Lori B. Chibnik

Major depressive disorder (MDD) significantly contributes to the mental health burden in Africa, requiring insights into prevalence and risk factors to inform culturally responsive care. This study assessed current and lifetime MDD prevalence and associated factors among 7,073 adults from hospital settings in Uganda, Kenya, Ethiopia, and South Africa within the NeuroGAP-Psychosis study. Prevalence was 0.9% for current MDD and 5.1% for lifetime MDD, substantially lower than prior estimates from the region. Lower rates may be due to the population studied or cultural variations in expression of symptoms. Multilevel logistic regression identified significant associations between current MDD and negative life events, alcohol use, and Kessler psychological distress scores, while lifetime MDD was linked to age, female sex, chronic pain, frequent headaches, and positive psychosis screening. These findings underscore the need for targeted mental health interventions tailored to the identified factors to reduce the burden of MDD in diverse African contexts.

Background: Approximately 1.3 million individuals in sub-Saharan Africa, as well as millions of others worldwide, live with psychotic disorders. However, there is limited mental health research based on these populations and even less of a focus on neuropsychiatric genetics research within these settings. Methods: To address this gap, the Neuropsychiatric Genetics of African Populations-Psychosis (NeuroGAP-Psychosis), a case-control study, collected data identifying genetic and environmental risk factors associated with psychotic disorders in Ethiopia, Kenya, South Africa, and Uganda. This paper describes baseline demographic and clinical characteristics of the 42,953 participants recruited between 2018–2023 and compares these characteristics by country and case status. Results: Overall, 57.3% of participants were male (ranging from 65.8% in Ethiopia to 46.6% in Uganda). Among cases, the clinical diagnosis of schizophrenia or psychotic disorder not otherwise specified (NOS) ranged from 75.5% in Ethiopia to 44.4% in Uganda. Specific to bipolar disorder or mania NOS, the highest proportion was 53.9% in Uganda, and the lowest was 24.0% in Ethiopia. There were country-level and case-status differences across all demographic and clinical (e.g., physical comorbidities, substance use) variables. Conclusion: Many factors, including language of consent, recruitment catchment areas, diagnostic practices across countries, and translation and/or cultural interpretation of the measures used in this study may account for the differences observed across countries. These findings suggest the importance of ongoing evaluation of cross-national differences to explore clinical implications and patterns of symptoms amongst geographically and culturally diverse populations. Future analyses should evaluate within-country differences to better explore these variations.

Alzheimer disease (AD) and its related disorders (ADRDs) are characterized by a high frequency of copathologies. We aimed to determine the specificity of plasma pTau217, glial fibrillary acidic protein (GFAP), and neurofilament light chain (NfL) for AD neuropathological change (ADNC) in the presence of common ADRD copathologies. pTau217, GFAP, and NfL were measured using S-PLEX immunoassays from Meso Scale Discovery in banked plasma samples from 2 groups of participants in the Massachusetts Alzheimer's Disease Research Center (MADRC) Longitudinal Cohort study: (1) participants spanning the cognitive spectrum, who underwent brain autopsy, and blood collection within 6 years before death, and (2) participants with normal cognition and no neurologic diagnosis during 5 years of follow-up, but no autopsy data (normal controls [NCs]). Cross-sectional associations between biomarker levels and ADNC, primary neuropathologic diagnosis (NPDx1), and presence of non-AD copathologies were evaluated using linear regression models controlling for age, sex, and time to death. One hundred eighty-seven participants with brain autopsy (NPDx1: AD n = 85; other n = 102; mean age: 74.3 years, 38.5% female; interval blood collection-death [mean ± SD]: 2.8 ± 1.6 years) and 67 NC without brain autopsy (mean age: 66.5 years, 71.6% female) were included. pTau217, but not GFAP, levels increased stepwise with increasing Thal phases (β = 0.61; 95% CI [0.24-0.97] to β = 0.91 [0.55-1.27]) and Braak stages (β = 0.59; [0.16-1.01] to β = 0.74 [0.33-1.15]). Although 23% of individuals with a non-AD NPDx1 had increased pTau217 levels using a cutoff defined by the contrast between ADNC and NC, the majority (62%) had intermediate/high ADNC copathology and the remaining pTau217+ individuals had borderline increased levels. By contrast, 48% of individuals without ADNC had increased GFAP levels. pTau217 and GFAP were not different in the presence or absence of cerebral amyloid angiopathy, α-synuclein or TDP-43 proteinopathies, or primary tauopathies. NfL was not specifically associated with ADNC. Plasma pTau217, but not GFAP or NfL, levels accurately reflect the presence of ADNC in the brain even in individuals with an NPDx1 of a non-AD dementia. Thus, a positive plasma pTau217 test in an individual with a suspected non-AD dementia should not necessarily be considered a misdiagnosis of the presumed non-AD dementia or as a false positive, but rather as evidence of ADNC copathology.

