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Ann Neurol (ann + neurol)
Selected Abstracts18F-flutemetamol amyloid imaging in Alzheimer disease and mild cognitive impairment: A phase 2 trialANNALS OF NEUROLOGY, Issue 3 2010Rik Vandenberghe MD Objective The most widely studied positron emission tomography ligand for in vivo ,-amyloid imaging is 11C-Pittsburgh compound B (11C-PIB). Its availability, however, is limited by the need for an on-site cyclotron. Validation of the 18F-labeled PIB derivative 18F-flutemetamol could significantly enhance access to this novel technology. Methods Twenty-seven patients with early-stage clinically probable Alzheimer disease (AD), 20 with amnestic mild cognitive impairment (MCI), and 15 cognitively intact healthy volunteers (HVs) above and 10 HVs below 55 years of age participated. The primary endpoint was the efficacy of blinded visual assessments of 18F-flutemetamol scans in assigning subjects to a raised versus normal uptake category, with clinical diagnosis as the standard of truth (SOT). As secondary objectives, we determined the correlation between the regional standardized uptake value ratios (SUVRs) for 18F-flutemetamol and its parent molecule 11C-PIB in 20 of the AD subjects and 20 of the MCI patients. We also determined test-retest variability of 18F-flutemetamol SUVRs in 5 of the AD subjects. Results Blinded visual assessments of 18F-flutemetamol scans assigned 25 of 27 scans from AD subjects and 1 of 15 scans from the elderly HVs to the raised category, corresponding to a sensitivity of 93.1% and a specificity of 93.3% against the SOT. Correlation coefficients between cortical 18F-flutemetamol SUVRs and 11C-PIB SUVRs ranged from 0.89 to 0.92. Test-retest variabilities of regional SUVRs were 1 to 4%. Interpretation 18F-Flutemetamol performs similarly to the 11C-PIB parent molecule within the same subjects and provides high test-retest replicability and potentially much wider accessibility for clinical and research use. ANN NEUROL 2010 [source] Xenon enhances hypothermic neuroprotection in asphyxiated newborn pigsANNALS OF NEUROLOGY, Issue 3 2010Elavazhagan Chakkarapani MBBS Objective To investigate whether inhaling 50% xenon during hypothermia (HT) offers better neuroprotection than xenon or HT alone. Methods Ninety-eight newborn pigs underwent a 45-minute global hypoxic-ischemic insult severe enough to cause permanent brain injury, and 12 pigs underwent sham protocol. Pigs then received intravenous anesthesia and were randomized to 6 treatment groups: (1) normothermia (NT; rectal temperature 38.5°C, n = 18); (2) 18 hours 50% xenon with NT (n = 12); (3) 12 hours HT (rectal temperature 33.5°C, n = 18); (4) 24 hours HT (rectal temperature 33.5°C, n = 17); (5) 18 hours 50% xenon with 12 hours HT (n = 18); and (6) 18 hours 50% xenon with 24 hours HT (n = 17). Fifty percent xenon was administered via a closed circle with 30% oxygen and 20% nitrogen. After 10 hours rewarming, cooled pigs remained normothermic until terminal perfusion fixation at 72 hours. Global and regional brain neuropathology and clinical neurological scores were performed. Results Xenon (p = 0.011) and 12 or 24 hours HT (p = 0.003) treatments offered significant histological global, and regional neuroprotection. Combining xenon with HT yielded an additive neuroprotective effect, as there was no interaction effect (p = 0.54). Combining Xenon with 24 hours HT offered 75% global histological neuroprotection with similarly improved regional neuroprotection: thalamus (100%), brainstem (100%), white matter (86%), basal ganglia (76%), cortical gray matter (74%), cerebellum (73%), and hippocampus (72%). Neurology scores improved in the 24-hour HT and combined xenon HT groups at 72 hours. Interpretation Combining xenon with HT is a promising therapy for severely encephalopathic infants, doubling the neuroprotection offered by HT alone. ANN NEUROL 2010 [source] Erythropoietin plus insulin-like growth factor-I protects against neuronal damage in a murine model of human immunodeficiency virus-associated neurocognitive disordersANNALS OF NEUROLOGY, Issue 3 2010Yeon-Joo Kang PhD Objective Prolonged human immunodeficiency virus-1 (HIV-1) infection leads to neurological debilitation, including motor dysfunction and frank dementia. Although pharmacological control of HIV infection is now possible, HIV-associated neurocognitive disorders (HAND) remain intractable. Here, we report that chronic treatment with erythropoietin (EPO) and insulin-like growth factor-I (IGF-I) protects against HIV/gp120-mediated neuronal damage in culture and in vivo. Methods Initially, we tested the neuroprotective effects of various concentrations of EPO, IGF-I, or EPO+IGF-I from gp120-induced damage in vitro. To assess the chronic effects of EPO+IGF-I administration in vivo, we treated HIV/gp120-transgenic or wild-type mice transnasally once a week for 4 months and subsequently conducted immunohistochemical analyses. Results Low concentrations of EPO+IGF-I provided neuroprotection from gp120 in vitro in a synergistic fashion. In vivo, EPO+IGF-I treatment prevented gp120-mediated neuronal loss, but did not alter microgliosis or astrocytosis. Strikingly, in the brains of both humans with HAND and gp120-transgenic mice, we found evidence for hyperphosphorylated tau protein (paired helical filament-I tau), which has been associated with neuronal damage and loss. In the mouse brain following transnasal treatment with EPO+IGF-I, in addition to neuroprotection we observed increased phosphorylation/activation of Akt (protein kinase B) and increased phosphorylation/inhibition of glycogen synthase kinase (GSK)-3,, dramatically decreasing downstream hyperphosphorylation of tau. These results indicate that the peptides affected their cognate signaling pathways within the brain parenchyma. Interpretation Our findings suggest that chronic combination therapy with EPO+IGF-I provides neuroprotection in a mouse model of HAND, in part, through cooperative activation of phosphatidylinositol 3-kinase/Akt/GSK-3, signaling. This combination peptide therapy should therefore be tested in humans with HAND. ANN NEUROL 2010;68:342,352 [source] Phasic muscle activity in sleep and clinical features of Parkinson diseaseANNALS OF NEUROLOGY, Issue 3 2010Donald L. Bliwise PhD Objective: The absence of atonia during rapid eye