Annals of Neurology
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Mesenchymal stem cells effectively modulate pathogenic immune response in experimental autoimmune encephalomyelitis Abstract Objective To evaluate the ability of mesenchymal stem cells (MSCs), a subset of adult stem cells from bone marrow, to cure experimental autoimmune encephalomyelitis. Methods The outcome of the injection of MSCs, in mice immunized with the peptide 139–151 of the proteolipid protein (PLP), was studied analyzing clinical and histological scores of treated mice. The fate of MSCs labeled with the green fluorescent protein was tracked in vivo by a photon emission imaging system and postmortem by immunofluorescence. The modulation of the immune response against PLP was studied through the analysis of in vivo T‐ and B‐cell responses and by the adoptive transfer of MSC‐treated encephalitogenic cells. Results MSC‐treated mice showed a significantly milder disease and fewer relapses compared with control mice, with decreased number of inflammatory infiltrates, reduced demyelination, and axonal loss. In contrast, no evidence of green fluorescent protein–labeled neural cells was detected inside the brain parenchyma, thus not supporting the hypothesis of MSCs transdifferentiation. In vivo, PLP‐specific T‐cell response and antibody titers were significantly lower in MSC‐treated mice. When adoptively transferred, encephalitogenic T cells activated against PLP139–151 in the presence of MSCs induced a milder disease compared with that induced by untreated encephalitogenic T cells. These cells showed decreased production of interferon‐γ and tumor necrosis factor‐α and did not proliferate on antigen recall, and thus were considered anergic. Interpretation Overall, these findings suggest that the beneficial effect of MSCs in experimental autoimmune encephalomyelitis is mainly the result of an interference with the pathogenic autoimmune response. Ann Neurol 2007;61:219–227
Annals of Neurology - Tập 61 Số 3 - Trang 219-227 - 2007
Aluminum chloride induced neurofibrillary changes in the developing rabbit: A chronic animal model Abstract Aluminum chloride injected into the brains of developing rabbits produced profound neurofibrillary changes in neurons of spinal cord and cerebrum similar to those produced in adult rabbits, along with a variety of clinical symptoms with the exception of seizures. Approximately half of the rabbits survived for more than three weeks, and many survived for several months. Many rabbits with large numbers of neurofibrillary changes had no clinical signs and symptoms. The dynamics and topography of the neurofibrillary changes induced by aluminum chloride are described over a period of several months. Many neurofibrillary tangles were seen in neurons of spinal cord and cerebrum up to 60 days after injection of aluminum chloride. There was no obvious correlation between the degree of neuroftbrillary changes and the severity of the clinical signs and symptoms. Animals examined at 85 and 100 days after injection of aluminum chloride had fewer neuronbrillary tangles or none at all, and apparently they had recovered from the neurofibrillary changes. This chronic animal model will allow better investigations of the biochemistry and pathology of neuronbrillary changes, and it will enable behavioral studies to be performed in animals with neuronbrillary changes.
Annals of Neurology - Tập 8 Số 5 - Trang 479-490 - 1980
Fingolimod provides long‐term protection in rodent models of cerebral ischemia Abstract Objective: The sphingosine‐1‐phosphate (S1P) receptor agonist fingolimod (FTY720), that has shown efficacy in advanced multiple sclerosis clinical trials, decreases reperfusion injury in heart, liver, and kidney. We therefore tested the therapeutic effects of fingolimod in several rodent models of focal cerebral ischemia. To assess the translational significance of these findings, we asked whether fingolimod improved long‐term behavioral outcomes, whether delayed treatment was still effective, and whether neuroprotection can be obtained in a second species. Methods: We used rodent models of middle cerebral artery occlusion and cell‐culture models of neurotoxicity and inflammation to examine the therapeutic potential and mechanisms of neuroprotection by fingolimod. Results: In a transient mouse model, fingolimod reduced infarct size, neurological deficit, edema, and the number of dying cells in the core and periinfarct area. Neuroprotection was accompanied by decreased inflammation, as fingolimod‐treated mice had fewer activated neutrophils, microglia/macrophages, and intercellular adhesion molecule‐1 (ICAM‐1)‐positive blood vessels. Fingolimod‐treated mice showed a smaller infarct and performed better in behavioral tests up to 15 days after ischemia. Reduced infarct was observed in a permanent model even when mice were treated 4 hours after ischemic onset. Fingolimod also decreased infarct size in a rat model of focal ischemia. Fingolimod did not protect primary neurons against glutamate excitotoxicity or hydrogen peroxide, but decreased ICAM‐1 expression in brain endothelial cells stimulated by tumor necrosis factor alpha. Interpretation: These findings suggest that anti‐inflammatory mechanisms, and possibly vasculoprotection, rather than direct effects on neurons, underlie the beneficial effects of fingolimod after stroke. S1P receptors are a highly promising target in stroke treatment. ANN NEUROL, 2010
Annals of Neurology - Tập 69 Số 1 - Trang 119-129 - 2011
