Showing papers in "Annals of Neurology in 2011"

Diagnostic criteria for multiple sclerosis: 2010 Revisions to the McDonald criteria

Abstract: New evidence and consensus has led to further revision of the McDonald Criteria for diagnosis of multiple sclerosis. The use of imaging for demonstration of dissemination of central nervous system lesions in space and time has been simplified, and in some circumstances dissemination in space and time can be established by a single scan. These revisions simplify the Criteria, preserve their diagnostic sensitivity and specificity, address their applicability across populations, and may allow earlier diagnosis and more uniform and widespread use.

Inflammation after trauma: Microglial activation and traumatic brain injury

Abstract: Objective Patient outcome after traumatic brain injury (TBI) is highly variable. The underlying pathophysiology of this is poorly understood, but inflammation is potentially an important factor. Microglia orchestrate many aspects of this response. Their activation can be studied in vivo using the positron emission tomography (PET) ligand [11C](R)PK11195 (PK). In this study, we investigate whether an inflammatory response to TBI persists, and whether this response relates to structural brain abnormalities and cognitive function. Methods Ten patients, studied at least 11 months after moderate to severe TBI, underwent PK PET and structural magnetic resonance imaging (including diffusion tensor imaging). PK binding potentials were calculated in and around the site of focal brain damage, and in selected distant and subcortical brain regions. Standardized neuropsychological tests were administered. Results PK binding was significantly raised in the thalami, putamen, occipital cortices, and posterior limb of the internal capsules after TBI. There was no increase in PK binding at the original site of focal brain injury. High PK binding in the thalamus was associated with more severe cognitive impairment, although binding was not correlated with either the time since the injury or the extent of structural brain damage. Interpretation We demonstrate that increased microglial activation can be present up to 17 years after TBI. This suggests that TBI triggers a chronic inflammatory response particularly in subcortical regions. This highlights the importance of considering the response to TBI as evolving over time and suggests interventions may be beneficial for longer intervals after trauma than previously assumed.

Longitudinal Assessment of Aβ and Cognition in Aging and Alzheimer Disease

Abstract: In vivo amyloid imaging with positron emission tomography (PET) allows longitudinal study of Aβ deposition in an individual and should provide unique information on the relationship between Aβ and cognitive decline. Although it is likely that Aβ plays a fundamental role in the development of dementia of the Alzheimer type (DAT),1 postmortem studies have not consistently demonstrated a relationship between the density of amyloid plaques and the severity of dementia.2–5 The time course of plaque formation is unclear. Studies comparing the plaque density at brain biopsy in DAT patients to that assessed in those same patients at postmortem several years later found little change in the majority of patients, but these studies had few participants.6–9 An additional perplexing postmortem observation is the high prevalence of amyloid plaques in the normal elderly. It has been postulated that this represents preclinical DAT, but this cannot be proven by autopsy-based studies. In vivo Aβ imaging provides the means to address these questions through longitudinal observation. Cross-sectional [11C]Pittsburgh compound B (PiB) PET studies have shown a robust difference between the retention patterns in DAT patients and healthy controls (HCs).10,11 In agreement with postmortem data,2 approximately 20 to 30% of elderly HC subjects show some degree of increased cortical PiB retention, predominantly in the prefrontal cortex and posterior cingulate/precuneus areas.10,12–14 Polymorphism of the apolipoprotein E (ApoE) allele is among the most consistent genetic risk factors associated with sporadic DAT, and its presence is thought to result in an earlier age of onset.15,16 Examination of ApoE e4 allele status revealed that healthy e4 carriers present with significantly higher PiB retention than e4 noncarriers and show increased retention at an earlier age, further emphasizing the crucial role that ApoE plays in the metabolism of Aβ.10,17–20 Recently, several studies have found significant increases in PiB retention in some individuals over 1 to 2 years, but no overall increase in mean PiB retention in groups of subjects with DAT or mild cognitive impairment (MCI). These studies did report a higher conversion rate from MCI to DAT in those with high PiB retention, despite a lack of significant change in PiB retention in those who progressed.21–24 The objectives of this study were to quantify the progression of Aβ plaque formation in the brain over time with PiB PET in a large number of individuals and to correlate Aβ plaque burden at baseline and follow-up with clinical measures of disease severity, cognitive decline, and ApoE status.

Faciobrachial dystonic seizures precede Lgi1 antibody limbic encephalitis.

