Annals of Neurology

OBJECTIVE: Determining if traumatic brain injury (TBI) and posttraumatic stress disorder (PTSD) are risk factors for Parkinson's disease (PD). This constitutes a research priority for the Veterans Administration (VA) with implications for screening policy and prevention. METHODS: Population-based, matched case-control study among veterans using VA healthcare facilities from 10/1/1999 to 09/30/2013. We identified 176,871 PD cases and 707,484 randomly selected PD-free matched controls...

OBJECTIVE: To explore the prevalence of the perfusion-weighted imaging (PWI) - diffusion-weighted imaging (DWI) mismatch and response to intravenous thrombolysis in the WAKE-UP trial. METHODS: We performed a prespecified post-hoc analysis of ischemic stroke patients screened for DWI - fluid-attenuated inversion recovery (FLAIR) mismatch in WAKE-UP who underwent PWI. We defined PWI-DWI mismatch as ischemic core volume < 70 ml, mismatch volume > 10 ml and mismatch ratio > 1...

OBJECTIVE: There is much controversy about the neurobiological mechanisms underlying the effects of sleep-disordered breathing on the brain. The aim of this study was to investigate the association between markers of sleep-related hypoxemia and brain anatomy. METHODS: We used data from a large-scale cohort from the general population (n = 775, 50.6% males, age range = 45-86 years, mean age = 60.3 ± 9.9) that underwent full polysomnography and brain MRI to correlate respiratory variables with regional brain volume estimates...

OBJECTIVE: Dominant optic atrophy (DOA) is the most common inherited optic neuropathy with a prevalence of 1:12,000 to 1:25,000. OPA1 mutations are found in 70% of DOA patients, with a significant number remaining undiagnosed. METHODS: We screened 286 index cases presenting optic atrophy, negative for OPA1 mutations, by targeted NGS or whole-exome sequencing. Pathogenicity and molecular mechanisms of the identified variants were studied in yeast and patient-derived fibroblasts...

OBJECTIVE: The mechanisms by which antiepileptic drugs (AEDs) cause birth defects (BDs) are unknown. Data suggest that AED-induced BDs may result from a genome-wide increase of de novo variants in the embryo, a mechanism which we investigated. METHODS: Whole-exome sequencing data from child-parent trios were interrogated for de novo single-nucleotide variants/indels (dnSNVs/indels) and copy number variants (dnCNVs). Generalized linear models were applied to assess de novo variant burdens in: children exposed prenatally to AEDs (AED-exposed children) vs children without BDs not exposed prenatally to AEDs (AED-unexposed unaffected children), and AED-exposed children with BDs vs those without BDs, adjusting for confounders...

OBJECTIVE: To characterize predictors of recovery and outcome following pediatric arterial ischemic stroke, hypothesizing that age influences recovery after stroke. METHODS: We studied children enrolled in the International Pediatric Stroke Study between January 1, 2003 and July 31, 2014 with two-year follow-up after arterial ischemic stroke. Outcomes were defined at discharge by clinician grading and at two years by Pediatric Stroke Outcome Measure (PSOM). Demographic, clinical, and radiologic outcome predictors were examined...

OBJECTIVE: Prospectively characterize changes in serum proteins following sport-related concussion and determine if candidate biomarkers discriminate concussed athletes from controls and are associated with duration of symptoms following concussion. METHODS: High school and collegiate athletes were enrolled between 2015 and 2018. Blood was collected at pre-injury baseline and within 6 hours (early-acute) and at 24-48 hours (late-acute) following concussion in football players (n = 106), matched uninjured football players (n = 84) and non-contact sport athletes (n = 50)...

Observational studies showed alcohol drinking behaviors may be associated with the risk of ALS, whereas contradictory findings emerged and whether such association is causal is unclear. We here investigate the causal relationship between alcohol consumption and ALS. By leveraging instruments from large-scale genome-wide association studies, we performed a comprehensive Mendelian randomization analysis and found alcohol consumption was causally associated with ALS, leading to ~1.5 fold (95%CI 1.4 - 3.4) higher risk of ALS for each approximately 10g/d increase in alcohol intake...

OBJECTIVE: Assess occurrence of the dendritic spine scaffolding protein Drebrin as pathophysiologically relevant autoantibody target in patients with recurrent seizures and suspected encephalitis as leading symptoms. METHODS: Sera of four patients with adult onset epilepsy and suspected encephalitis of unresolved etiology and equivalent results in autoantibody screening were subjected to epitope identification. We combined a wide array of approaches ranging from immunoblotting, immunoprecipitation and mass-spectrometry, subcellular binding pattern analyses in primary neuronal cultures, immunohistochemistry in brains of wildtype and Drebrin knockout mice to in vitro analyses on impaired synapse formation, morphology and aberrant neuronal excitability by antibody exposure...

