Faculty Bibliography

OBJECTIVE:This study assesses whether longitudinal quantitative pupillometry predicts neurological deterioration after large middle cerebral artery (MCA) stroke and determines how early changes are detectable. METHODS:This prospective, single-center observational cohort study included patients with large MCA stroke admitted to Boston Medical Center's intensive care unit (2019-2024). Associations between time-to-neurologic deterioration and quantitative pupillometry, including Neurological Pupil Index (NPi), were assessed using Cox proportional hazards models with time-dependent covariates adjusted for age, sex, and Alberta Stroke Program Early CT Score. Models using dilation velocity were compared with partial likelihood ratio tests. Pupillometric changes over 2-h intervals in the 12 h preceding deterioration were analyzed with linear mixed-effects modeling and Tukey's test. Matched referents (age, sex, stroke side, follow-up duration) were used for comparison. Optimal thresholds were identified using the Youden Index. RESULTS:Among 71 patients (mean age 66.5 years; 59.2% women), 32 (45.1%) experienced deterioration. A 1-unit decrease in NPi was associated with a higher hazard of deterioration (hazard ratio 2.46; 95% confidence interval 1.68-3.61). Dilation velocity improved model performance compared to NPi alone. NPi was significantly lower at 0-2 h (3.81 vs. 4.38, p = 0.001) and 2-4 h (3.71 vs. 4.38, p < 0.001) before deterioration compared to 10-12 h prior. Optimal thresholds were 4.01 for NPi, 0.49 mm/s for dilation velocity, and -0.15 change in NPi over 12 h. INTERPRETATION/CONCLUSIONS:Quantitative pupillometry predicts neurological deterioration in MCA stroke, with declines detectable up to 12 h prior. Dilation velocity shows promise as a novel biomarker. ANN NEUROL 2025.

Down syndrome (DS) is strongly associated with Alzheimer's disease (AD) due to APP overexpression, exhibiting Amyloid-β (Aβ) and Tau pathology similar to early-onset (EOAD) and late-onset AD (LOAD). We evaluated the Aβ plaque proteome of DS, EOAD, and LOAD using unbiased localized proteomics on post-mortem paraffin-embedded tissues from four cohorts (n = 20/group): DS (59.8 ± 4.99 y/o), EOAD (63 ± 4.07 y/o), LOAD (82.1 ± 6.37 y/o), and controls (66.4 ± 13.04). We identified differentially abundant proteins when comparing Aβ plaques and neighboring non-plaque tissue (FDR < 5%, fold-change > 1.5) in DS (n = 132), EOAD (n = 192), and LOAD (n = 128), with 43 plaque-associated proteins shared across all groups. Positive correlations were observed between plaque-associated proteins in DS and EOAD (R² = .77), DS and LOAD (R² = .73), and EOAD and LOAD (R² = .67). Top gene ontology biological processes (GOBP) included lysosomal transport (p = 1.29 × 10^-5) for DS, immune system regulation (p = 4.33 × 10^-5) for EOAD, and lysosome organization (p = 0.029) for LOAD. Protein networks revealed a plaque-associated protein signature involving APP metabolism, immune response, and lysosomal functions. In DS, EOAD, and LOAD non-plaque vs. control tissue, we identified 263, 269, and 301 differentially abundant proteins, with 65 altered proteins shared across all cohorts. Non-plaque proteins in DS showed modest correlations with EOAD (R² = .59) and LOAD (R² = .33) compared to the correlation between EOAD and LOAD (R² = .79). Top GOBP term for all groups was chromatin remodeling (p < 0.001), with additional terms for DS including extracellular matrix, and protein-DNA complexes and gene expression regulation for EOAD and LOAD. Our study reveals key functional characteristics of the amyloid plaque proteome in DS, compared to EOAD and LOAD, highlighting shared pathways in endo/lysosomal functions and immune responses. The non-plaque proteome revealed distinct alterations in ECM and chromatin structure, underscoring unique differences between DS and AD subtypes. Our findings enhance our understanding of AD pathogenesis and identify potential biomarkers and therapeutic targets.

OBJECTIVE:The neuropsychological adverse effects of antiseizure medications (ASMs) influence the tolerability, and in turn effectiveness of these medications, which can occur in a dose-dependent fashion. In this study, we examine the neuropsychological effects of perampanel (PER) at 4 mg daily as this dose has not been previously assessed with objective cognitive tests. METHODS:The study was originally designed to assess (1) effects of perampanel at 4 mg using different titration rates, and (2) habituation over time. Due to the COVID-19 pandemic, the study was halted, limiting the sample size needed to analyze titration and habituation effects. Therefore, we compared the neuropsychological effects of perampanel 4 mg daily from non-drug baseline to the end of drug titration and end of drug maintenance in this randomized double-blind study of healthy volunteers. Treatment period was 6 weeks total with 2 weeks of variable titration followed by 4-week maintenance. Composite Z-scores were calculated by combining Z-scores from both cognitive (computerized and non-computerized) and behavioral tests. Secondary analyses were conducted on the independent cognitive and behavioral domain Z-scores, and on the raw scores from 19 items in the full battery. RESULTS:The overall composite Z-scores did not differ across baseline, the end of titration, and the end of maintenance. Similarly, individual cognitive and behavioral domain Z-scores did not differ across the three titration rates. Exploratory analyses of the raw scores were marginally significant on only two of the 19 neuropsychological measures. CONCLUSIONS:Perampanel 4 mg daily was well tolerated with few neuropsychological effects in healthy volunteers.

