Objective

While black-white and regional disparities in U.S. stroke mortality rates are well documented, the contribution of disparities in stroke incidence is unknown. We provide national estimates of stroke incidence by race and region, contrasting these to publicly available stroke mortality data.

Methods

This analysis included 27,744 men and women without prevalent stroke (40.4% black), aged ≥45 years from the REasons for Geographic And Racial Differences in Stroke (REGARDS) national cohort study, enrolled 2003–2007. Incident stroke was defined as first occurrence of stroke over 4.4 years of follow-up. Age-sex–adjusted stroke mortality rates were calculated using data from the Centers for Disease Control and Prevention (CDC) Wide-Ranging Online Data for Epidemiological Research (WONDER) System.

Results

There were 460 incident strokes over 113,469 person-years of follow-up. Relative to the rest of the United States, incidence rate ratios (IRRs) of stroke in the southeastern stroke belt and stroke buckle were 1.06 (95% confidence interval [CI], 0.87–1.29) and 1.19 (95% CI, 0.96–1.47), respectively. The age-sex–adjusted black/white IRRblack was 1.51 (95% CI, 1.26–1.81), but for ages 45–54 years the IRRblack was 4.02 (95% CI, 1.23–13.11) while for ages 85+ it was 0.86 (95% CI, 0.33–2.20). Generally, the IRRsblack were less than the mortality rate ratios (MRRs) across age groups; however, only in ages 55–64 years and 65–74 years did the 95% CIs of IRRsblack not include the MRRblack. The MRRs for regions were within 95% CIs for IRRs.

Interpretation

National patterns of black-white and regional differences in stroke incidence are similar to those for stroke mortality; however, the magnitude of differences in incidence appear smaller.

Objective

A workgroup commissioned by the Alzheimer’s Association (AA) and the National Institute on Aging (NIA) recently published research criteria for preclinical Alzheimer’s disease (AD). We performed a preliminary assessment of these guidelines.

Methods

We employed Pittsburgh compound B positron emission tomography (PET) imaging as our biomarker of cerebral amyloidosis and 18fluorodeoxyglucose PET imaging and hippocampal volume as biomarkers of neurodegeneration. A group of 42 clinically diagnosed AD subjects was used to create imaging biomarker cut-points. A group of 450 cognitively normal (CN) subjects from a population based sample was used to develop cognitive cut-points and to assess population frequencies of the different preclinical AD stages using different cut-point criteria.

Results

The new criteria subdivide the preclinical phase of AD into stages 1–3. To classify our CN subjects, two additional categories were needed. Stage 0 denotes subjects with normal AD biomarkers and no evidence of subtle cognitive impairment. Suspected Non-AD Pathophysiology (SNAP) denotes subjects with normal amyloid PET imaging, but abnormal neurodegeneration biomarker studies. At fixed cut-points corresponding to 90% sensitivity for diagnosing AD and the 10th percentile of CN cognitive scores, 43% of our sample was classified as stage 0; 16% stage 1; 12 % stage 2; 3% stage 3; and 23% SNAP.

Interpretation

This cross-sectional evaluation of the NIA-AA criteria for preclinical AD indicates that the 1–3 staging criteria coupled with stage 0 and SNAP categories classify 97% of CN subjects from a population-based sample, leaving just 3% unclassified. Future longitudinal validation of the criteria will be important.

Objective

The cellular basis of cognitive abnormalities in preterm infants with periventricular leukomalacia (PVL) is uncertain. One important possibility is that damage to white matter and subplate neurons which are critical to the formation of the cerebral cortex occurs in conjunction with oligodendrocyte and axonal injury in PVL. We tested the hypothesis that the overall density of neurons in the white matter and subplate region is significantly lower in PVL cases compared to non-PVL controls.

Methods

We used a computer-based method for the determination of the density of MAP2-immunolabeled neurons in the ventricular/subventricular region, periventricular white matter, central white matter, and subplate region in PVL cases and controls.

Results

There were five subtypes of subcortical neurons: granular, unipolar, bipolar, inverted pyramidal, and multipolar. The neuronal density of the granular neurons in each of the four regions was 54–80% lower (p≤0.01) in the PVL cases (n=15) compared to controls adjusted for age and postmortem interval (n=10). The overall densities of unipolar, bipolar, multipolar, and inverted pyramidal neurons did not differ significantly between the PVL cases and controls. No granular neurons expressed markers of neuronal and glial immaturity (Tuj1, doublecortin, or NG1).

