Use a modified Delphi approach to develop competencies for neurologists completing >1 year of advanced global neurology training.

An expert panel of 19 US-based neurologists involved in global health was recruited from the American Academy of Neurology Global Health Section and the American Neurological Association International Outreach Committee. An extensive list of global health competencies was generated from review of global health curricula and adapted for global neurology training. Using a modified Delphi method, US-based neurologists participated in three rounds of voting on a survey with potential competencies rated on a 4-point Likert scale. A final group discussion was held to reach consensus. Proposed competencies were then subjected to a formal review from a group of seven neurologists from low- and middle-income countries (LMICs) with experience working with neurology trainees from high-income countries (HICs) who commented on potential gaps, feasibility, and local implementation challenges of the proposed competencies. This feedback was used to modify and finalize competencies.

Three rounds of surveys, a conference call with US-based experts, and a semi-structured questionnaire and focus group discussion with LMIC experts were utilized to discuss and reach consensus on the final competencies. This resulted in a competency framework consisting of 47 competencies across eight domains: (1) Cultural Context, Social Determinants of Health and Access to Care; (2) Clinical and Teaching Skills and Neurological Medical Knowledge; (3) Team-Based Practice; (4) Developing Global Neurology Partnerships; (5) Ethics; (6) Approach to Clinical Care; (7) Community Neurological Health; (8) Health Care Systems and Multinational Health Care Organizations.

These proposed competencies can serve as a foundation on which future global neurology training programs can be built and trainees evaluated. It may also serve as a model for global health training programs in other medical specialties as well as a framework to expand the number of neurologists from HICs trained in global neurology.

Behaviorally, meta-analyses showed a circadian pattern of attacks in 50.1% (2698/5385) of participants across eight studies, with a clear circadian trough between 23:00-07:00 and a broad circannual peak between April-October. Chronotype was highly variable across studies. At the systems level, urinary melatonin levels were lower in migraine participants and even lower during an attack. At the cellular level, migraine was associated with core circadian genes CK1 and RORα, and 110 of the 168 migraine susceptibility genes were CCGs.

Cluster headache and migraine are highly circadian at multiple levels, reinforcing the importance of the hypothalamus. This review provides a pathophysiological foundation for circadian-targeted research into these disorders.

The study was registered with PROSPERO (registration number CRD42021234238).

This prospective cohort study recruited newborns ≥36 weeks PMA around 6 hours of life between August 2014 to November 2019 from a Neonatal Intensive Care Unit. Participants underwent continuous electroencephalography for at least 48 hours, brain MRI within 3-5 days of life, and structured follow-up at 18 months. Electrographic seizures were identified by board-certified neurophysiologists, and quantified as total seizure burden and maximum hourly seizure burden. A medication exposure score was calculated based on all anti-seizure medications given during NICU admission. Brain MRI injury severity was classified based on basal ganglia and watershed scores. Developmental outcomes were measured using the Bayley Scales of Infant Development, 3^rd Edition. Multivariable regression analyses were performed, adjusting for significant potential confounders.

Of 108 enrolled subjects, 98 subjects had cEEG and MRI data collected, of which 5 were lost to follow-up, and 6 died before age 18 months. All subjects with moderate-severe encephalopathy completed therapeutic hypothermia. cEEG-confirmed neonatal seizures occurred in 21(24%) newborns, with a total seizure burden mean of 12.5 ± 36.4 minutes, and a maximum hourly seizure burden mean of 4 ± 10 min/hr. After adjusting for MRI brain injury severity and medication exposure, total seizure burden was significantly associated with lower cognitive (-0.21, 95%CI -0.33 – -0.08, p=0.002) and language (-0.25, 95%CI -0.39 – -0.11, p=0.001) scores at 18 months. Total seizure burden of 60 minutes was associated with 15-point decline in language scores, and 70 minutes for cognitive scores. However, seizure burden was not significantly associated with epilepsy, neuromotor score, or cerebral palsy (p>0.1).

Higher seizure burden during neonatal encephalopathy was independently associated with worse cognitive and language scores at 18 months, even after adjusting for exposure to anti-seizure medications and severity of brain injury. These observations support the hypothesis that neonatal seizures occurring during neonatal encephalopathy independently contribute to long-term outcomes.

Practice patterns for surgical IIH treatment in the United States are rapidly evolving, and VSS is becoming increasingly common. These findings highlight the urgency of randomized controlled trials to investigate the comparative effectiveness and safety of VSS, CSF shunts, ONSF, and standard medical treatments.

Although recovery of functional independence after late window EVT was not more common in patients selected by CTP as compared to patients selected by NCCT only, patients selected by CTP had lower mortality.

In this quasi-experimental health services research intervention study we implemented a TIA management algorithm across the entire province, centered around a 24-hour physician’s TIA Hotline as well as public and health provider education on TIA. From administrative databases we linked emergency department discharge abstracts to hospital discharge abstracts to identify incident TIAs and recurrent strokes at 90 days across a single payer system with validation of recurrent stroke events. The primary outcome was recurrent stroke; with a secondary composite outcome of recurrent stroke, acute coronary syndrome, and all cause death. We used an interrupted time series regression analysis of age and sex-adjusted stroke recurrence rates after TIA incorporating a two-year pre-implementation period (2007-2009), a 15 month implementation period, and a two-year post-implementation period (2010-2012). Logistic regression was used to examine outcomes that did not fit the time series model.

We assessed 6 715 patients pre- and 6 956 patients post-implementation. The 90-day stroke recurrence rate in the pre-ASPIRE period was 4.5% compared to 5.3% during the post-ASPIRE period. There was neither a step change (estimate 0.38; p=0.65) nor slope change (parameter estimate 0.30; p=0.12) in recurrent stroke rates associated with the ASPIRE intervention implementation period. Adjusted all-cause mortality (OR 0.71 95%CI [0.56, 0.89]) was significantly lower following the ASPIRE intervention.

The ASPIRE TIA triaging and management interventions did not further reduce stroke recurrence in the context of an organized stroke system. The apparent lower mortality post intervention may be related to improved surveillance following events identified as TIAs but secular trends cannot be excluded.

To evaluate brain volume changes caused by different sub-classes of anti-amyloid beta (Aβ) drugs trialled in patients with Alzheimer’s disease.

PubMed, Embase and Clinicaltrial.gov databases were searched for clinical trials of anti-Aβ drugs. This systematic review and meta-analysis included adults enrolled in randomized controlled trials of anti-Aβ drugs (n=8062 to 10279). The inclusion criteria were as follows: (1) randomized controlled trials of patients treated with anti-Aβ drugs that have demonstrated to favourably change at least one biomarker of pathological Aβ; and (2) detailed MRI data sufficient to assess the volumetric changes in at least one brain region. MRI brain volumes were used as the primary outcome measure; brain regions commonly reported include the hippocampus, lateral ventricle and whole brain. Amyloid-Related Imaging Abnormalities (ARIA) were investigated when reported in clinical trials. Of the 145 trials reviewed, 31 were included in the final analyses.