movement (REM) sleep and dream-enactment behavior (REM sleep behavior disorder [RBD]) are common features of sleep in the alpha-synucleinopathies. This study examined this phenomenon quantitatively, using the phasic electromyographic metric (PEM), in relation to clinical features of idiopathic Parkinson disease (PD). Based on previous studies suggesting that RBD may be prognostic for the development of later parkinsonism, we hypothesized that clinical indicators of disease severity and more rapid progression would be related to PEM. Methods: A cross-sectional convenience sample of 55 idiopathic PD patients from a movement disorders clinic in a tertiary care medical center underwent overnight polysomnography. PEM, the percentage of 2.5-second intervals containing phasic muscle activity, was quantified separately for REM and non-REM (NREM) sleep from 5 different electrode sites. Results: Higher PEM rates were seen in patients with symmetric disease, as well as in akinetic-rigid versus tremor-predominant patients. Men had higher PEM relative to women. Results occurred in all muscle groups in both REM and NREM sleep. Interpretation: Although our data were cross-sectional, phasic muscle activity during sleep suggests disinhibition of descending motor projections in PD broadly reflective of more advanced and/or progressive disease. Elevated PEM during sleep may represent a functional window into brainstem modulation of spinal cord activity and is broadly consistent with the early pathologic involvement of non-nigral brainstem regions in PD, as described by Braak. ANN NEUROL 2010 [source] Role of interleukin-1, in postoperative cognitive dysfunctionANNALS OF NEUROLOGY, Issue 3 2010Mario Cibelli MD Objective: Although postoperative cognitive dysfunction (POCD) often complicates recovery from major surgery, the pathogenic mechanisms remain unknown. We explored whether systemic inflammation, in response to surgical trauma, triggers hippocampal inflammation and subsequent memory impairment, in a mouse model of orthopedic surgery. Methods: C57BL/6J, knock out (lacking interleukin [IL]-1 receptor, IL-1R,/,) and wild type mice underwent surgery of the tibia under general anesthesia. Separate cohorts of animals were tested for memory function with fear conditioning tests, or euthanized at different times to assess levels of systemic and hippocampal cytokines and microglial activation; the effects of interventions, designed to interrupt inflammation (specifically and nonspecifically), were also assessed. Results: Surgery caused hippocampal-dependent memory impairment that was associated with increased plasma cytokines, as well as reactive microgliosis and IL-1, transcription and expression in the hippocampus. Nonspecific attenuation of innate immunity with minocycline prevented surgery-induced changes. Functional inhibition of IL-1,, both in mice pretreated with IL-1 receptor antagonist and in IL-1R,/, mice, mitigated the neuroinflammatory effects of surgery and memory dysfunction. Interpretation: A peripheral surgery-induced innate immune response triggers an IL-1,-mediated inflammatory process in the hippocampus that underlies memory impairment. This may represent a viable target to interrupt the pathogenesis of postoperative cognitive dysfunction. ANN NEUROL 2010;68:360,368 [source] B-cell activation influences T-cell polarization and outcome of anti-CD20 B-cell depletion in central nervous system autoimmunity,ANNALS OF NEUROLOGY, Issue 3 2010Martin S. Weber MD Objective Clinical studies indicate that anti-CD20 B-cell depletion may be an effective multiple sclerosis (MS) therapy. We investigated mechanisms of anti-CD20-mediated immune modulation using 2 paradigms of experimental autoimmune encephalomyelitis (EAE). Methods Murine EAE was induced by recombinant myelin oligodendrocyte glycoprotein (rMOG), a model in which B cells are considered to contribute pathogenically, or MOG peptide (p)35-55, which does not require B cells. Results In EAE induced by rMOG, B cells became activated and, when serving as antigen-presenting cells (APCs), promoted differentiation of proinflammatory MOG-specific Th1 and Th17 cells. B-cell depletion prevented or reversed established rMOG-induced EAE, which was associated with less central nervous system (CNS) inflammation, elimination of meningeal B cells, and reduction of MOG-specific Th1 and Th17 cells. In contrast, in MOG p35-55-induced EAE, B cells did not become activated or efficiently polarize proinflammatory MOG-specific T cells, similar to naive B cells. In this setting, anti-CD20 treatment exacerbated EAE, and did not impede development of Th1 or Th17 cells. Irrespective of the EAE model used, B-cell depletion reduced the frequency of CD4+CD25+Foxp3+ regulatory T cells (Treg), and increased the proinflammatory polarizing capacity of remaining myeloid APCs. Interpretation Our study highlights distinct roles for B cells in CNS autoimmunity. Clinical benefit from anti-CD20 treatment may relate to inhibition of proinflammatory B cell APC function. In certain clinical settings, however, elimination of unactivated B cells, which participate in regulation of T cells and other APC, may be undesirable. Differences in immune responses to MOG protein and peptide may be important considerations when choosing an EAE model for testing novel B cell-targeting agents for MS. ANN NEUROL 2010 [source] Pathological gambling in Parkinson disease is reduced by amantadineANNALS OF NEUROLOGY, Issue 3 2010Astrid Thomas MD To investigate the possible efficacy of amantadine in the control of pathological gambling (PG) associated with Parkinson disease (PD), 17 PD patients with PG were randomly selected for a double-blind crossover study with amantadine 200mg/day versus placebo and an open follow-up. Assessments included PG-specific scales (Yale-Brown Obsessive-Compulsive Scale for PG, Gambling-Symptom Assessment Scale, South Oaks Gambling Screen) and assessment of expenditures and time spent gambling. Amantadine abolished or reduced PG in all treated patients, as confirmed by scale score and daily expenditure reduction. Amantadine might be useful to treat PG. The effect of amantadine, acting as an antiglutamatergic agent, also opens new insights into the pathogenesis of PG. ANN NEUROL 2010 [source] Central facial palsy revisited: A clinical-radiological study,ANNALS OF