Interpretation

These data suggest that quantitative deficits in susceptible granular neurons occur in the white matter distant from periventricular foci, including the subplate region, in PVL, and may contribute to abnormal cortical formation and cognitive dysfunction in preterm survivors.

Objective

To identify the causative gene in an autosomal dominant limb-girdle muscular dystrophy (LGMD) with skeletal muscle vacuoles.

Methods

Exome sequencing was used to identify candidate mutations in the studied pedigree. Genome-wide linkage was then used to narrow the list of candidates to a single disease-associated mutation. Additional pedigrees with dominant or sporadic myopathy were screened for mutations in the same gene (DNAJB6) using exome sequencing. Skeletal muscle from affected patients was evaluated with histochemistry and immunohistochemical stains for dystrophy-related proteins, SMI-31, TDP43, and DNAJB6.

Results

Exome analysis in three affected individuals from a family with dominant limb-girdle muscular dystrophy and vacuolar pathology identified novel candidate mutations in 22 genes. Linkage analysis excluded all variants except a Phe93Leu mutation in the G/F domain of the DNAJB6 gene, which resides within the LGMD 1E locus at 7q36. Analysis of exome sequencing data from other pedigrees with dominant myopathy identified a second G/F domain mutation (Pro96Arg) in DNAJB6. Affected muscle showed mild dystrophic changes, vacuoles, and abnormal aggregation of proteins, including TDP-43 and DNAJB6 itself.

Interpretation

Mutations within the G/F domain of DNAJB6 are a novel cause of dominantly-inherited myopathy. DNAJB6 is a member of the HSP40/DNAJ family of molecular co-chaperones tasked with protecting client proteins from irreversible aggregation during protein synthesis or during times of cellular stress. The abnormal accumulation of several proteins in patient muscle, including DNAJB6 itself, suggest that DNAJB6 function is compromised by the identified G/F domain mutations.

Objective

Neuromyelitis optica (NMO) is an inflammatory demyelinating disease of the central nervous system. Circulating autoantibodies (NMO-IgG) against astrocyte water channel aquaporin-4 (AQP4) cause complement- and cell-mediated astrocyte damage with consequent neuroinflammation and demyelination. Current NMO therapies, which have limited efficacy, include immunosuppression and plasma exchange. The objective of this study was to develop a potential new NMO therapy based on blocking of pathogenic NMO-IgG to its target, AQP4.

Methods

We generated non-pathogenic recombinant monoclonal anti-AQP4 antibodies that selectively block NMO-IgG binding to AQP4. These antibodies comprise a tight-binding anti-AQP4 Fab and a mutated Fc that lacks functionality for complement- and cell-mediated cytotoxicity. The efficacy of the blocking antibodies was studied using cell culture, spinal cord slice and in vivo mouse models of NMO.

Results

In AQP4-expressing cell cultures, the non-pathogenic competing antibodies blocked binding of NMO-IgG in human sera, reducing to near zero complement- and cell-mediated cytotoxicity. The antibodies prevented the development of NMO lesions in an ex vivo spinal cord slice model of NMO and in an in vivo mouse model, without causing cytotoxicity.

Interpretation

Our results provide proof-of-concept for therapy of NMO with blocking antibodies. The broad efficacy of antibody inhibition is likely due to steric competition because of its large physical size compared to AQP4. Blocker therapy to prevent binding of pathogenic autoantibodies to their targets may be useful for treatment of other autoimmune diseases as well.

We report the first case of a missense mutation in MPZ causing a gain of glycosylation in Myelin Protein Zero (P0), the main protein of peripheral nervous system myelin. The patient was affected by a severe demyelinating neuropathy caused by a missense mutation, D32N, that created a new glycosylation sequence. We confirmed that the mutant protein is hyperglycosylated, is partially retained into the Golgi apparatus in vitro and disrupts intercellular adhesion. By sequential experiments, we demonstrated that hyperglycosylation is the main mechanism of this mutation. Gain of glycosylation is a new mechanism in CMT1B.

Objective

Test the hypothesis that autoimmunity induced by inhalation of aerosolized brain tissue caused outbreaks of sensory-predominant polyradiculoneuropathy among swine abattoir employees in Midwestern USA

Methods

Mice were exposed intranasally, 5 days weekly, to liquefied brain tissue. Serum from exposed mice, patients and unaffected abattoir employees were analyzed for clinically pertinent neural autoantibodies.