A meta-analysis on the highest dose of each trial on hippocampus, ventricle, and whole brain revealed drug-induced acceleration of volume changes that varied by anti-Aβ drug class. Secretase inhibitors accelerated atrophy to the hippocampus (mean difference: -37.1 µL [-19.6% relative to change in placebo]; 95% confidence interval: -47.0 to -27.1) and whole brain (-3.3mL [-21.8% relative to change in placebo]; 95% confidence interval: -4.1 to 2.5). Conversely, ARIA-inducing monoclonal antibodies accelerated ventricular enlargement (mean difference: +2.1mL [+38.7% relative to change in placebo]; 95% confidence interval: 1.5 to 2.8) where a striking correlation between ventricular volume and ARIA frequency was observed (r=0.86, p=6.22x10^-7). Mild Cognitively Impaired participants treated with anti-Aβ drugs were projected to have a material regression toward brain volumes typical of Alzheimer’s dementia ~8 months earlier than if they were untreated.

These findings reveal the potential for anti-Aβ therapies to compromise long-term brain health by accelerating brain atrophy, and provide new insight into the adverse impact of ARIA. Six recommendations emerge from these findings.

The spectrum of ANAN is wide ranging from: 1) a pure sensory neuropathy with areflexia, limb and gait ataxia, neuropathic pain and unevocable sensory responses to 2) a motor axonal neuropathy with low-amplitude motor responses without conduction slowing, block, or dispersion, and 3) a mixed sensorimotor axonal polyneuropathy. Specific micronutrient deficiencies or risk factors do not predict neuropathy subtype. The sub-group of ANAN patients with documented thiamine deficiency also range from pure sensory to pure motor, and only a minority have Wernicke’s encephalopathy. We do not know whether co-existent micronutrient deficiencies may help explain the wide clinical spectrum of thiamine-deficient ANAN. The prognosis of ANAN is guarded due to residual neuropathic pain and slow recovery of independent ambulation. Therefore, early recognition of patients at risk is important.

Of the 1221 EVT patients in INSPIRE, 323 patients were selected, of which 82 patients received direct EVT and 241 patients received bridging IVT. Bridging IVT was associated with a higher rate of good clinical outcome amongst patients with fast core growth (39% vs 7% for direct EVT, odds ratio=8.75 [1.96-39.1], p=0.005), but the difference was not significant for patients with slow core growth (55% vs 55% for direct EVT, odds ratio=1.00 [0.53-1.87], p=0.989). In patients with fast core growth, the bridging and direct EVT patients showed no difference in the reperfusion rate (80% vs. 76%, p=0.616). However, patients who received bridging IVT were more likely to achieve reperfusion earlier (the median groin to reperfusion time of 63.0 vs 94.0 minutes p=0.005).

Patients with fast core growth were more likely to benefit from bridging intravenous thrombolysis. This is likely because prior intravenous thrombolysis facilitates clot removal and thus reduces time to reperfusion.

Hierarchical cluster analysis identified six seizure profiles regarding the first abnormality on scalp EEG. None of them was specific of a single intra-cerebral localization. Nevertheless, the strong relationships between the "temporal", "frontal", "diffuse suppression" and "posterior" profiles and intra-cerebral discharges localizations may contribute to hierarchize hypotheses derived from ictal scalp EEG analysis regarding intra-cerebral seizure onset.

& Objective: Low bone mineral density and dementia commonly co-occur in the elderly, with bone loss accelerating in dementia patients due to physical inactivity and poor nutrition. However, uncertainty persists over the extent to which bone loss already exists prior to the onset of dementia. Therefore, we investigated how dementia risk was affected by bone mineral density at various skeletal regions in community-dwelling older adults.

In a prospective population-based cohort study, bone mineral density at the femoral neck, lumbar spine, and total body and the trabecular bone score were obtained using dual-energy X-ray absorptiometry (DXA) in 3,651 participants free from dementia between 2002-2005. Persons at risk of dementia were followed up until 1 January 2020. For analyses of the association between bone mineral density at baseline and the risk of incident dementia, we used Cox proportional-hazards regression analyses, adjusting for age, sex, educational attainment, physical activity, smoking status, body mass index, systolic blood pressure, diastolic blood pressure, cholesterol level, high-density lipoprotein cholesterol, history of comorbidities (stroke and diabetes mellitus), and APOE genotype.

Among the 3,651 participants (median age 72.3±10.0 years, 57.9% women), 688 (18.8%) developed incident dementia during a median of 11.1 years, of whom 528 (76.7%) developed Alzheimer’s disease. During the whole follow-up, participants with lower bone mineral density at the femoral neck (per SD decrease) were more likely to develop all-cause dementia (Hazard ratio [HR] _{total follow-up}: 1.12, 95% Confidential interval [CI]: 1.02-1.23) and Alzheimer’s disease (HR _{total follow-up}: 1.14, 95% CI: 1.02-1.28). Within the first ten years following baseline, the risk of dementia was greatest for groups with the lowest tertile of bone mineral density (femoral neck bone mineral density, HR_0-10years 2.03; 95% CI, 1.39–2.96; total body bone mineral density, HR_0-10years 1.42; 95% CI, 1.01–2.02; trabecular bone score, HR_0-10years 1.59; 95% CI, 1.11–2.28).

In conclusion, participants with low femoral neck and total body bone mineral density and low trabecular bone score were more likely to develop dementia. Further studies should focus on the predictive ability of bone mineral density for dementia.

Post-traumatic epilepsy is associated with impaired recovery from severe TBI and poor functional outcomes. Early screening and treatment of PTE may improve patient outcomes.

This study showed excess mortality in PWE, even in those without comorbidities and those receiving monotherapy. Regional disparities and sustained risks of deaths from external causes over ten years imply potential points of intervention. In addition to active control of seizures, education about injury prevention, monitoring for suicidal ideation and efforts to improve accessibility to epilepsy care are all required to reduce mortality.

In this post hoc analysis of the RESCUE BT trial, tirofiban was an effective and well-tolerated adjuvant medication of endovascular thrombectomy for patients with large vessel occlusion due to intracranial atherosclerosis. These findings need to be confirmed in future trials.

Limbic predominant age related TDP-43 (LATE) impacts similar neuroanatomical networks as Alzheimer’s disease (AD) and is often comorbid with AD, though frequently missed in clinical diagnosis. The primary aim of this study was to elucidate the clinical and cognitive differences at baseline between patients with autopsy confirmed LATE, compared to patients with AD and comorbid LATE+AD.

Clinical and neuropathological datasets were requested from the National Alzheimer’s Coordination Center (NACC). Baseline data from individuals 75+ years at time of death without neuropathological indication of frontotemporal lobar degeneration were included in analyses. Pathologically defined groups reflecting LATE, AD, and comorbid LATE+AD were identified. Group differences in clinical characteristics and cognition were explored through analysis of variance and chi-square using measures from the Uniform Data Set measures.