Stroke is one of the most common causes of adult-onset epilepsy. We aimed to develop a model to predict poststroke epilepsy (PSE) after a first-ever ischemic stroke, incorporating neuroimaging features of incident stroke. We analyzed clinical and neuroimaging features of patients with first-ever acute ischemic stroke consecutively admitted to Massachusetts General Hospital, United States. We performed competing risk regression with all-cause mortality as a competing event and derived the final multivariable model using backward stepwise elimination by the Akaike Information Criterion. We externally validated the model in 3 international cohorts in Hong Kong (Queen Mary Hospital [HK-QMH], Ruttonjee Hospital [HK-RH]) and Japan (National Cerebral and Cardiovascular Center) by discrimination and calibration and compared its performance with the SeLECT and SeLECT2.0 scores. We included a final derivative cohort of 1,436 patients with a mean age of 67.4 years and a slight male predominance (54.7%), along with a total of 2,534 patients in the validation cohorts. PSE, defined as the occurrence or recurrence of unprovoked seizure >7 days after stroke, occurred in 5.5% of the overall study population. Six variables (infarct size [Is], cortical involvement [C], hemorrhagic transformation [H], early seizures [E], MCA involvement [Mi], and age younger than 65 [A]) were independent predictors included in the final model and formed the IsCHEMiA score. Model discrimination was consistent across all cohorts, with c-statistics of 0.870 (United States), 0.852 (HK-QMH), 0.857 (HK-RH), and 0.826 (Japan). The model was well calibrated at 1 and 3 years after stroke in the overall validation cohort. The IsCHEMiA score improved the prediction of PSE compared with SeLECT in all cohorts and the overall study population (c-statistic 0.848 vs 0.782, z = 5.170, p < 0.0001). For example, an IsCHEMiA score of 3 predicts a low risk of PSE at 1 year (2%) and 5 years (6%) while an IsCHEMiA score ≥8 predicts a high risk at 1 year (67%) and 5 years (78%). The IsCHEMiA score is an improved and readily applicable predictive model developed and validated using international stroke cohorts in the modern era of reperfusion therapies. It serves as a foundation for personalized management and may guide future clinical trials on antiepileptogenic therapies in acute ischemic stroke.

Objective: Late‐onset unexplained epilepsy (LoUE), defined as epilepsy onset after age 55 without an obvious cause, is an important risk factor for dementia. Studies have shown that 10%–25% of individuals with LoUE develop dementia within 3–4 years following their first seizure. However, the mechanisms underlying progression from LoUE to dementia remain poorly understood. The goals of the ELUCID study are to identify risk factors associated with the development of cognitive decline and dementia in LoUE and to develop tools to identify patients at a high risk for these outcomes and thereby establish a foundation for dementia prevention strategies in this population. Methods and Analysis: ELUCID is a multi‐center prospective longitudinal observational study that will enroll 600 participants aged 55 or older with LoUE across seven U.S. medical centers. Participants will undergo a baseline evaluation that includes a detailed clinical history, cognitive testing, brain MRI, overnight scalp EEG, and blood biomarkers. Participants will be followed at 6‐month intervals for up to 5 years, to record cognitive and neurological changes, with the primary outcomes of interest being the development of mild cognitive impairment and/or dementia. This study aims to establish LoUE disease subtypes based on biomarkers, cognitive trajectories, and imaging features and to develop a risk stratification tool for predicting cognitive decline and dementia in patients presenting with LoUE. Ethics and Dissemination: ELUCID has obtained IRB approval (no. 2023P001566, August 2023), with the Mass General Brigham IRB serving as the single IRB of record. All de‐identified study data will be made publicly available on completion of the study. Plain Language Summary: The ELUCID study is a research project involving several medical centers across the U.S. It will focus on older adults who have recently developed seizures without a clear cause. Participants undergo an initial evaluation that includes questions about their medical history, a brain MRI , an overnight scalp EEG (brain wave study), and a blood draw. They will be followed over time with health questionnaires and yearly tests of memory and thinking. The purpose of the study is to learn what factors increase the risk of dementia in this population and to develop tools to predict which individuals are at the highest risk.