Results

Patients, coworkers and mice exposed to liquefied brain tissue had an autoantibody profile dominated by neural cation channel IgGs. The most compelling link between patients and exposed mice was MRI evidence of grossly swollen spinal nerve roots. Autoantibody responses in patients and mice were dose-dependent and declined after antigen exposure ceased. Autoantibodies detected most frequently, and at high levels, bound to detergent-solubilized macromolecular complexes containing neuronal voltage-gated potassium channels ligated with a high affinity Kv1 channel antagonist, 125I-α-dendrotoxin. Exposed mice exhibited a behavioral phenotype consistent with potassium channel dysfunction recognized in drosophila with mutant (“shaker”) channels: reduced sensitivity to isoflurane-induced anesthesia. Pathological and electrophysiological findings in patients supported peripheral nerve hyperexcitability over destructive axonal loss. The pain-predominant symptoms were consistent with sensory nerve hyperexcitability

Interpretation

Our observations establish that inhaled neural antigens readily induce neurological autoimmunity and identify voltage-gated potassium channel complexes as a major immunogen.

Objective

Genome-wide association (GWAS) methods have identified genes contributing to Parkinson disease (PD); we sought to identify additional genes associated with PD susceptibility.

Methods

A two stage design was used. First, individual level genotypic data from five recent PD GWAS (Discovery Sample: 4,238 PD cases and 4,239 controls) were combined. Following imputation, a logistic regression model was employed in each dataset to test for association with PD susceptibility and results from each dataset were meta-analyzed. Second, 768 SNPs were genotyped in an independent Replication Sample (3,738 cases and 2,111 controls).

Results

Genome-wide significance was reached for SNPs in SNCA (rs356165, G: odds ratio (OR)=1.37; p=9.3 × 10−21), MAPT (rs242559, C: OR=0.78; p=1.5 × 10−10), GAK/DGKQ (rs11248051, T:OR=1.35; p=8.2 × 10−9/ rs11248060, T: OR=1.35; p=2.0×10−9), and the HLA region (rs3129882, A: OR=0.83; p=1.2 × 10−8), which were previously reported. The Replication Sample confirmed the associations with SNCA, MAPT, and the HLA region and also with GBA (E326K OR=1.71; p=5 × 10−8 Combined Sample) (N370 OR=3.08; p=7 × 10−5 Replication sample). A novel PD susceptibility locus, RIT2, on chromosome 18 (rs12456492; p=5 × 10−5 Discovery Sample; p=1.52 × 10−7 Replication sample; p=2 × 10−10 Combined Sample) was replicated. Conditional analyses within each of the replicated regions identified distinct SNP associations within GBA and SNCA, suggesting that there may be multiple risk alleles within these genes.

Interpretation

We identified a novel PD susceptibility locus, RIT2, replicated several previously identified loci, and identified more than one risk allele within SNCA and GBA.

A new protocol suggests that patients with amyotrophic lateral sclerosis (ALS) are a viable source of tissue for organ transplantation. However, multiple lines of evidence suggest that many neurodegenerative diseases, including ALS, might progress due to transcellular propagation of protein aggregation among neurons. Transmission of the disease state from donor to host thus may be possible under the permissive circumstances of graft transplantation. We argue for careful patient selection and close longitudinal follow-up of recipients when harvesting organs from individuals with neurodegenerative disease, especially dominantly inherited forms.

To investigate the putative interaction between chronic exposure to adenosine receptor antagonist caffeine and genetic influences on Parkinson’s disease (PD) we determined whether deletion of the adenosine A2A receptor in knockout (KO) mice protects against dopaminergic neuron degeneration induced by a mutant human α-synuclein (hm2-αSYN) transgene containing both A53T and A30P. The A2A KO completely prevented loss of dopamine and dopaminergic neurons caused by the mutant α-synuclein transgene without altering levels of its expression. The adenosine A2A receptor appears required for neurotoxicity in a mutant α-synuclein model of PD. Together with prior studies the present findings indirectly support the neuroprotective potential of caffeine and more specific A2A antagonists.

