Faculty Bibliography

Underdiagnosis of cardiometabolic risk factors (CMRFs) may represent an unrecognised biological pathway contributing to dementia risk; yet remains poorly characterised in African and African diaspora populations. We quantified the prevalence and determinants of underdiagnosed hypertension and abnormal glycaemia across four cohorts comprising up to 7000 adults aged ≥40 years from Nigeria, Kenya, and The United States: Indianapolis, and North Texas. Underdiagnosis was defined as absence of self-reported diagnosis despite elevated systolic blood pressure ( ≥130 mmHg) or fasting blood glucose ( ≥100 mg/dL). Cohort-stratified analyses examined demographic, socioeconomic, cognitive, Alzheimer's genetic, and blood-based biomarker correlates. Underdiagnosis was pervasive in African cohorts. Elevated fasting glucose was associated with cognitive impairment in Kenya and North Texas, while severe hypertension and diabetes were linked to Alzheimer's disease-related biomarkers [pTau217/181, NFL and Aβ42/40] in North Texas (all p ≤ 0.05). These findings identify context-specific diagnostic gaps in populations at high dementia risk and highlight cardiometabolic detection as a mechanistic target for prevention.

Protein folding dynamics emerge from subtle changes in intramolecular interactions, where hydration shapes free energy landscapes and influences conformational ensembles and supramolecular assembly. While these shape-shifting principles have been primarily explored in well-behaved systems with sharp transitions, their applicability to multidomain protein assemblies, particularly those containing partially folded or disordered regions, remains unclear. Here, we investigate how a single leucine-to-alanine mutation modulates the hierarchical interplay between folding, micelle formation, and macroscopic biomaterial behavior using two diblock protein block copolymers (BCPs): CE and C_L44AE. In solution, both BCPs exhibit spectral features consistent with their C/C_L44A monoblocks, with CE showing α-helical features and C_L44AE more disordered ones. Upon dehydration, however, both systems display increased structural order, with CE favoring β-sheets and C_L44AE adopting α-helical content. At the mesoscale, both BCPs assemble into amphiphilic micelles, but CE forms smaller, densely packed micelles, whereas C_L44AE generates larger micelles that template film networks of varying pore size depending on their packing density. These differences lead to distinct solvation behavior, with C_L44AE exhibiting greater uptake of predominantly mobile water, approximately twice that of CE, culminating in an actuation energy density of 2,043 kJ/m³, the highest reported for protein BCPs to date. Despite this increased uptake, C_L44AE shows reduced mechanical relaxation and a rougher DSC/TGA thermogram, indicative of a broader conformational ensemble compared to CE. Comparisons to monoblocks (C, C_L44A, E) and previously reported triblocks (CEC, C_L44AEC_L44A) further highlight the importance of asymmetric diblock architectures in promoting hydration-sensitive assemblies, laying the rational design groundwork for future high-performance, water-responsive protein biomaterials.

BACKGROUND AND OBJECTIVES/OBJECTIVE:Direct electrocortical stimulation (DES) is the gold standard for mapping eloquent cortex, yet existing functional atlases are limited by sampling biases and density-based methods that obscure a region's true functional probability. Consequently, interpatient variability and the functional contributions of nontraditional language areas, such as the middle frontal gyrus, remain poorly characterized, particularly in epilepsy populations where functional reorganization is common. We therefore developed a probabilistic functional atlas of extraoperative DES and applied data-driven methods to characterize the functional organization of language, motor, and sensory cortex. METHODS:This was a retrospective observational study of patients undergoing intracranial monitoring for drug-resistant epilepsy (2008-2023). Electrical stimulation was delivered to intracranial electrodes during language tasks, and language, motor, and sensory findings were recorded. Positive and negative stimulation sites were analyzed in standard patient space and using the Human Connectome Project parcellation atlas. A multilevel statistical framework, including probability mapping, bootstrapped region-of-interest analyses, and kernel density estimation, defined structure-function relationships. Generalized linear mixed-effects models assessed the influence of clinical variables on language disruption. RESULTS:= 0.003) independently predicted a lower probability of language disruption in the temporal lobe. DISCUSSION/CONCLUSIONS:This extraoperative DES atlas provides a comprehensive benchmark for understanding functional cortical organization in epilepsy. We add evidence to the growing literature that language and motor systems are more distributed and variable than classically described. Substantial interpatient variability underscores the necessity of individualized mapping to guide safe neurosurgical planning. Limitations include the retrospective design and sampling bias inherent to electrode placement.