Validation of a new coma scale: The FOUR score Abstract The Glasgow Coma Scale (GCS) has been widely adopted. Failure to assess the verbal score in intubated patients and the inability to test brainstem reflexes are shortcomings. We devised a new coma score, the FOUR (Full Outline of UnResponsiveness) score. It consists of four components (eye, motor, brainstem, and respiration), and each component has a maximal score of 4. We prospectively studied the FOUR score in 120 intensive care unit patients and compared it with the GCS score using neuroscience nurses, neurology residents, and neurointensivists. We found that the interrater reliability was excellent with the FOUR score (κw = 0.82) and good to excellent for physician rater pairs. The agreement among raters was similar with the GCS (κw = 0.82). Patients with the lowest GCS score could be further distinguished using the FOUR score. We conclude that the agreement among raters was good to excellent. The FOUR score provides greater neurological detail than the GCS, recognizes a locked‐in syndrome, and is superior to the GCS due to the availability of brainstem reflexes, breathing patterns, and the ability to recognize different stages of herniation. The probability of in‐hospital mortality was higher for the lowest total FOUR score when compared with the lowest total GCS score. Ann Neurol 2005;58:585–593
Annals of Neurology - Tập 58 Số 4 - Trang 585-593 - 2005
The “neuro” of neuroblastoma: <scp>N</scp>euroblastoma as a neurodevelopmental disorder Neuroblastoma is a childhood cancer derived from cells of neural crest origin. The hallmarks of its enigmatic character include its propensity for spontaneous regression under some circumstances and its association with paraneoplastic opsoclonus, myoclonus, and ataxia. The neurodevelopmental underpinnings of its origins may provide important clues for development of novel therapeutic and preventive agents for this frequently fatal malignancy and for the associated paraneoplastic syndromes. Ann Neurol 2016;80:13–23
Annals of Neurology - Tập 80 Số 1 - Trang 13-23 - 2016
Salience network and parahippocampal dopamine dysfunction in memory‐impaired Parkinson disease Objective Patients with Parkinson disease (PD) and mild cognitive impairment (MCI) are vulnerable to dementia and frequently experience memory deficits. This could be the result of dopamine dysfunction in corticostriatal networks (salience, central executive networks, and striatum) and/or the medial temporal lobe. Our aim was to investigate whether dopamine dysfunction in these regions contributes to memory impairment in PD. Methods We used positron emission tomography imaging to compare D2 receptor availability in the cortex and striatal (limbic and associative) dopamine neuron integrity in 4 groups: memory‐impaired PD (amnestic MCI; n = 9), PD with nonamnestic MCI (n = 10), PD without MCI (n = 11), and healthy controls (n = 14). Subjects were administered a full neuropsychological test battery for cognitive performance. Results Memory‐impaired patients demonstrated more significant reductions in D2 receptor binding in the salience network (insular cortex and anterior cingulate cortex [ACC] and the right parahippocampal gyrus [PHG]) compared to healthy controls and patients with no MCI. They also presented reductions in the right insula and right ACC compared to nonamnestic MCI patients. D2 levels were correlated with memory performance in the right PHG and left insula of amnestic patients and with executive performance in the bilateral insula and left ACC of all MCI patients. Associative striatal dopamine denervation was significant in all PD patients. Interpretation Dopaminergic differences in the salience network and the medial temporal lobe contribute to memory impairment in PD. Furthermore, these findings indicate the vulnerability of the salience network in PD and its potential role in memory and executive dysfunction. Ann Neurol 2015;77:269–280
Annals of Neurology - Tập 77 Số 2 - Trang 269-280 - 2015
Ceruloplasmin dysfunction and therapeutic potential for Parkinson disease Ceruloplasmin is an iron‐export ferroxidase that is abundant in plasma and also expressed in glia. We found a ∼80% loss of ceruloplasmin ferroxidase activity in the substantia nigra of idiopathic Parkinson disease (PD) cases, which could contribute to the pro‐oxidant iron accumulation that characterizes the pathology. Consistent with a role for ceruloplasmin in PD etiopathogenesis, ceruloplasmin knockout mice developed parkinsonism that was rescued by iron chelation. Additionally, peripheral infusion of ceruloplasmin attenuated neurodegeneration and nigral iron elevation in the 1‐methyl‐4‐phenyl‐1,2,3,6‐tetrahydropyridine mouse model for PD. These findings show, in principle, that intravenous ceruloplasmin may have therapeutic potential in PD. Ann Neurol 2013;73:554–559
Annals of Neurology - Tập 73 Số 4 - Trang 554-559 - 2013
Seasonal (circannual) periodicity of spontaneous intracerebral hemorrhage in minnesota Abstract Seasonal periodicity in the onset of spontaneous intracerebral hemorrhage was studied in 118 consecutive cases occurring during a six‐year span. The patients were urban residents of eastern Minnesota, a region characterized by wide seasonal fluctuations in daylight and temperature. The greatest number of cases consistently occurred each year during January and February. Circsianual (about one year) periodicity was demonstrated by statistical analysis using rhythmometric techniques. This periodicity coincided with that reported for mortality from cerebrovascular and cardiovascular diseases in the United States and elsewhere. Available information suggests that in populations at high risk for vascular diseases, climatic conditions might act as synchronizers to endogenous rhythms influencing the periodic occurrence of pathological vascular events.
