Citations

Abstract Reported prevalence estimates of Lewy body pathology (LBP) vary widely, often without considering brain regional distributions or demographic influences. Large, population-representative autopsy cohorts are needed to provide estimates and clarify the distribution and clinical implications of LBP. Neuropathological, genetic, and clinical data were pooled from nine community- or population-based brain autopsy cohorts in the USA (n=6), Brazil, Austria, and Finland (n=7309 total; 59% women; mean age of death 84.2 years). Cognitive status was available for 6166 participants: dementia (38.5%), mild cognitive impairment (14.8%), and cognitively unimpaired (47.0%). Frequency of LBP was examined by anatomical distribution (neocortical, limbic, brainstem, amygdala, olfactory) and stratified by covariates. Prevalence was calculated in meta-analysis, and mixed-effect logistic regression examined associations with sex, cognitive status, Alzheimer’s disease neuropathological change (ADNC), and limbic-predominant age-related TDP-43 encephalopathy neuropathologic change (LATE-NC) co-pathology. Overall, 27.3% of participants had LBP: neocortical 8.4%, limbic 6.8%, brainstem 4.8%, amygdala 3.7%, and olfactory 3.6%. Neocortical LBP was associated with dementia (present in 15%; OR=4.06 [95%CI 3.24-5.10]) and with increased odds of ADNC (OR=2.30 [95%CI 1.88–2.81]) and LATE-NC (OR=2.03 [95%CI 1.69-2.44]). Sex differences were not observed in the frequencies of neocortical or limbic LBP. However, amygdala-predominant LBP was more frequent in women (OR=1.53 [95%CI 1.06-2.21]) whereas brainstem-predominant LBP was more common in men (OR=0.64 [95%CI 0.49-0.84]). Additionally, amygdala-predominant LBP was associated with increased odds of comorbid ADNC (OR=12.7 [95%CI 5.30–30.6]) while brainstem-predominant LBP was not associated with greater odds of ADNC co-pathology (OR=0.88 [95%CI 0.67–1.16]). Pooling data from large, international community-based autopsy cohorts allows for more robust estimates of region-specific LBP prevalence and their associations with cognitive status. The observed sex- and co-pathology–specific differences in brainstem and amygdala-predominant LBP highlight potential biological heterogeneity and suggest that distinct disease pathways may underlie these patterns.

Abstract Background IDH-mutant astrocytomas are classified as WHO grade 4 in the presence of conventional high-grade histologic features and/or homozygous CDKN2A/B deletion in the 5th edition of the WHO Classification of Central Nervous System Tumour guidelines. However, work over the past decade has indicated a number of other molecular alterations that warrant consideration as potential prognostic markers. Methods We used univariate Kaplan-Meier and multivariate Cox proportional hazards regression analysis to evaluate the prognostic effects of homozygous CDKN2A/B deletion, CDK4 amplification, CCND2 amplification, PDGFRA amplification/mutation, PIK3R1 mutation, PIK3CA mutation, MYCN amplification, EGFR amplification/mutation, TERT promoter mutation, and grade 4 histologic features in two independent cohorts of WHO grade 2-4 IDH-mutant astrocytoma (n = 840 and n = 367). Results The presence of CDK4 amplification, CCND2 amplification, PDGFRA alteration, PIK3R1 mutation, MYCN amplification, and EGFR alteration were each associated with reduced overall survival compared to WHO grade 2/3 astrocytomas without these molecular features. 17.7% (148/837) of otherwise grade 2/3 astrocytomas had one or more of these molecular criteria, with resulting intermediate clinical outcome in terms of overall survival (median survival of 67.3-82.0 months) compared to grade 2/3 astrocytomas without these molecular features (median survival of 135.0-140.7 months) and grade 4 astrocytomas (median survival of 35.3-45.0 months). Conclusions The presence of CDK4, CCND2, PDGFRA, PIK3R1, MYCN, and EGFR alterations result in an intermediate patient survival in IDH-mutant astrocytoma. Adding these molecular alterations should be considered in future diagnostic classification systems to improve stratification of high-risk patients.

Abstract The role of the epigenome in age-related neurodegenerative disorders remains understudied. Here, we analyzed circulating cell-free DNA (cfDNA) from blood to detect methylation changes as a liquid-biopsy for Amyotrophic Lateral Sclerosis (ALS). Our study included 20 patients with sporadic ALS, 10 patients with C9orf72-associated ALS, 10 asymptomatic carriers of the C9orf72 repeat expansion mutation, and 21 non-disease controls. Following targeted enzymatic methyl-sequencing (EM-seq) of ∼4 million CpG sites, we detected numerous differentially methylated genes, including several implicated in ALS disease risk and pathogenesis. By integrating multiple epigenetic features, we delineated a distinct epigenetic signature, which achieved an average area under the curve (AUC) of 0.91 ± 0.10 upon receiver operator characteristic (ROC) analysis, which enabled detection of ∼70% of ALS patients with close to 100% specificity. Furthermore, we also identified a set of genes whose methylation status significantly correlated with clinical disease progression and cerebrospinal fluid (CSF) neurofilament levels. Our results reveal the potential of cfDNA-based biomarkers to accurately diagnose ALS and potentially predict disease progression.

