progressive multifocal leukoencephalopathy. N. Engl. J. Med. 366, 1870–1880 (2012).",{"doi":6966},"10.1056\u002FNEJMoa1107829",{"id":24,"text":6968,"url":24,"identifiers":6969},"O'Connor, P. W. et al. Disease activity return during natalizumab treatment interruption in patients with multiple sclerosis. Neurology 76, 1858–1865 (2011).",{"doi":6970},"10.1212\u002FWNL.0b013e31821e7c8a",{"id":24,"text":6972,"url":24,"identifiers":6973},"Cohen, M. et al. Switching from natalizumab to fingolimod in multiple sclerosis: a French prospective study. JAMA Neurol. 71, 436–441 (2014).",{"doi":6974},"10.1001\u002Fjamaneurol.2013.6240",{"id":24,"text":6976,"url":24,"identifiers":6977},"Iaffaldano, P. et al. Fingolimod versus interferon beta\u002Fglatiramer acetate after natalizumab suspension in multiple sclerosis. Brain 138, 3275–3286 (2015). The first comparative study demonstrating the superiority of fingolimod versus BRACE therapy in controlling diseases reactivation after natalizumab suspension in a real-world context.",{"doi":6978},"10.1093\u002Fbrain\u002Fawv260",{"id":24,"text":6980,"url":24,"identifiers":6981},"Sorensen, P. S. et al. Recurrence or rebound of clinical relapses after discontinuation of natalizumab therapy in highly active MS patients. J. Neurol. 261, 1170–1177 (2014).",{"doi":6982},"10.1007\u002Fs00415-014-7325-8",{"id":24,"text":6984,"url":24,"identifiers":6985},"Clerico, M. et al. Treatment of relapsing–remitting multiple sclerosis after 24 doses of natalizumab: evidence from an Italian spontaneous, prospective, and observational study (the TY-STOP Study). JAMA Neurol. 71, 954–960 (2014).",{"doi":6986},"10.1001\u002Fjamaneurol.2014.1200",{"id":24,"text":6988,"url":24,"identifiers":6989},"Jokubaitis, V. G. et al. Fingolimod after natalizumab and the risk of short-term relapse. Neurology 82, 1204–1211 (2014).",{"doi":6990},"10.1212\u002FWNL.0000000000000283",{"id":24,"text":6992,"url":24,"identifiers":6993},"Alping, P. et al. Rituximab versus fingolimod after natalizumab in multiple sclerosis patients. Ann. Neurol. 79, 950–958 (2016).",{"doi":6994},"10.1002\u002Fana.24651",{"id":24,"text":6996,"url":24,"identifiers":6997},"Parsons, L. S. Reducing bias in a propensity score matched pair sample using greedy matching techniques. SAS http:\u002F\u002Fwww2.sas.com\u002Fproceedings\u002Fsugi26\u002Fp214-26.pdf (2001).",{},{"id":24,"text":6999,"url":24,"identifiers":7000},"Trojano, M. et al. New natural history of interferon-beta-treated relapsing multiple sclerosis. Ann. Neurol. 61, 300–306 (2007). The first study addressing the issue of long-term effectiveness of IFN-β treatment in MS by using propensity score technique.",{"doi":7001},"10.1002\u002Fana.21102",{"id":24,"text":7003,"url":24,"identifiers":7004},"Lunceford, J. K. & Davidian, M. Stratification and weighting via the propensity score in estimation of causal treatment effects: a comparative study. Stat. Med. 23, 2937–2960 (2004).",{"doi":7005},"10.1002\u002Fsim.1903",{"id":24,"text":7007,"url":24,"identifiers":7008},"Bergamaschi, R. et al. Immunomodulatory therapies delay disease progression in multiple sclerosis. Mult. Scler. 22, 1732–1740 (2016).",{"doi":7009},"10.1177\u002F1352458512445941",{"id":24,"text":7011,"url":24,"identifiers":7012},"Gilks, R. & Berzuini, C. Following a moving target — Monte Carlo inference for dynamic Bayesian models. J. R. Stat. Soc. B 63, 127–146 (2001).",{"doi":7013},"10.1111\u002F1467-9868.00280",{"id":24,"text":7015,"url":24,"identifiers":7016},"Tedeholm, H. et al. Time to secondary progression in patients with multiple sclerosis treated with first generation immunomodulating drugs. Mult. Scler. 19, 765–774 (2013).",{"doi":7017},"10.1177\u002F1352458512463764",{"id":24,"text":7019,"url":24,"identifiers":7020},"Shirani, A. et al. Association between use of interferon beta and progression of disability in patients with relapsing–remitting multiple sclerosis. JAMA 308, 247–256 (2012).",{},{"id":24,"text":7022,"url":24,"identifiers":7023},"Palace, J. et al. Effectiveness and cost-effectiveness of interferon beta and glatiramer acetate in the UK Multiple Sclerosis Risk Sharing Scheme at 6 years: a clinical cohort study with natural history comparator. Lancet Neurol. 14, 497–505 (2015). The first study assessing cost–utility ratios and cost-effectiveness in patients with MS treated with BRACE therapies over a 6-year period.",{"doi":7024},"10.1016\u002FS1474-4422(15)00018-6",{"id":24,"text":7026,"url":24,"identifiers":7027},"Craig, B. A. & Sendi, P. P. Estimation of the transition matrix of a discrete-time Markov chain. Health Econ. 11, 33–42 (2002).",{"doi":7028},"10.1002\u002Fhec.654",{"id":24,"text":7030,"url":24,"identifiers":7031},"Jackson, C. H., Sharples, L. S., Thompson, S. G. & Couto, E. Multistate Markov models for disease progression with classification error. J. R. Stat. Soc. D 52, 193–209 (2003).",{"doi":7032},"10.1111\u002F1467-9884.00351",{"id":24,"text":7034,"url":24,"identifiers":7035},"Kalincik, T. et al. Defining reliable disability outcomes in multiple sclerosis. Brain 138, 3287–3298 (2015).",{"doi":7036},"10.1093\u002Fbrain\u002Fawv258",{"id":24,"text":7038,"url":24,"identifiers":7039},"Lorscheider, J. et al. Defining secondary progressive multiple sclerosis. Brain 139, 2395–2405 (2016).",{"doi":7040},"10.1093\u002Fbrain\u002Faww173",{"id":24,"text":7042,"url":24,"identifiers":7043},"Ziemssen, T., Kern, R. & Cornelissen, C. The PANGAEA study design — a prospective, multicenter, non-interventional, long-term study on fingolimod for the treatment of multiple sclerosis in daily practice. BMC Neurol. 