Pathology groups included 31 individuals with LATE (M_age: 80.6±5.4), 393 with AD (M_age: 77.8±6.4), and 262 with LATE+AD (M_age: 77.8±6.6) without significant differences in sex, education, or race. Compared to participants with AD and LATE+AD pathology, participants with LATE pathology lived significantly longer (M_visits: LATE=7.3±3.7; AD=5.8±3.0; LATE+AD=5.8±3.0; F(2,683)=3.7, p<.05), reported later onset of cognitive decline (M_onset: LATE=78.8±5.7; AD=72.5±7.0; LATE+AD=72.9±7.0; F(2,516)=6.2, p<.01), and were more likely to be diagnosed as cognitively normal at baseline (LATE=41.9%; AD=25.4%; LATE+AD=12%; ²=38.7, p<.001). Individuals with LATE (45.2%) also reported fewer memory complaints than those with AD (74.4%) or LATE+AD (66.4%; ²=13.3, p=.001) and were less likely to be classified as Impaired on the Mini Mental State Exam (LATE=6.5%; AD=24.2%; LATE+AD=40.1%; ²=29.20, p<.001). Across all neuropsychological measures, participants with LATE+AD pathology performed significantly worse than the AD and LATE groups.

Those with LATE pathology were older when cognitive symptoms began and lived longer than participants with AD or LATE+AD pathology. Participants with LATE pathology were also more likely to be classified as "cognitively normal" based on objective screening and self-report measures, and they had higher scores on neuropsychological testing. Consistent with prior literature, comorbid pathologies led to more significant cognitive and functional impairment. Early disease characteristics based on clinical presentation alone were insufficient for differentiating LATE from AD, reiterating the need for a validated biomarker.

56 patients with treatment-naïve ATTRv with symptoms/signs of peripheral neuropathy or cardiomyopathy and confirmatory genetic testing presenting with Val122Ile (N=31), late-onset Val30Met (N=12) and Leu58His ATTRv (N=13) were included. The age at onset and gender distributions were similar (V122I: 71.5±8.0, V30M: 64.8±2.6, L58H: 62.4±9.8years; 26, 25, 31% female).

Only 10% of patients with V122I and 17% of patients with V30M were aware of an ATTRv family history, while 69% of patients with L58H were. Peripheral neuropathy was present in all three variants at diagnosis (90, 100, 100%) though neurological impairment scores differed: V122I: 22±16, V30M: 61±31 and L58H: 57±25. Most points (deficits) were attributed to loss of strength. Carpal tunnel syndrome (CTS) and a positive Romberg sign were common across all groups (V122I: 97%, 39%; V30M: 58%, 58%; L58H: 77%, 77%).

ProBNP levels and interventricular septum thickness were highest among patients with V122I (5939±962pg/mL, 1.70±0.29cm) followed by V30M (796±970pg/mL, 1.42±0.38cm) and L58H (404±677pg/mL, 1.23±0.36cm). Atrial fibrillation was present among 39% of V122I cases and only 8% of V30M and L58H cases. Gastrointestinal symptoms were rare (6%) among patients with V122I and common in patients with V30M (42%) and L58H (54%).

Important clinical differences exist between ATTRv genotypes. While V122I is perceived to be a cardiac disease, peripheral neuropathy is common and clinically relevant. Most patients with V30M and V122I were diagnosed de-novo and therefore require clinical suspicion for diagnosis.A history of CTS and a positive Romberg sign are helpful diagnostic clues.

Cross-sectional study where consecutive patients with polysomnographic-confirmed IRBD and age-matched controls without RBD underwent skin biopsy and lumbar puncture the same day. 3-mm skin punch biopsies were obtained bilaterally in cervical region from dorsal C7 and C8 dermatomes, and in distal legs. RT-QuIC assessed misfolded α-synuclein in these six skin sites and CSF.

We recruited 91 IRBD patients and 41 controls. In skin, sensitivity to detect misfolded α-synuclein was 76.9% (95%CI 66.9–85.1), specificity 97.6% (95%CI 87.1–99.9) positive predictive value 98.6% (95%CI 91.0-99.8), negative predictive value 65.6% (95%CI 56.6-73.6) and accuracy 83.3% (95%CI 75.9–89.3). In CSF, sensitivity was 75.0% (95% CI 64.6–83.6), specificity 97.5% (95%CI 86.8–99.9) positive predictive value 98.5% (95%CI 90.5-99.8), negative predictive value 63.9% (95%CI 55.2-71.9) and accuracy 82.0% (95%CI 74.3–88.3). Results in skin and CSF samples showed 99.2% agreement. Compared with negative patients, RT-QuIC α-synuclein positive patients had higher likelihood ratio of prodromal Parkinson disease (p<0.001) and showed more frequently hyposmia (p<0.001), DAT-SPECT deficit (p=0.002) and orthostatic hypotension (p=0.014). No severe or moderate adverse effects were reported. There was no difference between percentage of participants reporting mild adverse events secondary to skin biopsy or lumbar puncture (9.1% versus 17.2%; p=0.053).83% participants stated they would accept to undergo again skin biopsy and 80% lumbar puncture, for research purposes.

Our study in IRBD shows that 1) RT-QuIC detects misfolded α-synuclein in skin and CSF with similar high sensitivity, specificity, and agreement, 2) α-synuclein RT-QuIC positivity is associated with supportive features and biomarkers of synucleinopathy, and 3) skin punch biopsy and lumbar puncture have comparable mild adverse effects, tolerance, and acceptance. α-synuclein RT-QuIC in skin or CSF might represent a patient selection strategy for future neuroprotective trials targeting α-synuclein in IRBD.

This study provides Class III evidence that RT-QuIC detected misfolded α-synuclein in the skin and CSF distinguishes patients with IRBD from controls.

We included dementia-free participants from nine diverse community-based cohorts with whole-genome sequencing in the Trans-Omics for Precision Medicine (TOPMed) program. Circulating mtDNA CN was estimated as twice the ratio of the average coverage of mtDNA to nuclear DNA. Brain MRI markers included total brain, hippocampal, and white matter hyperintensity volumes. General cognitive function was derived from distinct cognitive domains. We performed cohort-specific association analyses of mtDNA CN with AD/ADRD endophenotypes assessed within ±5 years (i.e., cross-sectional analyses) or 5 to 20 years after blood draw (i.e., prospective analyses) adjusting for potential confounders. We further explored associations stratified by sex and age (<60 vs. ≥60 years). Fixed-effects or sample size-weighted meta-analyses were performed to combine results. Finally, we performed Mendelian randomization (MR) analyses to assess causality.

We included up to 19,152 participants (mean age 59 years, 57% women). Higher mtDNA CN was cross-sectionally associated with better general cognitive function (Beta=0.04; 95% CI 0.02, 0.06) independent of age, sex, batch effects, race/ethnicity, time between blood draw and cognitive evaluation, cohort-specific variables, and education. Additional adjustment for blood cell counts or cardiometabolic traits led to slightly attenuated results. We observed similar significant associations with cognition in prospective analyses, although of reduced magnitude. We found no significant associations between mtDNA CN and brain MRI measures in meta-analyses. MR analyses did not reveal a causal relation between mtDNA CN in blood and cognition.

