Faculty Bibliography

Biomarkers of cerebral amyloid angiopathy (CAA) are critically needed. We recently identified semaphorin 3G (SEMA3G) as a novel protein selectively enriched in CAA. Here, we aimed to determine if SEMA3G was a selective marker of CAA in a large cohort of human brain tissue spanning multiple neurodegenerative diseases and three brain regions, and to determine if SEMA3G directly interacts with amyloid beta (Aβ). Multiplexed immunofluorescence showed that SEMA3G significantly accumulated only in CAA⁺ blood vessels in the brain in all cases. We also showed that SEMA3G preferentially associated with Aβ₄₀, Aβ_pS8 and Aβ_pE3, but not Aβ₄₂. Thioflavin T assays and transmission electron microscopy showed that SEMA3G directly interacted with Aβ and slowed Aβ aggregation in vitro, and that this effect was more pronounced for Aβ₄₀ than Aβ₄₂. Together our results demonstrate that SEMA3G is a highly specific marker of CAA in the brain.

Sensory processing is fundamentally shaped by stimulation history. For example, in visual cortex, neural responses are reduced for repeated or sustained stimuli (adaptation). These phenomena are well characterized and effectively modeled by divisive normalization. We asked whether these same computational principles govern somatosensory processing. We used fMRI (6 participants, all female) and intracranial electroencephalography (iEEG, 2 participants, both male) to measure responses to time-varying vibrotactile stimuli in human somatosensory cortex. Stimuli consisted of single- and paired-pulses with durations and interstimulus intervals ranging from 0.05 to 1.2 s. We extracted BOLD time courses to capture neural response amplitudes, and high-frequency iEEG broadband envelopes to capture fast neural dynamics. In both experiments, we observed pronounced sub-additive temporal summation. Responses to longer or repeated stimuli were consistently lower than predicted by linear integration. Computational modeling revealed that divisive normalization models outperformed linear models in cross-validated accuracy across both datasets. These results demonstrate that somatosensory temporal dynamics closely mirror those in the visual system. Our findings suggest that the nervous system employs similar computational principles across modalities to encode sensory information across time.Significance statement How the brain integrates sensory information over time is a fundamental question in neuroscience. While nonlinear temporal integration is well documented in visual cortex, it has not been extensively mapped in the human somatosensory system. By combining fMRI with intracranial EEG in humans, we demonstrate that somatosensory responses to tactile stimulation exhibit subadditive temporal summation. This nonlinearity is accurately captured by a divisive normalization model, matching observations in the visual system. Our results suggest that normalization is a canonical computation shared across different modalities to manage temporal dynamics, providing a unified framework for understanding how the brain encodes dynamic sensory stimuli.

Hyperhomocysteinemia (HHcy), a risk factor for cardiovascular, neurodegenerative, and metabolic dysfunctions in humans, has been recapitulated in murine models by genetic and dietary modifications. The relevance of HHcy in clinical and experimental settings has led to the development of various analytical techniques with varying sensitivity and sample volume requirements. This study uses a fit-for-purpose, small-volume LC-MS/MS workflow to quantify plasma homocysteine (Hcy), methionine (Met), and cysteine (Cys) in a diet-induced HHcy mouse model. Using these assays that overcome limitations imposed by sample availability in small animals, our study evaluated circulating levels of these amino acids in C57BL/6 mice fed a HHcy-inducing diet rich in Met and lacking vitamins B6, B9, and B12. The increased Hcy and decreased Cys plasma concentrations observed in these mice correlated with decreased glutathione concentrations in brain homogenates and concomitant increase in the activity of the antioxidant enzyme Glutathione-S-Transferase and in the levels of the lipid peroxidation marker malondialdehyde. Overall, our work links plasma HHcy to the induction of brain oxidative stress, supporting the role of dietary modifications as complementary therapeutic strategies for neurodegenerative conditions.

BACKGROUND/UNASSIGNED:Atrial fibrillation (AF) is the most common cardiac arrhythmia worldwide and is associated with an increased risk of adverse outcomes. Age is an important risk factor for AF with a sharp rise in prevalence after the age of 60 years. Despite a rising share of older adults in Africa, there is a paucity of data regarding AF burden in this demographic. OBJECTIVE/UNASSIGNED:This study aimed to determine the prevalence, clinical characteristics, and associated factors of AF among adults 60 years and older attending noncardiac outpatient clinics at a tertiary hospital in Tanzania. METHODS/UNASSIGNED:We conducted a cross-sectional study among consenting adults aged 60 years and older at noncardiac outpatient clinics of Muhimbili National Hospital from June 2021 to February 2022. A structured questionnaire was used to collect sociodemographic and clinical characteristics of participants. They were screened for AF using a smartphone-connected single-lead electrocardiography (ECG) device (KardiaMobile, AliveCor). Probable AF was confirmed by 12-lead ECG. Multivariable logistic regression was used to determine factors associated with AF. Data analysis was performed using Stata version 13 (StataCorp LLC). RESULTS/UNASSIGNED:< .001) were independently associated with AF. CONCLUSION/UNASSIGNED:AF is common and underdiagnosed and carries a high stroke risk among elderly outpatients in Tanzania. Opportunistic screening of the elderly for AF in low-resource countries with 1-lead ECG is feasible and has the potential to reduce the burden of stroke.