15, 93 (2015).",{"doi":7044},"10.1186\u002Fs12883-015-0342-0",{"id":24,"text":7046,"url":24,"identifiers":7047},"Linker, R. A. & Wendt, G. Cardiac safety profile of first dose of fingolimod for relapsing–remitting multiple sclerosis in real-world settings: data from a German prospective multi-center observational study. Neurol. Ther. http:\u002F\u002Fdx.doi.org\u002F10.1007\u002Fs40120-016-0051-7 (2016).",{"doi":7048},"10.1007\u002Fs40120-016-0051-7",{"id":24,"text":7050,"url":24,"identifiers":7051},"Miclea, A. et al. Safety and efficacy of dimethyl fumarate in multiple sclerosis: a multi-center observational study. J. Neurol. 263, 1626–1632 (2016).",{"doi":7052},"10.1007\u002Fs00415-016-8175-3",{"id":24,"text":7054,"url":24,"identifiers":7055},"Frisell, T. et al. Comparative analysis of first-year fingolimod and natalizumab drug discontinuation among Swedish patients with multiple sclerosis. Mult. Scler. 22, 85–93 (2016).",{"doi":7056},"10.1177\u002F1352458515579216",{"id":24,"text":7058,"url":24,"identifiers":7059},"Butzkueven, H. et al. Efficacy and safety of natalizumab in multiple sclerosis: interim observational programme results. J. Neurol. Neurosurg. Psychiatry 85, 1190–1197 (2014).",{"doi":7060},"10.1136\u002Fjnnp-2013-306936",{"id":24,"text":7062,"url":24,"identifiers":7063},"Zhang, T. et al. Examining the effects of comorbidities on disease-modifying therapy use in multiple sclerosis. Neurology 86, 1287–1295 (2016).",{"doi":7064},"10.1212\u002FWNL.0000000000002543",{"id":24,"text":7066,"url":24,"identifiers":7067},"Issa, N. T., Byers, S. W. & Dakshanamurthy, S. Big data: the next frontier for innovation in therapeutics and healthcare. Expert Rev. Clin. Pharmacol. 7, 293–298 (2014).",{"doi":7068},"10.1586\u002F17512433.2014.905201",{"id":24,"text":7070,"url":24,"identifiers":7071},"Thorpe, K. E. et al. A pragmatic-explanatory continuum indicator summary (PRECIS): a tool to help trial designers. J. Clin. Epidemiol. 62, 464–475 (2009).",{"doi":7072},"10.1016\u002Fj.jclinepi.2008.12.011",{"id":24,"text":7074,"url":24,"identifiers":7075},"van Staa, T. P. et al. The opportunities and challenges of pragmatic point-of-care randomised trials using routinely collected electronic records: evaluations of two exemplar trials. Health Technol. Assess. 18, 1–146 (2014).",{"doi":7076},"10.3310\u002Fhta18430",{"id":24,"text":7078,"url":24,"identifiers":7079},"Fiore, L. D. & Lavori, P. W. Integrating randomized comparative effectiveness research with patient care. N. Engl. J. Med. 374, 2152–2158 (2016).",{"doi":7080},"10.1056\u002FNEJMra1510057",{"id":24,"text":7082,"url":24,"identifiers":7083},"Patsopoulos, N. A. A pragmatic view on pragmatic trials. Dialogues Clin. Neurosci. 13, 217–224 (2011).",{"doi":7084},"10.31887\u002FDCNS.2011.13.2\u002Fnpatsopoulos",{"id":24,"text":7086,"url":24,"identifiers":7087},"Saaga, K. G. et al. Improving the efficiency and effectiveness of pragmatic clinical trials in older adults in the United States. Contemp. Clin. Trials 33, 1211–1216 (2012).",{"doi":7088},"10.1016\u002Fj.cct.2012.07.002",{"id":7090,"createTime":7091,"updateTime":7091,"relativeEntities":7092,"slug":7093,"properties":7094,"entityType":143,"verifyStatus":144,"verifyTime":7091,"verifyNote":146,"languages":7107,"translateLanguages":24,"viewCount":25,"primaryUrl":7108,"fullTextUrl":24,"authors":7109,"publicationType":213,"publisherRelationship":7167,"citationCount":7220,"citationInfo":7221,"publishDate":7232,"publishYear":3728,"citationAnalyzeStatus":23,"lastCitationAnalyze":24,"indexDatabases":7233,"openAccess":24,"references":7234,"isForceReanalyzing":1636},"ce1ed7b8-38c5-443a-93e2-1d2beec48202","2024-11-28T22:22:18.897+00:00",[],"The-secretases-enzymes-with-therapeutic-potential-in-Alzheimer-disease",{"openalex":7095,"mag":7097,"title":7099,"pm":7101,"doi":7103,"pmc":7105},{"VOID":7096},"W2068042361",{"VOID":7098},"2068042361",{"EN":7100},"The secretases: enzymes with therapeutic potential in Alzheimer disease",{"VOID":7102},"20139999",{"VOID":7104},"10.1038\u002Fnrneurol.2009.218",{"VOID":7106},"2879045",[148],"https:\u002F\u002Fwww.nature.com\u002Farticles\u002Fnrneurol.2009.218",[7110,7129,7148],{"id":7111,"sortIndex":25,"researcher":24,"roles":7112,"affiliations":7113,"properties":7122,"displayName":7126,"givenName":24,"familyName":24},"bc77fe1d-b41f-4d32-bbf6-0e9f35bcc0e7",[],[7114],{"id":7115,"sortIndex":25,"affiliation":7116,"properties":24},"e69595d2-a8b7-4ab5-b0b1-e6a32208a652",{"id":7115,"createTime":24,"updateTime":24,"relativeEntities":7117,"slug":24,"properties":7118,"entityType":24,"verifyStatus":24,"verifyTime":24,"verifyNote":24,"languages":24,"translateLanguages":24,"viewCount":24,"url":24,"parentIds":7121,"statistic":24},[],{"title":7119},{"VI":7120},"KU, Leuven",[],{"orcid":7123,"title":7125,"openalex":7127},{"VOID":7124},"https:\u002F\u002Forcid.org\u002F0000-0001-5455-5819",{"EN":7126},"Bart