NEUROLOGY, Issue 3 2010Luigi Cattaneo MD We investigated the pattern of volitional facial motor deficits in acute stroke patients. We assessed the strength of single facial movements and correlated it to the site of infarct classified on computed tomography scans. Exclusion criteria were previous stroke, cerebral hemorrhage, and subcortical stroke. Results showed that weakness in eyelid closure was associated with anterior cerebral artery (ACA) stroke. Weakness in lip opening was associated with middle cerebral artery (MCA) stroke. We suggest that sparing of upper facial movements in MCA stroke is due to the presence of an upper face motor representation in both the MCA and ACA territories. ANN NEUROL 2010;68:404,408 [source] A review of paroxysmal sympathetic hyperactivity after acquired brain injuryANNALS OF NEUROLOGY, Issue 2 2010Iain Perkes BMedSc Severe excessive autonomic overactivity occurs in a subgroup of people surviving acquired brain injury, the majority of whom show paroxysmal sympathetic and motor overactivity. Delayed recognition of paroxysmal sympathetic hyperactivity (PSH) after brain injury may increase morbidity and long-term disability. Despite its significant clinical impact, the scientific literature on this syndrome is confusing; there is no consensus on nomenclature, etiological information for diagnoses preceding the condition is poorly understood, and the evidence base underpinning our knowledge of the pathophysiology and management strategies is largely anecdotal. This systematic literature review identified 2 separate categories of paroxysmal autonomic overactivity, 1 characterized by relatively pure sympathetic overactivity and another group of disorders with mixed parasympathetic/sympathetic features. The PSH group comprised 349 reported cases, with 79.4% resulting from traumatic brain injury (TBI), 9.7% from hypoxia, and 5.4% from cerebrovascular accident. Although TBI is the dominant causative etiology, there was some suggestion that the true incidence of the condition is highest following cerebral hypoxia. In total, 31 different terms were identified for the condition. Although the most common term in the literature was dysautonomia, the consistency of sympathetic clinical features suggests that a more specific term should be used. The findings of this review suggest that PSH be adopted as a more clinically relevant and appropriate term. The review highlights major problems regarding conceptual definitions, diagnostic criteria, and nomenclature. Consensus on these issues is recommended as an essential basis for further research in the area. ANN NEUROL 2010;68:126,135 [source] Visceral fat is associated with lower brain volume in healthy middle-aged adultsANNALS OF NEUROLOGY, Issue 2 2010Stéphanie Debette MD Objective Midlife obesity has been associated with an increased risk of dementia. The underlying mechanisms are poorly understood. Our aim was to examine the cross-sectional association of body mass index (BMI), waist circumference (WC), waist-to-hip ratio (WHR), and computed tomography (CT)-based measurements of subcutaneous (SAT) and visceral (VAT) adipose tissue with various magnetic resonance imaging (MRI) markers of brain aging in middle-aged community adults. Methods Participants from the Framingham Offspring cohort were eligible if in addition to having measurements of BMI, WC, WHR, SAT, and VAT, they had undergone a volumetric brain MRI scan with measurements of total brain volume (TCBV), temporal horn volume (THV), white matter hyperintensity volume (WMHV), and MRI-defined brain infarcts (BI). All analyses were adjusted for age, sex, and time interval between abdominal CT and brain MRI. Results In a sample of 733 community participants (mean age, 60 years; 53% women), we observed an inverse association of BMI (estimate by standard deviation unit ± standard error = ,0.27 ± 0.12; p = 0.02), WC (,0.30 ± 0.12; p = 0.01), WHR (,0.37 ± 0.12; p = 0.02), SAT (,0.23 ± 0.11; p = 0.04), and VAT (,0.36 ± 0.12; p = 0.002) with TCBV, independent of vascular risk factors. The association between VAT and TCBV was the strongest and most robust, and was also independent of BMI (,0.35 ± 0.15; p = 0.02) and insulin resistance (,0.32 ± 0.13; p = 0.01). When adjusting for C-reactive protein levels, the associations were attenuated (,0.17 ± 0.13; p = 0.17 for VAT). No consistently significant association was observed between the anthropometric or CT-based abdominal fat measurements and THV, WMHV, or BI. Interpretation In middle-aged community participants, we observed a significant inverse association of anthropometric and CT-based measurements of abdominal, especially visceral, fat with total brain volume. ANN NEUROL 2010 [source] Pilot trial of low-dose naltrexone and quality of life in multiple sclerosis,ANNALS OF NEUROLOGY, Issue 2 2010Bruce A. C. Cree MD Objective To evaluate the efficacy of 4.5mg nightly naltrexone on the quality of life of multiple sclerosis (MS) patients. Methods This single-center, double-masked, placebo-controlled, crossover study evaluated the efficacy of 8 weeks of treatment with 4.5mg nightly naltrexone (low-dose naltrexone, LDN) on self-reported quality of life of MS patients. Results Eighty subjects with clinically definite MS were enrolled, and 60 subjects completed the trial. Ten withdrew before completing the first trial period: 8 for personal reasons, 1 for a non,MS-related adverse event, and 1 for perceived benefit. Database management errors occurred in 4 other subjects, and quality of life surveys were incomplete in 6 subjects for unknown reasons. The high rate of subject dropout and data management errors substantially reduced the trial's statistical power. LDN was well tolerated, and serious adverse events did not occur. LDN was associated with significant improvement on the following mental health quality of life measures: a 3.3-point improvement on the Mental Component Summary score of the Short Form-36 General Health Survey (p = 0.04), a 6-point improvement on the Mental Health Inventory (p < 0.01), a 1.6-point improvement on the Pain Effects Scale (p =.04), and a 2.4-point improvement on the Perceived Deficits Questionnaire (p = 0.05). Interpretation LDN significantly improved mental health quality of life indices. Further studies with LDN in MS are warranted. ANN NEUROL 2010 [source] Human prion strain selection