Faculty Bibliography

INTRODUCTION/BACKGROUND:Measuring plasma biomarkers effectively assesses early-stage Alzheimer's disease. METHODS:Subjects were categorized as cognitively unimpaired (CU) (n = 66), CU with subjective cognitive decline (SCD) (n = 100), and mild cognitive impairment (MCI) (n = 25). Plasma biomarkers measured were amyloid beta (Aβ) 40, Aβ42, neurofilament light chain (NfL), glial fibrillary acidic protein (GFAP), tau phosphorylated at threonine 181 (pTau181), neuroinflammatory biomarkers, and blood-brain barrier biomarkers. Amyloid and tau positron emission tomography (PET) imaging was performed in 186 and 144 subjects, respectively. RESULTS:Comparing those having MCI, both CU and SCD participants had significantly lower amyloid PET standardized uptake value ratio (SUVR) (p < 0.001; p = 0.005). Higher amyloid PET SUVR was significantly associated with higher pTau181 (p = 0.001) and a higher pTau181/Aβ42 ratio (p < 0.001). Higher tau PET SUVR was associated with lower plasma Aβ42 (p = 0.020), older age (p = 0.005), higher GFAP (p = 0.020), and lower interleukin-8 levels (p < 0.001). DISCUSSION/CONCLUSIONS:Our study supports plasma biomarker monitoring of at-risk patients at various stages of pre-dementia.

Reliable structural brain measurements are essential for studying neurodegeneration and for designing adequately powered aging and Alzheimer's disease (AD) research. We evaluated the test-retest reliability of FreeSurfer 7.1 morphometric measures in 100 older adults (mean age 73.5 years) ranging from cognitively unimpaired to dementia. Each participant underwent two T1-weighted 3T MRI scans on the same scanner within a short interval (mean 5.5 weeks), minimizing biological change. Segmentation was performed in both standard cross-sectional and longitudinal FreeSurfer modes, focusing on AD-relevant volumes of entorhinal cortex, hippocampus, lateral ventricles, choroid plexus, and the AD cortical thickness signature. Reliability was quantified using absolute and root-mean-square test-retest differences, standard deviation of differences, and intraclass correlation coefficients. Longitudinal processing improved precision by 15-50% across most measures compared with cross-sectional processing, with the largest gain observed for entorhinal thickness. Larger, anatomically well-defined regions (e.g., hippocampus, AD signature) demonstrated higher reliability than small structures or those with complex geometry (e.g., entorhinal cortex, choroid plexus). Image quality, indexed by the Euler characteristic, was the only factor significantly associated with measurement variability; reliability was unrelated to age, sex, cognitive status, inter-scan interval, or amyloid/tau PET burden. Power analyses indicated that detecting a 1% within-individual change requires sample sizes ranging from 36 (AD signature) to >300 (entorhinal cortex). We observed low reliability of choroid plexus volumetry by FreeSurfer 7. These results provide practical benchmarks for expected FreeSurfer measurement variability in older adults. They highlight the advantages of longitudinal processing and rigorous quality control for research on brain aging and AD.

Understanding the heterogeneous experiences of violence experienced by Black and Latina women over the life course is critical to prevention. We identified four physical violence trajectories experienced by 361 Black and Latina women followed from ages 14 to 39: low/none (44.0%), persistent-moderate (36.8%), peak in the 20s (11.9%), and persistent-high (7.2%) violence exposure. Childhood abuse predicted membership in the three violence-exposed groups, whereas parental closeness, school academic orientation, and neighborhood safety were protective factors. Public health interventions aimed at preventing childhood trauma and ensuring safe interpersonal relationships and environments for girls to thrive are urgently needed.

BACKGROUND:Obstructive sleep apnea (OSA) is associated with Alzheimer's disease (AD) risk. Racial-, ethnic-, and sex-specific mechanisms of OSA and AD risk were examined. METHODS:We analyzed data from 3978 polysomnography patients without cognitive decline aged ≥ 60 including 663 OSA+ patients (284 non-Hispanic White, 207 Black, 172 Hispanic) matched to OSA- cohorts (1:1, n = 663; 1:4, n = 2652) and followed for AD through 2013. RESULTS:During the 8.5 (standard deviation 1.4) year period, 358 patients developed AD. AD risk was higher for Black (adjusted hazard ratio [aHR] 2.24 [1.24-2.71]), Hispanic (aHR 1.73, [1.38-3.51]), White (aHR 1.83, [1.21-3.37]), male (aHR 2.38, [1.31-3.47]), and female (aHR 1.37, [1.14-2.41]) patients. Hypoxia, sleep fragmentation, and sleep duration (p < 0.01) were associated with increased risk. Black and Hispanic, and female patients showed stronger effects for hypoxia and duration, and fragmentation, respectively. DISCUSSION/CONCLUSIONS:Hypoxia, fragmentation, and duration may underlie racial-, ethnic-, and sex-specific effects of AD risk.

Problem alcohol use is prevalent among women who experience male-perpetrated intimate partner violence (IPV). However, the pathways by which this occurs remain poorly understood and understudied among African American women. This study sought to examine context-specific social and psychological mediators of this association. Using structural equation modeling (SEM), we tested a conceptual framework predicting problem alcohol use within 3 months of experiencing physical and/or sexual IPV. The sample included 508 young African American women (median age 21, interquartile range 19-22 years). A modified SEM met prespecified global and local fit index criteria. The model identified four indirect paths from IPV to problem alcohol use. Three of the paths were through the endorsement of drinking contexts: negative coping, social drinking, and intimate drinking. Negative coping and social drinking emerged as the most salient pathways (β = .431, 95% CI [0.107, 0.754]; β = .472 [0.103, 0.841], respectively). A fourth path operated via depressive symptomatology and negative coping. The model predictors explained 35% of the variance in problem alcohol use; findings were consistent with full mediation of IPV and problem drinking. These findings increase the understanding of problem alcohol use among African American women who experience IPV and identify modifiable context-specific risk factors for problem alcohol use. Interventions to reduce problem drinking could incorporate trauma-informed counseling, as part of integrated IPV and substance use care, to reduce depressive symptomatology and enhance drinking refusal skills in response to situational drinking.