Discussion:

Higher mtDNA CN in blood is associated with better current and future general cognitive function in large and diverse communities across the US. Although MR analyses did not support a causal role, additional research is needed to assess causality. Circulating mtDNA CN could serve nevertheless as a biomarker of current and future cognitive function in the community.

There is consistent evidence that epilepsy surgery is a cost-effective treatment for eligible candidates with DRE. Limited evidence suggests that VNS, RNS, and DBS may be cost-effective therapies for DRE, although more health economic evaluations alongside prospective clinical trials are needed to validate these findings.

To (1) characterize short-term outcomes in episodic memory, as assessed by the Children’s Memory Scale (CMS), following temporal lobe resection in children with epilepsy using empirical methods for assessing cognitive change (i.e., reliable change indices: RCIs and standardized regression-based change scores: SRBs) and (2) develop and internally validate clinically-applicable models to predict postoperative memory decline.

This retrospective cohort study included children aged 6-16 years who underwent resective epilepsy surgery that included the temporal lobe (temporal-only: "temporal" and multilobar: "temporal-plus") and who completed pre- and postoperative neuropsychological assessments including the CMS. Change scores on CMS delayed memory subtests (Faces, Stories, and Word Pairs) were classified as decline, no change, or improvement using epilepsy-specific RCIs and SRBs. Logistic regression models for predicting postoperative memory decline were developed and internally validated with bootstrapping.

Of the 126 children included, most demonstrated either no significant RCI change (54-69%) or improvement (8-14%) in memory performance on individual measures a median of 7 months after surgery. A subset of children (23-33%) showed postoperative declines. Change distributions obtained using RCIs and SRBs were not statistically significantly different from each other. Preoperative memory test score, surgery side, surgery extent, and preoperative full scale IQ were predictors of memory decline. Prediction models for memory decline included subsets of these variables with bias-corrected concordance (c) statistics ranging from 0.70-0.75. The models were well calibrated although slightly overestimated the probability of verbal memory decline in high risk patients.

This study used empiric methodology to characterize memory outcome in children following temporal lobe resection. Provided online calculator and nomograms may be used by clinicians to estimate the risk of postoperative memory decline for individual patients prior to surgery.

Among 319 patients with spontaneous ICH (median age was 69 [IQR, 60-77] years, 60% male), 30- and 90-day mortality were 16% and 22%, respectively, and unfavorable functional outcome (mRS 4-6) was 50% at a median 3.1-months after ICH. Admission predictors of mortality mirrored those of the original ICH score. Unfavorable outcomes for ICH score 3 and 4 were 73% and 86%, respectively. The most common adjudicated primary causes of mortality were direct effect or progression of the ICH (54%), refractory cerebral edema (21%), and medical complications (11%). In matched analyses, lifesaving surgery for supratentorial ICH did not significantly alter mortality or unfavorable functional outcome in patients overall. In subgroup analyses restricted to (1) surgery with hematoma evacuation, and (2) ICH score 3 and 4 patients, the odds of 30-day mortality were reduced by 71% (OR, 0.29, 95% CI, 0.09-0.9, p=0.032) and 80% (OR, 0.2, 95% CI, 0.04-0.91, p=0.038), respectively, but no difference was observed for 90-day mortality or unfavorable functional outcome.

This study demonstrates that poor outcomes after ICH prevail despite aggressive treatment. Unfavorable outcomes appear related to direct effects of the primary injury and not to premature care limitations. Lifesaving surgery for supratentorial lesions delayed mortality but did not alter functional outcomes.

NfL might help to differentiate PLS from ALS patients and to predict prognosis in patients with an UMN-syndrome.

We identified 147 patients with RSE treated with IVAD. Among 102 patients without cerebral anoxia, incomplete burst-suppression was achieved in 14 (14%) with a median of 23 hours (interquartile range [IQR] 1-29) and complete burst-suppression was achieved in 21 (21%) with a median of 51 hours (IQR 16-104). Age, Charlson comorbidity Index, RSE with motor symptoms, and the Status Epilepticus Severity Score (STESS) were identified as potential confounders in univariable comparisons between patients with and without any burst-suppression. Multivariable analyses revealed no associations between any burst-suppression and the predefined endpoints. However, among 45 patients with cerebral anoxia, induced burst-suppression was associated with persistent seizure termination (72% without vs. 29% with burst-suppression, p=0.004) and survival (50% vs. 14% p=0.005).

In adult patients with RSE treated with IVAD, burst-suppression with ≥50% suppression proportion was achieved in every fifth patient and not associated with persistent seizure termination, in-hospital survival or return to premorbid neurologic function.

Dyslexia, developmental speech disorders and left-handedness were not associated with any PPA subtype (P > 0.05). The genetic proxy of cortical asymmetry in left handedness was significantly associated with agrammatic PPA (beta = 4.3, P= 0.007), but not with other PPA subtypes. This association was driven by microtubule-related genes, primarily by a variant that is in complete linkage disequilibrium with MAPT gene. Sensitivity analyses were overall consistent with the primary analyses.

Our results do not support a causal association between dyslexia, developmental speech disorders, or handedness with any of the PPA subtypes. Our data suggests a complex association between cortical asymmetry genes and agrammatic PPA. Whether the additional association with left handedness is necessary remains to be determined but is unlikely given the absence of association between left handedness and PPA. Genetic proxy of brain asymmetry (regardless of handedness) was not tested as an exposure due to lack of suitable genetic proxy. Furthermore, the genes related to cortical asymmetry associated with agrammatic PPA are implicated in microtubule-related proteins (TUBA1B, TUBB, and MAPT), which is keeping with the association of tau-related neurodegeneration in this PPA variant.

Diet may reduce Alzheimer’s dementia risk and slow cognitive decline, but the understanding of the relevant neuropathologic mechanisms remains limited. The association of dietary patterns with Alzheimer’s disease (AD) pathology has been suggested using neuroimaging biomarkers. This study examined the association of MIND and Mediterranean dietary patterns with beta-amyloid load, phosphorylated tau tangles, and global AD pathology in postmortem brain tissue of older adults.

Autopsied participants of the Rush Memory and Aging Project) with complete dietary information (collected through a validated food frequency questionnaire) and AD pathology data (beta-amyloid load, phosphorylated tau tangles, and global AD pathology [summarized neurofibrillary tangles, neuritic and diffuse plaques]) were included in this study. Linear regression models controlled for age at death, sex, education, APO-4 status, and total calories were used to investigate the dietary patterns (MIND and Mediterranean diet) and dietary components associated with AD pathology. Further effect modification was tested for APO-4 status and sex.

