Annals of Neurology
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Fixation‐off—sensitive epilepsy in eyelid myoclonia with absence seizuresAbstract Fixation‐off—sensitive epilepsy is documented in a patient with eyelid myoclonia with absences. A series of simple electroencephalographic techniques showed that elimination of visual fixation is the actual stimulus for the eyelid myoclonus.
Annals of Neurology - Tập 22 Số 1 - Trang 87-89 - 1987
Neonatal intensive care unit stress is associated with brain development in preterm infantsAbstract Objective: Although many perinatal factors have been linked to adverse neurodevelopmental outcomes in very premature infants, much of the variation in outcome remains unexplained. The impact on brain development of 1 potential factor, exposure to stressors in the neonatal intensive care unit, has not yet been studied in a systematic, prospective manner. Methods: In this prospective cohort study of infants born at <30 weeks gestation, nurses were trained in recording procedures and cares. These recordings were used to derive Neonatal Infant Stressor Scale scores, which were employed to measure exposure to stressors. Magnetic resonance imaging (brain metrics, diffusion, and functional magnetic resonance imaging) and neurobehavioral examinations at term equivalent postmenstrual age were used to assess cerebral structure and function. Simple and partial correlations corrected for confounders, including immaturity and severity of illness, were used to explore these relations. Results: Exposure to stressors was highly variable, both between infants and throughout a single infant's hospital course. Exposure to a greater number of stressors was associated with decreased frontal and parietal brain width, altered diffusion measures and functional connectivity in the temporal lobes, and abnormalities in motor behavior on neurobehavioral examination. Interpretation: Exposure to stressors in the Neonatal Intensive Care Unit is associated with regional alterations in brain structure and function. Further research into interventions that may decrease or mitigate exposure to stressors in the neonatal intensive care unit is warranted. ANN NEUROL 2011;
Annals of Neurology - Tập 70 Số 4 - Trang 541-549 - 2011
Mechanisms of fingolimod's efficacy and adverse effects in multiple sclerosisAbstract Until recently, all approved multiple sclerosis (MS) disease treatments were administered parenterally. Oral fingolimod was approved in September 2010 by the US Food and Drug Administration to reduce relapses and disability progression in relapsing forms of MS. In the clinical trials that led to approval, fingolimod reduced not only acute relapses and magnetic resonance imaging lesion activity but also disability progression and brain volume loss, suggesting preservation of tissue. Fingolimod's mechanism of action in MS is not known with certainty. Its active form, fingolimod‐phosphate (fingolimod‐P), is a sphingosine 1‐phosphate receptor (S1PR) modulator that inhibits egress of lymphocytes from lymph nodes and their recirculation, potentially reducing trafficking of pathogenic cells into the central nervous system (CNS). Fingolimod also readily penetrates the CNS, and fingolimod‐P formed in situ may have direct effects on neural cells. Fingolimod potently inhibits the MS animal model, experimental autoimmune encephalomyelitis, but is ineffective in mice with selective deficiency of the S1P1 S1PR subtype on astrocytes despite normal expression in the immune compartment. These findings suggest that S1PR modulation by fingolimod in both the immune system and CNS, producing a combination of beneficial anti‐inflammatory and possibly neuroprotective/reparative effects, may contribute to its efficacy in MS. In clinical trials, fingolimod was generally safe and well tolerated. Its interaction with S1PRs in a variety of tissues largely accounts for the reported adverse effects, which were seen more frequently with doses 2.5 to 10× the approved 0.5mg dose. Fingolimod's unique mechanism of action distinguishes it from all other currently approved MS therapies. Ann Neurol 2011;69:759–777
Annals of Neurology - Tập 69 Số 5 - Trang 759-777 - 2011
1,026 Experimental treatments in acute strokeAbstract Objective Preclinical evaluation of neuroprotectants fostered high expectations of clinical efficacy. When not matched, the question arises whether experiments are poor indicators of clinical outcome or whether the best drugs were not taken forward to clinical trial. Therefore, we endeavored to contrast experimental efficacy and scope of testing of drugs used clinically and those tested only experimentally. Methods We identified neuroprotectants and reports of experimental efficacy via a systematic search. Controlled in vivo and in vitro experiments using functional or histological end points were selected for analysis. Relationships between outcome, drug mechanism, scope of testing, and clinical trial status were assessed statistically. Results There was no evidence that drugs used clinically (114 drugs) were more effective experimentally than those tested only in animal models (912 drugs), for example, improvement in focal models averaged 31.3 ± 16.7% versus 24.4 ± 32.9%, p > 0.05, respectively. Scope of testing using Stroke Therapy Academic Industry Roundtable (STAIR) criteria was highly variable, and no relationship was found between mechanism and efficacy. Interpretation The results question whether the most efficacious drugs are being selected for stroke clinical trials. This may partially explain the slow progress in developing treatments. Greater rigor in the conduct, reporting, and analysis of animal data will improve the transition of scientific advances from bench to bedside. Ann Neurol 2006
Annals of Neurology - Tập 59 Số 3 - Trang 467-477 - 2006
