Faculty Bibliography

Water diffusion gives rise to micron-scale sensitivity of diffusion MRI (dMRI) to cellular-level tissue structure. Precision medicine and quantitative imaging depend on uncovering the information content of dMRI and establishing its parsimonious hardware-independent fingerprint. Based on the rotational SO(3) symmetry, we study the geometry of the dMRI signal and the topology of its acquisition, identify irreducible components and a full set of invariants for the cumulant tensors, and relate them to tissue properties. Including all kurtosis invariants improves multiple sclerosis classification in a cohort of 1189 subjects. We design the shortest acquisitions based on icosahedral vertices to determine the most used invariants in only 1-2 minutes for whole brain. Representing dMRI via scalar invariant maps with definite symmetries will underpin machine learning classifiers of pathology, development, and aging, while fast protocols will enable translation of advanced dMRI into clinic.

PURPOSE/UNASSIGNED:To investigate the short-T1 fraction as a potential biomarker of white matter myelin integrity, using myelin histology as ground truth. METHODS/UNASSIGNED:short-T1 fraction data were acquired from two elderly volunteers with WMHs to demonstrate translational feasibility. RESULTS/UNASSIGNED:significant reductions in short-T1 fractions were detected within WMHs. CONCLUSION/UNASSIGNED:The short-T1 fraction correlated with myelin content in postmortem brain white matter, supporting its potential as a clinically translatable biomarker of myelin integrity.

Subjective cognitive decline (SCD) refers to cognitive concerns that may occur with or without objective impairment on standardized testing. Studies suggest that SCD may be an early clinical marker of Alzheimer's disease and related dementias, and that it can predict future objective cognitive decline and progression to dementia. However, the research that supports these conclusions is primarily based on samples with homogeneous socioeconomic and cultural backgrounds. The limited studies in samples with more diverse representations of racial, ethnic, gender, and sexual orientation characteristics show varying SCD prevalence, correlates, and outcomes. Here, we review this literature, focusing on how to apply the findings to advance our understanding of SCD. We further evaluate how our findings inform a roadmap for future research. Overall, we conclude that broader investigations across more diverse populations enhance our understanding of the factors that may differentially contribute to SCD and shape its utility as a clinical metric.

INTRODUCTION/BACKGROUND:Down syndrome (DS) is caused by a complete or partial trisomy of chromosome 21, resulting in variable intellectual disabilities and a high risk for early-onset Alzheimer's disease (DS-AD). Dysregulation of the mammalian target of rapamycin (mTOR) and insulin (INS) signaling pathways has been reported in DS. We hypothesized that upstream alterations in these two pathways contribute to hippocampal dysfunction in DS-AD. METHODS:We used spatial transcriptomics and localized proteomic techniques to examine mTOR/INS signaling pathways in subregions of the hippocampus in post mortem tissue from individuals with DS-AD and age-matched neurotypical controls. RESULTS:mTOR pathways were significantly altered in specific hippocampal subfields in DS-AD, and INS pathways were significantly altered in dentate granule neurons. DISCUSSION/CONCLUSIONS:These preliminary spatial transcriptomics and localized proteomics findings demonstrate an interplay between select hippocampal mTOR/INS pathways and cellular populations, suggesting potential novel drug targets and early biomarkers for DS.

BACKGROUND AND PURPOSE/OBJECTIVE:Although visibility of Deep Medullary Veins (DMVs) has been suggested as an imaging biomarker for cerebral small vessel disease (CSVD) and brain atrophy, qualitative visual assessment of DMVs may lack reliability. In this study, we used a rigorous, automated approach to segment DMVs on SWI and to estimate a vein voxel fraction (VVF). We hypothesized that VVF would be associated with vascular risk factors, imaging markers of CSVD, and brain volumes. MATERIAL AND METHODS/METHODS:A retrospective analysis of data from participants enrolled in studies of brain aging and prediction of Alzheimer's disease. All underwent 3T MRI (T1WI, FLAIR, SWI, and arterial spin labeling), clinical evaluations, and laboratory tests to assess vascular risks. A SWI image processing pipeline included denoising, bias field correction, adaptive histogram equalization, and multi-scale Jerman filtering that yielded vesselness maps. The vein voxel fraction (VVF) was calculated as a ratio of DMVs voxels in a periventricular region to the volume of the periventricular region. White matter hyperintensities, microbleeds, brain volumes, and CBF were also assessed. RESULTS:This study included 131 cognitively healthy participants, 71 (65, 76) years (median, Q1, Q3), (51%) female, and a subgroup of subjects with cognitive impairment (n=30, 69 (59, 76) years, 43% female). In the unimpaired group, the VVF positively correlated with systolic blood pressure and body mass index. It showed an inverse association with lateral ventricle volume (all at p < 0.05). It was related to white matter hyperintensities volume only in unadjusted analysis. CONCLUSION/CONCLUSIONS:Vein voxel fraction was associated with increased weight and high blood pressure. Possibly, these observations reflect venous stasis. These factors should be accounted for while evaluating brain venous system with SWI. In addition, subcortical atrophy was related to less visible DMVs.