Abstract: Objective: To describe a distinctive seizure semiology that closely associates with voltage-gated potassium channel (VGKC)-complex/Lgi1 antibodies and commonly precedes the onset of limbic encephalitis (LE). Methods: Twenty-nine patients were identified by the authors (n ¼ 15) or referring clinicians (n ¼ 14). The temporal progression of clinical features and serum sodium, brain magnetic resonance imaging (MRI), positron emission tomography/single photon emission computed tomography, and VGKC-complex antibodies was studied. Results: Videos and still images showed a distinctive adult-onset, frequent, brief dystonic seizure semiology that predominantly affected the arm and ipsilateral face. We have termed these faciobrachial dystonic seizures (FBDS). All patients tested during their illness had antibodies to VGKC complexes; the specific antigenic target was Lgi1 in 89%. Whereas 3 patients never developed LE, 20 of the remaining 26 (77%) experienced FBDS prior to the development of the amnesia and confusion that characterize LE. During the prodrome of FBDS alone, patients had normal sodium and brain MRIs, but electroencephalography demonstrated ictal epileptiform activity in 7 patients (24%). Following development of LE, the patients often developed other seizure semiologies, including typical mesial temporal lobe seizures. At this stage, investigations commonly showed hyponatremia and MRI hippocampal high T2 signal; functional brain imaging showed evidence of basal ganglia involvement in 5/8. Antiepileptic drugs (AEDs) were generally ineffective and in 41% were associated with cutaneous reactions that were often severe. By contrast, immunotherapies produced a clear, and often dramatic, reduction in FBDS frequency. Interpretation: Recognition of FBDS should prompt testing for VGKC-complex/Lgi1 antibodies. AEDs often produce adverse effects; treatment with immunotherapies may prevent the development of LE with its potential for cerebral atrophy and cognitive impairment. ANN NEUROL 2010;000:000–000

Pathogenic protein seeding in Alzheimer disease and other neurodegenerative disorders.

Abstract: The misfolding and aggregation of specific proteins is a seminal occurrence in a remarkable variety of neurodegenerative disorders. In Alzheimer’s disease (the most prevalent cerebral proteopathy), the two principal aggregating proteins are β-amyloid (Aβ) and tau. The abnormal assemblies formed by conformational variants of these proteins range in size from small oligomers to the characteristic lesions that are visible by optical microscopy, such as senile plaques and neurofibrillary tangles. Pathologic similarities with prion disease suggest that the formation and spread of these proteinaceous lesions might involve a common molecular mechanism – corruptive protein templating. Experimentally, cerebral β-amyloidosis can be exogenously induced by exposure to dilute brain extracts containing aggregated Aβ seeds. The amyloid-inducing agent probably is Aβ itself, in a conformation generated most effectively in the living brain. Once initiated, Aβ lesions proliferate within and among brain regions. The induction process is governed by the structural and biochemical nature of the Aβ seed, as well as the attributes of the host, reminiscent of pathogenically variant prion strains. The concept of prion-like induction and spreading of pathogenic proteins recently has been expanded to include aggregates of tau, α-synuclein, huntingtin, superoxide dismutase-1, and TDP-43, which characterize such human neurodegenerative disorders as frontotemporal lobar degeneration, Parkinson’s/Lewy body disease, Huntington’s disease, and amyotrophic lateral sclerosis. Our recent finding that the most effective Aβ seeds are small and soluble intensifies the search in bodily fluids for misfolded protein seeds that are upstream in the proteopathic cascade, and thus could serve as predictive diagnostics and the targets of early, mechanism-based interventions. Establishing the clinical implications of corruptive protein templating will require further mechanistic and epidemiologic investigations. However, the theory that many chronic neurodegenerative diseases can originate and progress via the seeded corruption of misfolded proteins has the potential to unify experimental and translational approaches to these increasingly prevalent disorders.

Cerebral amyloid angiopathy in the elderly

Abstract: Cerebral amyloid angiopathy (CAA) results from deposition of β-amyloid in the media and adventitia of small arteries and capillaries of the leptomeninges and cerebral cortex and is a major cause of lobar intracerebral hemorrhage and cognitive impairment in the elderly. CAA is associated with a high prevalence of magnetic resonance imaging markers of small vessel disease, including cerebral microbleeds and white matter hyperintensities. Although advanced CAA is present in approximately ¼ of brains with Alzheimer disease (AD), fewer than half of CAA cases meet pathologic criteria for AD. This review will discuss the pathophysiology of CAA and focus on new imaging modalities and laboratory biomarkers that may aid in the clinical diagnosis of individuals with the disease.