BACKGROUND:Lipids are of particular interest for the study of neuroinjury and neuroinflammation as structural lipids are major components of myelin, and a variety of lipid species modulate inflammation. In this study, we performed an in-depth lipidomics analysis to identify lipids associated with injury and disease activity. METHODS:Plasma samples were collected from paediatric-onset multiple sclerosis (MS) cases within 4 years of disease onset from 17 sites. The lipidome was measured using untargeted and targeted mass spectrometry. For cross-sectional analyses, the agreement between multiple machine learning models was used to predict neurofilament light chain (NfL) levels. In longitudinal analyses, the association between clinical (relapse count) and imaging (MRI count with ≥1 enhancing or new T2 lesion) outcomes with each metabolite was estimated using adjusted negative binomial regression. RESULTS:At sample collection, 68% of the 435 included individuals were treatment-naive, with a median disease duration of 0.8 years (IQR 0.3-1.7). For longitudinal analyses, 381 and 335 subjects had at least 1 year of clinical and imaging follow-up, respectively. In cross-sectional analyses, NfL chain levels identified structural lipids (phosphatidylcholines and phosphatidylethanolamines) as the highest-performing predictors, including external validation. In contrast, longitudinal analyses found polyunsaturated fatty acids (PUFAs) and their derivatives to be protective from subsequent disease activity (q<0.001, multiple outcomes). CONCLUSION/CONCLUSIONS:There are two categories of lipids associated with MS processes. First, structural lipids strongly associated with NfL levels may result from cell lysis secondary to acute inflammation. In contrast, PUFAs, especially ω-3, had a protective effect on subsequent disease activity.

Neurologic conditions are a leading cause of morbidity and mortality within the United States and worldwide. Brain health is a global concern, and the American Academy of Neurology's Brain Health Initiative promises to drive progress in this field over the next decades. Neurologists with detailed training and insight into brain function are uniquely positioned to apply emerging preventive health data to promote healthy brain development and maintain optimal brain function throughout the lifespan. The neurologist's role in promoting brain health is also vital in patients with active neurologic disease, in whom preventive measures may reduce recurrence or slow progression of disease and may enhance quality of life and overall function. In this Emerging Issues in Neurology article, we present the factors that may protect brain function and frame a practical approach to screening assessments and preventive interventions that neurology clinicians may consider to improve the brain health of patients at all life stages.

IMPORTANCE/UNASSIGNED:A substantial number of individuals worldwide experience long COVID, or post-COVID condition. Other postviral and autoimmune conditions have a female predominance, but whether the same is true for long COVID, especially within different subgroups, is uncertain. OBJECTIVE/UNASSIGNED:To evaluate sex differences in the risk of developing long COVID among adults with SARS-CoV-2 infection. DESIGN, SETTING, AND PARTICIPANTS/UNASSIGNED:This cohort study used data from the National Institutes of Health (NIH) Researching COVID to Enhance Recovery (RECOVER)-Adult cohort, which consists of individuals enrolled in and prospectively followed up at 83 sites in 33 US states plus Washington, DC, and Puerto Rico. Data were examined from all participants enrolled between October 29, 2021, and July 5, 2024, who had a qualifying study visit 6 months or more after their initial SARS-CoV-2 infection. EXPOSURE/UNASSIGNED:Self-reported sex (male, female) assigned at birth. MAIN OUTCOMES AND MEASURES/UNASSIGNED:Development of long COVID, measured using a self-reported symptom-based questionnaire and scoring guideline at the first study visit that occurred at least 6 months after infection. Propensity score matching was used to estimate risk ratios (RRs) and risk differences (95% CIs). The full model included demographic and clinical characteristics and social determinants of health, and the reduced model included only age, race, and ethnicity. RESULTS/UNASSIGNED:Among 12 276 participants who had experienced SARS-CoV-2 infection (8969 [73%] female; mean [SD] age at infection, 46 [15] years), female sex was associated with higher risk of long COVID in the primary full (RR, 1.31; 95% CI, 1.06-1.62) and reduced (RR, 1.44; 95% CI, 1.17-1.77) models. This finding was observed across all age groups except 18 to 39 years (RR, 1.04; 95% CI, 0.72-1.49). Female sex was associated with significantly higher overall long COVID risk when the analysis was restricted to nonpregnant participants (RR, 1.50; 95%: CI, 1.27-1.77). Among participants aged 40 to 54 years, the risk ratio was 1.42 (95% CI, 0.99-2.03) in menopausal female participants and 1.45 (95% CI, 1.15-1.83) in nonmenopausal female participants compared with male participants. CONCLUSIONS AND RELEVANCE/UNASSIGNED:In this prospective cohort study of the NIH RECOVER-Adult cohort, female sex was associated with an increased risk of long COVID compared with male sex, and this association was age, pregnancy, and menopausal status dependent. These findings highlight the need to identify biological mechanisms contributing to sex specificity to facilitate risk stratification, targeted drug development, and improved management of long COVID.