Annals of Neurology - Tập 8 Số 5 - Trang 539-541 - 1980
Magnetic brain stimulation: Central motor conduction studies in multiple sclerosis Abstract Central motor conduction (CMC) was evaluated in 32 normal subjects and 83 patients with multiple sclerosis, and the findings were correlated with clinical signs and evoked potential data. CMC time was obtained from the latency difference in responses from the abductor muscle of the little finger to magnetic stimulation of the motor cortex and electrical stimulation at the C‐7/T‐1 interspace. Mean CMC time in normal subjects was 6.2 msec (SD 0.86 msec), and amplitudes of responses to cortical stimuli were at least 18% of those obtained with stimuli at the wrist. CMC was abnormal in 60 patients with multiple sclerosis (72%); this correlated well with brisk finger flexor jerks (p < 0.005). CMC was abnormal in 79% of patients with weakness of the abductor muscle of the little finger and in 54% with a normal muscle. Neurological examination was normal in 7 arms with abnormal CMC. Visual evoked potentials were abnormal in 67%, somatosensory evoked potentials in 59%, and brainstem auditory evoked potentials in 39% of those tested. For each procedure more subjects had abnormal CMC and normal evoked potentials than the reverse. The technique is of value for demonstrating and documenting central motor pathway lesions in multiple sclerosis, especially when physical signs are equivocal.
Annals of Neurology - Tập 22 Số 6 - Trang 744-752 - 1987
TDP‐43 immunoreactivity in hippocampal sclerosis and Alzheimer's disease Abstract Objective This study aimed to determine the frequency of frontotemporal lobar degeneration with ubiquitinated inclusions (FTLD‐U) in the setting of hippocampal sclerosis (HpScl) and Alzheimer's disease (AD) using immunohistochemistry for TAR DNA binding protein 43 (TDP‐43), a putative marker for FTLD‐U. Methods Initially, 21 cases of HpScl associated with a variety of other pathological processes and 74 cases of AD were screened for FTLD‐U with TDP‐43 immunohistochemistry. A confirmation study was performed on 93 additional AD cases. Specificity of TDP‐43 antibodies was assessed using double‐immunolabeling confocal microscopy, immunoelectron microscopy, and biochemistry. Results TDP‐43 immunoreactivity was detected in 71% of HpScl and 23% of AD cases. Double immunostaining of AD cases for TDP‐43 and phospho‐tau showed that the TDP‐43–immunoreactive inclusions were usually distinct from neurofibrillary tangles. At the ultrastructural level, TDP‐43 immunoreactivity in AD was associated with granular and filamentous cytosolic material and only occasionally associated with tau filaments. Western blots of AD cases showed a band that migrated at a higher molecular weight than normal TDP‐43 that was not present in AD cases without TDP‐43 immunoreactivity. Interpretation These results suggest that as many as 20% of AD cases and more than 70% of HpScl cases have pathology similar to that found in FTLD‐U. Whether this represents concomitant FTLD‐U or is analogous to colocalization of α‐synuclein and tau in AD, reflecting a propensity for codeposition of abnormal protein conformers, remains to be determined. Ann Neurol 2007;61:435–445
Annals of Neurology - Tập 61 Số 5 - Trang 435-445 - 2007
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