in transgenic mice,ANNALS OF NEUROLOGY, Issue 2 2010Kurt Giles DPhil Objective: Transgenic (Tg) mice expressing chimeras of mouse and human prion proteins (PrPs) have shorter incubation periods for Creutzfeldt-Jakob disease (CJD) prions than mice expressing full-length human PrP. Increasing the sequence similarity of the chimeric PrP to mouse PrP, by reverting human residues to mouse, resulted in a Tg line, denoted Tg22372, which was susceptible to sporadic (s) CJD prions in ,110 days. Methods: Mice expressing chimeric mouse/human PrP transgenes were produced. The mice were inoculated intracerebrally with extracts prepared from the brains of patients who died of CJD. Onset of neurological dysfunction marked the end of the incubation time. After sacrifice of the Tg mice, their brains were analyzed for PrPSc and neuropathological changes. Results: Reversion of 1 additional residue (M111V) resulted in a new Tg line, termed Tg1014, susceptible to sCJD prions in ,75 days. Tg1014 mice also have shorter incubation periods for variant (v) CJD prions, providing a more tractable model for studying this prion strain. Transmission of vCJD prions to Tg1014 mice resulted in 2 different strains, determined by neuropathology and biochemical analysis, which correlated with the length of the incubation time. One strain had the biochemical, neuropathological, and transmission characteristics, including longer incubation times, of the inoculated vCJD strain; the second strain produced a phenotype resembling that of sCJD prions including relatively shorter incubation periods. Mice with intermediate incubation periods for vCJD prions had a mixture of the 2 strains. Both strains were serially transmitted in Tg1014 mice, which led to further reduction in incubation periods. Conversion of vCJD-like to sCJD-like strains was favored in Tg1014 mice more than in the Tg22372 line. The single amino acid difference therefore appears to offer selective pressure for propagation of the sCJD-like strain. Interpretation: These 2 Tg mouse lines provide relatively rapid models to study human prion diseases as well as the evolution of human prion strains. ANN NEUROL 2010;68:151,161 [source] Variably protease-sensitive prionopathy: A new sporadic disease of the prion protein,ANNALS OF NEUROLOGY, Issue 2 2010Wen-Quan Zou MD Objective: The objective of the study is to report 2 new genotypic forms of protease-sensitive prionopathy (PSPr), a novel prion disease described in 2008, in 11 subjects all homozygous for valine at codon 129 of the prion protein (PrP) gene (129VV). The 2 new PSPr forms affect individuals who are either homozygous for methionine (129MM) or heterozygous for methionine/valine (129MV). Methods: Fifteen affected subjects with 129MM, 129MV, and 129VV underwent comparative evaluation at the National Prion Disease Pathology Surveillance Center for clinical, histopathologic, immunohistochemical, genotypical, and PrP characteristics. Results: Disease duration (between 22 and 45 months) was significantly different in the 129VV and 129MV subjects. Most other phenotypic features along with the PrP electrophoretic profile were similar but distinguishable in the 3 129 genotypes. A major difference laid in the sensitivity to protease digestion of the disease-associated PrP, which was high in 129VV but much lower, or altogether lacking, in 129MV and 129MM. This difference prompted the substitution of the original designation with "variably protease-sensitive prionopathy" (VPSPr). None of the subjects had mutations in the PrP gene coding region. Interpretation: Because all 3 129 genotypes are involved, and are associated with distinguishable phenotypes, VPSPr becomes the second sporadic prion protein disease with this feature after Creutzfeldt-Jakob disease, originally reported in 1920. However, the characteristics of the abnormal prion protein suggest that VPSPr is different from typical prion diseases, and perhaps more akin to subtypes of Gerstmann-Sträussler-Scheinker disease. ANN NEUROL 2010;68:162,172 [source] No cerebrocervical venous congestion in patients with multiple sclerosis,ANNALS OF NEUROLOGY, Issue 2 2010Florian Doepp MD Objective: Multiple sclerosis (MS) is characterized by demyelination centered around cerebral veins. Recent studies suggested this topographic pattern may be caused by venous congestion, a condition termed chronic cerebrospinal venous insufficiency (CCSVI). Published sonographic criteria of CCSVI include reflux in the deep cerebral veins and/or the internal jugular and vertebral veins (IJVs and VVs), stenosis of the IJVs, missing flow in IJVs and VVs, and inverse postural response of the cerebral venous drainage. Methods: We performed an extended extra- and transcranial color-coded sonography study including analysis of extracranial venous blood volume flow (BVF), cross-sectional areas, IJV flow analysis during Valsalva maneuver (VM), and CCSVI criteria. Fifty-six MS patients and 20 controls were studied. Results: Except for 1 patient, blood flow direction in the IJVs and VVs was normal in all subjects. In none of the subjects was IJV stenosis detected. IJV and VV BVF in both groups was equal in the supine body position. The decrease of total jugular BVF on turning into the upright position was less pronounced in patients (173 ± 235 vs 362 ± 150ml/min, p < 0.001), leading to higher BVF in the latter position (318ml/min ± 242 vs 123 ± 109ml/min; p < 0.001). No differences between groups were seen in intracranial veins and during VM. None of the subjects investigated in this study fulfilled >1 criterion for CCSVI. Interpretation: Our results challenge the hypothesis that cerebral venous congestion plays a significant role in the pathogenesis of MS. Future studies should elucidate the difference between patients and healthy subjects in BVF regulation. ANN NEUROL 2010;68:173,183 [source] Apoptosis-inducing factor deficiency sensitizes dopaminergic neurons to parkinsonian neurotoxinsANNALS OF NEUROLOGY, Issue 2 2010Celine Perier PhD Objective Mitochondrial complex I deficits have long been associated with Parkinson disease (PD). However, it remains unknown whether such defects represent a primary event in dopaminergic neurodegeneration. Methods Apoptosis-inducing factor (AIF) is a mitochondrial protein that, independently of its proapoptotic properties, plays an essential physiologic