PMID- 36514441 OWN - NLM STAT- PubMed-not-MEDLINE LR - 20230423 IS - 2352-8737 (Electronic) IS - 2352-8737 (Linking) VI - 8 IP - 1 DP - 2022 TI - Genetic expression changes and pathologic findings associated with hyperhomocysteinemia in human autopsy brain tissue. PG - e12368 LID - 10.1002/trc2.12368 [doi] LID - e12368 AB - INTRODUCTION: Vascular contributions to cognitive impairment and dementia (VCID) are a leading cause of dementia. An underappreciated, modifiable risk factor for VCID is hyperhomocysteinemia (HHcy), defined by elevated levels of plasma homocysteine, most often due to impaired B vitamin absorption in aged persons. Studies aimed at identifying neuropathologic features and gene expression profiles associated with HHcy have been lacking. METHODS: A subset of research volunteers from the University of Kentucky Alzheimer's Disease Research Center longitudinal cohort came to autopsy and had ante mortem plasma homocysteine levels available. Brain tissue and blood plasma drawn closest to death were used to measure homocysteine and related metabolites in the current pilot study. Genetic expression profiles of inflammatory markers were evaluated using the Human Neuroinflammation NanoString panel. Further analyses included an evaluation of plasma homocysteine effects on amyloid beta, tau, ionized calcium-binding adaptor molecule 1, and glial fibrillary acidic protein immunohistochemistry in the frontal and occipital cortices. Analytes and other study outcomes were evaluated in relation to ante mortem HHcy status: We identified 13 persons with normal ante mortem plasma homocysteine levels (<14 micromol/L) and 18 who had high plasma homocysteine levels (>/=14 micromol/L). RESULTS: Participants with HHcy demonstrated increased levels of several plasma homocysteine cycle metabolites such as total cysteine, S-adenosyl-homocysteine, cystathionine, and choline. Inflammatory gene expression profiles showed a general downregulation in the setting of elevated plasma homocysteine. HHcy was associated with more and longer microglial processes, but smaller and fewer astrocytes, especially in participants of older age at death. HHcy in older participants was also associated with occipital cortex microhemorrhages and increased severity of atherosclerosis throughout the cerebral vasculature. CONCLUSIONS: Increased plasma homocysteine and older age were associated with the downregulation of inflammatory gene expression markers in association with significant glial and vascular pathology changes. Impaired immune function is a plausible mechanism by which HHcy increases cerebrovascular damage leading to impaired cognitive function. CI - (c) 2022 The Authors. Alzheimer's & Dementia: Translational Research & Clinical Interventions published by Wiley Periodicals LLC on behalf of Alzheimer's Association. FAU - Weekman, Erica M AU - Weekman EM AD - Sanders-Brown Center on Aging University of Kentucky Lexington Kentucky USA. FAU - Winder, Zach AU - Winder Z AD - Sanders-Brown Center on Aging University of Kentucky Lexington Kentucky USA. FAU - Rogers, Colin B AU - Rogers CB AD - Sanders-Brown Center on Aging University of Kentucky Lexington Kentucky USA. FAU - Abner, Erin L AU - Abner EL AD - Sanders-Brown Center on Aging University of Kentucky Lexington Kentucky USA. FAU - Sudduth, Tiffany L AU - Sudduth TL AD - Sanders-Brown Center on Aging University of Kentucky Lexington Kentucky USA. FAU - Patel, Ela AU - Patel E AD - Sanders-Brown Center on Aging University of Kentucky Lexington Kentucky USA. FAU - Dugan, Adam J AU - Dugan AJ AD - Sanders-Brown Center on Aging University of Kentucky Lexington Kentucky USA. FAU - Fister, Shuling X AU - Fister SX AD - Sanders-Brown Center on Aging University of Kentucky Lexington Kentucky USA. FAU - Wasek, Brandi AU - Wasek B AD - Baylor Scott and White Research Institute Center of Metabolomics Institute of Metabolic Disease Dallas Texas USA. FAU - Nelson, Peter T AU - Nelson PT AD - Sanders-Brown Center on Aging University of Kentucky Lexington Kentucky USA. FAU - Jicha, Gregory A AU - Jicha GA AD - Sanders-Brown Center on Aging University of Kentucky Lexington Kentucky USA. FAU - Bottiglieri, Teodoro AU - Bottiglieri T AD - Baylor Scott and White Research Institute Center of Metabolomics Institute of Metabolic Disease Dallas Texas USA. FAU - Fardo, David W AU - Fardo DW AD - Sanders-Brown Center on Aging University of Kentucky Lexington Kentucky USA. FAU - Wilcock, Donna M AU - Wilcock DM AD - Sanders-Brown Center on Aging University of Kentucky Lexington Kentucky USA. LA - eng GR - P30 AG072946/AG/NIA NIH HHS/United States PT - Journal Article DEP - 20221208 PL - United States TA - Alzheimers Dement (N Y) JT - Alzheimer's & dementia (New York, N. Y.) JID - 101650118 PMC - PMC9732462 OTO - NOTNLM OT - Alzheimer's disease OT - astrocytes OT - atherosclerosis OT - hyperhomocysteinemia OT - microglia OT - microhemorrhages OT - neuroinflammation OT - vascular contributions to cognitive impairment and dementia COIS- The authors declare they have no conflicts of interest. Author disclosures are available in the supporting information. EDAT- 2022/12/15 06:00 MHDA- 2022/12/15 06:01 PMCR- 2022/12/08 CRDT- 2022/12/14 01:56 PHST- 2022/07/12 00:00 [received] PHST- 2022/11/09 00:00 [revised] PHST- 2022/11/11 00:00 [accepted] PHST- 2022/12/14 01:56 [entrez] PHST- 2022/12/15 06:00 [pubmed] PHST- 2022/12/15 06:01 [medline] PHST- 2022/12/08 00:00 [pmc-release] AID - TRC212368 [pii] AID - 10.1002/trc2.12368 [doi] PST - epublish SO - Alzheimers Dement (N Y). 2022 Dec 8;8(1):e12368. doi: 10.1002/trc2.12368. eCollection 2022.