Among our study participants (N=581, age at death: 91.0 ± 6.3 years; mean age at first dietary assessment: 84.2 ±5.8; 73% female; 6.8 ± 3.9 years of follow-up) dietary patterns were associated with lower global AD pathology (MIND: β= -0.022, p=0.034, standardized β=-2.0; Mediterranean: β=-0.007, p=0.039, standardized β=-2.3) and specifically less beta-amyloid load (MIND: β=-0.068, p=0.050, standardized β=-2.0; Mediterranean: β=-0.040, p=0.004, standardized β=-2.9). The findings persisted when further adjusted for physical activity, smoking, and vascular disease burden. The associations were also retained when participants with mild cognitive impairment or dementia at the baseline dietary assessment were excluded. Those in the highest tertile of green leafy vegetables intake had less global AD pathology when compared to those in the lowest tertile (Tertile-3 vs. Tertile-1: β= -0.115, p=0.0038).

The MIND and Mediterranean diets are associated with less postmortem AD pathology, primarily beta-amyloid load. Among dietary components, green leafy vegetables inversely correlate with AD pathology.

and Objectives

Small vessel disease (SVD) and neuroinflammation both occur in Alzheimer’s disease (AD), and other neurodegenerative diseases. It is unclear if these processes are related or independent mechanisms in AD, especially in the early stages of disease. We therefore investigated the association between white matter lesions (WML; the most common manifestation of SVD), and CSF biomarkers of neuroinflammation and their effects on cognition in a population without dementia.

Methods

Individuals without dementia from the Swedish BioFINDER study were included. CSF was analyzed for proinflammatory markers (interleukin [IL]–6, IL-8), cytokines (IL-7, IL-15, IL-16), chemokines (interferon-–induced protein 10 [IP-10], monocyte chemoattractant protein 1, markers of vascular injury (soluble intercellular adhesion molecule 1, soluble vascular adhesion molecule 1), and markers of angiogenesis (placental growth factor [PlGF], soluble fms-related tyrosine kinase 1 [sFlt-1], vascular endothelial growth factors [VEGF-A, and VEFG-D]), and Aβ42, Aβ40 and P-tau 217. WML volumes were determined at baseline and longitudinally over six years. Cognition was measured at baseline and follow-up over eight years. Linear regression models were used to test associations.

Results

495 cognitively unimpaired (CU) elderly and 247 patients with mild cognitive impairment (MCI) were included. There was significant worsening in cognition over time, measured by MMSE, CDR and mPACC in CU and MCI, with more rapid worsening in MCI for all cognitive tests. At baseline, higher levels of PlGF (β=0.156, p<0.001), lower levels of sFlt-1 (β=-0.086, p=0.003), and higher levels of IL-8 (β=0.07, p=0.030) were associated with more WML in CU. In MCI, higher levels of PlGF (β=0.172, p=0.001), IL-16 (β=0.125, p=0.001), IL-8 (β=0.096, p=0.013), IL-6 (β=0.088, p=0.023), VEGF-A (β=0.068, p=0.028), and VEGF-D (β=0.082, p=0.028) were associated with more WML. PlGF was the only biomarker that was associated with WML independent of Aβ status and cognitive impairment. Longitudinal analyses of cognition showed independent effects of CSF inflammatory markers and WML on longitudinal cognition, especially in people without cognitive impairment at baseline.

Discussion

Most neuroinflammatory CSF biomarkers were associated with WML in individuals without dementia. Our findings especially highlight a role for PlGF, which was associated with WML independent of Aβ status and cognitive impairment.

Functional outcomes, mortality, and symptomatic intracranial hemorrhage did not significantly differ between tenecteplase and alteplase treated tandem lesion patients.

This study provides Class III evidence that tenecteplase is associated with similar rates of intracranial reperfusion, functional outcome, mortality, and symptomatic intracranial hemorrhage compared with alteplase, in patients with acute stroke due to tandem lesions. However, the confidence intervals do not rule out clinically important differences.

SPaRCNet matches or exceeds most experts in classifying IIIC events based on both calibration and discrimination metrics. For SZ, LPD, GPD, LRDA, GRDA, and "Other" classes, SPaRCNet exceeds the following percentages of 20 experts – ROC: 45%, 20%, 50%, 75%, 55%, 40%; PRC: 50%, 35%, 50%, 90%, 70%, 45%; and calibration: 95%, 100%, 95%, 100%, 100%, 80%, respectively.

SPaRCNet is the first algorithm to match expert performance in detecting seizures and other seizure-like events in a representative sample of EEGs. With further development, SPaRCNet may thus be a valuable tool for expedited review of EEGs.

Among 404 patients with seizures, 51% had SE. Compared to patients with isolated seizures, patients with SE had a lower median Charlson comorbidity index(CCI)(3 versus 5, p<0.001), fewer fatal etiologies (43.6% versus 80.5%, p<0.001), higher median Glasgow Coma Scores (7 versus 5, p<0.001), fever more frequently (27.5% versus 7.5%, p<0.001), shorter median ICU and hospital stay (ICU: 4 versus 5 days, p=0.039; hospital stay: 13 versus 15 days, p=0.045), and recovered to premorbid function more often (36.8% versus 17%, p<0.001). Multivariable analyses revealed decreased odds ratios(OR) for SE with increasing CCI (OR=0.91, 95%confidence interval[CI] 0.83-0.99), fatal etiology (OR=0.15, 95%CI 0.08-0.29), and epilepsy (OR=0.32, 95%CI 0.16-0.63). Systemic inflammation was an additional association with SE after excluding patients with seizures as the reason for ICU admission (OR_{for CRP}=1.01, 95%CI 1.00-1.01; OR_{for fever}=7.35, 95%CI). While fatal etiologies and increasing CCI remained associated with low odds for SE after excluding anesthetized patients and hypoxic-ischemic encephalopathy, inflammation remained associated in all subgroups except patients with epilepsy.

Among all ICU patients with seizures, SE emerged frequently and seen in every second patient. Besides the unexpected low odds for SE with higher CCI, fatal etiology, and epilepsy, the association of inflammation with SE in the critically ill without epilepsy represents a potential treatment target and deserves further attention.

Plasma p-tau181/NfL can potentially be used to monitor large-scale population interventions in CU individuals. The enrollment of CU with intermediate Aβ levels constitutes the alternative with the largest effect size and most cost-effective for trials testing drug effect on changes in plasma p-tau181 and NfL.

Women with a history of HDP, especially PE/E, are at greater risk of cognitive decline in later life.

Higher structural network organization in bilingual individuals with LTLE suggests a neuromodulatory effect of bilingualism on whole-brain connectivity in epilepsy, providing evidence for neural reserve. This may reflect attenuation of or compensation for epilepsy-related dysfunction of the left hemisphere, potentially driven by increased efficiency of frontal-executive networks that mediate dual-language control. This highlights a potential role of bilingualism as a protective factor in epilepsy, motivating further research across neurological disorders to define mechanisms and develop interventions.

The University of Pennsylvania Smell Identification Test (UPSIT) is commonly used to assess olfaction and screen for early detection of disorders including Parkinson’s (PD) and Alzheimer’s disease. Our objective was to develop updated percentiles, based on substantially larger samples than previous norms, to more finely discriminate age- and sex-specific UPSIT performance among ≥50-year-old adults who may be candidates for studies of prodromal neurodegenerative diseases.