role in maintaining a fully functional complex I. We used AIF-deficient harlequin (Hq) mice, which exhibit structural deficits in assembled complex I, to determine whether primary complex I defects linked to AIF depletion may cause dopaminergic neurodegeneration. Results Despite marked reductions in mitochondrial complex I protein levels, Hq mice did not display apparent alterations in the dopaminergic nigrostriatal system. However, these animals were much more susceptible to exogenous parkinsonian complex I inhibitors, such as 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP). Subtoxic doses of MPTP, unable to cause damage to wild-type animals, produced marked nigrostriatal dopaminergic degeneration in Hq mice. This effect was associated with exacerbated complex I inhibition and increased production of mitochondrial-derived reactive oxygen species (ROS) in Hq brain mitochondria. The antioxidant superoxide dismutase-mimetic compound tempol was able to reverse the increased susceptibility of Hq mice to MPTP. Supporting an instrumental role for mitochondrial-derived ROS in PD-related neurodegeneration, transgenic mice overexpressing mitochondrially targeted catalase exhibited an attenuation of MPTP-induced mitochondrial ROS and dopaminergic cell death. Interpretation Structural complex I alterations linked to AIF deficiency do not cause dopaminergic neurodegeneration but increase the susceptibility of dopaminergic neurons to exogenous parkinsonian neurotoxins, reinforcing the concept that genetic and environmental factors may interact in a common molecular pathway to trigger PD. ANN NEUROL 2010;68:184,192 [source] Higher 25-hydroxyvitamin D is associated with lower relapse risk in multiple sclerosis,ANNALS OF NEUROLOGY, Issue 2 2010Steve Simpson Jr. MPH Objective A protective association between higher vitamin D levels and the onset of multiple sclerosis (MS) has been demonstrated; however, its role in modulating MS clinical course has been little studied. We investigated whether higher levels of serum 25-hydroxyvitamin D (25-OH-D) were associated with a lower risk of relapses in people with MS. Methods We conducted a prospective cohort study of 145 participants with relapsing-remitting MS from 2002 to 2005. Serum 25-OH-D levels were measured biannually, and the hazard of relapse was assessed using survival analysis. Results There was an inverse linear relationship between 25-OH-D levels and the hazard of relapse over the subsequent 6 months, with hazard ratio (HR) 0.91 (95% confidence interval [CI]: 0.85,0.97) per 10nmol/l increase in 25-OH-D level (p = 0.006). When variation due to timing of blood collection was removed by estimating 25-OH-D at the start of each season, this association persisted, with HR 0.90 (95% CI, 0.83,0.98) per 10nmol/l increase (p = 0.016). Taking into account the biological half-life of 25-OH-D, we estimated 25-OH-D at monthly intervals, resulting in a slightly enhanced association, with HR 0.88 (95% CI, 0.82,0.95) per 10nmol/l increase (p = 0.001). Adjusting for potential confounders did not alter these findings. Interpretation In this prospective population-based cohort study, in a cohort largely on immunomodulatory therapy, higher 25-OH-D levels were associated with a reduced hazard of relapse. This occurred in a dose-dependent linear fashion, with each 10nmol/l increase in 25-OH-D resulting in up to a 12% reduction in risk of relapse. Clinically, raising 25-OH-D levels by 50nmol/l could halve the hazard of a relapse. ANN NEUROL 2010;68:193,203 [source] Altered inflammatory responses in preterm children with cerebral palsyANNALS OF NEUROLOGY, Issue 2 2010Chang-Yi Lin BS Objective Perinatal inflammatory responses contribute to periventricular leukomalacia (PVL) and cerebral palsy (CP) in preterm infants. Here, we examined whether preterm children with CP had altered inflammatory responses when school-aged. Methods Thirty-two preterm children with PVL-induced CP (mean [±standard deviation] age, 7.2 ± 3.6 years) and 32 control preterm children with normal neurodevelopment (6.2 ± 2.2 years) and matched for gestational age were recruited. We measured tumor necrosis factor (TNF)-, levels in the plasma and the supernatants of peripheral blood mononuclear cells (PBMCs) before and after lipopolysaccharide (LPS) stimulation, and proinflammatory gene expression in the PBMCs. Results TNF-, expression was significantly higher in the plasma (p < 0.001) and supernatants of LPS-stimulated PBMCs (p = 0.003) in the CP group than in the control group. After LPS stimulation, the intracellular TNF-, level in the PBMCs was significantly lower in the control group (p = 0.016) and significantly higher in the CP group (p = 0.01). The CP group also had, in their nonstimulated PBMCs, significantly higher mRNA levels of inflammatory molecules: toll-like receptor 4 (TLR-4) (p = 0.0023), TNF-, (p = 0.0016), transforming growth factor-,,activated kinase 1 (p = 0.038), I,B kinase-, (p = 0.029), and c-Jun N-terminal kinase (p = 0.045). The TLR-4 mRNA levels in the PBMCs were highly correlated with TNF-, levels in LPS-stimulated PBMCs (Spearman rank correlation = 0.38, p = 0.03). Interpretation The finding that preterm children with PVL-induced CP have altered inflammatory responses indicates the possibility of programming effect of PVL or inflammation-related events during early life. ANN NEUROL 2010;68:204,212 [source] Coagulopathy and embolic signal in cancer patients with ischemic strokeANNALS OF NEUROLOGY, Issue 2 2010Jin Myoung Seok MD Objective It has been reported that embolic signal (ES) detected by transcranial Doppler (TCD) has clinical significance, especially in patients with recent stroke attributable to arterial or cardiac embolism. Therefore, we conducted this study to determine whether the prevalence of ES is high in ischemic stroke patients with cancer and related to hypercoagulopathy. Methods We prospectively studied cancer patients with acute ischemic stroke within the middle cerebral artery (MCA) distribution on diffusion-weighted imaging. Conventional stroke mechanisms (CSMs) were determined using cardiologic and vascular studies. Additionally, the coagulation status was assessed based on the serum D-dimer levels, and TCD monitoring was performed on both MCAs for 30 minutes to detect ES. Clinical features including vascular risk factors, characteristics