Therapeutic devices provide new options for treating drug-resistant epilepsy. These devices act by a variety of mechanisms to modulate neuronal activity. Only vagus nerve stimulation, which continues to develop new technology, is approved for use in the United States. Deep brain stimulation (DBS) of anterior thalamus for partial epilepsy recently was approved in Europe and several other countries. Responsive neurostimulation, which delivers stimuli to one or two seizure foci in response to a detected seizure, recently completed a successful multicenter trial. Several other trials of brain stimulation are in planning or underway. Transcutaneous magnetic stimulation (TMS) may provide a noninvasive method to stimulate cortex. Controlled studies of TMS split on efficacy, and may depend on whether a seizure focus is near a possible region for stimulation. Seizure detection devices in the form of “shake” detectors via portable accelerometers can provide notification of an ongoing tonic-clonic seizure, or peace of mind in the absence of notification. Prediction of seizures from various aspects of EEG is in early stages. Prediction appears to be possible in a subpopulation of people with refractory seizures and a clinical trial of an implantable prediction device is underway. Cooling of neocortex or hippocampus reversibly can attenuate epileptiform EEG activity and seizures, but engineering problems remain in its implementation. Optogenetics is a new technique that can control excitability of specific populations of neurons with light. Inhibition of epileptiform activity has been demonstrated in hippocampal slices, but use in humans will require more work. In general, devices provide useful palliation for otherwise uncontrollable seizures, but with a different risk profile than with most drugs. Optimizing the place of devices in therapy for epilepsy will require further development and clinical experience.

Objective

Neuroimaging is an essential component of the acute stroke evaluation. MRI is more accurate than CT for the diagnosis of stroke, but is more costly and time consuming. We sought to describe changes in MRI utilization from 1999–2008.

Methods

We performed a serial cross-sectional study with time trends of neuroimaging in patients with a primary ICD-9-CM discharge diagnosis of stroke admitted through the Emergency Department in the State Inpatient Databases (SID) from 10 states. MRI utilization was measured by Healthcare Cost and Utilization Project (HCUP) criteria. Data were included for states from 1999–2008 where MRI utilization could be identified.

Results

624,842 patients were hospitalized for stroke in the period of interest. MRI utilization increased in all states. Overall, MRI absolute utilization increased 38 percentage points, and relative utilization increased 235% (28% of strokes in 1999 to 66% in 2008). Over the same interval, CT utilization changed little (92% in 1999 to 95% in 2008). MRI use varied widely by state. In 2008, MRI utilization ranged from a low of 55% of strokes in Oregon to a high of 79% in Arizona. Diagnostic imaging was the fastest growing component of total hospital costs (213% increase from 1999–2007).

Interpretation

MRI utilization during stroke hospitalization increased substantially with wide geographic variation. Rather than replacing CT, MRI is supplementing it. Consequently, neuroimaging has been the fastest growing component of hospitalization cost in stroke. Recent neuroimaging practices in stroke are not standardized and may represent an opportunity to improve the efficiency of stroke care.

Objective

To determine the prevalence, characteristics, risk factors and temporal profile of concurrent ischemic lesions in patients with acute primary intracerebral hemorrhage (ICH).

Methods

Patients were recruited within a prospective, longitudinal, magnetic resonance imaging (MRI) based study of primary ICH. Clinical, demographic, and MRI data were collected on all subjects at baseline and 1 month.

Results

Of the 138 patients enrolled, mean age was 59 years, 54% were male, 73% black, and 84% had a history of hypertension. At baseline, ischemic lesions on diffusion-weighted imaging (DWI) were found in 35% of patients. At 1 month, lesions were present in 27%, and of these lesions, 83% were new and not present at baseline. ICH volume (p=0.025), intraventricular hemorrhage (p=0.019), presence of microbleeds (p=0.024), and large, early reductions in mean arterial pressure (p=0.003) were independent predictors of baseline DWI lesions. A multivariate logistical model predicting the presence of 1 month DWI lesions included history of any prior stroke (p=0.012), presence of 1 or more microbleeds (p=0.04), black race (p=0.641), and presence of a DWI lesion at baseline (p=0.007)

Interpretation

This study demonstrates that more than 1/3 of patients with primary ICH have active cerebral ischemia at baseline remote from the index hematoma, and 1/4 of patients experience ongoing, acute ischemic events at 1 month. Multivariate analyses implicate blood pressure reductions in the setting of an active vasculopathy as a potential underlying mechanism. Further studies are needed to determine the impact of these lesions on outcome and optimal management strategies to arrest vascular damage.