De Strooper",{"VOID":7128},"A5021772353",{"id":7130,"sortIndex":93,"researcher":24,"roles":7131,"affiliations":7132,"properties":7141,"displayName":7145,"givenName":24,"familyName":24},"e1290b8f-0253-4d02-bfc3-156a2a576885",[],[7133],{"id":7134,"sortIndex":25,"affiliation":7135,"properties":24},"bbe12045-3e49-4856-b672-3ce58cd0a124",{"id":7134,"createTime":24,"updateTime":24,"relativeEntities":7136,"slug":24,"properties":7137,"entityType":24,"verifyStatus":24,"verifyTime":24,"verifyNote":24,"languages":24,"translateLanguages":24,"viewCount":24,"url":24,"parentIds":7140,"statistic":24},[],{"title":7138},{"VI":7139},"Department of Cell and Molecular Biology, Northwestern University, Chicago, USA",[],{"orcid":7142,"title":7144,"openalex":7146},{"VOID":7143},"https:\u002F\u002Forcid.org\u002F0000-0002-1358-504X",{"EN":7145},"Robert Vassar",{"VOID":7147},"A5028697711",{"id":7149,"sortIndex":193,"researcher":24,"roles":7150,"affiliations":7151,"properties":7160,"displayName":7164,"givenName":24,"familyName":24},"7202b166-40de-44a1-9730-d9779024d82f",[],[7152],{"id":7153,"sortIndex":25,"affiliation":7154,"properties":24},"104306c4-8788-49f4-b969-678a6410079f",{"id":7153,"createTime":24,"updateTime":24,"relativeEntities":7155,"slug":24,"properties":7156,"entityType":24,"verifyStatus":24,"verifyTime":24,"verifyNote":24,"languages":24,"translateLanguages":24,"viewCount":24,"url":24,"parentIds":7159,"statistic":24},[],{"title":7157},{"EN":7158},"Department of Neuroscience, Mayo Clinic College of Medicine, Mayo Clinic Florida, Jacksonville, USA",[],{"orcid":7161,"title":7163,"openalex":7165},{"VOID":7162},"https:\u002F\u002Forcid.org\u002F0000-0003-1867-7071",{"EN":7164},"Todd E. 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S. Mediterranean diet and late-life cognitive impairment: a taste of benefit. JAMA 302, 686–687 (2009).",{"doi":7238},"10.1001\u002Fjama.2009.1149",{"id":24,"text":7240,"url":24,"identifiers":7241},"Lazarov, O.  et al. Environmental enrichment reduces Aβ levels and amyloid deposition in transgenic mice. Cell 120, 701–713 (2005).",{"doi":7242},"10.1016\u002Fj.cell.2005.01.015",{"id":24,"text":7244,"url":24,"identifiers":7245},"Hardy, J. & Selkoe, D. J. The amyloid hypothesis of Alzheimer's disease: progress and problems on the road to therapeutics. Science 297, 353–356 (2002).",{"doi":7246},"10.1126\u002Fscience.1072994",{"id":24,"text":7248,"url":24,"identifiers":7249},"Reinhard, C., Hebert, S. S. & De Strooper, B. The amyloid-β precursor protein: integrating structure with biological function. EMBO J. 24, 3996–4006 (2005).",{"doi":7250},"10.1038\u002Fsj.emboj.7600860",{"id":24,"text":7252,"url":24,"identifiers":7253},"Sisodia, S. S., Koo, E. H., Beyreuther, K., Unterbeck, A. & Price, D. L. Evidence that beta-amyloid protein in Alzheimer's disease is not derived by normal processing. Science 248, 492–495 (1990).",{"doi":7254},"10.1126\u002Fscience.1691865",{"id":24,"text":7256,"url":24,"identifiers":7257},"Weidemann, A.  et al. Proteolytic processing of the Alzheimer's disease amyloid precursor protein within its cytoplasmic domain by caspase-like proteases. J. Biol. Chem. 274, 5823–5829 (1999).",{"doi":7258},"10.1074\u002Fjbc.274.9.5823",{"id":24,"text":7260,"url":24,"identifiers":7261},"Seubert, P.  et al. Secretion of β-amyloid precursor protein cleaved at the amino terminus of the beta-amyloid peptide. Nature 361, 260–263 (1993).",{"doi":7262},"10.1038\u002F361260a0",{"id":24,"text":7264,"url":24,"identifiers":7265},"Golde, T. E., Estus, S., Younkin, L. H., Selkoe, D. J. & Younkin, S. G. Processing of the amyloid protein precursor to potentially amyloidogenic derivatives. Science 255, 728–730 (1992).",{"doi":7266},"10.1126\u002Fscience.1738847",{"id":24,"text":7268,"url":24,"identifiers":7269},"Haass, C., Koo, E. H., Mellon, A., Hung, A. Y. & Selkoe, D. J. Targeting of cell-surface β-amyloid precursor protein to lysosomes: alternative processing into amyloid-bearing fragments. Nature 357, 500–503 (1992).",{"doi":7270},"10.1038\u002F357500a0",{"id":24,"text":7272,"url":24,"identifiers":7273},"De Strooper, B.  et al. Deficiency of presenilin-1 inhibits the normal cleavage of amyloid precursor protein. Nature 391, 387–390 (1998).",{"doi":7274},"10.1038\u002F34910",{"id":24,"text":7276,"url":24,"identifiers":7277},"Haass, C. & Selkoe, D. J. Cellular processing of β-amyloid precursor protein and the genesis of amyloid beta-peptide. Cell 75, 1039–1042 (1993).",{"doi":7278},"10.1016\u002F0092-8674(93)90312-E",{"id":24,"text":7280,"url":24,"identifiers":7281},"Hung, A. Y.  et al. Activation of protein kinase C inhibits cellular production of the amyloid β-protein. J. Biol. Chem. 268, 22959–22962 (1993).",{"doi":7282},"10.1016\u002FS0021-9258(19)49409-X",{"id":24,"text":7284,"url":24,"identifiers":7285},"Skovronsky, D. M., Moore, D. B., Milla, M. E., Doms, R. W. & Lee, V. M. Protein kinase C-dependent α-secretase competes with β-secretase for cleavage of amyloid-β precursor protein in the trans-golgi network. J. Biol. Chem. 275, 2568–2575 (2000).",{"doi":7286},"10.1074\u002Fjbc.275.4.2568",{"id":24,"text":7288,"url":24,"identifiers":7289},"Rossner, S.  et al. Constitutive overactivation of protein kinase C in guinea pig brain increases α-secretory APP processing without decreasing β-amyloid generation. Eur. J. Neurosci. 