of ischemic stroke, and cancer and laboratory findings associated with the presence of ES were evaluated. Results A total of 74 patients were finally included in this study. ES was more commonly observed in patients without CSMs (22 of 38 patients, 57.9%) than in those with CSMs (12 of 36 patients, 33.3%) (p = 0.034). Moreover, ES was more commonly detected in patients with high D-dimer levels (p < 0.001), and D-dimer levels were significantly correlated with the number of ESs in patients without CSMs (r = 0.732, p < 0.001), but were poorly correlated in patients with CSMs (r = 0.152, p = 0.375). Higher levels of D-dimer (odds ratio [OR], 1.082 per 1,g/ml increase; 95% confidence interval [CI], 1.014,1.154) and adenocarcinoma (OR, 3.829; 95% CI, 1.23,13.052) were independently associated with the presence of ES. The use of anticoagulants dramatically decreased the D-dimer levels. Interpretation A high prevalence of ES was observed in cancer patients with ischemic stroke, especially in those without CSMs. Elevated D-dimer levels were independently associated with ES, and decreased dramatically with the use of anticoagulants. ANN NEUROL 2010;68:213,219 [source] Days to criterion as an indicator of toxicity associated with human Alzheimer amyloid-, oligomersANNALS OF NEUROLOGY, Issue 2 2010Sam Gandy MD Objective Recent evidence suggests that high molecular weight soluble oligomeric A, (oA,) assemblies (also known as A,-derived diffusible ligands, or ADDLs) may represent a primary neurotoxic basis for cognitive failure in Alzheimer disease (AD). To date, most in vivo studies of oA,/ADDLs have involved injection of assemblies purified from the cerebrospinal fluid of human subjects with AD or from the conditioned media of A,-secreting cells into experimental animals. We sought to study the bioactivities of endogenously formed oA,/ADDLs generated in situ from the physiological processing of human amyloid precursor protein (APP) and presenitin1 (PS1) transgenes. Methods We produced and histologically characterized single transgenic mice overexpressing APPE693Q or APPE693Q X PS1,E9 bigenic mice. APPE693Q mice were studied in the Morris water maze (MWM) task at 6 and 12 months of age. Following the second MWM evaluation, mice were sacrificed, and brains were assayed for A,total, A,40, A,42, and oA,/ADDLs by enzyme-linked immunosorbent assay (ELISA) and were also histologically examined. Based on results from the oA,/ADDL ELISA, we assigned individual APPE693Q mice to either an undetectable oA,/ADDLs group or a readily detectable oA,/ADDLs group. A days to criterion (DTC) analysis was used to determine delays in acquisition of the MWM task. Results Both single transgenic and bigenic mice developed intraneuronal accumulation of APP/A,, although only APPE693Q X PS1,9 bigenic mice developed amyloid plaques. The APPE693Q mice did not develop amyloid plaques at any age studied, up to 30 months. APPE693Q mice were tested for spatial learning and memory, and only 12-month-old APPE693Q mice with readily detectable oA,/ADDLs displayed a significant delay in acquisition of the MWM task when compared to nontransgenic littermates. Interpretation These data suggest that cerebral oA,/ADDL assemblies generated in brain in situ from human APP transgenes may be associated with cognitive impairment. We propose that a DTC analysis may be a sensitive method for assessing the cognitive impact in mice of endogenously generated oligomeric human A, assemblies. ANN NEUROL 2010 [source] Voxel-based morphometry depicts central compensation after vestibular neuritisANNALS OF NEUROLOGY, Issue 2 2010Peter zu Eulenburg MD Objective Patients who have had vestibular neuritis (VN) show a remarkable clinical improvement especially in gait and posture >6 months after disease onset. Methods Voxel-based morphometry was used to detect the VN-induced changes in gray and white matter by means of structural magnetic resonance imaging. Twenty-two patients were compared an average 2.5 years after onset of VN to a healthy sex-and age-matched control group. Results Our analysis revealed that all patients had signal intensity increases for gray matter in the medial vestibular nuclei and the right gracile nucleus and for white matter in the area of the pontine commissural vestibular fibers. A relative atrophy was observed in the left posterior hippocampus and the right superior temporal gyrus. Patients with a residual canal paresis also showed an increase of gray matter in middle temporal (MT)/V5 bilaterally. Interpretation These findings indicate that the processes of central compensation after VN seem to occur in 3 different sensory systems. First of all, the vestibular system itself showed a white matter increase in the commissural fibers as a direct consequence of an increased internuclei vestibular crosstalk of the medial vestibular nuclei. Second, to regain postural stability, there was a shift to the somatosensory system due to an elevated processing of proprioceptive information in the right gracile nucleus. Third, there was a bilateral increase in the area of MT/V5 in VN patients with a residual peripheral vestibular hypofunction. This seems to be the result of an increased importance of visual motion processing. ANN NEUROL 2010;68:241,249 [source] Disrupted SOX10 regulation of GJC2 transcription causes Pelizaeus-Merzbacher-like diseaseANNALS OF NEUROLOGY, Issue 2 2010Hitoshi Osaka MD Mutations in the gap junction protein gamma-2 gene, GJC2, cause a central hypomyelinating disorder; Pelizaeus-Merzbacher-like disease (PMLD; MIM311601). Using a homozygosity mapping and positional candidate gene approach, we identified a homozygous mutation (c.