Background

Motor symptoms such as mild parkinsonian signs are common in older persons, but little is known about their underlying neuropathology. We tested the hypothesis that nigral pathology is related to parkinsonism in older persons without Parkinson’s disease (PD).

Methods

More than 2,500 persons participating in the Religious Orders Study or the Memory and Aging Project agreed to annual assessment of parkinsonism with a modified version of the Unified Parkinson’s Disease Rating Scale(mUPDRS) and brain donation. Brains from744 deceased participants without PD were assessed for nigral neuronal loss and α-synuclein immunopositive Lewy bodies.

Results

Mean age at death was 88.5. Mean global parkinsonism was 18.6(SD, 11.90). About of cases had mild or more severe nigral neuronal loss and about 17% had Lewy bodies. In separate regression models which adjusted for age, sex and education, nigral neuronal loss and Lewy bodies were both related to global parkinsonism[(Neuronal loss, Estimate, 0.231, S.E, 0.068, p<0.001); (Lewy bodies, Estimate, 0.291, S.E, 0.133, p=0.029)]. Employing a similar regression model which included both measures, neuronal loss remained associated with global parkinsonism(Neuronal loss, Estimate, 0.206, S.E, 0.075,p=0.006). By contrast, the association between Lewy bodies and global parkinsonism was attenuated by more than 60%and was no longer significant(Lewy bodies, Estimate, 0.112, S.E, 0.148, p=0.447), suggesting that neuronal loss may mediate the association of Lewy bodies with global parkinsonism.

Interpretation

Nigral pathology is common in persons without PD and may contribute to loss of motor function in old age.

Objective

Myoclonus is characterized by sudden, brief involuntary movements and its presence is debilitating. We identified a family suffering from adult-onset, cortical myoclonus without associated seizures. We performed clinical, electrophysiological, and genetic studies to define this phenotype.

Methods

A large, four-generation family with history of myoclonus underwent careful questioning, examination, and electrophysiological testing. Thirty-five family members donated blood samples for genetic analysis, which included SNP mapping, microsatellite linkage, targeted massively parallel sequencing, and Sanger sequencing. In silico and in vitro experiments were performed to investigate functional significance of the mutation.

Results

We identified 11 members of a Canadian Mennonite family suffering from adult-onset, slowly progressive, disabling, multifocal myoclonus. Somatosensory evoked potentials indicated a cortical origin of the myoclonus. There were no associated seizures. Some severely affected individuals developed signs of progressive cerebellar ataxia of variable severity late in the course of their illness. The phenotype was inherited in an autosomal dominant fashion. We demonstrated linkage to chromosome 16q21-22.1. We then sequenced all coding sequence in the critical region, identifying only a single co-segregating, novel, nonsynonymous mutation, which resides in the gene NOL3. Furthermore, this mutation was found to alter post-translational modification of NOL3 protein in vitro.

Interpretation

We propose that Familial Cortical Myoclonus (FCM) is a novel movement disorder that may be caused by mutation in NOL3. Further investigation of the role of NOL3 in neuronal physiology may shed light on neuronal membrane hyperexcitability and pathophysiology of myoclonus and related disorders.

Objective

REM sleep behavior disorder (RBD) is associated with neurodegenerative disease and particularly with the synucleinopathies. Convenience samples involving subjects with idiopathic RBD have suggested an increased risk of incident mild cognitive impairment (MCI), dementia (usually dementia with Lewy bodies) or Parkinson’s disease (PD). There is no data on such risk in a population-based sample.

Methods

Cognitively normal subjects aged 70–89 in a population-based study of aging who screened positive for probable RBD using the Mayo Sleep Questionnaire were followed at 15 month intervals. In a Cox Proportional Hazards Model, we measured the risk of developing MCI, dementia, PD among the exposed (pRBD+) and unexposed (pRBD−) cohorts.

Results

Forty-four subjects with pRBD+ at enrollment (median duration of pRBD features was 7.5 years), and 607 pRBD− subjects, were followed prospectively for a median of 3.8 years. Fourteen of the pRBD+ subjects developed MCI and one developed PD (15/44=34% developed MCI / PD); none developed dementia. After adjustment for age, sex, education, and medical comorbidity, pRBD+ subjects were at increased risk of MCI / PD [Hazard Ratio (HR) 2.2, 95% Confidence Interval (95%CI) 1.3 – 3.9; p=0.005]. Inclusion of subjects who withdrew from the study produced similar results, as did exclusion of subjects with medication-associated RBD. Duration of pRBD symptoms did not predict the development of MCI / PD (HR 1.05 per 10 years, 95%CI 0.84 – 1.3; p=0.68).