12, 3191–3200 (2000).",{"doi":7290},"10.1046\u002Fj.1460-9568.2000.00211.x",{"id":24,"text":7292,"url":24,"identifiers":7293},"Gowing, E.  et al. Chemical characterization of Aβ 17–42 peptide, a component of diffuse amyloid deposits of Alzheimer disease. J. Biol. Chem. 269, 10987–10990 (1994).",{"doi":7294},"10.1016\u002FS0021-9258(19)78080-6",{"id":24,"text":7296,"url":24,"identifiers":7297},"Higgins, L. S., Murphy, G. M. Jr, Forno, L. S., Catalano, R. & Cordell, B. P3 beta-amyloid peptide has a unique and potentially pathogenic immunohistochemical profile in Alzheimer's disease brain. Am. J. Pathol. 149, 585–596 (1996).",{},{"id":24,"text":7299,"url":24,"identifiers":7300},"Ring, S.  et al. The secreted β-amyloid precursor protein ectodomain APPsα is sufficient to rescue the anatomical, behavioral, and electrophysiological abnormalities of APP-deficient mice. J. Neurosci. 27, 7817–7826 (2007).",{"doi":7301},"10.1523\u002FJNEUROSCI.1026-07.2007",{"id":24,"text":7303,"url":24,"identifiers":7304},"Lammich, S.  et al. Constitutive and regulated α-secretase cleavage of Alzheimer's amyloid precursor protein by a disintegrin metalloprotease. Proc. Natl Acad. Sci. USA 96, 3922–3927 (1999).",{"doi":7305},"10.1073\u002Fpnas.96.7.3922",{"id":24,"text":7307,"url":24,"identifiers":7308},"Postina, R.  et al. A disintegrin-metalloproteinase prevents amyloid plaque formation and hippocampal defects in an Alzheimer disease mouse model. J. Clin. Invest. 113, 1456–1464 (2004).",{"doi":7309},"10.1172\u002FJCI20864",{"id":24,"text":7311,"url":24,"identifiers":7312},"Asai, M.  et al. Putative function of ADAM9, ADAM10, and ADAM17 as APP α-secretase. Biochem. Biophys. Res. Commun. 301, 231–235 (2003).",{"doi":7313},"10.1016\u002FS0006-291X(02)02999-6",{"id":24,"text":7315,"url":24,"identifiers":7316},"Buxbaum, J. D.  et al. Evidence that tumor necrosis factor alpha converting enzyme is involved in regulated α-secretase cleavage of the Alzheimer amyloid protein precursor. J. Biol. Chem. 273, 27765–27767 (1998).",{"doi":7317},"10.1074\u002Fjbc.273.43.27765",{"id":24,"text":7319,"url":24,"identifiers":7320},"Koike, H.  et al. Membrane-anchored metalloprotease MDC9 has an α-secretase activity responsible for processing the amyloid precursor protein. Biochem. J. 343, 371–375 (1999).",{"doi":7321},"10.1042\u002Fbj3430371",{"id":24,"text":7323,"url":24,"identifiers":7324},"Tanabe, C.  et al. ADAM19 is tightly associated with constitutive Alzheimer's disease APP α-secretase in A172 cells. Biochem. Biophys. Res. Commun. 352, 111–117 (2007).",{"doi":7325},"10.1016\u002Fj.bbrc.2006.10.181",{"id":24,"text":7327,"url":24,"identifiers":7328},"Farzan, M., Schnitzler, C. E., Vasilieva, N., Leung, D. & Choe, H. BACE2, a β-secretase homolog, cleaves at the β site and within the amyloid-β region of the amyloid-β precursor protein. Proc. Natl Acad. Sci. USA 97, 9712–9717 (2000).",{"doi":7329},"10.1073\u002Fpnas.160115697",{"id":24,"text":7331,"url":24,"identifiers":7332},"Yan, R., Munzner, J. B., Shuck, M. E. & Bienkowski, M. J. BACE2 functions as an alternative α-secretase in cells. J. Biol. Chem. 276, 34019–34027 (2001).",{"doi":7333},"10.1074\u002Fjbc.M105583200",{"id":24,"text":7335,"url":24,"identifiers":7336},"Weskamp, G.  et al. Mice lacking the metalloprotease-disintegrin MDC9 (ADAM9) have no evident major abnormalities during development or adult life. Mol. Cell. Biol. 22, 1537–1544 (2002).",{"doi":7337},"10.1128\u002FMCB.22.5.1537-1544.2002",{"id":24,"text":7339,"url":24,"identifiers":7340},"Hartmann, D.  et al. The disintegrin\u002Fmetalloprotease ADAM 10 is essential for Notch signalling but not for α-secretase activity in fibroblasts. Hum. Mol. Genet. 11, 2615–2624 (2002).",{"doi":7341},"10.1093\u002Fhmg\u002F11.21.2615",{"id":24,"text":7343,"url":24,"identifiers":7344},"Black, R. A.  et al. A metalloproteinase disintegrin that releases tumour-necrosis factor-α from cells. Nature 385, 729–733 (1997).",{"doi":7345},"10.1038\u002F385729a0",{"id":24,"text":7347,"url":24,"identifiers":7348},"Maretzky, T.  et al. ADAM10 mediates E-cadherin shedding and regulates epithelial cell–cell adhesion, migration, and β-catenin translocation. Proc. Natl Acad. Sci. USA 102, 9182–9187 (2005).",{"doi":7349},"10.1073\u002Fpnas.0500918102",{"id":24,"text":7351,"url":24,"identifiers":7352},"Reiss, K.  et al. ADAM10 cleavage of N-cadherin and regulation of cell-cell adhesion and β-catenin nuclear signalling. EMBO J. 24, 742–752 (2005).",{"doi":7353},"10.1038\u002Fsj.emboj.7600548",{"id":24,"text":7355,"url":24,"identifiers":7356},"Allinson, T. M., Parkin, E. T., Turner, A. J. & Hooper, N. M. ADAMs family members as amyloid precursor protein α-secretases. J. Neurosci. Res. 74, 342–352 (2003).",{"doi":7357},"10.1002\u002Fjnr.10737",{"id":24,"text":7359,"url":24,"identifiers":7360},"Bandyopadhyay, S., Goldstein, L. E., Lahiri, D. K. & Rogers, J. T. Role of the