The UPSIT was administered cross-sectionally to participants recruited between 2007-2010 and 2013-2015 for the Parkinson Associated Risk Syndrome (PARS) and Parkinson’s Progression Markers Initiative (PPMI) cohort studies, respectively. Exclusion criteria included age <50 years and a confirmed or suspected PD diagnosis. Demographics, family history, and prodromal features of PD including self-reported hyposmia were collected. Normative data including means, standard deviations, and percentiles were derived by age and sex.

The analytic sample included 9,396 individuals (5,336 females, 4,060 males), aged 50-95, who were predominantly White, non-Hispanic US residents. UPSIT percentiles were derived and are provided across seven age categories (50-54, 55-59, 60-64, 65-69, 70-74, 75-79, and ≥80) for females and males separately; relative to existing norms, subgroups included between 2.4-20 times as many participants. Olfactory function declined with age and was better among women than men; accordingly, the percentile corresponding to a given raw score varied markedly by age and sex. UPSIT performance was comparable among individuals with vs without first-degree family history of PD. Comparisons of self-reported hyposmia vs UPSIT percentiles indicated a strong association (chi-squared P<0.0001), but minimal agreement (Cohen’s simple kappa [95% CI]: = 0.32 [0.28-0.36] for females; 0.34 [0.30-0.38] for males).

Updated age/sex-specific UPSIT percentiles are provided for ≥50-year-old adults who reflect a population likely to be recruited into studies of prodromal neurodegenerative diseases. Our findings highlight the potential advantages of evaluating olfaction relative to age and sex instead of in absolute terms (e.g., based on raw UPSIT scores) or based on subjective (i.e., self-reported) measures. This information addresses the need to support studies of disorders including PD and Alzheimer’s disease by providing updated normative data from a larger sample of older adults.

Participants with a RMC had two visits: during menstruation on menstrual cycle day 2 ± 2 and in the periovulatory period on day 13 ± 2. Participants with COC were examined at day 4 ± 2 of the hormone-free interval (HFI) and between days 7-14 of hormone intake (HI). Postmenopausal participants were assessed once at a random time point. Plasma and tear fluid samples were collected at each visit for determination of CGRP levels with an enzyme-linked immunosorbent assay.

A total of 180 female participants (n=30 per group) completed the study. Participants with migraine and a RMC showed statistically significantly higher CGRP concentrations in plasma and tear fluid during menstruation compared to female participants without migraine [plasma: 5.95 pg/ml (IQR 4.37 – 10.44) vs. 4.61 pg/ml (IQR 2.83 – 6.92), p=0.020 (Mann-Whitney U test); tear fluid: 1.20 ng/ml (IQR 0.36 – 2.52) vs. 0.4 ng/ml (IQR 0.14 – 1.22), p=0.005 (Mann-Whitney U test)]. In contrast, female participants with COC and in the postmenopause had similar CGRP levels in the migraine and the control groups. In migraine participants with a RMC, tear fluid but not plasma CGRP concentrations during menstruation were statistically significantly higher compared to migraine participants under COC (p=0.015 vs. HFI and p=0.029 vs. HI, Mann-Whitney U test).

Different sex hormone profiles may influence CGRP concentrations in people, with current or past capacity to menstruate, with migraine. Measurement of CGRP in tear fluid was feasible and warrants further investigation.

Among the 502,229 participants with a mean age of 56.5 (SD=8.1) at baseline, 273,251 (54.4%) were female, and 18,235 (3.6%) reported regular use of laxatives. Over a mean follow-up of 9.8 years, 218 (1.3%) participants with regular use of laxatives and 1,969 (0.4%) with no regular use developed all-cause dementia. Multivariable analyses showed that regular use of laxatives was associated with increased risk of all-cause dementia (hazard ratio [HR] 1.51; 95% confidence interval 1.30-1.75) and vascular dementia (HR 1.65; 1.21-2.27), with no significant association observed for Alzheimer’s disease (HR 1.05; 0.79-1.40). The risk of both all-cause dementia and vascular dementia increased with the number of regularly used laxative types (P-trend 0.001 and 0.04, respectively). Among the participants who clearly reported that they were using just one type of laxative (n=5800), only those using osmotic laxatives showed a statistically significantly higher risk of all-cause dementia (HR 1.64 [1.20-2.24]) and vascular dementia (HR 1.97 [1.04-3.75]). These results remained robust in various subgroup and sensitivity analyses.

Regular use of laxatives was associated with a higher risk of all-cause dementia, particularly in those who used multiple laxative types or osmotic laxative.

Important risk factors for epilepsy were seizures during admission for brain abscess, neurosurgery, alcoholism, frontal lobe abscess, and stroke. Epilepsy was associated with increased mortality. Anti-epileptic treatment may be guided by individual risk profiles and specialized follow-up is highlighted by increased mortality in survivors with epilepsy.

RST was well tolerated and led to improvements in some, but not all, short- and long-term outcomes. RST represents a proactive rehabilitative intervention that could increase physiologic capacity of specific breathing and airway clearance functions during the early stages of ALS. Further work is needed to determine optimal training intensity, resistance load specifications, and potential long-term functional outcomes.

READISCA showed the feasibility of harmonized data acquisition in a multi-national network. NfL alterations, early sensory ataxia and corticospinal signs were quantifiable between preataxic participants and controls. Patients with ataxia differed in many parameters from controls and mutation carriers without ataxia, with a graded increase of abnormal measures from control to preataxic to ataxic cohorts.

After exclusions, 905,784 patients were included in the mortality analysis and 915,993 were included in the readmission analysis. After adjustment for age, sex, race/ethnicity, comorbidity burden, and individual socioeconomic status, patients from low SES neighborhoods had higher 30-day mortality rates compared to patients from high SES neighborhoods for all disease categories except for multiple sclerosis: magnitudes of the effect ranged from an adjusted odds ratio (aOR) of 2.46 (95% Confidence Interval [CI] 1.60-3.78) for the non-traumatic coma group to 1.23 (95% CI 1.19-1.28) for the stroke group. After adjustment, no significant differences in readmission rates were observed for any of the groups.

Neighborhood socioeconomic status is strongly associated with 30-day mortality for many common neurological conditions even after accounting for baseline comorbidity burden and individual socioeconomic status. Strategies to improve health equity should explicitly consider the effect of neighborhood environments on health outcomes.

We included 71 stroke (age 66±12, 22 women) and 36 control participants (age 69±5, 13 women). We observed extensive white matter structural degeneration across the whole brain, particularly affecting the thalamic, cerebellar, striatal, and superior longitudinal tracts, and corpus callosum. Importantly, follow up regression analyses in 72 pre-defined tracts showed that the decline in fiber density and cross-section from 3 months to 3 years was associated with worse cognitive performance at 3 years after stroke, especially affecting visuospatial processing, processing speed, language, and recognition memory.

