Longitudinal Neurometabolic Outcomes of Traumatic Stress-Related Accelerated Cellular Aging

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Early onset of age-related diseases, such as cardiometabolic disorders, inflammatory syndromes, and neurodegenerative conditions, exact a large personal, economic, and societal toll and lead to shortened healthspan and lifespan. Traumatic stress (trauma-related psychiatric symptoms) and genetic factors increase the risk for an acceleration in the underlying pace of biological aging, as indicated by changes in peripheral DNA methylation patterns (e.g., estimates of “epigenetic age”), increased inflammation, and metabolic pathology. Alterations in these processes may hold predictive value for subsequent brain health. The aims of this project are to examine traumatic stress-related accelerated aging in the periphery as an early predictor of alterations in the neurochemistry of the brain and in neurocognitive performance over time. The study will also examine genetic factors that may accentuate these associations. This project will build on two waves of existing data, which include genotypes, psychological and neuropsychological assessments, and banked plasma samples, by recruiting 160 participants in late middle age/early old age (all of whom have trauma exposure and symptoms of traumatic stress) to return for a third assessment that is 5-15 years after baseline. Participants will undergo cutting-edge magnetic resonance spectroscopy to asses for alterations in prefrontal neurometabolites (including those relevant to neuroinflammation and neuronal viability, such as myo-inositol and n-acetyl aspartate, respectively) and to examine neurocognitive performance, including assessment of mild cognitive impairment. Banked DNA and plasma samples from the initial two time points, and new peripheral samples from the third time point will be used to examine biomarkers that predict subsequent brain health. The study will obtain measures of inflammation (e.g., cytokines) and neuropathology (e.g., amyloid beta and total tau) using state-of-the-art Simoa® technology which yields extremely sensitive and precise estimates of each analyte. Epigenome-wide DNA methylation will be obtained to examine accelerated epigenetic age (i.e., when estimates of cellular age from established DNA methylation algorithms exceed chronological age). Using longitudinal path analyses across the three time points of data, the study will examine peripheral biomarkers (accelerated epigenetic age, inflammation, metabolic- and neuro-pathology) as mediators of the association between prior traumatic stress and subsequent neural health. The study will examine genetic variables, such as genome-wide risk scores for Alzheimer’s disease, cardiometabolic pathology, and inflammation as well as genotypes relevant to dementia (i.e., in apolipoprotein or APOE) that may moderate these associations. Ultimately, the study will identify early, peripheral prognostic markers of subsequent accelerated aging in the brain, delineate the subpopulations at greatest risk by virtue of psychiatric, genetic, and peripheral biomarker profiles, and substantially advance the science of accelerated cellular aging across the periphery and brain.