APP non-amyloidogenic signaling pathway and targeting α-secretase as an alternative drug target for treatment of Alzheimer's disease. Curr. Med. Chem. 14, 2848–2864 (2007).",{"doi":7361},"10.2174\u002F092986707782360060",{"id":24,"text":7363,"url":24,"identifiers":7364},"Tippmann, F., Hundt, J., Schneider, A., Endres, K. & Fahrenholz, F. Up-regulation of the α-secretase ADAM10 by retinoic acid receptors and acitretin. FASEB J. 6, 1643–1654 (2009).",{"doi":7365},"10.1096\u002Ffj.08-121392",{"id":24,"text":7367,"url":24,"identifiers":7368},"Caccamo, A.  et al. M1 receptors play a central role in modulating AD-like pathology in transgenic mice. Neuron 49, 671–682 (2006).",{"doi":7369},"10.1016\u002Fj.neuron.2006.01.020",{"id":24,"text":7371,"url":24,"identifiers":7372},"Wolf, B. A.  et al. Muscarinic regulation of Alzheimer's disease amyloid precursor protein secretion and amyloid β-protein production in human neuronal NT2N cells. J. Biol. Chem. 270, 4916–4922 (1995).",{"doi":7373},"10.1074\u002Fjbc.270.9.4916",{"id":24,"text":7375,"url":24,"identifiers":7376},"Zimmermann, M.  et al. Acetylcholinesterase inhibitors increase ADAM10 activity by promoting its trafficking in neuroblastoma cell lines. J. Neurochem. 90, 1489–1499 (2004).",{"doi":7377},"10.1111\u002Fj.1471-4159.2004.02680.x",{"id":24,"text":7379,"url":24,"identifiers":7380},"Hussain, I.  et al. Identification of a novel aspartic protease (Asp 2) as β-secretase. Mol. Cell. Neurosci. 14, 419–427 (1999).",{"doi":7381},"10.1006\u002Fmcne.1999.0811",{"id":24,"text":7383,"url":24,"identifiers":7384},"Vassar, R.  et al. β-Secretase cleavage of Alzheimer's amyloid precursor protein by the transmembrane aspartic protease BACE. Science 286, 735–741 (1999).",{"doi":7385},"10.1126\u002Fscience.286.5440.735",{"id":24,"text":7387,"url":24,"identifiers":7388},"Yan, R.  et al. Membrane-anchored aspartyl protease with Alzheimer's disease β-secretase activity. Nature 402, 533–537 (1999).",{"doi":7389},"10.1038\u002F990107",{"id":24,"text":7391,"url":24,"identifiers":7392},"Sinha, S.  et al. Purification and cloning of amyloid precursor protein β-secretase from human brain. Nature 402, 537–540 (1999).",{"doi":7393},"10.1038\u002F990114",{"id":24,"text":7395,"url":24,"identifiers":7396},"Lin, X.  et al. Human aspartic protease memapsin 2 cleaves the β-secretase site of β-amyloid precursor protein. Proc. Natl Acad. Sci. USA 97, 1456–1460 (2000).",{"doi":7397},"10.1073\u002Fpnas.97.4.1456",{"id":24,"text":7399,"url":24,"identifiers":7400},"Cole, S. L. & Vassar, R. The role of amyloid precursor protein processing by BACE1, the β-secretase, in Alzheimer disease pathophysiology. J. Biol. Chem. 283, 29621–29625 (2008).",{"doi":7401},"10.1074\u002Fjbc.R800015200",{"id":24,"text":7403,"url":24,"identifiers":7404},"Luo, Y.  et al. Mice deficient in BACE1, the Alzheimer's β-secretase, have normal phenotype and abolished β-amyloid generation. Nat. Neurosci. 4, 231–232 (2001).",{"doi":7405},"10.1038\u002F85059",{"id":24,"text":7407,"url":24,"identifiers":7408},"Cai, H.  et al. BACE1 is the major β-secretase for generation of Aβ peptides by neurons. Nat. Neurosci. 4, 233–234 (2001).",{"doi":7409},"10.1038\u002F85064",{"id":24,"text":7411,"url":24,"identifiers":7412},"Roberds, S. L.  et al. BACE knockout mice are healthy despite lacking the primary β-secretase activity in brain: implications for Alzheimer's disease therapeutics. Hum. Mol. Genet. 10, 1317–1324 (2001).",{"doi":7413},"10.1093\u002Fhmg\u002F10.12.1317",{"id":24,"text":7415,"url":24,"identifiers":7416},"Dominguez, D.  et al. Phenotypic and biochemical analyses of BACE1- and BACE2-deficient mice. J. Biol. Chem. 280, 30797–30806 (2005).",{"doi":7417},"10.1074\u002Fjbc.M505249200",{"id":24,"text":7419,"url":24,"identifiers":7420},"Ohno, M.  et al. BACE1 deficiency rescues memory deficits and cholinergic dysfunction in a mouse model of Alzheimer's disease. Neuron 41, 27–33 (2004).",{"doi":7421},"10.1016\u002FS0896-6273(03)00810-9",{"id":24,"text":7423,"url":24,"identifiers":7424},"Laird, F. M.  et al. BACE1, a major determinant of selective vulnerability of the brain to amyloid-β amyloidogenesis, is essential for cognitive, emotional, and synaptic functions. J. Neurosci. 25, 11693–11709 (2005).",{"doi":7425},"10.1523\u002FJNEUROSCI.2766-05.2005",{"id":24,"text":7427,"url":24,"identifiers":7428},"McConlogue, L.  et al. Partial reduction of BACE1 has dramatic effects on Alzheimer plaque and synaptic pathology in APP transgenic mice. J. Biol. Chem. 282, 26326–26334 (2007).",{"doi":7429},"10.1074\u002Fjbc.M611687200",{"id":24,"text":7431,"url":24,"identifiers":7432},"Nishitomi, K.  et al. BACE1 inhibition reduces endogenous Abeta and alters APP processing in wild-type mice. J. Neurochem. 99, 1555–1563 (2006).",{"doi":7433},"10.1111\u002Fj.1471-4159.2006.04178.x",{"id":24,"text":7435,"url":24,"identifiers":7436},"Singer, O.  et al. Targeting BACE1 with siRNAs ameliorates Alzheimer disease neuropathology in a transgenic model. Nat. Neurosci. 