BACKGROUND:Family caregivers of people living with Lewy body dementia (PLBD) experience significant strain and adverse health outcomes that consequently affect the health of their loved ones with Lewy Body Dementia (LBD). Effective LBD caregiver interventions are needed. Building on pilot work, our objective is to test the effects of PERSEVERE (Peer Mentor Support and Caregiver Education)- a 12-week peer mentor-supported, LBD-specific educational intervention -on caregiver knowledge, attitudes, strain, and PLBD quality of life and healthcare utilization in a national, virtual, randomized controlled trial. METHODS:Partnering with LBD caregiver advisors and advocacy organizations, we are recruiting and enrolling 180 seasoned caregivers (having cared for a PLBD with ≥3 years of cognitive symptoms) and 502 novice LBD family caregivers (<3 years of cognitive symptoms). Seasoned caregivers train as Mentors. Novice caregivers are randomized 1:1 in cohorts of 100 to (1) the Mentee group receiving weekly Mentor calls covering a novel LBD curriculum focused on symptom management, future planning, and caregiver support, or (2) the attention-control group receiving pre-existing resources for self-directed learning. Primary outcomes include change from baseline in caregiver knowledge and attitudes at 12 weeks (post-intervention) and caregiver strain at nine months (follow-up). Secondary outcomes include engagement with materials and/or mentor, satisfaction, future interest, and change in PLBD quality of life and PLBD healthcare utilization at nine months. DISCUSSION/CONCLUSIONS:A peer mentor-delivered LBD-focused curriculum may improve caregiver and PLBD outcomes in a cost-effective, scalable manner. PERSEVERE has experienced robust national enrollment and retention within the first 18 months of recruitment, with outcomes forthcoming. Trial Registration https://clinicaltrials.gov/study/NCT06389032, registered on April 24, 2024.

BACKGROUND:Visual evoked potential (VEP) P100 latency is routinely used to assess optic nerve demyelination. However, there is no established methodology for disentangling whether shifts in VEP P100 latency may reflect upstream changes in the visual pathway, such as the level of the retina, or whether these delays could be reflective of downstream disturbances in broader brain structure and functioning. OBJECTIVE:To determine the relationship between VEP-based P100 and MRI-based outcomes in people with MS (PwMS) after accounting for structural retinal changes assessed by spectral domain optical coherence tomography (OCT). METHODS:64 study participants underwent OCT, VEP, and MRI. Standardized VEP assessment derived monocular P100 latency for both eyes. Similarly, OCT performed on Heidelberg Spectralis hardware provided peripapillary retinal nerve fiber layer (pRNFL) thickness. Mediation analyses were performed to assess the relationship between P100 and MRI-based outcomes, adjusting for mediating effects of pRNFL and age. RESULTS:VEP-based P100 was significantly associated with lower whole brain volume (WBV) (p=0.0037), with 87.8% of the total effect being both direct and independent from RNFL and the significant age-WBV covariate effect. Similarly, greater VEP-based P100 latency was directly and independently predictive of lower gray matter volume (GMV) (p=0.015) and greater T2-FLAIR LV (p=0.0036) after adjusting for RNFL and age mediating effects. CONCLUSION/CONCLUSIONS:VEP-based P100 latency shows both age- and RNFL-independent associations with MRI-based MS outcomes. In addition to their established diagnostic utility, VEP measures may provide a neurophysiological, objective metric to assess neurodegeneration.

OBJECTIVE/UNASSIGNED:Little is known about shifting from pediatric to adult-focused multiple sclerosis (MS) care. This study aims to explore transition of care and follow-up in the US pediatric-onset MS (POMS) population. METHODS/UNASSIGNED:Surveys were distributed to 10 sites in the US Network of Pediatric MS Centers (US NPMSC) about transition-of-care practices. A cohort of POMS/clinically isolated syndrome (CIS) at 12 US NPMSC sites was analyzed. The primary comparison was between < 18 and ≥ 18-years of age. The primary outcome was 1- and 2-year lapse in last follow-up visit, measured from last recorded database visit to data lock date or, if ≥ 18 years of age, up to 1 year after a patient reached their site's typical transition age, if earlier. Secondary outcomes were baseline factors associated with follow-up lapse. The model was adjusted for preidentified confounders. RESULTS/UNASSIGNED: = 0.007). Platform injectable disease-modifying therapy was associated with greater and intravenous with lesser hazard of lapse in follow-up, while MS was associated with lower hazard than CIS. CONCLUSION/UNASSIGNED:Variable transition-of-care practices and barriers were reported by major US POMS centers. Before typical transition age, age ≥ 18 was associated with greater hazard of 1- and 2-year follow-up lapse than < 18. Developing standardized, targeted transition-of-care practices in POMS may be important.