Resolving postoperative neuroinflammation and cognitive decline

Abstract: Objective Cognitive decline accompanies acute illness and surgery, especially in the elderly. Surgery engages the innate immune system that launches a systemic inflammatory response which, if unchecked, can cause multiple organ dysfunction. We sought to understand the mechanisms whereby the brain is targeted by the inflammatory response and how this can be resolved.

Narcolepsy onset is seasonal and increased following the 2009 H1N1 pandemic in China.

Abstract: Objective: Narcolepsy is caused by the loss of hypocretin/orexin neurons in the hypothalamus, which is likely the result of an autoimmune process. Recently, concern has been raised over reports of narcolepsy in northern Europe following H1N1 vaccination. Methods: The study is a retrospective analysis of narcolepsy onset in subjects diagnosed in Beijing, China (1998– 2010). Self-reported month and year of onset were collected from 629 patients (86% children). Graphical presentation, autocorrelations, chi-square, and Fourier analysis were used to assess monthly variation in onset. Finally, 182 patients having developed narcolepsy after October 2009 were asked for vaccination history. Results: The occurrence of narcolepsy onset was seasonal, significantly influenced by month and calendar year. Onset was least frequent in November and most frequent in April, with a 6.7-fold increase from trough to peak. Studying year-to-year variation, we found a 3-fold increase in narcolepsy onset following the 2009 H1N1 winter influenza pandemic. The increase is unlikely to be explained by increased vaccination, as only 8 of 142 (5.6%) patients recalled receiving an H1N1 vaccination. Cross-correlation indicated a significant 5- to 7-month delay between the seasonal peak in influenza/cold or H1N1 infections and peak in narcolepsy onset occurrences. Interpretation: In China, narcolepsy onset is highly correlated with seasonal and annual patterns of upper airway infections, including H1N1 influenza. In 2010, the peak seasonal onset of narcolepsy was phase delayed by 6 months relative to winter H1N1 infections, and the correlation was independent of H1N1 vaccination in the majority of the sample. ANN NEUROL 2011;70:410–417

Neonatal intensive care unit stress is associated with brain development in preterm infants.

Abstract: 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;70:541–549

Current concepts and management of glioblastoma.

Abstract: Glioblastoma is the most common malignant primary brain tumor in adults. Its often rapid clinical course, with many medical and psychosocial challenges, requires a multidisciplinary management. Modern multimodality treatment and care improve patients' life expectancy and quality of life. This review covers major aspects of care of glioblastoma patients with a focus on the management of common symptoms and complications. We aim to provide a guide for clinicians confronted with glioblastoma patients in their everyday practice.

Autoantibodies to low-density lipoprotein receptor-related protein 4 in myasthenia gravis.

Abstract: Myasthenia gravis (MG) is an autoimmune disease of the neuromuscular junction, where acetylcholine receptor (AChR), muscle-specific kinase (MuSK), and low-density lipoprotein (LDL) receptor-related protein 4 (Lrp4) are essential. About 80% and 0% to 10% of patients with generalized MG have autoantibodies to AChR and MuSK, respectively, but pathogenic factors are elusive in others. Here we show that a proportion of AChR antibody-negative patients have autoantibodies to Lrp4. These antibodies inhibit binding of Lrp4 to its ligand and predominantly belong to the immunoglobulin G1 (IgG1) subclass, a complement activator. These findings together indicate the involvement of Lrp4 antibodies in the pathogenesis of AChR antibody-negative MG.

Charcot-Marie-Tooth Disease Subtypes and Genetic Testing Strategies

Abstract: Objective: Charcot-Marie-Tooth disease (CMT) affects 1 in 2,500 people and is caused by mutations in more than 30 genes. Identifying the genetic cause of CMT is often necessary for family planning, natural history studies, and for entry into clinical trials. However genetic testing can be both expensive and confusing to patients and physicians. Methods: We analyzed data from 1,024 of our patients to determine the percentage and features of each CMT subtype within this clinic population. We identified distinguishing clinical and physiological features of the subtypes that could be used to direct genetic testing for patients with CMT. Results: Of 1,024 patients evaluated, 787 received CMT diagnoses. A total of 527 patients with CMT (67%) received a genetic subtype, while 260 did not have a mutation identified. The most common CMT subtypes were CMT1A, CMT1X, hereditary neuropathy with liability to pressure palsies (HNPP), CMT1B, and CMT2A. All other subtypes accounted for less than 1% each. Eleven patients had >1 genetically identified subtype of CMT. Patients with genetically identified CMT were separable into specific groups based on age of onset and the degree of slowing of motor nerve conduction velocities. Interpretation: Combining features of the phenotypic and physiology groups allowed us to identify patients who were highly likely to have specific subtypes of CMT. Based on these results, we propose a strategy of focused genetic testing for CMT, illustrated in a series of flow diagrams created as testing guides. ANN NEUROL 2011;69:22–33