8, 1343–1349 (2005).",{"doi":7437},"10.1038\u002Fnn1531",{"id":24,"text":7439,"url":24,"identifiers":7440},"Yan, R., Han, P., Miao, H., Greengard, P. & Xu, H. The transmembrane domain of the Alzheimer's β-secretase (BACE1) determines its late Golgi localization and access to β-amyloid precursor protein (APP) substrate. J. Biol. Chem. 276, 36788–36796 (2001).",{"doi":7441},"10.1074\u002Fjbc.M104350200",{"id":24,"text":7443,"url":24,"identifiers":7444},"Kitazume, S.  et al. Alzheimer's β-secretase, β-site amyloid precursor protein-cleaving enzyme, is responsible for cleavage secretion of a Golgi-resident sialyltransferase. Proc. Natl Acad. Sci. USA 98, 13554–13559 (2001).",{"doi":7445},"10.1073\u002Fpnas.241509198",{"id":24,"text":7447,"url":24,"identifiers":7448},"Lichtenthaler, S. F.  et al. The cell adhesion protein P-selectin glycoprotein ligand-1 is a substrate for the aspartyl protease BACE1. J. Biol. Chem. 278, 48713–48719 (2003).",{"doi":7449},"10.1074\u002Fjbc.M303861200",{"id":24,"text":7451,"url":24,"identifiers":7452},"Li, Q. & Sudhof, T. C. Cleavage of amyloid-β precursor protein and amyloid-β precursor-like protein by BACE 1. J. Biol. Chem. 279, 10542–10550 (2004).",{"doi":7453},"10.1074\u002Fjbc.M310001200",{"id":24,"text":7455,"url":24,"identifiers":7456},"Pastorino, L.  et al. BACE (β-secretase) modulates the processing of APLP2 in vivo. Mol. Cell. Neurosci. 25, 642–649 (2004).",{"doi":7457},"10.1016\u002Fj.mcn.2003.12.013",{"id":24,"text":7459,"url":24,"identifiers":7460},"Eggert, S.  et al. The proteolytic processing of the amyloid precursor protein gene family members APLP-1 and APLP-2 involves α-, β-, γ-, and ε-like cleavages: modulation of APLP-1 processing by n-glycosylation. J. Biol. Chem. 279, 18146–18156 (2004).",{"doi":7461},"10.1074\u002Fjbc.M311601200",{"id":24,"text":7463,"url":24,"identifiers":7464},"von Arnim, C. A.  et al. The low density lipoprotein receptor-related protein (LRP) is a novel β-secretase (BACE1) substrate. J. Biol. Chem. 280, 17777–17785 (2005).",{"doi":7465},"10.1074\u002Fjbc.M414248200",{"id":24,"text":7467,"url":24,"identifiers":7468},"Wong, H. K.  et al. β Subunits of voltage-gated sodium channels are novel substrates of β-site amyloid precursor protein-cleaving enzyme (BACE1) and γ-secretase. J. Biol. Chem. 280, 23009–23017 (2005).",{"doi":7469},"10.1074\u002Fjbc.M414648200",{"id":24,"text":7471,"url":24,"identifiers":7472},"Kim, D.Y.  et al. BACE1 regulates voltage-gated sodium channels and neuronal activity. Nat. Cell Biol. 9, 755–764 (2007).",{"doi":7473},"10.1038\u002Fncb1602",{"id":24,"text":7475,"url":24,"identifiers":7476},"Hu, X.  et al. Genetic deletion of BACE1 in mice affects remyelination of sciatic nerves. FASEB J. 22, 2970–2980 (2008).",{"doi":7477},"10.1096\u002Ffj.08-106666",{"id":24,"text":7479,"url":24,"identifiers":7480},"Willem, M.  et al. Control of peripheral nerve myelination by the beta-secretase BACE1. Science 314, 664–666 (2006).",{"doi":7481},"10.1126\u002Fscience.1132341",{"id":24,"text":7483,"url":24,"identifiers":7484},"Hu, X  et al. Bace1 modulates myelination in the central and peripheral nervous system. Nat. Neurosci. 9, 1520–1525 (2006).",{"doi":7485},"10.1038\u002Fnn1797",{"id":24,"text":7487,"url":24,"identifiers":7488},"Silvestri, R. Boom in the development of non-peptidic β-secretase (BACE1) inhibitors for the treatment of Alzheimer's disease. Med. Res. Rev. 29, 295–338 (2009).",{"doi":7489},"10.1002\u002Fmed.20132",{"id":24,"text":7491,"url":24,"identifiers":7492},"Hills, I. D. & Vacca, J. P. Progress toward a practical BACE-1 inhibitor. Curr. Opin. Drug Discov. Devel. 10, 383–391 (2007).",{},{"id":24,"text":7494,"url":24,"identifiers":7495},"Rajendran, L.  et al. Efficient inhibition of the Alzheimer's disease β-secretase by membrane targeting. Science 320, 520–523 (2008).",{"doi":7496},"10.1126\u002Fscience.1156609",{"id":24,"text":7498,"url":24,"identifiers":7499},"De Strooper, B. Aph-1, Pen-2, and nicastrin with presenilin generate an active γ-secretase complex. Neuron 38, 9–12 (2003).",{"doi":7500},"10.1016\u002FS0896-6273(03)00205-8",{"id":24,"text":7502,"url":24,"identifiers":7503},"Wolfe, M. S. & Kopan, R. Intramembrane proteolysis: theme and variations. Science 305, 1119–1123 (2004).",{"doi":7504},"10.1126\u002Fscience.1096187",{"id":24,"text":7506,"url":24,"identifiers":7507},"Takasugi, N.  et al. The role of presenilin cofactors in the γ-secretase complex. Nature 422, 438–441 (2003).",{"doi":7508},"10.1038\u002Fnature01506",{"id":24,"text":7510,"url":24,"identifiers":7511},"Edbauer, D.  et al. Reconstitution of γ-secretase activity. Nat. Cell Biol. 5, 486–488 (2003).",{"doi":7512},"10.1038\u002Fncb960",{"id":24,"text":7514,"url":24,"identifiers":7515},"Shah, S.  et al. Nicastrin functions as a γ-secretase-substrate receptor. Cell 122, 435–447 (2005).",{"doi":7516},"10.1016\u002Fj.cell.2005.05.022",{"id":24,"text":7518,"url":24,"identifiers":7519},"Chavez-Gutierrez, L.  et al. Glu(332) in the nicastrin ectodomain is essential for γ-secretase complex maturation but not for its activity. J. Biol. Chem. 283, 20096–20105 (2008).",{"doi":7520},"10.1074\u002Fjbc.M803040200",{"id":24,"text":7522,"url":24,"identifiers":7523},"Hébert, S. S.  et al. Coordinated and widespread expression of γ-secretase in vivo: evidence for size and molecular heterogeneity. Neurobiol. Dis. 17, 260–272 (2004).",{"doi":7524},"10.1016\u002Fj.nbd.2004.08.002",{"id":24,"text":7526,"url":24,"identifiers":7527},"Shirotani, K., Edbauer, D., Prokop, S., Haass, C. & Steiner, H. Identification of distinct γ-secretase complexes with different APH-1 variants. J. Biol. Chem. 279, 41340–41345 (2004).",{"doi":7528},"10.1074\u002Fjbc.M405768200",{"id":24,"text":7530,"url":24,"identifiers":7531},"Ma, G., Li, T., Price, D. L. & Wong, P. C. APH-1a is the principal mammalian APH-1 isoform present in γ-secretase complexes during embryonic development. J. Neurosci. 