-167A>G) within the GJC2 promoter at a potent SOX10 binding site in a patient with mild PMLD. Functionally, this mutation completely abolished the SOX10 binding and attenuated GJC2 promoter activity. These findings suggest not only that the SOX10 -to- GJC2 transcriptional dysregulation is a cause of PMLD, but also that GJC2 may be in part responsible for the central hypomyelination caused by SOX10 mutations. ANN NEUROL 2010;68:250,254 [source] Venous and cerebrospinal fluid flow in multiple sclerosis: A case-control studyANNALS OF NEUROLOGY, Issue 2 2010Peter Sundström MD The prevailing view on multiple sclerosis etiopathogenesis has been challenged by the suggested new entity chronic cerebrospinal venous insufficiency. To test this hypothesis, we studied 21 relapsing-remitting multiple sclerosis cases and 20 healthy controls with phase-contrast magnetic resonance imaging. In addition, in multiple sclerosis cases we performed contrast-enhanced magnetic resonance angiography. We found no differences regarding internal jugular venous outflow, aqueductal cerebrospinal fluid flow, or the presence of internal jugular blood reflux. Three of 21 cases had internal jugular vein stenoses. In conclusion, we found no evidence confirming the suggested vascular multiple sclerosis hypothesis. ANN NEUROL 2010;68:255,259 [source] Mutations in PEX10 are a cause of autosomal recessive ataxiaANNALS OF NEUROLOGY, Issue 2 2010Luc Régal MD Peroxisomal biogenesis disorders typically cause severe multisystem disease and early death. We describe a child and an adult of normal intelligence with progressive ataxia, axonal motor neuropathy, and decreased vibration sense. Both patients had marked cerebellar atrophy. Peroxisomal studies revealed a peroxisomal biogenesis disorder. Two mutations in PEX10 were found in the child, c.992G>A (novel) and c.764_765insA, and in the adult, c.2T>C (novel) and c.790C>T. Transfection with wild-type PEX10 corrected the fibroblast phenotype. Bile acid supplements and dietary restriction of phytanic acid were started. Peroxisomal biogenesis disorders should be considered in the differential diagnosis of autosomal recessive ataxia. ANN NEUROL 2010;68:259,263 [source] Residual tumor cells are unique cellular targets in glioblastoma,ANNALS OF NEUROLOGY, Issue 2 2010Martin Glas MD Residual tumor cells remain beyond the margins of every glioblastoma (GBM) resection. Their resistance to postsurgical therapy is considered a major driving force of mortality, but their biology remains largely uncharacterized. In this study, residual tumor cells were derived via experimental biopsy of the resection margin after standard neurosurgery for direct comparison with samples from the routinely resected tumor tissue. In vitro analysis of proliferation, invasion, stem cell qualities, GBM-typical antigens, genotypes, and in vitro drug and irradiation challenge studies revealed these cells as unique entities. Our findings suggest a need for characterization of residual tumor cells to optimize diagnosis and treatment of GBM. ANN NEUROL 2010;68:264,269 [source] Multiple sclerosis and virusesANNALS OF NEUROLOGY, Issue 1 2010Michel Brahic MD Discussing the problem of multiple sclerosis and viruses should not be limited to reviewing the epidemiological evidence in favor, or against, a particular candidate, such as Epstein-Barr virus or human herpes virus 6. In this text, I discuss the difficulty of going from association to causation in human epidemiology; the fact that viruses can trigger or prevent autoimmunity; the problem of our very limited knowledge of the viruses that we harbor as part of our metagenome; and the role of such viral flora in multifactorial diseases and also, possibly, in health. ANN NEUROL 2010;68:6,8 [source] Yield of systematic transcranial doppler in patients with transient ischemic attackANNALS OF NEUROLOGY, Issue 1 2010Elena Meseguer MD Objective Urgent evaluation and treatment of transient ischemic attack (TIA) patients in a dedicated TIA clinic may reduce the 90-day stroke risk by 80%. ABCD2 (Age, Blood pressure, Clinical features, Duration, Diabetes) score and magnetic resonance imaging abnormalities help to identify patients at high risk of stroke. Our aim was to determine whether the use of transcranial Doppler (TCD) examination on arrival at the TIA clinic yields additional information that facilitates the identification of patients at high risk of stroke recurrence. Methods Between January 2003 and December 2007, 1,881 patients were admitted to SOS-TIA clinic (a TIA clinic with around-the-clock access). Clinical and vascular assessment included TCD performed by a neurologist immediately after admission. Stroke prevention measures were initiated on arrival, in accordance with guidelines. All patients were followed for 1 year after presentation to the SOS-TIA clinic. Results A total of 1,823 TCD examinations were performed within 4 hours of admission. Intracranial narrowing or occlusion was found in 8.8% of patients, and was independently associated with age, hypertension, and diabetes. After 1-year follow-up on best preventive therapy, the incidence of recurrent vascular events (intracranial revascularization for TIA recurrence, stroke, myocardial infarction, and vascular death combined) was 7.0% in patients with intracranial narrowing or occlusion and 2.4% in those without (log-rank, p = 0.007). The hazard ratio of combined outcome for the presence of intracranial narrowing or occlusion was 2.29 (95% confidence interval [CI], 1.15-4.56; p = 0.02) in multivariate analysis including age, gender, hypertension, and diabetes, and was 2.50 (95%CI, 1.24,5.05; p = 0.01) in multivariate analysis including ABCD2 score ,4. Interpretation Immediate TCD examination on arrival at the TIA clinic is feasible and could help to identify patients at high risk of vascular events recurrence. This study supports a systematic intracranial vascular examination in the initial management of TIA. ANN NEUROL 2010;68:9,17 [source] Initiating levodopa/carbidopa therapy with and without entacapone in early Parkinson disease: The STRIDE-PD studyANNALS OF NEUROLOGY, Issue 1 2010Fabrizio Stocchi MD Objective L-dopa is the most widely used and most effective therapy for Parkinson disease (PD), but chronic treatment is associated with motor complications in the majority of patients. It has been hypothesized that providing more continuous delivery of L-dopa to the brain would reduce the risk of motor complications, and that this might be accomplished by combining L-dopa with entacapone, an inhibitor of catechol-O-methyltransferase, to extend its elimination half-life. Methods We performed a prospective 134-week double-blind trial comparing the risk of developing dyskinesia in 747 PD patients randomized to initiate L-dopa therapy with L-dopa/carbidopa (LC) or L-dopa/carbidopa/entacapone (LCE), administered 4× daily at 3.5-hour intervals. The primary endpoint was time to onset of dyskinesia. Results In comparison to LC, patients receiving LCE had a shorter time to onset