Disparities in stroke incidence contributing to disparities in stroke mortality

Abstract: Stroke mortality rates declined dramatically in the 20th century, yielding 1 of the top 10 public health achievements of that era.1 Despite this, rates have remained consistently higher among blacks than any other race/ethnic group in the United States.2–5 This disparity in stroke mortality is largest at younger ages; at age 45 years, the mortality rate is 3 times higher for blacks than whites, with a decreasing racial disparity with increasing age: by age 85 years the difference is no longer apparent.2–4,6 There are also substantial geographic disparities in stroke mortality with higher rates in the southeastern United States, termed the “stroke belt.” First identified in 1965, excess stroke mortality rates in this region have existed since at least 1940 and have persisted.6–8 A 153-county region including the coastal plain of North Carolina, South Carolina, and Georgia is referred to as the “stroke buckle” due to even higher stroke mortality than the rest of the stroke belt.9 Because the stroke belt and buckle contain counties with very high stroke mortality rates and counties with average or even low stroke mortality, the overall stroke mortality is approximately 20% higher in the stroke belt than rest of the nation, with rates in the stroke buckle approximately 40% higher than rest of the nation.6–9 In the Greater Cincinnati/Northern Kentucky Stroke Study (GCNKSS), the black-white disparity in stroke mortality was primarily due to higher stroke incidence among blacks, with little contribution of case fatality, the other potential contributor to disparities in stroke mortality.10 National racial and geographic disparities in stroke mortality are documented based on death certificates through the national vital statistics system. National data on stroke incidence based on validated stroke events are not available. The goal of this report was to describe black-white and geographic differences in stroke incidence in a national population-based cohort and assess if the pattern and magnitude of stroke incidence rates mirror the disparities in stroke mortality.

A mutation in sigma-1 receptor causes juvenile amyotrophic lateral sclerosis.

Abstract: Objective: Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disorder characterized by loss of motor neurons in the brain and spinal cord, leading to muscle weakness and eventually death from respiratory failure. ALS is familial in about 10% of cases, with SOD1 mutations accounting for 20% of familial cases. Here we describe a consanguineous family segregating juvenile ALS in an autosomal recessive pattern and describe the genetic variant responsible for the disorder. Methods: We performed homozygosity mapping and direct sequencing to detect the genetic variant and tested the effect of this variant on a motor neuron-like cell line model (NSC34) expressing the wild-type or mutant gene. Results: We identified a shared homozygosity region in affected individuals that spans ∼120kbp on chromosome 9p13.3 containing 9 RefSeq genes. Sequencing the SIGMAR1 gene revealed a mutation affecting a highly conserved amino acid located in the transmembrane domain of the encoded protein, sigma-1 receptor. The mutated protein showed an aberrant subcellular distribution in NSC34 cells. Furthermore, cells expressing the mutant protein were less resistant to apoptosis induced by endoplasmic reticulum stress. Interpretation: Sigma-1 receptors are known to have neuroprotective properties, and recently Sigmar1 knockout mice have been described to have motor deficiency. Our findings emphasize the role of sigma-1 receptors in motor neuron function and disease. ANN NEUROL 2011;

Circadian activity rhythms and risk of incident dementia and mild cognitive impairment in older women

