Sex differences in in vivo tau neuropathology in a multiethnic sample of late middle-aged adults.
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ABSTRACT:
SUBMITTER: Palta P
PROVIDER: S-EPMC8178209 | biostudies-literature | 2021 Jul
REPOSITORIES: biostudies-literature
Publications
Sex differences in in vivo tau neuropathology in a multiethnic sample of late middle-aged adults.
Palta Priya P Rippon Brady B Tahmi Mouna M Pardo Michelle M Johnson Aubrey A Tomljanovic Zeljko Z He Hengda H Laing Krystal K KK Razlighi Qolamreza R QR Teresi Jeanne A JA Moreno Herman H Brickman Adam M AM Kreisl William C WC Luchsinger José A JA
Neurobiology of aging 20210323
It is unclear whether women have higher brain tau pathology. The objective of this study was to examine whether women have higher tau burden than men, and whether tau differences are independent of amyloid β (Aβ) burden. We conducted a cross-sectional analysis of a multiethnic sample of 252 nondemented late middle-aged (mean age: 64.1 years) adults with tau and amyloid Positron Emission Tomography (PET) data. Tau burden was measured as global standardized uptake value ratio (SUVR) in the middle/ ...[more]
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Project description:BackgroundFrailty is a clinical syndrome described as reduced physiological reserve and increased vulnerability. Typically examined in older adults, recent work shows frailty occurs in middle-aged individuals and is associated with increased mortality. Previous investigation of global transcriptome changes in a middle-aged cohort from the Healthy Aging in Neighborhoods of Diversity across the Life Span (HANDLS) study demonstrated inflammatory genes and pathways were significantly altered by frailty status and race. Transcriptome differences in frailty by sex remain unclear. We sought to discover novel genes and pathways associated with sex and frailty in a diverse middle-aged cohort using RNA-Sequencing.MethodsDifferential gene expression and pathway analyses were performed in peripheral blood mononuclear cells for 1) frail females (FRAF, n = 4) vs non-frail females (NORF, n = 4), 2) frail males (FRAM, n = 4) vs non-frail males (NORM, n = 4), 3) FRAM vs FRAF, and 4) NORM vs NORF. We evaluated exclusive significant genes and pathways, as well as overlaps, between the comparison groups.ResultsOver 80% of the significant genes exclusive to FRAF vs NORF, FRAM vs NORM, and FRAM vs FRAF, respectively, were novel and associated with various biological functions. Pathways exclusive to FRAF vs NORF were associated with reduced inflammation, while FRAM vs NORM exclusive pathways were related to aberrant musculoskeletal physiology. Pathways exclusive to FRAM vs FRAF were associated with reduced cell cycle regulation and activated catabolism and Coronavirus pathogenesis.ConclusionsOur results indicate sex-specific transcriptional changes occur in middle-aged frailty, enhancing knowledge on frailty progression and potential therapeutic targets to prevent frailty.
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Project description:IntroductionWe examined networks of tau connectivity between brain regions based on correlations of their [18F]flortaucipir positron emission tomography (PET) uptake to evaluate sex-specific differences in brain-wide tau propagation.MethodsPET data of clinically normal and mild cognitive impairment (MCI) subjects from the Alzheimer's Disease Neuroimaging Initiative (ADNI) were used to examine differences in network architectures across the groups.ResultsThe tau-based network architecture resembled progression of tauopathy from Braak stage I to VI regions. Compared to men, women had higher network density and an increased number of direct regional connections in co-occurrence with increased brain-wide tau burden, particularly at MCI. Several regions, including superior parietal lobe and parahippocampus served as connecting bridges between communities at different Braak stages.DiscussionNetwork characteristics in women may favor an accelerated brain-wide tau spread leading to a higher tau burden in women than men with MCI with implications for the greater female preponderance in Alzheimer's disease diagnosis.
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Project description:A clinically and pathologically heterogeneous type of frontotemporal lobar degeneration has abnormal tau pathology in neurons and glia (FTLD-tau). Familial FTLD-tau is usually due to mutations in the tau gene (MAPT). Even FTLD-tau determined by MAPT mutations has clinical and pathologic heterogeneity. Tauopathies are subclassified according to the predominant species of tau that accumulates, with respect to alternative splicing of MAPT, with tau proteins containing three (3R) or four repeats (4R) of ~32 amino acids in the microtubule binding domain. In Pick's disease (PiD), 3R tau predominates, whereas 4R tau is characteristic of corticobasal degeneration (CBD) and progressive supranuclear palsy (PSP). Depending upon the specific mutation in MAPT, familial FTLD-tau can have 3R, 4R or a combination of 3R and 4R tau. PiD is the least common FTLD-tau characterized by neuronal Pick bodies in a stereotypic neuroanatomical distribution. PSP and CBD are more common than PiD and have extensive clinical and pathologic overlap, with no distinctive clinical syndrome or biomarker that permits their differentiation. Diagnosis rests upon postmortem examination of the brain and demonstration of globose tangles, oligodendroglial coiled bodies and tufted astrocytes in PSP or threads, pretangles and astrocytic plaques in CBD. The anatomical distribution of tau pathology determines the clinical presentation of PSP and CBD, as well as PiD. The basis for this selective cortical vulnerability in FTLD-tau is unknown.
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