PURPOSE/OBJECTIVE:The objective of this study was to describe electrocardiogram (ECG) abnormalities captured during video electroencephalogram monitoring in a series of children and adolescents. METHODS:This is a multicenter case series from four pediatric comprehensive epilepsy centers. There was no systematic review of a database; this was a case series with variable methods of patient recall/identification. Patients were divided into three groups according to ECG findings: (1) ictal ECG abnormalities (excluding sinus tachycardia), (2) cardiac disease mimicking seizures, and (3) incidental ECG abnormalities found during electroencephalogram/video-electroencephalogram monitoring. Ictal asystole was defined as an RR interval longer than 3 seconds and at least twice as long as the previous RR interval. RESULTS:There were 22 patients identified with pathologic ECG findings (7 females, 15 males), ranging from 5 months old to 17 years old (mean = 9.3 years). Ictal ECG abnormalities were seen in five patients: asystole in three, and bradycardia and second-degree heart block in one each. Cardiac arrhythmia triggering syncope/altered mental status was seen in 11 patients: asystole in three; Wolff-Parkinson-White syndrome in three; premature ventricular contraction in two; and ventricular tachycardia, second-degree heart block, and Brugada syndrome in one each. Incidental ECG abnormalities were found in six patients (premature ventricular contraction in four, second-degree heart block and bradycardia in one each). CONCLUSIONS:The identification of cardiac abnormalities in children undergoing evaluation for a possible seizure disorder allows not only optimization of seizure management but also guides differential diagnosis, specific cardiological interventions, and avoidance of antiseizure medication that might exacerbate cardiac arrhythmias. It is crucial to pay attention to the ECG channel of the electroencephalogram recordings, especially in the peri-ictal period.

IMPORTANCE/UNASSIGNED:Antibiotic prescribing varies across primary care physicians (PCPs) and disproportionately harms older adults, yet whether residency training is a factor in this variation is unknown. OBJECTIVE/UNASSIGNED:To evaluate whether PCPs' Accreditation Council for Graduate Medical Education (ACGME) competency ratings toward the end of residency are associated with their early-career pattern of antibiotic prescribing to older adults. DESIGN, SETTING, AND PARTICIPANTS/UNASSIGNED:This cohort study involved graduates of US ACGME-accredited internal medicine and family medicine residency programs between January 1, 2015, and December 31, 2020, who were in their first 5 years of primary care practice. Their ACGME Milestone ratings (hereafter competency ratings) were linked to Medicare Parts B and D public claims from January 1, 2015, to December 31, 2022. Data analysis was conducted between March 2024 and May 2026. EXPOSURE/UNASSIGNED:Overall competency rating in the middle of the final year of residency. Ratings for 22 subcompetencies (5-point developmental scale) were averaged within 6 core competency domains (patient care, medical knowledge, professionalism, interpersonal and communication skills, systems-based practice, and practice-based learning and improvement), averaged across domains, and then standardized at the residency program level. MAIN OUTCOME AND MEASURE/UNASSIGNED:Annual antibiotic prescription rate. This primary outcome was expressed as an incidence rate ratio (IRR) adjusted for physician, residency program, practice location, and patient-panel factors. Residency training program was examined as a secondary factor. RESULTS/UNASSIGNED:The analysis included 31 800 PCPs (mean [SD] age on practice entry, 32.8 [4.2] years; 15 990 females [50%]) who graduated from 1090 residency programs, representing 129 225 physician-years of prescribing data. Among these physicians, 58% graduated from a US medical school, 90% earned an MD degree, and 51% specialized in internal medicine and 49% specialized in family medicine. Each physician panel had a mean (SD) of 169 (144) Medicare beneficiaries per year (mean [SD] age, 70.3 [3.5] years; 59% female patients). Physicians prescribed a mean (SD) of 54.1 (52.2) antibiotics per year, and the full cohort wrote 7 664 372 antibiotic prescriptions across the study period. In unadjusted analyses, graduates from internal medicine and family medicine residency programs with highest vs lowest quintile prescribing rates prescribed a difference of 14.9 (95% CI, 13.8-15.9; P < .001) and 18.8 (95% CI, 17.9-19.7; P < .001) additional antibiotics per 100 beneficiaries per year, respectively. In adjusted analysis, each 1-SD increase in overall competency rating was associated with 0.7 (95% CI, 0.5-0.9) fewer antibiotic prescriptions per 100 beneficiaries per year (adjusted IRR, 0.98; 95% CI, 0.97-0.99; P < .001). Each year of experience was associated with higher antibiotic prescribing (IRR, 1.01; 95% CI, 1.01-1.02; P < .001), even accounting for the reduction in prescribing that occurred across study years. CONCLUSIONS AND RELEVANCE/UNASSIGNED:This study found that higher assessed competence near the end of residency was associated with lower antibiotic prescribing in early primary care practice. Competency assessments may inform prescribing variation-focused efforts during training and early practice.