We conclude that white matter neurodegeneration in ipsi- and contra-lesional- thalamic, striatal and cerebellar tracts continues to be greater in stroke survivors compared to stroke-free controls. White matter degeneration persists even years after stroke and is associated with post-stroke cognitive impairment.

Using nationwide longitudinal data of DM patients from the Korean National Health Insurance Service DM cohort (2002–2017), we investigated the association of pioglitazone use with incident dementia in patients with new-onset type 2 DM. The heterogeneity of the treatment effect was examined using exploratory analyses. Using a multi-state model, we assessed the extent to which incident stroke affects the association between pioglitazone use and dementia.

Pioglitazone use was associated with a reduced risk of dementia, compared with non-use (adjusted hazard ratio (HR) = 0.84, 95% CI, 0.75-0.95); the risk reduction in dementia was greater among patients with a history of ischemic heart disease or stroke before DM onset (adjusted HR = 0.46, 95% CI, 0.24-0.90, adjust HR = 0.57, 95% CI, 0.38-0.86, respectively). The incidence of stroke was also reduced by pioglitazone use (adjusted HR = 0.81, 95% CI, 0.66-1.00). However, when the stroke developed during the observation period of pioglitazone use, such lowered risk of dementia was not observed (adjusted HR = 1.27, 95% CI, 0.80-2.04).

Pioglitazone use is associated with a lower risk of dementia in DM patients, particularly in those with a history of stroke or ischemic heart disease, suggesting the possibility of applying a personalized approach when choosing pioglitazone to suppress dementia in DM patients.

Female hormone therapy use is associated with a higher risk of intracranial hemorrhage from cerebral cavernous malformations. These findings raise questions about the safety of female hormone therapy in clinical practice in patients with cerebral cavernous malformation. Further studies evaluating clinical factors raising risk of thrombosis may be useful to determine which patients may be most susceptible to intracranial hemorrhage.

This study provides Class III evidence that female hormone therapy increased the risk of intracranial hemorrhage in patients with CCM.

Patient and disease characteristics and PROs measuring symptom burden, interference, psychologic distress, functional impairment, and health-related quality of life (HRQOL) from participants enrolled an IRB-approved observational study at the US National Institutes of Health’s Neuro-Oncology Branch were collected between 9/2016-12/2019. Descriptive statistics, tests of association, and comparison of group means were used to describe and evaluate PROs.

Of the 277 participants diagnosed with a PCNST, 57% were male and 43% were female. Participants reported their race as White, non-Hispanic (78%); White, Hispanic/Latino (9%); Asian (7%); Black (4%); Native Hawaiian/Pacific Islander (1%); other (2%) with 8% missing. The median age of the overall cohort was 45 years (range 18-74). Hispanic participants in the overall sample were 2.3 times more likely, and in the brain tumor group 3.2 times more likely, to report unemployment (p=.043, OR=2.3, 95% CI [1.0, 5.4] and p=.008, OR=3.2, 95% CI [1.3, 7.9], respectively). The 77 (28%) individuals unemployed due to tumor reported more functional impairment with walking, washing, dressing, performing usual activities, and reduced HRQOL (p<.001). More unemployed participants in the total sample reported moderate-to-severe depressive symptoms (25%) than those employed (8%) (X²(1)=13.9, p<.001, OR=3.7, 95% CI [1.8, 7.8]) and more moderate-to-severe anxiety symptoms (30%) than those employed (15%) (X²(1)=7.8, p=.005, OR=2.4, 95% CI [1.3, 4.5]). Unemployed brain tumor participants reported on average 3 more symptoms as moderate-to-severe compared to those employed (t(83)=-4.0, 95% CI _difference [-5, -2], p<.001, Hedge’s g=.70).

Being unemployed due to a PCNST strongly correlated with high symptom burden, functional impairment, psychological distress and reduced HRQOL which may be impediments to returning to work that warrant intervention. Lack of employer-based health insurance and reduced earnings are financial sequelae of unemployment superimposed on the physical, social, and cognitive effects of living with a PCNST. Innovations to screen for and address financial toxicity and its contributing factors are needed.

We showed that proportions of patients with CSE, NCSE and SUDEP differ for commonly encountered genetic DEEs. The estimates for each genetic DEE studied will inform early diagnosis and management of status epilepticus and SUDEP and inform disease-specific counselling for patients and families in this high-risk group of conditions.

The findings suggest that there is poor agreement between aSAH survivors’ self-assessed outcome, their actual mRS score and the dichotomization of the mRS score into good/poor outcomes. Patient-centered and -informed outcome measurement tools are needed to guide the aSAH research agenda.

377 people with IIH agreed to participate in the IIH Life maternal health study. Mean follow up was 17.5 months (standard deviation (SD) 20.5). IIH diagnosed in pregnancy was rare. Patients diagnosed with IIH whilst pregnant had greater papilloedema (mean OCT total retinal thickness +11.59 µm/month (95% CI: 1.25, 21.93)), although they had comparable visual field and acuity measures compared to those with established IIH who became pregnant during their disease course (-1.2 µm/month (95% CI: -2.6, 0.21)). In those with established IIH, pregnancy did not adversely affect visual or headache outcomes over time and the trajectory was akin to those with IIH that never had a pregnancy. Headache outcomes showed variability reflecting the IIH cohort as a whole.

A diagnosis of IIH whilst pregnant was rare but associated with more severe papilloedema. Long term visual outcomes in IIH were analogous irrespective of the timing of the pregnancy. This data is reassuring however close vigilance of IIH clinical features during pregnancy is recommended.

& Objectives: Damage to small nerve fibers is common in diabetic polyneuropathy (DPN) and the diagnosis of DPN relies on subjective symptoms and signs in a combination with objective confirmatory tests, typically electrophysiology or intraepidermal nerve fiber density (IENFD) from skin biopsy. Corneal confocal microscopy (CCM) has been introduced as a tool to detect DPN. However, it is unclear if CCM can reliably be used to diagnose DPN and how the technique compares with other commonly used measures of small fiber damage, such as IENFD, cold detection threshold (CDT) and warm detection threshold (WDT). Therefore, we assessed and compared the use of CCM, IENFD, CDT and WDT in the diagnosis of DPN in patients with type 2 diabetes.

In this cohort study, the participants underwent detailed neurological examination, electrophysiology, quantification of IENFD, CCM, and quantitative sensory testing. Definition of DPN was made in accordance with the Toronto criteria for diabetic neuropathy (without relying on IENFD and thermal thresholds).

A total of 214 patients with at least probable DPN, 63 patients without DPN and 97 controls without diabetes were included. Patients with DPN had lower CCM measures (corneal nerve fiber length (CNFL), nerve fiber density and branch density), IENFD, CDT, and WDT compared to patients without DPN (p=<0.001, <0.001, 0.002, p<0.001, p=0.003 and <0.005, respectively), whereas there was no difference between controls and diabetes patients without DPN. All three CCM measures showed a very low diagnostic sensitivity with CNFL showing the highest (14.4% (95% CI 9.8;18.4)) and a specificity of 95.7% (88.0;99.1). In comparison, the sensitivity of abnormal CDT and/or WDT was 30.5% (24.4;37.0) with a specificity of 84.9% (74.6;92.2). The sensitivity of abnormal IENFD was highest among all measures with a value of 51.1% (43.7;58.5) and a specificity of 90% (79.5;96.2). CCM measures did not correlate with IENFD, CDT/WDT or neuropathy severity in the group of patients with DPN.

