Wilcock, D. M. | bioRxiv Science

bioRxiv2023

Terminally differentiated effector memory T cells associate with cognitive and AD-related biomarkers in an aging-based community cohort

Background and PurposeThe immune response changes during aging and the progression of Alzheimers disease (AD) and related dementia (ADRD). Terminally differentiated effector memory T cells (called TEMRA) are important during aging and AD due to their cytotoxic phenotype and association with cognitive decline. However, it is not clear if the changes seen in TEMRAs are specific to AD-related cognitive decline specifically or are more generally correlated with cognitive decline. This study aimed to examine whether TEMRAs are associated with cognition and plasma biomarkers of AD, neurodegeneration, and neuroinflammation in a community-based cohort of older adults. MethodsStudy participants from a University of Kentucky Alzheimers Disease Research Center (UK-ADRC) community-based cohort of aging and dementia were used to test our hypothesis. There were 84 participants, 44 women and 40 men. Participants underwent physical examination, neurological examination, medical history, cognitive testing, and blood collection to determine plasma biomarker levels (A{beta}42/A{beta}40 ratio, total tau, Neurofilament Light chain (Nf-L), Glial Fibrillary Acidic Protein (GFAP)) and to isolate peripheral blood mononuclear cells (PBMCs). Flow cytometry was used to analyze PBMCs from study participants for effector and memory T cell populations, including CD4+ and CD8+ central memory T cells (TCM), Naive T cells, effector memory T cells (TEM), and effector memory CD45RA+ T cells (TEMRA) immune cell markers. ResultsCD8+ TEMRAs were positively correlated with Nf-L and GFAP. We found no significant difference in CD8+ TEMRAs based on cognitive scores and no associations between CD8+ TEMRAs and AD-related biomarkers. CD4+ TEMRAs were associated with cognitive impairment on the MMSE. Gender was not associated with TEMRAs, but it did show an association with other T cell populations. ConclusionThese findings suggest that the accumulation of CD8+ TEMRAs may be a response to neuronal injury (Nf-L) and neuroinflammation (GFAP) during aging or the progression of AD and ADRD. As our findings in a community-based cohort were not clinically- defined AD participants but included all ADRDs, this suggests that TEMRAs may be associated with changes in systemic immune T cell subsets associated with the onset of pathology.

neuroscience↗

bioRxiv2022

Evaluation of Blood-Based Exosomes as Biomarkers for Aging-Related TDP-43 pathology

INTRODUCTIONLimbic predominant age related TDP-43 encephalopathy (LATE) is a recently characterized brain disease that mimics Alzheimers disease (AD) clinically. To date, LATE is difficult to diagnose antemortem using clinical information or biomarkers. Recent studies suggest concentrations of exosomal protein cargo derived from neuronal and glial cells may serve as useful diagnostic biomarkers for AD and other neurodegenerative diseases. METHODSTDP-43 was evaluated in neuronal (NDE), astrocyte (ADE), and microglial derived exosomes (MDE). Exosome preparations were isolated from the plasma of research subjects with autopsy-confirmed diagnoses, including many with LATE. Quantified TDP-43 concentrations were compared to cohort that included healthy controls, mild cognitively impairment (MCI), and AD dementia with diagnoses other than LATE. RESULTSTDP-43 was significantly elevated in plasma ADEs derived from autopsy confirmed LATE-NC subjects, with or without comorbid AD pathology. Measurable levels of TDP-43 were also detected in exosome depleted plasma; however, TDP-43 levels were not significantly different between persons with and without eventual autopsy confirmed LATE-NC. No correlation was observed between exosomal TDP-43 levels with cognition-based variables, sex, and APOE carrier status. DISCUSSIONBlood-based exosomes, specifically measuring TDP-43 accumulation in ADEs, may serve as a powerful diagnostic tool to rapidly identify subjects who are currently living with LATE-NC.

neuroscience↗