Interpretation

In this population-based cohort study, we observed that pRBD confers a 2.2-fold increased risk of developing MCI / PD over four years.

Objective

To test the hypothesis that variability in SNCA Rep1, a polymorphic dinucleotide microsatellite in the promoter region of the gene encoding α-synuclein, modifies the association between head injury and Parkinson’s disease (PD) risk.

Methods

Participants in Farming and Movement Evaluation (FAME) and Study of Environmental Association and Risk of Parkinsonism using Case-Control Historical Interviews (SEARCH), two independent case-control studies, were genotyped for Rep1 and interviewed regarding head injuries with loss of consciousness or concussion prior to PD diagnosis. Logistic regression modeling adjusted for potential confounding variables and tested interaction between Rep1 genotype and head injury.

Results

Consistent with prior reports, relative to medium-length Rep1, short Rep1 genotype was associated with reduced PD risk (pooled odds ratio (OR) 0.7, 95% confidence interval (CI) 0.5-0.9), and long Rep1 with increased risk (pooled OR 1.4, 95%CI 0.95-2.2). Overall, head injury was not significantly associated with PD (pooled OR 1.3, 95%CI 0.9-1.8). However, head injury was strongly associated with PD in those with long Rep1 (FAME OR 5.4, 95%CI 1.5-19; SEARCH OR 2.3, 95%CI 0.6-9.2; pooled OR 3.5, 95%CI 1.4-9.2, p-interaction 0.02). Individuals with both head injury and long Rep1 were diagnosed 4.9 years earlier than those with neither risk factor (p = 0.03).

Interpretation

While head injury alone was not associated with PD risk, our data suggest head injury may initiate and/or accelerate neurodegeneration when levels of synuclein are high, as in those with Rep1 expansion. Given the high population frequency of head injury, independent verification of these results is essential.

Objective

The 12-15Lipoxygenase (12-15LO) is an enzyme widely distributed in the central nervous system and it has been involved in the neurobiology of Alzheimer’s disease (AD). However, the mechanism involved remains elusive.

Methods

We investigated the molecular mechanism by which 12-15LO regulates Amyloid β/APP metabolism in vivo and in vitro by genetic and pharmacologic approaches.

Results

Here we show that over-expression of 12-15LO leads to increased levels of BACE1 mRNA and protein, a significant elevation in Aβ levels and deposition, and a worsening of memory deficits in AD transgenic mice.

In vitro and in vivo studies demonstrate that 12-15LO regulates BACE1 mRNA expression levels via the activation of the transcription factor Sp1. Thus, 12-15LO-overexpressing mice had elevated levels of Sp1 and BACE1, whereas 12/15LO-deficient mice had reduced levels of both. Preventing Sp1 activation by pharmacologic inhibition or dominant negative mutant blocks the 12-15LO-dependent elevation of Aβ and BACE1 levels.

Interpretation

Our findings demonstrate a novel pathway by which 12-15LO increases the amyloidogenic processing of APP through a Sp1-mediated transcriptional control of BACE1 levels that could have implications for AD pathogenesis and therapy.

Objective

The major form of MRI-defined white matter injury (WMI) comprises diffuse lesions where the burden of small necrotic foci (microscopic necrosis) is poorly defined. We hypothesized that myelination failure associated with diffuse WMI involves an aberrant injury response linked to arrested pre-oligodendrocyte (preOL) maturation in reactive astrocyte-rich lesions.

Methods

A retrospective autopsy series (1983–2000) was selected for cases with diffuse WMI and analyzed relative to prospectively-collected contemporary cases (2003–2010). Controls were age and region-matched to address regional variation in preOL maturation. Successive oligodendrocyte stages were analyzed with lineage-specific markers. Microscopic necrosis was quantified with microglial markers. Axon injury markers defined the burden of axonopathy. Extracellular matrix remodelling was defined by detection of hyaluronic acid (HA), an inhibitor of preOL maturation, and the HA receptor, CD44.