Abstract: Objective Previous cross-sectional studies have observed alterations in activity rhythms in dementia patients but the direction of causation is unclear. We determined whether circadian activity rhythms measured in community-dwelling older women are prospectively associated with incident dementia or mild cognitive impairment (MCI). Methods Activity rhythm data were collected from 1,282 healthy community-dwelling women from the Study of Osteoporotic Fractures (SOF) cohort (mean age 83 years) with wrist actigraphy for a minimum of three 24-hour periods. Each participant completed a neuropsychological test battery and had clinical cognitive status (dementia, MCI, normal) adjudicated by an expert panel approximately 5 years later. All analyses were adjusted for demographics, body mass index (BMI), functional status, depression, medications, alcohol, caffeine, smoking, health status, and comorbidities. Results After 4.9 years of follow-up, 195 (15%) women had developed dementia and 302 (24%) had developed MCI. Older women with decreased activity rhythms had a higher likelihood of developing dementia or MCI when comparing those in the lowest quartiles of amplitude (odds ratio [OR] = 1.57; 95% CI, 1.09-2.25) or rhythm robustness (OR = 1.57; 95% CI, 1.10-2.26) to women in the highest quartiles. An increased risk of dementia or MCI (OR = 1.83; 95% CI, 1.29-2.61) was found for women whose timing of peak activity occurred later in the day (after 3:51 PM) when compared to those with average timing (1:34 PM-3:51 PM). Interpretation Older, healthy women with decreased circadian activity rhythm amplitude and robustness, and delayed rhythms have increased odds of developing dementia and MCI. If confirmed, future studies should examine whether interventions (physical activity, bright light exposure) that influence activity rhythms will reduce the risk of cognitive deterioration in the elderly.

Cerebrospinal fluid biomarkers for Parkinson disease diagnosis and progression.

Abstract: Background— There is a clear need to develop biomarkers for Parkinson disease (PD) diagnosis,differential diagnosis of parkinsonian disorders, and monitoring disease progression. We andothers have demonstrated that a decrease in DJ-1 and/or α-synuclein in the cerebrospinal fluid(CSF) is a potential index for PD diagnosis, but not for PD severity. Methods— Using highly sensitive and quantitative Luminex assays, we measured total tau,phosphorylated tau, amyloid beta peptide 1-42 (Aβ 1-42 ), Flt3 ligand and fractalkine levels in CSFin a large cohort of PD patients at different stages as well as healthy and diseased controls. Theutility of these five markers was evaluated for disease diagnosis and severity/progression * Address correspondence to: Jing Zhang, Department of Pathology, University of Washington School of Medicine, HMC Box 359635,325 9th Ave, Seattle, WA 98104, USA. Phone: 1-206-897-5245, Fax: 1-206-897-5452, zhangj@uw.edu. NIH Public Access Author Manuscript Ann Neurol

Impulse control disorders in parkinson disease: A multicenter case–control study

Abstract: Objective: To assess factors associated with impulse control disorders (ICDs) in Parkinson disease (PD) using a multicenter case–control design. Methods: Patients enrolled in the DOMINION study, a multicenter study assessing the cross-sectional frequency of ICDs in PD, were eligible to participate in the case–control study. PD patients with and without an ICD (n ¼ 282 each) (compulsive gambling, buying, sexual behavior, and eating) were matched individually on age, gender, and dopamine agonist treatment. Subjects were assessed with a comprehensive neurological, psychiatric, and cognitive assessment battery. Results: ICD patients reported more functional impairment (p < 0.001); greater depressive (p < 0.0001), state (p < 0.0001), and trait (p < 0.0001) anxiety; greater obsessive–compulsive symptoms (p < 0.0001); higher novelty-seeking (p < 0.001) and impulsivity (p < 0.001); and differences in reward preference reflecting greater choice impulsivity (p < 0.05). Patients with multiple ICDs had greater dyskinesia scores compared to those with single ICDs. Interpretation: ICDs in PD are associated with multiple psychiatric and cognitive impairments, including affective and anxiety symptoms, as well as elevated obsessionality, novelty seeking, and impulsivity. These results highlight the importance of assessing multiple mental health domains in individuals with PD and ICDs, and suggest possible pathophysiological mechanisms and risk indicators for these disorders. ANN NEUROL 2011;69:986–996

Investigations of caspr2, an autoantigen of encephalitis and neuromyotonia.

Abstract: Objective To report clinical and immunological investigations of contactin-associated protein-like 2 (Caspr2), an autoantigen of encephalitis and peripheral nerve hyperexcitability (PNH) previously attributed to voltage-gated potassium channels (VGKC).

Mechanisms of fingolimod's efficacy and adverse effects in multiple sclerosis

Abstract: 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 10x the approved 0.5 mg dose. Fingolimod's unique mechanism of action distinguishes it from all other currently approved MS therapies.

Arterial ischemic stroke risk factors: the International Pediatric Stroke Study.