IMPORTANCE/UNASSIGNED:Antiseizure medications (ASMs) are potential teratogens commonly prescribed for multiple indications. ASM fetal exposure can impair neurodevelopment. Folate improves pregnancy outcomes, but higher doses may pose risks. OBJECTIVES/UNASSIGNED:To compare the outcomes of 6-year-old children of women with epilepsy (WWE) vs those of healthy women (HW), and assess the association of outcomes to third-trimester ASM exposures. DESIGN, SETTING, AND PARTICIPANTS/UNASSIGNED:After informed consent, pregnant WWE and HW were enrolled from 2012 through 2016 in this prospective, multicenter, nonrandomized clinical trial. Children were assessed at 6 years of age (2019-2022). Participants were recruited from 20 US epilepsy centers. Study data were analyzed from August 2023 to August 2024. EXPOSURES/UNASSIGNED:Fetal ASM exposures. MAIN OUTCOMES AND MEASURES/UNASSIGNED:The a priori main neurodevelopmental outcome was the blindly assessed Verbal Index Score in 6-year-old children. The Verbal Index Score is calculated as the mean of the scores from the Word Definitions and Verbal Similarities subtests from the Differential Ability Scales, Expressive One-Word Picture Vocabulary Test, Phonological Processing, Comprehension of Instructions, and Sentence Repetition subtests from the Neuropsychological Assessment and Peabody Picture Vocabulary Test. The 2 primary analyses (1) compared children of WWE and HW using linear regression and (2) examined the outcomes of fetal exposure via ASM blood concentrations. Analyses were adjusted for multiple potential confounding factors. Other outcomes and folate exposure-related outcomes were assessed. RESULTS/UNASSIGNED:A total of 1123 pregnant women were screened, and 456 were enrolled (426 did not meet criteria, and 241 chose not to participate). A total of 298 children of WWE (mean [SD] age, 6.4 [4.2] years; 158 female [53.0%]; 140 male [47.0%]) vs 89 children of HW (mean [SD] age, 6.4 [4.2] years; 41 female [46.1%]; 48 male [53.9%]) did not differ on Verbal Index Score (parameter estimate, -0.6; 95% CI, -3.2 to 1.9; P = .64). Exposure-dependent outcomes differed across ASMs. Assessment of other ASMs was limited because 232 of 298 WWE (78%) were taking lamotrigine or levetiracetam alone or in combination. Folate supplementation during the first 12 weeks of pregnancy had positive associations with cognition and behavior with no signal for risks at higher folate doses. CONCLUSIONS AND RELEVANCE/UNASSIGNED:Results of this prospective nonrandomized clinical trial suggest that verbal abilities in children of WWE vs HW did not differ. Exposure-dependent outcomes of ASMs highlight the importance of dosing high enough to protect the mother and fetus from seizures but low enough to protect the fetus. Folate supplementation early in pregnancy including higher doses was associated with improved cognitive and behavioral outcomes. Additional research is needed for ASMs with inadequate information on fetal exposure risks. TRIAL REGISTRATION/UNASSIGNED:ClinicalTrials.gov Identifier: NCT01730170.

INTRODUCTION/BACKGROUND:We evaluated whether higher Dietary Inflammatory Index (DII) scores were associated with increased incidence of all-cause dementia and Alzheimer's disease (AD) dementia over 22.3 years of follow-up in the community-based Framingham Heart Study Offspring cohort. METHODS:One thousand four hundred eighty-seven participants (mean ± standard deviation, age in years 69 ± 6) completed food frequency questionnaires (FFQs) and had incident all-cause dementia and AD surveillance data available. RESULTS:Two hundred forty-six participants developed all-cause dementia (including AD, n = 187) over a median follow-up time of 13.1 years. Higher DII scores, averaged across a maximum of three timepoints, were associated with an increased incidence of all-cause dementia and AD after adjustment for demographic, lifestyle, and clinical covariates (hazard ratio [HR] 1.21, 95% confidence interval [CI] 1.10-1.33, P < 0.001; HR 1.20, 95% CI: 1.07-1.34d, P = 0.001, respectively). DISCUSSION/CONCLUSIONS:Higher DII scores were associated with a higher risk of incident all-cause dementia and AD. Although these promising findings need to be replicated and further validated, our results suggest that diets that correlate with low DII scores may prevent late-life dementia. HIGHLIGHTS/CONCLUSIONS:Higher Dietary Inflammatory Index (DII) scores were associated with an increased incidence of all-cause dementia. Higher DII scores were associated with an increased incidence of Alzheimer's disease dementia. Diets that correlate with low DII scores may prevent late-life dementia.