Results

In the contemporary case series, diffuse WMI was accompanied by a significant reduction in the burden of microscopic necrosis and axonopathy. Diffuse astrogliosis extended into the lesion surround with elevated HA and astrocyte-expressed CD44. The total population of OL lineage stages was significantly increased in lesions. This increase coincided with significant expansion of the preOL pool.

Interpretation

Although these data confirm that microscopic necrosis occurs in contemporary cases, the markedly decreased burden supports that it does not contribute substantially to myelination failure. The primary mechanism of myelination failure involves a disrupted cellular response whereby preOLs fail to differentiate in diffuse astrogliotic lesions. Pre-oligodendrocyte maturation arrest converts chronic WMI to a more immature state related to the burden of astrogliosis.

There is an increasing awareness that impulse control disorders (ICDs), including compulsive gambling, buying, sexual behavior, and eating, can occur as a complication of Parkinson’s disease (PD). In addition, other impulsive or compulsive disorders have been reported to occur, including dopamine dysregulation syndrome (DDS) and punding. Case reporting and prospective studies have reported an association between ICDs and the use of dopamine agonists (DAs), particularly at greater dosages, whereas dopamine dysregulation syndrome has been associated with greater dosages of levodopa or short-acting DAs. Data suggest that risk factors for an ICD may include male sex, younger age or younger age at PD onset, a pre-PD history of ICD symptoms, personal or family history of substance abuse or bipolar disorder, and a personality style characterized by impulsiveness. Although psychiatric medications are used clinically in the treatment of ICDs, there is no empiric evidence supporting their use in PD. Therefore, management for clinically significant ICD symptoms should consist of modifications to dopamine replacement therapy, particularly DAs, and there is emerging evidence that such management is associated with an overall improvement in ICD symptomatology. It is important that PD patients be aware that DA use may lead to the development of an ICD, and that clinicians monitor patients as part of routine clinical care. As empirically validated treatments for ICDs are emerging, it will be important to examine their efficacy and tolerability in individuals with cooccurring PD and ICDs.

Objective

Inflammation promotes epidermal wound healing but is considered detrimental to recovery from CNS injury. Sick infants have increased levels of cytokines in their CSF that correlate with poor neurological outcome. In this study we investigated the role of neuroinflammation and more specifically, IL-6, in the amplification of subventricular zone (SVZ) and subgranular zone (SGZ) neural precursors after neonatal brain injury.

Methods

Neonatal hypoxia/ischemia (H/I) was induced in P6 rat pups and IL-6 was quantified with or without Indomethacin administration. Neural precursor responses were evaluated by neurosphere assays as well as by stereological analyses. Studies were performed to determine how IL-6 and LIF affect SVZ cell expansion, proliferation and self-renewal.

Results

Consistent with earlier studies, SVZ cells expanded after H/I. Contrary to our expectations, Indomethacin significantly decreased both the initial reactive increase in these precursors as well as their ability to self-renew. By contrast, Indomethacin increased proliferation in the SGZ and lateral SVZ. Indomethacin diminished the accumulation of microglia/macrophages and IL-6 production after H/I. In vitro IL-6 enhanced neurosphere growth, self-renewal and tripotentiality and was more effective than LIF in promoting self-renewal. Enhanced precursor self-renewal also was obtained using PGE2, which is downstream of cyclooxygenase-2 and a target of Indomethacin.

Interpretation

These data implicate neuroinflammation and in particular IL-6 as a positive effector of primitive neural precursor expansion after neonatal brain injury. These findings have important clinical implications, as Indomethacin and other anti-inflammatory agents are administered to premature infants for a variety of reasons.

To test whether the synucleinopathies Parkinson’s disease and multiple system atrophy (MSA) share a common genetic etiology, we performed a candidate single nucleotide polymorphism (SNP) association study of the 384 most associated SNPs in a genome-wide association study of Parkinson’s disease in 413 MSA cases and 3,974 control subjects. The 10 most significant SNPs were then replicated in additional 108 MSA cases and 537 controls. SNPs at the SNCA locus were significantly associated with risk for increased risk for the development of MSA (combined p = 5.5 × 1012; odds ratio 6.2).

Objective

Multiple sclerosis (MS) is a multifactorial neurologic disease characterized by modest but tractable heritability. Genome Wide Association Studies (GWAS) have identified and/or validated multiple polymorphisms in approximately 16 genes associated with susceptibility. We aimed at investigating the aggregation of genetic MS-risk markers in individuals by comparing multi and single-case families.