of dyskinesia (hazard ratio, 1.29; p = 0.04) and increased frequency at week 134 (42% vs 32%; p = 0.02). These effects were more pronounced in patients receiving dopamine agonists at baseline. Time to wearing off and motor scores were not significantly different, but trended in favor of LCE treatment. Patients in the LCE group received greater L-dopa dose equivalents than LC-treated patients (p < 0.001). Interpretation Initiating L-dopa therapy with LCE failed to delay the time of onset or reduce the frequency of dyskinesia compared to LC. In fact, LCE was associated with a shorter time to onset and increased frequency of dyskinesia compared to LC. These results may reflect that the treatment protocol employed did not provide continuous L-dopa availability and the higher L-dopa dose equivalents in the LCE group. ANN NEUROL 2010;68:18,27 [source] Levodopa, methylmalonic acid, and neuropathy in idiopathic Parkinson diseaseANNALS OF NEUROLOGY, Issue 1 2010Cory Toth MD Objective Peripheral neuropathy (PN) is thought to be coincidental in patients with idiopathic Parkinson disease (IPD). We sought to examine the prevalence of PN in a population of IPD patients and a potential relationship to levodopa use and fasting methylmalonic acid (MMA) levels. Methods In a prospective cohort study, IPD patients randomly selected from a comprehensive database were compared to control subjects regarding the presence and severity of PN using clinical and electrophysiological measures. IPD severity was determined using the Unified Parkinson's Disease Rating Scale (UPDRS). We determined the relation of levodopa use with serum levels of cobalamin, MMA, and homocysteine (Hcy). We also explored the association between presence and severity of PN and age, duration of IPD, cumulative levodopa dosing, cobalamin, MMA, and Hcy levels. Results Fifty-eight randomly selected IPD patients were compared to 58 age- and sex-matched controls. PN was present in 55% of IPD patients and 9% of controls. Patients with IPD had greater prevalence of PN and fasting MMA/Hcy levels than controls. IPD patients with PN were older and exhibited higher UPDRS scores, fasting MMA/Hcy levels, and cumulative levodopa exposure. PN severity in IPD subjects positively correlated with both levodopa exposure and MMA levels. Interpretation IPD patients have a higher prevalence of PN than controls. Although causality is not established, levodopa exposure is associated with MMA elevation and sensorimotor neuropathy in IPD patients. Cobalamin replacement concurrent with levodopa therapy should be considered to protect against development of PN in IPD patients. ANN NEUROL 2010;67:28,36 [source] T2*-weighted magnetic resonance imaging with hyperoxia in acute ischemic strokeANNALS OF NEUROLOGY, Issue 1 2010Krishna A. Dani MBChB Objective We describe the first clinical application of transient hyperoxia ("oxygen challenge") during T2*-weighted magnetic resonance imaging (MRI), to detect differences in vascular deoxyhemoglobin between tissue compartments following stroke. Methods Subjects with acute ischemic stroke were scanned with T2*-weighted MRI and oxygen challenge. For regions defined as infarct core (diffusion-weighted imaging lesion) and presumed penumbra (perfusion-diffusion mismatch [threshold = Tmax ,4 seconds], or regions exhibiting diffusion lesion expansion at day 3), T2*-weighted signal intensity,time curves corresponding to the duration of oxygen challenge were generated. From these, the area under the curve, gradient of incline of the signal increase, time to maximum signal, and percentage signal change after oxygen challenge were measured. Results We identified 25 subjects with stroke lesions >1ml. Eighteen subjects with good quality T2*-weighted signal intensity,time curves in the contralateral hemisphere were analyzed. Curves from the diffusion lesion had a smaller area under the curve, percentage signal change, and gradient of incline, and longer time to maximum signal (p < 0.05, n = 17) compared to normal tissue, which consistently showed signal increase during oxygen challenge. Curves in the presumed penumbral regions (n = 8) showed varied morphology, but at hyperacute time points (<8 hours) showed a tendency to greater percentage signal change. Interpretation Differences in T2*-weighted signal intensity,time curves during oxygen challenge in brain regions with different pathophysiological states after stroke are likely to reflect differences in deoxyhemoglobin concentration, and therefore differences in metabolic activity. Despite its underlying complexities, this technique offers a possible novel mode of metabolic imaging in acute stroke. ANN NEUROL 2010;68:37,47 [source] Nogo-A antibodies and training reduce muscle spasms in spinal cord-injured ratsANNALS OF NEUROLOGY, Issue 1 2010Roman R. Gonzenbach MD Objective Spinal cord injury (SCI) leads to permanent motor and sensory deficits due to the damage of ascending and descending fiber tracts. In addition, malfunctions such as neuropathic pain or muscle spasms develop in many patients, possibly caused by injury-induced plastic changes of neuronal circuits above and below the lesion. New treatment strategies for spinal cord injury aim at enhancing plasticity and neurite growth, for example, by blocking the key neurite growth inhibitor Nogo-A or its downstream effectors. It is therefore crucial to investigate potential effects of such treatments on malfunctions such as muscle spasms. In addition, locomotor training, now a standard therapeutic tool to improve walking ability in incomplete SCI subjects, can be expected to influence the rearrangement of spinal cord circuits and the development of muscle spasms and other malfunctions. Methods and Results Here we present and validate a new rat model for muscle spasms after incomplete SCI and show that both intrathecal anti,Nogo-A antibody treatment and locomotor training, started early after injury, permanently reduce the development of muscle spasms. Interpretation The results show that an antibody-mediated suppression of the growth inhibitory protein Nogo-A leads to functional recovery and a lower level of malfunctions, suggesting the formation of functionally meaningful connections in the damaged spinal cord. Treadmill training early after SCI also has a beneficial effect. ANN NEUROL 2010;68:48,57 [source] | ||||||||||