25, 192–198 (2005).",{"doi":7532},"10.1523\u002FJNEUROSCI.3814-04.2005",{"id":24,"text":7534,"url":24,"identifiers":7535},"Serneels, L.  et al. Differential contribution of the three Aph1 genes to γ-secretase activity in vivo. Proc. Natl Acad. Sci. USA 102, 1719–1724 (2005).",{"doi":7536},"10.1073\u002Fpnas.0408901102",{"id":24,"text":7538,"url":24,"identifiers":7539},"Serneels, L.  et al. γ-Secretase heterogeneity in the Aph1 subunit: relevance for Alzheimer's disease. Science 324, 639–642 (2009).",{"doi":7540},"10.1126\u002Fscience.1171176",{"id":24,"text":7542,"url":24,"identifiers":7543},"Wolfe, M. S.  et al. Two transmembrane aspartates in presenilin-1 required for presenilin endoproteolysis and γ-secretase activity. Nature 398, 513–517 (1999).",{"doi":7544},"10.1038\u002F19077",{"id":24,"text":7546,"url":24,"identifiers":7547},"Osenkowski, P.  et al. Cryoelectron microscopy structure of purified γ-secretase at 12 A resolution. J. Mol. Biol. 385, 642–652 (2009).",{"doi":7548},"10.1016\u002Fj.jmb.2008.10.078",{"id":24,"text":7550,"url":24,"identifiers":7551},"Lazarov, V. K.  et al. Electron microscopic structure of purified, active γ-secretase reveals an aqueous intramembrane chamber and two pores. Proc. Natl Acad. Sci. USA 103, 6889–6894 (2006).",{"doi":7552},"10.1073\u002Fpnas.0602321103",{"id":24,"text":7554,"url":24,"identifiers":7555},"Tolia, A., Chavez-Gutierrez, L. & De Strooper, B. Contribution of presenilin transmembrane domains 6 and 7 to a water-containing cavity in the γ-secretase complex. J. Biol. Chem. 281, 27633–27642 (2006).",{"doi":7556},"10.1074\u002Fjbc.M604997200",{"id":24,"text":7558,"url":24,"identifiers":7559},"Sato, C., Morohashi, Y., Tomita, T. & Iwatsubo, T. Structure of the catalytic pore of γ-secretase probed by the accessibility of substituted cysteines. J. Neurosci. 26, 12081–12088 (2006).",{"doi":7560},"10.1523\u002FJNEUROSCI.3614-06.2006",{"id":24,"text":7562,"url":24,"identifiers":7563},"Kopan, R. & Ilagan, M. X. γ-Secretase: proteasome of the membrane? Nat. Rev. Mol. Cell Biol. 5, 499–504 (2004).",{"doi":7564},"10.1038\u002Fnrm1406",{"id":24,"text":7566,"url":24,"identifiers":7567},"Kakuda, N.  et al. Equimolar production of amyloid β-protein and amyloid precursor protein intracellular domain from β-carboxyl-terminal fragment by γ-secretase. J. Biol. Chem. 281, 14776–14786 (2006).",{"doi":7568},"10.1074\u002Fjbc.M513453200",{"id":24,"text":7570,"url":24,"identifiers":7571},"Golde, T. E., Eckman, C. B. & Younkin, S. G. Biochemical detection of Aβ isoforms: implications for pathogenesis, diagnosis, and treatment of Alzheimer's disease. Biochim. Biophys. Acta 1502, 172–187 (2000).",{"doi":7572},"10.1016\u002FS0925-4439(00)00043-0",{"id":24,"text":7574,"url":24,"identifiers":7575},"Jarrett, J. T., Berger, E. P. & Lansbury, P. T. Jr. The carboxy terminus of β amyloid protein is critical for the seeding of amyloid formation: Implications for pathogenesis of Alzheimer's disease. Biochemistry 32, 4693–4697 (1993).",{"doi":7576},"10.1021\u002Fbi00069a001",{"id":24,"text":7578,"url":24,"identifiers":7579},"McGowan, E.  et al. Aβ42 is essential for parenchymal and vascular amyloid deposition in mice. Neuron 47, 191–199 (2005).",{"doi":7580},"10.1016\u002Fj.neuron.2005.06.030",{"id":24,"text":7582,"url":24,"identifiers":7583},"Wang, R., Wang, B., He, W. & Zheng, H. Wild-type presenilin 1 protects against Alzheimer's disease mutation-induced amyloid pathology. J. Biol. Chem. 281, 15330–15336 (2006).",{"doi":7584},"10.1074\u002Fjbc.M512574200",{"id":24,"text":7586,"url":24,"identifiers":7587},"Kim, J.  et al. Aβ40 inhibits amyloid deposition in vivo. J. Neurosci. 27, 627–633 (2007).",{"doi":7588},"10.1523\u002FJNEUROSCI.4849-06.2007",{"id":24,"text":7590,"url":24,"identifiers":7591},"Wolfe, M. S. Inhibition and modulation of γ-secretase for Alzheimer's disease. Neurotherapeutics 5, 391–398 (2008).",{"doi":7592},"10.1016\u002Fj.nurt.2008.05.010",{"id":24,"text":7594,"url":24,"identifiers":7595},"Bateman, R. J.  et al. A γ-secretase inhibitor decreases amyloid-β production in the central nervous system. Ann. Neurol. 66, 48–54 (2009).",{"doi":7596},"10.1002\u002Fana.21623",{"id":24,"text":7598,"url":24,"identifiers":7599},"Siemers, E. R.  et al. Safety, tolerability, and effects on plasma and cerebrospinal fluid amyloid-β after inhibition of γ-secretase. Clin. Neuropharmacol. 30, 317–325 (2007).",{"doi":7600},"10.1097\u002FWNF.0b013e31805b7660",{"id":24,"text":7602,"url":24,"identifiers":7603},"Dovey, H. F.  et al. Functional gamma-secretase inhibitors reduce beta-amyloid peptide levels in brain. J. Neurochem. 