In 2016, the National Institutes of Health designated LGBTQ+ individuals (ie, lesbian, gay, bisexual, transgender, queer, and all sexual and gender minorities) as a health disparities population. The growing interest in studying the health of LGBTQ+ populations merits revisiting the methodological approaches researchers employ. We elucidate how researchers can identify appropriate adjustment sets for causal questions using directed acyclic graphs (DAGs). To illustrate these points, we simulated a simplified example using pregnancy loss as the outcome wherein we generate 1000 datasets with a sample size of 10 000 individuals. We motivate why covariates that are commonly used in LGBTQ+ health disparities research (eg, use of medically assisted reproduction) are mediators, not confounders, and how adjusting for these variables in causal research can induce bias by blocking part of the indirect effect of exposure on the outcome. Next, we illustrate the complexity of mediation analyses with social exposures due to mediator-outcome confounding induced by exposure and compare potential approaches. Then we demonstrate how collider stratification bias can arise from our sample recruitment and selection. Finally, we demonstrate how incorporating heterosexism (ie, stigma and discrimination) as an unobserved node in our DAG can guide decision-making on appropriate adjustment sets. This article is part of a Special Collection on Methods in Social Epidemiology.

Introduction/Aims: Expanded access protocols (EAPs) allow individuals ineligible for clinical trials to receive investigational products. EAP data can be collected in parallel to randomized clinical trials (RCTs) and serve as a source of evidence in clinical practice. Here, we present the results of a National Institutes of Health (NIH)‐funded EAP for amyotrophic lateral sclerosis (ALS). Methods: Participants received trehalose, a drug studied in a parallel RCT, for up to 24 weeks; clinical and biomarker data were collected throughout the study. Results: Seventy participants were enrolled at 20 study centers across the United States. Treatment with trehalose did not affect the levels of neurofilament light chain [estimated flat slope per month was −0.005, SE = 0.0078; 95% CI (−0.021, 0.011)] or disease progression [estimated least square mean change of the ALS Functional Rating Scale—Revised total score and slow vital capacity (percent predicted) from baseline to Week 24 were −5.6 (0.67); 95% CI (−7.0, −4.3) and −4.53 (4.308); 95% CI (−13.55, 4.48)], respectively. No unexpected treatment‐related risks were identified. Serious adverse events were deemed not related to trehalose (20 occurrences in 13 [18.6%] participants with eight deaths). Discussion: This EAP establishes a framework for implementing multi‐center EAPs that complement data collected from RCTs. Additional NIH‐funded EAPs are currently underway. Data and additional serum samples collected in this study are available to the research community for further study. Trial Registration: ClinicalTrials.gov: NCT05597436

There is an unmet need for reliable biomarkers for amyotrophic lateral sclerosis (ALS). Recent studies demonstrated that the levels of the microtubule-associated protein tau are altered in plasma and cerebrospinal fluid (CSF) from people living with ALS. Our previous findings revealed that while the ratio between tau and phosphorylated tau at T181 (pTau-T181) is lower in ALS CSF compared to healthy controls (HC), higher CSF tau levels correlated with faster disease progression. Here, we measured total tau and pTau-T181 in plasma samples from two cohorts of participants with ALS and HC using two platforms: Quanterix Simoa and Meso Scale Discovery (MSD). Both assays demonstrated significantly higher pTau-T181 and pTau-T181:tau ratio levels in ALS compared to HC. Longitudinal analysis revealed that higher pTau-T181 levels at baseline correlated with faster decline on the revised ALS functional rating scale (ALSFRS-R). Although the MSD analysis revealed higher plasma tau levels in ALS, the Quanterix Simoa assay demonstrated lower total tau levels in ALS plasma than in HC. To investigate the source of this discrepancy, we measured brain-derived tau (BD-tau) using a new Quanterix assay that specifically detects tau originating from the central nervous system (CNS). This analysis demonstrated significantly elevated plasma BD-tau levels in ALS, mirroring the results obtained with the MSD assay, suggesting that the elevated plasma tau observed in ALS is primarily CNS-derived. Collectively, our data indicate that plasma BD-tau and pTau-T181 levels are elevated in ALS, and future studies will aim to define their potential utility as diagnostic or prognostic biomarkers.