BACKGROUND: Elevated systolic blood pressure (SBP) after successful revascularization via endovascular therapy (EVT) is a known predictor of poor outcome. However, the optimal SBP goal following EVT is still unknown. OBJECTIVE: To compare functional and safety outcomes between different SBP goals after EVT with successful revascularization (SR). METHODS: An international multicenter study that included 8 comprehensive stroke centers. Patients with anterior circulation LVO who were treated with EVT and achieved SR were included...

OBJECTIVE: Neuronal loss in the substantia nigra pars compacta (SNpc) in Parkinson's disease (PD) is not uniform as dopamine neurons from the ventral tier are lost more rapidly than those of the dorsal tier. Identifying the intrinsic differences that account for this differential vulnerability may provide a key for developing new treatments for PD. METHOD: Here we compared the RNA-sequenced transcriptomes of ~100 laser captured micro-dissected SNpc neurons from each tier from seven healthy controls...

OBJECTIVE: Multiple sclerosis (MS) is a neurological disease with a substantial genetic component and immune-mediated neurodegeneration. Patients with MS show structural brain differences relative to individuals without MS, including smaller regional volumes and alterations in white matter (WM) microstructure. Whether genetic risk for MS is associated with brain structure during early neurodevelopment remains unclear. In this study, we explore the association between MS polygenic risk scores (PRS) and brain imaging outcomes from a large, population-based pediatric sample to gain insight into the underlying neurobiology of MS...

No abstract text is available yet for this article.

OBJECTIVE: To characterize trajectories of normative cognitive aging METHODS: Older persons without dementia at study enrollment (n = 1,010) had annual cognitive testing for up to 24 years (mean = 9.9 years, SD = 5.0), died, and underwent a neuropathologic examination to quantify 9 postmortem markers of common neurodegenerative and cerebrovascular conditions. To accommodate the heterogeneity in cognitive trajectories, we used functional mixed effects models which allow individuals to have different patterns of cognitive decline under a unified model structure...

OBJECTIVE: Rett syndrome (RTT) is an X-linked dominant neurodevelopmental disorder due to pathogenic mutations in the MECP2 gene. Motor impairment constitutes the core diagnostic feature of RTT. Preclinical studies have consistently demonstrated alteration of excitation/inhibition (E/I) balance and aberrant synaptic plasticity at cortical level. Herein we aimed at understanding neurobiological mechanisms underlying motor deficit by assessing in "vivo" synaptic plasticity and E/I balance in the primary motor cortex (M1)...

Insufficient sleep has been considered a seizure trigger in people with epilepsy for thousands of years. Here, we reviewed the evidence upon which this axiomatic association might be predicated. After evaluating evidence suggesting insufficient sleep as an EEG activator, we systematically reviewed the literature for longitudinal studies measuring the effect of insufficient sleep on seizure risk. Ultimately, published works designed to prove a causal relationship were of low level of evidence and disagreed with one another...

OBJECTIVE: The identification of sensitive biomarkers is essential to validate therapeutics for Huntington's disease (HD). We directly compare structural imaging markers across the largest collective imaging HD dataset, to identify a set of imaging markers robust to multi-centre variation and to derive upper estimates on sample sizes for clinical trials in HD. METHODS: We used one post-processing pipeline to retrospectively analyse T1-weighted magnetic resonance imaging (MRI) scans from 624 participants at three time points, from the PREDICT-HD, TRACK-HD and IMAGE-HD studies...

Expanding use of immune-checkpoint inhibitors (ICIs) underscores the importance of accurate diagnosis and timely management of neurological immune-related adverse events (irAE-N). We evaluate the real-world frequency, phenotypes, co-occurring immune-related adverse events (irAEs), and long-term outcomes of severe, grade III-V irAE-N at a tertiary-care center over 6 years. We analyze how our experience supports published literature and professional society guidelines. We also discuss these data with regard to common clinical scenarios, such as combination therapy, ICI re-challenge and risk of relapse of irAE-N, and corticosteroid taper, which are not specifically addressed by current guidelines and/or have limited data...

OBJECTIVE: We aimed to determine the association between striatal dopaminergic depletion, cerebral β-amyloid deposition, and cognitive dysfunction in Lewy body disease (LBD). METHODS: This cross-sectional study recruited 48 LBD patients (30 with dementia and 18 with mild cognitive impairment) and 15 control subjects from a university-based hospital. We measured the striatal dopamine transporter (DAT) activity and regional β-amyloid burden using18 F-FP-CIT positron emission tomography (PET) and 18 F-florbetaben (FBB) PET, respectively...

OBJECTIVE: Clinical trials in amyotrophic lateral sclerosis (ALS) continue to rely on survival or functional scales as endpoints, despite the emergence of quantitative biomarkers. Neuroimaging-based biomarkers in ALS have been shown to detect ALS-associated pathology in vivo, although anatomical patterns of disease spread are poorly characterized. The objective of this study is to simulate disease propagation using network analyses of cerebral MRI data to predict disease progression. METHODS: Using brain networks of ALS patients (n=208) and matched controls across longitudinal time points, network-based statistics unraveled progressive network degeneration originating from the motor cortex and expanding in a spatiotemporal manner...