Abstract: Objective To describe presumptive risk factors (RFs) for childhood arterial ischemic stroke (AIS) and explore their relationship with presentation, age, geography, and infarct characteristics. Methods Children (29 days–18 years) were prospectively enrolled in the International Pediatric Stroke Study. Risk factors, defined conditions thought to be associated with childhood AIS, were divided into 10 categories. Chi-square tests were used to compare RFs prevalence across regions and age; logistic regression was used to determine whether RFs were associated with particular features at presentation or infarct characteristics. Results A total of 676 children were included. No identifiable RFs was present in 54 (9%). RFs in others included arteriopathies (53%), cardiac disorders (CDs) (31%), infection (24%), acute head and neck disorders (AHNDs) (23%), acute systemic conditions (ASCs) (22%), chronic systemic conditions (CSCs) (19%), prothrombotic states (PTSs) (13%), chronic head and neck disorders (CHNDs) (10%), atherosclerosis-related RFs (2%), and other (22%). Fifty-two percent had multiple RFs. There was lower prevalence of arteriopathy in Asia, lower prevalence of CSCs in Europe and Australia, higher prevalence of PTSs in Europe, and higher prevalence of ASCs in Asia and South America. Prevalence of CDs and ASCs was highest in preschoolers, arteriopathies in children 5 to 9 years old, and CHNDs were highest in children aged 10 to 14 years. Arteriopathies were associated with focal signs and ASCs, CHNDs, and AHNDs with diffuse signs. Arteriopathies, CSCs, and ASCs were associated with multiple infarcts and CDs with hemorrhagic conversion. Interpretation RFs, especially arteriopathy, are common in childhood AIS. Variations in RFs by age or geography may inform prioritization of investigations and targeted preventative strategies. Ann Neurol 2011;69:130–140.

Pallidal dysfunction drives a cerebellothalamic circuit into Parkinson tremor.

Abstract: Objective: Parkinson disease (PD) is characterized by striatal dopamine depletion, which explains clinical symptoms such as bradykinesia and rigidity, but not resting tremor. Instead, resting tremor is associated with increased activity in a distinct cerebellothalamic circuit. To date, it remains unknown how the interplay between basal ganglia and the cerebellothalamic circuit can result in resting tremor. Methods: We studied 21 tremor-dominant PD patients, 23 nontremor PD patients, and 36 controls. Using functional magnetic resonance imaging, we measured functional connectivity between basal ganglia nuclei (globus pallidus internus [GPi], globus pallidus externus [GPe], putamen, caudate) and the cerebellothalamic circuit. Using electromyography during scanning, we measured tremor-related activity in the basal ganglia and cerebellothalamic circuit. We also quantified striatopallidal dopamine depletion using iodine-123-N-omega-fluoropropyl-2 beta-carbomethoxy-3 beta-(4-iodophenyl)tropane [[I-123]FP-CIT] single photon emission computed tomography. Results: Pallidal (but not striatal) dopamine depletion correlated with clinical tremor severity. The GPi, GPe, and putamen were transiently activated at the onset of tremor episodes, whereas activity in the cerebellothalamic circuit cofluctuated with tremor amplitude. The GPi and putamen of tremor-dominant PD patients had increased functional connectivity with the cerebellothalamic circuit, which was relegated through the motor cortex. Interpretation: Resting tremor may result from a pathological interaction between the basal ganglia and the cerebellothalamic circuit. The cerebellothalamic circuit, which controls tremor amplitude, appears to be driven into tremor generation when receiving transient signals from the dopamine-depleted basal ganglia. This may explain why basal ganglia dysfunction is required for developing resting tremor, although a cerebellothalamic circuit produces it. Our model also clarifies why neurosurgical interventions targeted at either the basal ganglia or the cerebellothalamic circuit can both suppress tremor.

Clinicopathological correlations in corticobasal degeneration

Abstract: Objective To characterize cognitive and behavioral features, physical findings and brain atrophy patterns in pathology-proven corticobasal degeneration (CBD) and corticobasal syndrome (CBS) with known histopathology.

Systemic inflammation disrupts the developmental program of white matter

Abstract: Perinatal inflammation is a major risk factor for neurological deficits in preterm infants. Several experimental studies have shown that systemic inflammation can alter the programming of the developing brain. However, these studies do not offer detailed pathophysiological mechanisms, and they rely on relatively severe infectious or inflammatory stimuli that most likely do not reflect the levels of systemic inflammation observed in many human preterm infants. The goal of the present study was to test the hypothesis that moderate systemic inflammation is sufficient to alter white matter development.