ABSTRACT Background and Aims Women now comprise over half of US medical school matriculants yet remain underrepresented in academic leadership, including emergency medicine (EM). Leadership training within medical education is variable, particularly in communication, conflict management, negotiation, and operations. Concurrently, large language models (LLMs) are emerging as accessible tools to support leadership skill development. This study aimed to develop and evaluate an AI‐augmented leadership skills workshop designed to address the leadership gap for women in academic emergency medicine. Materials and Methods The Academy for Women in Academic Emergency Medicine (AWAEM) developed and piloted a leadership development workshop at the 2025 Society for Academic Emergency Medicine Annual Meeting. The curriculum integrated evidence‐based leadership frameworks with experiential small‐group learning and structured demonstrations of LLM use. Educational strategies included brief didactics, reflection on lived leadership challenges, peer discussion, and guided LLM‐supported simulation of leadership conversations. Pre‐workshop and postworkshop surveys and qualitative feedback were collected to assess participant confidence and perceived utility. Results Participants demonstrated increased confidence in navigating power‐differential conversations and initiating negotiations following the workshop. There was greater reported intent to apply leadership frameworks and to utilize LLMs for leadership‐related tasks. Qualitative feedback highlighted themes of empowerment, practical applicability, and the importance of a psychologically safe, gender‐informed learning environment. Participants identified LLMs as a novel and accessible adjunct to traditional leadership development resources. Discussion and Conclusions An AI‐augmented, experiential leadership workshop is a feasible and scalable approach to addressing persistent leadership development gaps for women in academic emergency medicine. Integrating LLM‐supported practice with established leadership frameworks may enhance learner confidence and engagement. This model offers a practical strategy to support leadership skills for women physicians needed to navigate systemic barriers and advance into leadership roles.

Abstract Background XK disease is a multisystem neurodegenerative disorder caused by mutations in the XK gene that codes for the lipid scramblase XK. Objective The aim was to describe the lipidomic spectrum in postmortem brain tissue from XK patients. Methods We measured the levels of 593 lipid species in the caudate nucleus (CN), putamen, and dorsolateral prefrontal cortex (DLPFC) from postmortem tissues of 5 XK patients and 6 controls. Results In XK patients, we observed increased levels of triacylglycerol, monoacylglycerol, phosphatidylserine, and ceramide in the CN. Acylated phosphatidylglycerol levels were reduced in both the CN and putamen. Acyl carnitine, dihydrosphingomyelin, and monosialodihexosylganglioside were reduced, whereas N ‐acyl phosphatidylethanolamine was increased in the DLPFC. N ‐Acyl serine was reduced in all three regions. Conclusions Our findings provide initial evidence of abnormal sphingolipid and phospholipid concentrations in the brains of XK patients and may provide insights into mechanisms of neurodegeneration in this disease. © 2026 International Parkinson and Movement Disorder Society.

BACKGROUND: Cerebral microbleeds (CMBs) are associated with dementia, but the impact of specific microbleed patterns (with distinct pathophysiologies) is unclear. Lobar CMBs commonly result from cerebral amyloid angiopathy (sometimes with cortical superficial siderosis [cSS]), while subcortical microbleeds indicate a hypertensive cause. This study investigates the association of CMB presence, patterns, and frequency with dementia risk. METHODS: Participants from the ARIC-NCS (Atherosclerosis Risk in Communities-Neurocognitive Study), a community-based longitudinal cohort, with a 3T research magnetic resonance imaging scan at visit 5 (2011–2013) and without prior intracerebral hemorrhage or dementia were included. CMB and cSS presence and location were evaluated using a T2* gradient-recalled echo sequence. Each individual’s pattern of CMBs was classified as no CMBs, subcortical only, mixed (subcortical and lobar±cSS), lobar±cSS only, or cSS. Dementia adjudication was determined by blinded review of cognitive testing, informant interviews, and hospital discharge codes or death certificates (from follow-up visits and ongoing surveillance). Cox proportional hazards models assessed associations between CMBs and incident dementia through 2020, adjusted for demographics, vascular risk factors, and white matter hyperintensities. RESULTS: Among 1583 participants (mean age, 76 years; 24.7% cumulative dementia incidence over a median of 23.6 follow-up years), 361 had CMBs. Compared with individuals without CMBs, those with mixed (hazard ratio, 1.99 [95% CI, 1.40–2.83]) or lobar±cSS (hazard ratio, 1.96 [95% CI, 1.30–2.97]) CMB patterns had increased dementia risk, whereas individuals with a subcortical-only pattern did not (hazard ratio, 1.04 [95% CI, 0.78–1.39]). cSS presence (n=21; versus absence) showed an increased risk of dementia (hazard ratio, 2.57 [95% CI, 1.36–4.89]). Greater numbers of microbleeds across all CMB subtypes exhibited an increased risk of dementia. CONCLUSIONS: Lobar and mixed CMB patterns and increasing numbers of CMBs are associated with incident dementia. Certain CMB patterns have differential associations with dementia, but severe enough disease burden, regardless of CMB distribution, is associated with increased dementia risk.