Over half of dementia cases remain undiagnosed, with persistent disparities across racial, ethnic, and socioeconomic groups. Dementia care navigation (DCN) has demonstrated value in post-diagnosis settings. If implemented earlier, DCN could address diagnostic delays and care gaps. We define the diagnostic window as the period from initial symptom awareness through diagnosis and early care planning. Drawing on deliberations from the Alzheimer's Association Dementia Care Navigation Roundtable, we present a pre-diagnosis DCN framework organized across six domains and describe navigator roles across three phases: pre-evaluation, diagnostic assessment, and immediate post-diagnosis and transition. We address special considerations, including people without a care partner and those with unmet care needs. The framework complements federal initiatives such as the Guiding an Improved Dementia Experience (GUIDE) Model and the National Alzheimer's Project Act and identifies existing reimbursement pathways for pre-diagnostic navigation activities. Generating evidence to refine these models across diverse settings will be essential to inform policy action and system-level integration.

OBJECTIVE:This study was undertaken to examine acute and chronic electroencephalographic (EEG) and seizure characteristics in new onset refractory status epilepticus (NORSE). METHODS:Multicenter inpatient and follow-up clinical and EEG data were analyzed using International League Against Epilepsy definitions and American Clinical Neurophysiology Society (ACNS) EEG terminology. RESULTS:Forty-four patients were included from the Yale NORSE/FIRES Biorepository (median age = 29 years, 33 female, 38 cryptogenic). Nine hundred twenty inpatient EEG days were reviewed (median = 13.5 days/patient). Presenting status epilepticus (SE) types included 24 convulsive SE (CSE), five focal-motor (FMSE), and 15 nonconvulsive (NCSE). Of 39 patients with post discharge follow-up (median = 14.7 months), 61.5% (n = 24) had seizures and required more antiseizure medications than seizure-free patients (median = 4 vs. 1, p < .001). Inpatient EEG captured epileptiform discharges in all and periodic discharges in 38 patients. Seizures were captured in 38 patients: 33 electrographic (11 only electrographic) and 27 electroclinical. Total seizure burden ranged 6.5-29 615.0 min (median = 50.7). Seizures fulfilling ACNS EEG criteria for SE were captured in 20 patients; two had CSE and the remainder NCSE with coma, nine of whom also had FMSE. Inpatient seizure days (median = 50.0 vs. 15.5%, p = .004) and seizure burden (median = 42.9 vs. 0 min, p = .009) were higher in the first half of monitored days. Interictal findings were equally present and did not predict postdischarge seizures, whereas electroclinical seizures (90.9% vs. 45.5%, p = .037), seizure burden (median = 116.8 vs. 32.5 min, p = .045), and proportion of seizure days (36.3% vs. 20.0%, p = .037) did. Among 12 patients with follow-up EEGs (median = 19.6 months post onset), posterior-dominant rhythm (PDR) returned in nine; five had periodic discharges, and three had seizure captured. SIGNIFICANCE/CONCLUSIONS:Seizures are most commonly convulsive upon presentation and nonconvulsive or clinically subtle throughout the inpatient course in NORSE. Inpatient seizures, but not interictal abnormalities, occur earlier in the inpatient course and presence of electroclinical seizures, seizure burden, and proportion of seizure days but not interictal findings are associated with postdischarge seizures. Although return of PDR reflects neurological recovery, seizure persistence and EEG abnormalities post-NORSE are common.