Genome-wide meta-analysis identifies novel multiple sclerosis susceptibility loci

Abstract: OBJECTIVE: To perform a 1-stage meta-analysis of genome-wide association studies (GWAS) of multiple sclerosis (MS) susceptibility and to explore functional consequences of new susceptibility loci. METHODS: We synthesized 7 MS GWAS. Each data set was imputed using HapMap phase II, and a per single nucleotide polymorphism (SNP) meta-analysis was performed across the 7 data sets. We explored RNA expression data using a quantitative trait analysis in peripheral blood mononuclear cells (PBMCs) of 228 subjects with demyelinating disease. RESULTS: We meta-analyzed 2,529,394 unique SNPs in 5,545 cases and 12,153 controls. We identified 3 novel susceptibility alleles: rs170934(T) at 3p24.1 (odds ratio [OR], 1.17; p = 1.6 × 10(-8)) near EOMES, rs2150702(G) in the second intron of MLANA on chromosome 9p24.1 (OR, 1.16; p = 3.3 × 10(-8)), and rs6718520(A) in an intergenic region on chromosome 2p21, with THADA as the nearest flanking gene (OR, 1.17; p = 3.4 × 10(-8)). The 3 new loci do not have a strong cis effect on RNA expression in PBMCs. Ten other susceptibility loci had a suggestive p < 1 × 10(-6) , some of these loci have evidence of association in other inflammatory diseases (ie, IL12B, TAGAP, PLEK, and ZMIZ1). INTERPRETATION: We have performed a meta-analysis of GWAS in MS that more than doubles the size of previous gene discovery efforts and highlights 3 novel MS susceptibility loci. These and additional loci with suggestive evidence of association are excellent candidates for further investigations to refine and validate their role in the genetic architecture of MS.

The blood-spinal cord barrier: morphology and clinical implications.

Abstract: The blood-spinal cord barrier (BSCB) is the functional equivalent of the blood-brain barrier (BBB) in the sense of providing a specialized microenvironment for the cellular constituents of the spinal cord. Even if intuitively the BSCB could be considered as the morphological extension of the BBB into the spinal cord, evidence suggests that this is not so. The BSCB shares the same principal building blocks with the BBB; nevertheless, it seems that morphological and functional differences may exist between them. Dysfunction of the BSCB plays a fundamental role in the etiology or progression of several pathological conditions of the spinal cord, such as spinal cord injury, amyotrophic lateral sclerosis, and radiation-induced myelopathy. This review summarizes current knowledge of the morphology of the BSCB, the methodology of studying the BSCB, and the potential role of BSCB dysfunction in selected disorders of the spinal cord, and finally summarizes therapeutic approaches to the BSCB.

Neuronal cell death in neonatal hypoxia-ischemia

Abstract: Perinatal hypoxic-ischemic encephalopathy (HIE) is a significant cause of mortality and morbidity in infants and young children. Therapeutic opportunities are very limited for neonatal and pediatric HIE. Specific neural systems and populations of cells are selectively vulnerable in HIE; however, the mechanisms of degeneration are unresolved. These mechanisms involve oxidative stress, excitotoxicity, inflammation, and the activation of several different cell death pathways. Decades ago the structural and mechanistic basis of the cellular degeneration in HIE was thought to be necrosis. Subsequently, largely due to advances in cell biology and to experimental animal studies, emphasis has been switched to apoptosis or autophagy mediated by programmed cell death (PCD) mechanisms as important forms of degeneration in HIE. We have conceptualized based on morphological and biochemical data that this degeneration is better classified according to an apoptosis-necrosis cell death continuum and that programmed cell necrosis has prominent contribution in the neurodegeneration of HIE in animal models. It is likely that neonatal HIE evolves through many cell death chreodes influenced by the dynamic injury landscape. The relevant injury mechanisms remain to be determined in human neonatal HIE, though preliminary work suggests a complexity in the cell death mechanisms greater than that anticipated from experimental animal models. The accurate identification of the various cell death chreodes and their mechanisms unfolding within the immature brain matrix could provide fresh insight for developing meaningful therapies for neonatal and pediatric HIE.

Activation of central trigeminovascular neurons by cortical spreading depression.