BackgroundSubjective cognitive decline (SCD) is increasingly recognized in some cases as an early clinical stage in the Alzheimer's disease continuum, yet the factors that predict which individuals will progress to objective impairment remain poorly understood.ObjectiveWe evaluated risk factor differences and cognitive domain markers associated with progression in participants with subjective cognitive decline (SCD) at baseline from the NYU Alzheimer's Disease Research Center.MethodsWe included SCD non-decliners (n = 27), who remained stable, and decliners (n = 24), who progressed to mild cognitive impairment or worse, between the second to sixth yearly follow-up visits. Adjusted mixed-effects models examined group differences and associations between demographic, APOE status, psychometric test performance and comorbidities with longitudinal-decline.ResultsOverall, mean (SD) age was 67.4 (9.2) and total follow-up time was 5.1 (1.8) years. Lower education (14.9 (3.2) versus 17.3 (2.1)), Hispanic ethnicity (50.0% versus 11.0%), and hypercholesterolemia (adjusted odds ratio: 6.67) were risk factors for progression in SCD, p ≤ 0.05, whereas APOE status was not. Notably, SCD decliners were at increased risk for both amnestic and non-amnestic cognitive-decline with psychometric changes in memory, executive, and language domains (p < 0.001 for all).ConclusionsThese findings inform further work on SCD outcomes and related biomarkers, as well as preventive studies that target modifiable risk factors for SCD progression.

INTRODUCTION/BACKGROUND:We assessed plasma biomarkers for the diagnosis of early Alzheimer's disease (AD). METHODS: = 45). Plasma assays for amyloid beta (Aβ) 40, Aβ42, neurofilament light chain protein, glial fibrillary acidic protein, and phosphorylated tau181 levels were measured using single molecule array (Simoa) technology. Neuroinflammation and blood-brain barrier (BBB) biomarkers were measured using the Corplex cytokine 10-Plex kit and the angiogenesis 6-Plex kit, respectively. RESULTS:Biomarker levels were regressed by cognitive group, age, sex, race, and apolipoprotein E apoE ε4 status, yielded significant positive associations between age and numerous AD, neuroinflammation, cytokine, and BBB plasma markers. DISCUSSION/CONCLUSIONS:Linear regression analysis, adjusted for age, sex, race, and ApoE status, revealed significant differences between cognitive groups in levels of several plasma biomarkers and associations with age and sex. Neuroinflammation and BBB dysfunction showed significant positive associations with age across different stages of AD.

INTRODUCTION/BACKGROUND:Blood-brain barrier (BBB) dysfunction is an early feature of Alzheimer's disease (AD). Fibrinogen represents a sensitive marker of BBB leakage, but whether it modifies longitudinal tau progression in cognitively unimpaired (CU) individuals remains unknown. METHODS:CU older adults underwent clinical evaluation and cerebrospinal fluid (CSF) assessment of fibrinogen, Aβ42, total tau (tTau), phosphorylated tau 181 (pTau181), and YKL-40. Linear regression tested baseline associations. Linear mixed-effects models tested whether baseline fibrinogen predicted longitudinal pTau181 change. RESULTS:Among 169 CU participants with baseline fibrinogen, 87 had longitudinal pTau181 measurements (mean follow-up 2.5-years). Higher fibrinogen was associated with elevated YKL-40 (β = 0.28, 95% confidence interval [CI] [0.11, 0.45]) but not Aβ42, tTau, or pTau181 at baseline. Baseline fibrinogen modified longitudinal pTau181 trajectories (interaction β = 0.11, 95% CI [0.04, 0.19]), with only participants above the median showing significant pTau181 increases (β = 0.13, 95% CI [0.08, 0.18]). DISCUSSION/CONCLUSIONS:CSF fibrinogen associates cross-sectionally with glial inflammation and predicts accelerated tau accumulation in preclinical AD.

BACKGROUND/UNASSIGNED:Lifestyle interventions are effective in reducing cardiovascular disease (CVD) risk, but few target mothers of toddlers and preschool-aged children. Cardiovascular risk factors may emerge or worsen during this life stage due to high child-rearing demands, with the potential to persist long-term. We scoped the literature to synthesize findings and highlight future research opportunities regarding CVD prevention interventions among mothers of young children. METHODS/UNASSIGNED:We searched PubMed, Scopus, Web of Science, CINAHL, Embase, and APA PsycINFO for 2010-2024 peer-reviewed, English-language articles about CVD risk reduction lifestyle interventions for mothers with young children aged 1-5 years. Due to limited initial results, we broadened this demographic criterion to include mothers with children either <1-5 years (infants to young children) or 1-12 years (young to school-age children). RESULTS/UNASSIGNED:= 2). None addressed nicotine exposure nor sleep. Five studies reported statistically significant results for at least one of their outcomes. CONCLUSION/UNASSIGNED:Very few studies discuss lifestyle interventions for CVD prevention among mothers of young children, highlighting a salient gap and opportunities for additional research in this population.