Histopathological correlates of magnetic resonance imaging–defined chronic perinatal white matter injuryAbstract Objective: Although magnetic resonance imaging (MRI) is the optimal imaging modality to define cerebral white‐matter injury (WMI) in preterm survivors, the histopathological features of MRI‐defined chronic lesions are poorly defined. We hypothesized that chronic WMI is related to a combination of delayed oligodendrocyte (OL) lineage cell death and arrested maturation of preoligodendrocytes (preOLs). We determined whether ex vivo MRI can distinguish distinct microglial and astroglial responses related to WMI progression and arrested preOL differentiation. Methods: We employed a preterm fetal sheep model of global cerebral ischemia in which acute WMI results in selective preOL degeneration. We developed novel algorithms to register histopathologically‐defined lesions with contrast‐weighted and diffusion‐weighted high‐field ex vivo MRI data. Results: Despite mild delayed preOL degeneration, preOL density recovered to control levels by 7 days after ischemia and was ∼2 fold greater at 14 days. However, premyelinating OLs were significantly diminished at 7 and 14 days. WMI evolved to mostly gliotic lesions where arrested preOL differentiation was directly proportional to the magnitude of astrogliosis. A reduction in cerebral WM volume was accompanied by four classes of MRI‐defined lesions. Each lesion type displayed unique astroglial and microglial responses that corresponded to distinct forms of necrotic or non‐necrotic injury. High‐field MRI defined 2 novel hypointense signal abnormalities on T2 ‐weighted images that coincided with microscopic necrosis or identified astrogliosis with high sensitivity and specificity. Interpretation: These studies support the potential of high‐field MRI for early identification of microscopic necrosis and gliosis with preOL maturation arrest, a common form of WMI in preterm survivors. ANN NEUROL 2011
Annals of Neurology - Tập 70 Số 3 - Trang 493-507 - 2011
Validation of a new coma scale: The FOUR scoreAbstract 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
Progressive dystonia with marked diurnal fluctuationAbstract Three children, 2 of them siblings, developed a progressive dystonic condition in the first decade of life. The symptoms and signs were milder in the mornings or after a daytime nap but worsened greatly later in the day. One patient became unable to walk by evening. Investigations in 2 patients revealed a reduced concentration of cerebrospinal fluid homovanillic acid. The 2 more severely affected patients showed dramatic and sustained improvement with levodopa therapy. The condition bears a clinical resemblance to some reported cases of juvenile Parkinson's disease but is probably a separate disorder.
Annals of Neurology - Tập 4 Số 5 - Trang 412-417 - 1978
Age differences in intercorrelations between regional cerebral metabolic rates for glucoseAbstract Patterns of cerebral metabolic intercorrelations were compared in the resting state in 15 healthy young men (ages 20 to 32 years) and 15 healthy elderly men (ages 64 to 83 years). Controlling for whole‐brain glucose metabolism, partial correlation coefficients were determined between pairs of regional cerebral metabolic rates for glucose determined by positron emission tomography using [18 F]fluorodeoxyglucose and obtained in 59 brain regions. Compared with the young men, the elderly men had fewer statistically significant correlations, with the most notable reductions observed between the parietal lobe regions, and between the parietal and frontal lobe regions. These results suggest that cerebral functional interactions are reduced in healthy elderly men.
Annals of Neurology - Tập 19 Số 1 - Trang 60-67 - 1986
A TREM 1 variant alters the accumulation of Alzheimer‐related amyloid pathologyObjective Genome‐wide association studies have linked variants in TREM2 (triggering receptor expressed on myeloid cells 2) and TREML2 with Alzheimer disease (AD) and AD endophenotypes. Here, we pursue a targeted analysis of the TREM locus in relation to cognitive decline and pathological features of AD. Methods Clinical, cognitive, and neuropathological phenotypes were collected in 3 prospective cohorts on aging (n = 3,421 subjects). Our primary analysis was an association with neuritic plaque pathology. To functionally characterize the associated variants, we used flow cytometry to measure TREM1 expression on monocytes. Results We provide evidence that an intronic variant, rs6910730G , in TREM1 , is associated with an increased burden of neuritic plaques (p = 3.7 × 10−4 ), diffuse plaques (p = 4.1 × 10−3 ), and Aβ density (p = 2.6 × 10−3 ) as well as an increased rate of cognitive decline (p = 5.3 × 10−3 ). A variant upstream of TREM2 , rs7759295C , is independently associated with an increased tau tangle density (p = 4.9 × 10−4 ), an increased burden of neurofibrillary tangles (p = 9.1 × 10−3 ), and an increased rate of cognitive decline (p = 2.3 × 10−3 ). Finally, a cytometric analysis shows that the TREM1 rs6910730G allele is associated with decreased TREM1 expression on the surface of myeloid cells (p = 1.7 × 10−3 ). Interpretation We provide evidence that 2 common variants within the TREM locus are associated with pathological features of AD and aging‐related cognitive decline. Our evidence suggests that these variants are likely to be independent of known AD variants and that they may work through an alteration of myeloid cell function. Ann Neurol 2015;77:469–477
Annals of Neurology - Tập 77 Số 3 - Trang 469-477 - 2015
Genetic linkage evidence for heterogeneity in Charcot‐Marie‐Tooth neuropathy (HMSN type I)Abstract A genetic linkage study performed on a large family with autosomal dominant Charcot‐Marie‐Tooth neuropathy (HMSN type I) showed affected family members to have slow motor nerve conduction velocities, hypoactive tendon reflexes, and distal muscle weakness and atrophy. Results excluded close linkage of the neuropathy in this family to the Duffy blood group locus on chromosome 1. Previous studies in other families have shown positive linkage of HMSN type I to the Duffy locus. The present results provide support for the concept of genetic heterogeneity in HMSN type I. Comparison of this new family with the previous families showing linkage to Duffy reveals that the hereditary neuropathy not linked to the Duffy locus may have less severe slowing of motor nerve conduction velocities and less prominent onion bulb change evident on sural nerve biopsy.
Annals of Neurology - Tập 14 Số 6 - Trang 679-684 - 1983
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