Methods

A weighted log-additive integrative approach termed MS Genetic Burden (MSGB) was used to account for the well-established genetic variants from previous association studies and meta-analyses. The corresponding genetic burden and its transmission was analyzed in 1213 independent MS families (810 sporadic and 403 multi-case families).

Results

MSGB analysis demonstrated a higher aggregation of susceptibility variants in multi-case, compared to sporadic MS families. In addition, the aggregation of non-MHC SNPs depended neither on gender nor on the presence or absence of HLA-DRB1*15:01 alleles. Interestingly, while a greater MSGB in siblings of MS patients was associated with an increased risk of MS (OR=2.1, p=0.001), ROC curves of MSGB differences between probands and sibs (AUROC 0.57 [0.53; 0.61]) show that case-control status prediction of MS cannot be achieved with the currently available genetic data.

Interpretation

The primary interest in the MSGB concept resides in its capacity to integrate cumulative genetic contributions to MS risk. This analysis underlines the high variability of family load with known common variants. This novel approach can be extended to other genetically complex diseases. Despite the emphasis in assembling large case-control datasets, multigenerational, multi-affected families remain an invaluable resource for advancing the understanding of the genetic architecture of complex traits.

Objective

Perihematomal edema results from disruption of the blood-brain barrier (BBB) by key mediators, such as thrombin, following intracerebral hemorrhage (ICH). Platelet derived growth factor receptor alpha (PDGFR-α), a tyrosine kinase receptor, was found in previous studies to play a role in orchestrating BBB impairment. In the present study, we investigated the role of PDGFR-α following ICH-induced brain injury in mice, specifically investigating its effect on BBB disruption.

Methods

Brain injury was induced by autologous arterial blood (30 μl) or thrombin (5 U)-injection into mice brains. A PDGFR antagonist (Gleevec) or agonist (PDGF-AA) was administered following ICH. PDGF-AA was injected with a thrombin inhibitor, hirudin in ICH mice. Thrombin-injected mice were given Gleevec or PDGF-AA neutralizing antibody. A p38 MAPK inhibitor, SB203580 was delivered with PDGF-AA in naïve animals. Post-assessment included neurological function tests, brain edema measurement, Evans blue extravasation, immunoprecipitation, western blot and immunohistology assay.

Results

PDGFR-α suppression prevented neurological deficits, brain edema and Evans blue extravasation at 24–72 hours following ICH. PDGFR-α activation led to BBB impairment and this was reversed by SB203580 in naïve mice. Thrombin inhibition suppressed PDGFR-α activation and exogenous PDGF-AA increased PDGFR-α activation, regardless of thrombin inhibition. Animals receiving a PDGF-AA neutralizing antibody or Gleevec showed minimized thrombin injection-induced BBB impairment.

Interpretation

PDGFR-α signaling may contribute to BBB impairment via p38 MAPK mediated MMP activation/expression following ICH and thrombin may be the key upstream orchestrator. The therapeutic interventions targeting the PDGFR-α signaling may be a novel strategy to prevent thrombin-induced BBB impairment following ICH.

Objective

Rare copy number variants (CNVs) – deletions and duplications – have recently been established as important risk factors for both generalized and focal epilepsies. A systematic assessment of the role of CNVs in epileptic encephalopathies, the most devastating and often etiologically obscure, group of epilepsies, has not been performed.

Methods

We evaluated 315 patients with epileptic encephalopathies characterized by epilepsy and progressive cognitive impairment for rare CNVs using a high-density, exon-focused whole-genome oligonucleotide array.

Results

We found that 25/315 (7.9%) of our patients carried rare CNVs that may contribute to their phenotype, with at least half being clearly or likely pathogenic. We identified two patients with overlapping deletions at 7q21 and two patients with identical duplications of 16p11.2. In our cohort, large deletions were enriched in affected individuals compared to controls, and four patients harbored two rare CNVs. We screened two novel candidate genes found within the rare CNVs in our cohort but found no mutations in our patients with epileptic encephalopathies. We highlight several additional novel candidate genes located in CNV regions.

Interpretation

Our data highlight the significance of rare copy number variants in the epileptic encephalopathies, and we suggest that CNV analysis should be considered in the genetic evaluation of these patients. Our findings also highlight novel candidate genes for further study.