CCM measures showed the lowest sensitivity compared to other small fiber measures, in the diagnosis of DPN. This indicates that CCM is not a sensitive method to detect DPN in recently diagnosed type 2 diabetes.

This study provides Class III evidence that CCM measures aid in the detection of diabetic polyneuropathy in recently diagnosed type 2 diabetics, but with a low sensitivity when compared to other small fiber measures.

From 2005 to 2015, infective endocarditis-related stroke was increasingly associated with intravenous drug use and fewer risk factors, specifically hypertension. These trends likely reflect the demographics of the opioid epidemic, which has affected younger patients with fewer comorbidities.

Non-standard Abbreviations and Acronyms

infective endocarditis-related stroke; IVDU: intravenous drug users; GCNKSS: Greater Cincinnati Northern Kentucky Stroke Study; NIHSS: National Institute of Health Stroke Scale; tPA: tissue plasminogen activator

Over 1,600 patient-years of follow-up (>700 patients) were studied from six real-world/natural history data sources (UZ Leuven, PRO-DMD-01 shared by CureDuchenne, iMDEX, North Star UK, Cincinnati Children’s Hospital Medical Center, and the DMD Italian Group), with genotypes classified as amenable to skipping exons 44, 45, 51 or 53, other skippable, nonsense, and other mutations. Associations between genotype class and 1-year changes in North Star Ambulatory Assessment total score (NSAA) and in 10-meter walk/run velocity (10MWR) were studied in each data source with and without adjustment for baseline prognostic factors.

The studied genotype classes accounted for approximately 2% of variation in NSAA outcomes after 12 months, whereas other prognostic factors explained >30% of variation in large data sources. Based on a meta-analysis across all data sources, pooled effect estimates for the studied skip-amenable mutation classes were all small in magnitude (<2 units in NSAA total score in 1-year follow up), smaller than clinically important differences in NSAA, and were precisely estimated with standard errors <1 unit after adjusting for non-genotypic prognostic factors.

These findings suggest viability of trial designs incorporating genotypically mixed or unmatched controls for up to 12 months in duration for motor function outcomes, which would ease recruitment challenges and reduce numbers of patients assigned to placebos. Such trial designs, including multi-genotype platform trials and hybrid designs, should ensure baseline balance between treatment and control groups for the most important prognostic factors, while accounting for small remaining genotype effects quantified in the present study.

Patients’ cumulative estrogen exposure due to reproductive factors could potentially be a valuable indicator for risk stratification of stroke events following menopause.

In the CHANCE-2 trial, patients with a minor stroke or transient ischemic attack (TIA) who carried CYP2C19 loss-of-function (LOF) alleles were randomly assigned within 24 hours after symptom onset, to either ticagrelor-aspirin (placebo clopidogrel plus a 180 mg loading dose of ticagrelor on Day 1, followed by 90 mg twice daily on Days 2–90) or clopidogrel-aspirin (placebo ticagrelor plus a 300 mg loading dose of clopidogrel on Day 1, followed by 75 mg daily on Days 2–90). Aspirin was applied during the first 21 days. Patients who had an SSSI (diffusion-weighted imaging lesion diameter ≤20 mm) were included in this analysis and further categorized into two types according to whether they had the responsible intracranial artery stenosis (ICAS): SSSI+ICAS and SSSI-ICAS. The primary efficacy outcome was a new stroke at 90 days.

Among 2,143 eligible patients, 340 had the responsible ICAS and 1,803 did not. Ticagrelor-aspirin reduced stroke recurrence among all SSSI patients (HR: 0.54; 95% CI: 0.38-0.79; P=0.001) compared to clopidogrel-aspirin. Stroke recurrence occurred in 35/901 (3.9%) patients with SSSI-ICAS on ticagrelor-aspirin and in 72/902 (8.0%) on clopidogrel-aspirin (HR: 0.45; 95% CI: 0.29-0.68; P<0.001). In patients with SSSI+ICAS, the corresponding event rates were 14/176 (8.2%) and 13/164 (7.9%), respectively (HR: 1.20; 95% CI: 0.45-3.23; P=0.71; P for interaction=0.08). The risk of moderate to severe bleeding only occurred in SSSI-ICAS patients (5/901 [0.6%] vs. 5/902 [0.6%]).

In this prespecified substudy, ticagrelor-aspirin was superior to clopidogrel-aspirin in reducing the risk of stroke at 90 days among SSSI patients who carried CYP2C19 LOF allele(s). Although there was no treatment-by-heterogeneous etiology interaction, a greater absolute risk reduction of stroke was observed in patients with SSSI-ICAS than in those with SSSI+ICAS.

We analyzed 5,940 stroke survivors. When comparing stroke survivors with very low versus very high PSH, the mean systolic BP was 137 (SD 18) versus 143 (SD 20, p<0.001), the mean diastolic BP was 81 (SD 10) versus 84 (SD 11, p<0001), the prevalence of uncontrolled BP was 42.8% versus 57.2% (p<0.001), and the prevalence of resistant hypertension was 3.9% versus 11% (p<0.001). Results remained significant using multivariable models (p<0.001) and were replicated in the VISP study (all tests with p<0.05).

A higher PSH is associated with worse BP control in stroke survivors. These findings point to genetic predisposition as an important determinant of poorly controlled BP in this population.

Swallow impairments were universal in children with type 1. Bronchiectasis was common in all paediatric SMA types, with a prevalence of 1 in 5. Routine monitoring and management of dysphagia/ recurrent respiratory infection should be implemented for improvement in lung health.

Patients with PD had reduced nerve fiber densities compared to patients with MSA (P<0.05, all fiber types). All patients with MSA and 51/54 with PD had evidence of phosphorylated alpha-synuclein in at least one skin biopsy. No phosphorylated alpha-synuclein was detected in controls. Patients with MSA had greater phosphorylated alpha-synuclein deposition (P<0.0001) and more widespread peripheral distribution (P<0.0001) than patients with PD. These results provided >90% sensitivity and specificity in distinguishing between the two disorders.

Alpha-synuclein is present in peripheral autonomic nerves of MSA patients, and when combined with synuclein distribution, accurately distinguishes MSA from PD.

This study provides Class II evidence that measurement of phosphorylated alpha-synuclein in skin biopsies can differentiate patients with MSA from those with PD.

Our results provide precise estimates of expert reliability from a large and diverse sample, and a parsimonious theory to explain the origin of disagreements between experts. The results also establish a standard for how well an automated IIIC classifier must perform to match experts.

This study provides Class II evidence that independent expert review reliably identifies ictal-interictal injury continuum patterns on EEG compared to expert consensus.