Diffusion magnetic resonance imaging offers unique in vivo sensitivity to tissue microstructure in brain white matter, which undergoes significant changes during development and is compromised in virtually every neurological disorder. Yet, the challenge is to develop biomarkers that are specific to micrometer-scale cellular features in a human MRI scan of a few minutes. Here, we quantify the sensitivity and specificity of a multicompartment diffusion modeling framework to the density, orientation, and integrity of axons. We demonstrate that using a machine learning-based estimator, our biophysical model captures the morphological changes of axons in early development, acute ischemia, and multiple sclerosis (total N = 821). The methodology of microstructure mapping is widely applicable in clinical settings and in large imaging consortium data to study development, aging, and pathology.

OBJECTIVE/UNASSIGNED:Young Latinas and Black women drink less than women of other racial/ethnic groups but experience more alcohol-related problems in midlife. This study aims to identify modifiable factors to prevent adult onset of alcohol use disorder (AUD) in this population. METHODS/UNASSIGNED:Data were collected at six time points as part of the Harlem Longitudinal Development Study from 365 Latinas (47%) and Black (53%) women (mean age at time 1 = 14, standard deviation 1.3). Structural equation modeling was used to test hypothesized pathways from childhood physical and sexual abuse to AUD via depressive mood, anxiety disorders, and somatic complaints in the 20s. We also tested the moderation effect of the high school academic environment by including in the structural equation model two latent variable interaction terms between the school environment and each of the abuse variables. RESULTS/UNASSIGNED: = -9.56, 95% CI [-13.95, -5.17]) in the early 20s. CONCLUSIONS/UNASSIGNED:Our findings underscore the need to invest in early violence prevention interventions and in education to ensure equitable access to quality, academically oriented, and safe schools.

PURPOSE/OBJECTIVE:The pathological hallmarks of Alzheimer's disease (AD), amyloid, tau, and associated neurodegeneration, are present in the cortical gray matter (GM) years before symptom onset, and at significantly greater levels in carriers of the apolipoprotein E4 (APOE4) allele. Their respective biomarkers, A/T/N, have been found to correlate with aspects of brain biochemistry, measured with magnetic resonance spectroscopy (MRS), indicating a potential for MRS to augment the A/T/N framework for staging and prediction of AD. Unfortunately, the relationships between MRS and A/T/N biomarkers are unclear, largely due to a lack of studies examining them in the context of the spatial and temporal model of T/N progression. Advanced MRS acquisition and post-processing approaches have enabled us to address this knowledge gap and test the hypotheses, that glutamate-plus-glutamine (Glx) and N-acetyl-aspartate (NAA), metabolites reflecting synaptic and neuronal health, respectively, measured from regions on the Braak stage continuum, correlate with: (i) cerebrospinal fluid (CSF) p-tau181 level (T), and (ii) hippocampal volume or cortical thickness of parietal lobe GM (N). We hypothesized that these correlations will be moderated by Braak stage and APOE4 genotype. METHODS:We conducted a retrospective imaging study of 34 cognitively unimpaired elderly individuals who received APOE4 genotyping and lumbar puncture from pre-existing prospective studies at the NYU Grossman School of Medicine between October 2014 and January 2019. Subjects returned for their imaging exam between April 2018 and February 2020. Metabolites were measured from the left hippocampus (Braak II) using a single-voxel semi-adiabatic localization by adiabatic selective refocusing sequence; and from the bilateral posterior cingulate cortex (PCC; Braak IV), bilateral precuneus (Braak V), and bilateral precentral gyrus (Braak VI) using a multi-voxel echo-planar spectroscopic imaging sequence. Pearson and Spearman correlations were used to examine the relationships between absolute levels of choline, creatine, myo-inositol, Glx, and NAA and CSF p-tau181, and between these metabolites and hippocampal volume or parietal cortical thicknesses. Covariates included age, sex, years of education, Fazekas score, and months between CSF collection and MRI exam. RESULTS:There was a direct correlation between hippocampal Glx and CSF p-tau181 in APOE4 carriers (Pearson's r = 0.76, p = 0.02), but not after adjusting for covariates. In the entire cohort, there was a direct correlation between hippocampal NAA and hippocampal volume (Spearman's r = 0.55, p = 0.001), even after adjusting for age and Fazekas score (Spearman's r = 0.48, p = 0.006). This relationship was observed only in APOE4 carriers (Pearson's r = 0.66, p = 0.017), and was also retained after adjustment (Pearson's r = 0.76, p = 0.008; metabolite-by-carrier interaction p = 0.03). There were no findings in the PCC, nor in the negative control (late Braak stage) regions of the precuneus and precentral gyrus. CONCLUSIONS:Our findings are in line with the spatially- and temporally-resolved Braak staging model of pathological severity in which the hippocampus is affected earlier than the PCC. The correlations, between MRS markers of synaptic and neuronal health and, respectively, T and N pathology, were found exclusively within APOE4 carriers, suggesting a connection with AD pathological change, rather than with normal aging. We therefore conclude that MRS has the potential to augment early A/T/N staging, with the hippocampus serving as a more sensitive MRS target compared to the PCC.