BACKGROUND/UNASSIGNED:Pediatric-onset multiple sclerosis (POMS) is a chronic, progressive neurologic condition requiring lifelong management and coordinated transition from pediatric to adult care. Evidence-based guidelines identify transition readiness assessment as a core component of successful transition; however, most POMS clinics do not formally assess readiness, and existing tools do not address POMS-specific challenges, such as fluctuating disability, complex treatment regimens, and cognitive impairment. This gap underscores the need for a transition readiness measure tailored to POMS. OBJECTIVE/UNASSIGNED:This paper aims to describe a stakeholder-engaged, implementation science-guided protocol for adapting the Transition Readiness Assessment Questionnaire (TRAQ) version 6.0 to reflect the unique developmental and clinical needs of youth with POMS. METHODS/UNASSIGNED:Using adaptation and participatory research as our guiding implementation strategies, surveys will be administered to patients, caregivers, and clinicians to identify barriers to and facilitators of transition to adult care and define essential self-management competencies in POMS. Survey content will be informed by constructs from the dynamic adaptation process framework and existing TRAQ 6.0 domains. Identified competencies will be refined using a Delphi consensus process. Through cognitive interviewing and a multidisciplinary focus group of collaborators, the adapted measure will be reviewed to assess clarity, relevance, and perceived clinical utility. RESULTS/UNASSIGNED:This project will generate a consensus-driven set of POMS-specific transition competencies and systematically adapt the TRAQ 6.0 to the POMS population. This study was funded in July 2025. The health care provider survey was disseminated in November 2025 across the 27 sites in the US Network of Pediatric Multiple Sclerosis Centers. The patient and caregiver surveys have been finalized, and distribution is projected to begin in June 2026, with a target of 15 patients and 15 caregivers. As of manuscript submission, no patients or caregivers have been recruited, and data analysis has not yet started. Data collection is expected to conclude by the end of 2026, and results are anticipated for publication in 2027. CONCLUSIONS/UNASSIGNED:This protocol outlines a rigorous, replicable approach to adapting a validated transition readiness measure to POMS. The adapted TRAQ 6.0 will support evidence-based transition planning and inform future psychometric testing and implementation research to improve the care of patients with POMS as they age.

INTRODUCTION/UNASSIGNED:Down syndrome (DS) confers a high risk of Alzheimer's disease (AD) and is a genetically determined form of AD. As such, DS provides a uniquely informative biological context in which to investigate AD initiation and progression. Defining the molecular mechanisms that link trisomy 21 to neurodegeneration has broad implications for AD biology and neurotherapeutic development. AREAS COVERED/UNASSIGNED:This review summarizes findings from brain, cerebrospinal fluid, and blood-based proteomic studies, integrated with transcriptomic and multiomics analyses, to characterize molecular pathways underlying AD in DS. The literature was identified through iterative PubMed/MEDLINE searches and manual review of reference lists, considering studies available through June 2026 with no limitation to publication dates. EXPERT OPINION/UNASSIGNED:Brain, lesion-specific, cerebrospinal fluid, and blood-based proteomics, interpreted alongside transcriptomic and complementary omics data, position DSAD as a network-level disorder in which amyloid and tau pathology interact with immune, vascular, metabolic, synaptic, and proteostasis pathways. This integrated proteomic framework helps define shared and subtype-specific mechanisms across DSAD, sporadic AD, and autosomal dominant AD, while supporting biological staging, patient stratification, and therapeutic target discovery.

BACKGROUND:Long-term effect of COVID-19 (Long COVID) may persist for months or years after SARS-CoV-2 infection, but longer-term cardiopulmonary manifestations have not been previously reported. OBJECTIVES/OBJECTIVE:The objective of the study was to characterize cardiopulmonary function after SARS-CoV-2 infection in a digital health substudy of the nationwide Researching COVID-19 to Enhance Recovery Adult Cohort Study. METHODS:Associations between wearable sensor device measures of cardiopulmonary fitness and survey-derived Long COVID symptoms were estimated over a 6-month window at least 6 months after infection using linear regression models adjusted for wear time, age, sex, race/ethnicity, and body mass index. RESULTS:Among 1,475 participants (72% female, 65% non-Hispanic White) a median of 21 months (IQR: 15-31 months) after infection, 498 (34%) had high symptom burden as characterized by the Researching COVID-19 to Enhance Recovery Long COVID Research Index (LCRI). High LCRI (vs low LCRI) was associated with significantly lower heart rate variability (-4.4 ms; 95% CI: -6.5 to -2.4; P < 0.001), higher resting heart rate (+1.5 beats/min [+0.7 to +2.4]; P < 0.001), fewer metabolic equivalent of task minutes (-96.3 [-128.8 to -63.8]; P < 0.001), lower step counts (-1,624 steps/day [-1,952 to -1,296]; P < 0.001), and lower activity levels (-7.9 minutes/day very or fairly active [-10.9 to -5.0]; P < 0.001). Hierarchal clustering analysis identified two subphenotypes with abnormal cardiovascular measures associated with low quality of life scores. CONCLUSIONS:Long COVID is associated with worse cardiovascular fitness. Additional studies are needed to determine if Long COVID is a novel risk factor for incident cardiovascular disease.