Abstract: Objective: Cortical spreading depression (CSD) has long been implicated in migraine attacks that begin with visual aura. Having shown that a wave of CSD can trigger long-lasting activation of meningeal nociceptors—the first-order neurons of the trigeminovascular pathway thought to underlie migraine headache—we now report that CSD can activate central trigeminovascular neurons in the spinal trigeminal nucleus (C1–2). Methods: Stimulation of the cortex with pinprick or KCl granule was used to induce CSD in anesthetized rats. Neuronal activity was monitored in C1–2 using single-unit recording. Results: In 25 trigeminovascular neurons activated by CSD, mean firing rate (spikes/s) increased from 3.6 ± 1.2 before CSD (baseline) to 6.1 ± 1.8 after CSD (p 13 minutes. Neuronal activity returned to baseline level after 30.0 ± 3.1 minutes in 14 units, and remained elevated for 66.0 ± 8.3 (22–108) minutes through the entire recording period in the other 11 units. Neuronal activation began within 0.9 ± 0.4 (0–2.5) minutes after CSD in 7 neurons located in laminae I–II, or after a latency of 25.1 ± 4.0 (7–75) minutes in 9 neurons located in laminae I–II, and 9 neurons located in laminae III–V. In 27 trigeminovascular neurons not activated by CSD, mean firing rate was 2.0 ± 0.7 at baseline and 1.8 ± 0.7 after CSD. Interpretation: We propose that CSD constitutes a nociceptive stimulus capable of activating peripheral and central trigeminovascular neurons that underlie the headache of migraine with aura. ANN NEUROL 2011;

Amyloid-β Associated Cortical Thinning in Clinically Normal Elderly

Abstract: Objective: Both amyloid-b (Ab) deposition and brain atrophy are associated with Alzheimer’s disease (AD) and the disease process likely begins many years before symptoms appear. We sought to determine whether clinically normal (CN) older individuals with Ab deposition revealed by positron emission tomography (PET) imaging using Pittsburgh Compound B (PiB) also have evidence of both cortical thickness and hippocampal volume reductions in a pattern similar to that seen in AD. Methods: A total of 119 older individuals (87 CN subjects and 32 patients with mild AD) underwent PiB PET and high-resolution structural magnetic resonance imaging (MRI). Regression models were used to relate PiB retention to cortical thickness and hippocampal volume. Results: We found that PiB retention in CN subjects was (1) age-related and (2) associated with cortical thickness reductions, particularly in parietal and posterior cingulate regions extending into the precuneus, in a pattern similar to that observed in mild AD. Hippocampal volume reduction was variably related to Ab deposition. Interpretation: We conclude that Ab deposition is associated with a pattern of cortical thickness reduction consistent with AD prior to the development of cognitive impairment. ANN NEUROL 2010;000:000–000

Altered functional magnetic resonance imaging resting-state connectivity in periaqueductal gray networks in migraine

Abstract: Objective: The periaqueductal gray matter (PAG), a known modulator of somatic pain transmission, shows evidence of interictal functional and structural abnormalities in migraineurs, which may contribute to hyperexcitability along spinal and trigeminal nociceptive pathways, and lead to the migraine attack. The aim of this study was to examine functional connectivity of the PAG in migraine.

Mitochondrial DNA deletions and neurodegeneration in multiple sclerosis

Abstract: Objective Cerebral atrophy is a correlate of clinical progression in multiple sclerosis (MS). Mitochondria are now established to play a part in the pathogenesis of MS. Uniquely, mitochondria harbor their own mitochondrial DNA (mtDNA), essential for maintaining a healthy central nervous system. We explored mitochondrial respiratory chain activity and mtDNA deletions in single neurons from secondary progressive MS (SPMS) cases. Methods Ninety-eight snap-frozen brain blocks from 13 SPMS cases together with complex IV/complex II histochemistry, immunohistochemistry, laser dissection microscopy, long-range and real-time PCR and sequencing were used to identify and analyze respiratory-deficient neurons devoid of complex IV and with complex II activity. Results The density of respiratory-deficient neurons in SPMS was strikingly in excess of aged controls. The majority of respiratory-deficient neurons were located in layer VI and immediate subcortical white matter (WM) irrespective of lesions. Multiple deletions of mtDNA were apparent throughout the gray matter (GM) in MS. The respiratory-deficient neurons harbored high levels of clonally expanded mtDNA deletions at a single-cell level. Furthermore, there were neurons lacking mtDNA-encoded catalytic subunits of complex IV. mtDNA deletions sufficiently explained the biochemical defect in the majority of respiratory-deficient neurons. Interpretation These findings provide evidence that neurons in MS are respiratory-deficient due to mtDNA deletions, which are extensive in GM and may be induced by inflammation. We propose induced multiple deletions of mtDNA as an important contributor to neurodegeneration in MS.