76, 173–181 (2001).",{"doi":7604},"10.1046\u002Fj.1471-4159.2001.00012.x",{"id":24,"text":7606,"url":24,"identifiers":7607},"Abramowski, D.  et al. Dynamics of Aβ turnover and deposition in different β-amyloid precursor protein transgenic mouse models following γ-secretase inhibition. J. Pharmacol. Exp. Ther. 327, 411–424 (2008).",{"doi":7608},"10.1124\u002Fjpet.108.140327",{"id":24,"text":7610,"url":24,"identifiers":7611},"De Strooper, B.  et al. A presenilin-1-dependent γ-secretase-like protease mediates release of Notch intracellular domain. Nature 398, 518–522 (1999).",{"doi":7612},"10.1038\u002F19083",{"id":24,"text":7614,"url":24,"identifiers":7615},"Wong, P. C.  et al. Presenilin 1 is required for Notch1 and DII1 expression in the paraxial mesoderm. Nature 387, 288–292 (1997).",{"doi":7616},"10.1038\u002F387288a0",{"id":24,"text":7618,"url":24,"identifiers":7619},"Shen, J.  et al. Skeletal and CNS defects in presenilin-1-deficient mice. Cell 89, 629–639 (1997).",{"doi":7620},"10.1016\u002FS0092-8674(00)80244-5",{"id":24,"text":7622,"url":24,"identifiers":7623},"Searfoss, G. H.  et al. Adipsin, a biomarker of gastrointestinal toxicity mediated by a functional γ-secretase inhibitor. J. Biol. Chem. 278, 46107–46116 (2003).",{"doi":7624},"10.1074\u002Fjbc.M307757200",{"id":24,"text":7626,"url":24,"identifiers":7627},"Wong, G. T.  et al. Chronic treatment with the γ-secretase inhibitor LY-411, 575 inhibits β-amyloid peptide production and alters lymphopoiesis and intestinal cell differentiation. J. Biol. Chem. 279, 12876–12882 (2004).",{"doi":7628},"10.1074\u002Fjbc.M311652200",{"id":24,"text":7630,"url":24,"identifiers":7631},"Li, T.  et al. Epidermal growth factor receptor and notch pathways participate in the tumor suppressor function of γ-secretase. J. Biol. Chem. 282, 32264–32273 (2007).",{"doi":7632},"10.1074\u002Fjbc.M703649200",{"id":24,"text":7634,"url":24,"identifiers":7635},"Yankner, B. A.  et al. Neurotoxicity of a fragment of the amyloid precursor associated with Alzheimer's disease. Science 245, 417–420 (1989).",{"doi":7636},"10.1126\u002Fscience.2474201",{"id":24,"text":7638,"url":24,"identifiers":7639},"Siemers, E. R.  et al. Effects of a γ-secretase inhibitor in a randomized study of patients with Alzheimer disease. Neurology 66, 602–604 (2006).",{"doi":7640},"10.1212\u002F01.WNL.0000198762.41312.E1",{"id":24,"text":7642,"url":24,"identifiers":7643},"Fraering, P. C.  et al. γ-Secretase substrate selectivity can be modulated directly via interaction with a nucleotide-binding site. J. Biol. Chem. 280, 41987–41996 (2005).",{"doi":7644},"10.1074\u002Fjbc.M501368200",{"id":24,"text":7646,"url":24,"identifiers":7647},"Netzer, W. J.  et al. Gleevec inhibits β-amyloid production but not Notch cleavage. Proc. Natl Acad. Sci. USA 100, 12444–12449 (2003).",{"doi":7648},"10.1073\u002Fpnas.1534745100",{"id":24,"text":7650,"url":24,"identifiers":7651},"Fagan, T. DC: New γ-secretase inhibitors hit APP, spare Notch. The AlzGene Database. Alzheimer Research Forum [online], (2008).",{},{"id":24,"text":7653,"url":24,"identifiers":7654},"Mayer, S. C.  et al. Discovery of begacestat, a Notch-1-sparing γ-secretase inhibitor for the treatment of Alzheimer's disease. J. Med. Chem. 51, 7348–7351 (2008).",{"doi":7655},"10.1021\u002Fjm801252w",{"id":24,"text":7657,"url":24,"identifiers":7658},"Weggen, S.  et al. A subset of NSAIDs lower amyloidogenic Abeta42 independently of cyclooxygenase activity. Nature 414, 212–216 (2001).",{"doi":7659},"10.1038\u002F35102591",{"id":24,"text":7661,"url":24,"identifiers":7662},"Kukar, T. & Golde, T. E. Possible mechanisms of action of NSAIDs and related compounds that modulate γ-secretase cleavage. Curr. Top. Med. Chem. 8, 47–53 (2008).",{"doi":7663},"10.2174\u002F156802608783334042",{"id":24,"text":7665,"url":24,"identifiers":7666},"Kukar, T.  et al. Diverse compounds mimic Alzheimer disease-causing mutations by augmenting Aβ42 production. Nat. Med. 11, 545–550 (2005).",{"doi":7667},"10.1038\u002Fnm1235",{"id":24,"text":7669,"url":24,"identifiers":7670},"Weggen, S.  et al. Evidence that nonsteroidal anti-inflammatory drugs decrease amyloid β42 production by direct modulation of γ-secretase activity. J. Biol. Chem. 278, 31831–31837 (2003).",{"doi":7671},"10.1074\u002Fjbc.M303592200",{"id":24,"text":7673,"url":24,"identifiers":7674},"Green, R. C.  et al. Effect of tarenflurbil on cognitive decline and activities of daily living in patients with mild Alzheimer disease: a randomized controlled trial. JAMA 302, 2557–2564 (2009).",{"doi":7675},"10.1001\u002Fjama.2009.1866",{"id":24,"text":7677,"url":24,"identifiers":7678},"Kukar, T. L.  et al. Substrate-targeting γ-secretase modulators. Nature 453, 925–929 (2008).",{"doi":7679},"10.1038\u002Fnature07055",{"id":24,"text":7681,"url":24,"identifiers":7682},"Pissarnitski, D. Advances in gamma-secretase modulation. Curr. Opin. Drug Discov. Devel. 10, 392–402 (2007).",{},{"id":24,"text":7684,"url":24,"identifiers":7685},"Klunk, W. E. & Mathis, C. A. The future of amyloid-beta imaging: a tale of radionuclides and tracer proliferation. Curr. Opin. Neurol. 21, 683–687 (2008).",{"doi":7686},"10.1097\u002FWCO.0b013e3283168e1a"]