Genetic expression changes and pathologic findings associated with hyperhomocysteinemia in human autopsy brain tissue
Abstract 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 absor...
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Wiley
2022-01-01
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| Series: | Alzheimer’s & Dementia: Translational Research & Clinical Interventions |
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| Online Access: | https://doi.org/10.1002/trc2.12368 |
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| author | Erica M. Weekman Zach Winder Colin B. Rogers Erin L. Abner Tiffany L. Sudduth Ela Patel Adam J. Dugan Shuling X. Fister Brandi Wasek Peter T. Nelson Gregory A. Jicha Teodoro Bottiglieri David W. Fardo Donna M. Wilcock |
| author_facet | Erica M. Weekman Zach Winder Colin B. Rogers Erin L. Abner Tiffany L. Sudduth Ela Patel Adam J. Dugan Shuling X. Fister Brandi Wasek Peter T. Nelson Gregory A. Jicha Teodoro Bottiglieri David W. Fardo Donna M. Wilcock |
| author_sort | Erica M. Weekman |
| collection | DOAJ |
| description | Abstract 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 µmol/L) and 18 who had high plasma homocysteine levels (≥14 µmol/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. |
| format | Article |
| id | doaj-art-30a063b788804c178a2bc50bdfe9de99 |
| institution | OA Journals |
| issn | 2352-8737 |
| language | English |
| publishDate | 2022-01-01 |
| publisher | Wiley |
| record_format | Article |
| series | Alzheimer’s & Dementia: Translational Research & Clinical Interventions |
| spelling | doaj-art-30a063b788804c178a2bc50bdfe9de992025-08-20T02:38:27ZengWileyAlzheimer’s & Dementia: Translational Research & Clinical Interventions2352-87372022-01-0181n/an/a10.1002/trc2.12368Genetic expression changes and pathologic findings associated with hyperhomocysteinemia in human autopsy brain tissueErica M. Weekman0Zach Winder1Colin B. Rogers2Erin L. Abner3Tiffany L. Sudduth4Ela Patel5Adam J. Dugan6Shuling X. Fister7Brandi Wasek8Peter T. Nelson9Gregory A. Jicha10Teodoro Bottiglieri11David W. Fardo12Donna M. Wilcock13Sanders‐Brown Center on Aging University of Kentucky Lexington Kentucky USASanders‐Brown Center on Aging University of Kentucky Lexington Kentucky USASanders‐Brown Center on Aging University of Kentucky Lexington Kentucky USASanders‐Brown Center on Aging University of Kentucky Lexington Kentucky USASanders‐Brown Center on Aging University of Kentucky Lexington Kentucky USASanders‐Brown Center on Aging University of Kentucky Lexington Kentucky USASanders‐Brown Center on Aging University of Kentucky Lexington Kentucky USASanders‐Brown Center on Aging University of Kentucky Lexington Kentucky USABaylor Scott and White Research Institute Center of Metabolomics Institute of Metabolic Disease Dallas Texas USASanders‐Brown Center on Aging University of Kentucky Lexington Kentucky USASanders‐Brown Center on Aging University of Kentucky Lexington Kentucky USABaylor Scott and White Research Institute Center of Metabolomics Institute of Metabolic Disease Dallas Texas USASanders‐Brown Center on Aging University of Kentucky Lexington Kentucky USASanders‐Brown Center on Aging University of Kentucky Lexington Kentucky USAAbstract 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 µmol/L) and 18 who had high plasma homocysteine levels (≥14 µmol/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.https://doi.org/10.1002/trc2.12368Alzheimer's diseaseastrocytesatherosclerosishyperhomocysteinemiamicrogliamicrohemorrhages |
| spellingShingle | Erica M. Weekman Zach Winder Colin B. Rogers Erin L. Abner Tiffany L. Sudduth Ela Patel Adam J. Dugan Shuling X. Fister Brandi Wasek Peter T. Nelson Gregory A. Jicha Teodoro Bottiglieri David W. Fardo Donna M. Wilcock Genetic expression changes and pathologic findings associated with hyperhomocysteinemia in human autopsy brain tissue Alzheimer’s & Dementia: Translational Research & Clinical Interventions Alzheimer's disease astrocytes atherosclerosis hyperhomocysteinemia microglia microhemorrhages |
| title | Genetic expression changes and pathologic findings associated with hyperhomocysteinemia in human autopsy brain tissue |
| title_full | Genetic expression changes and pathologic findings associated with hyperhomocysteinemia in human autopsy brain tissue |
| title_fullStr | Genetic expression changes and pathologic findings associated with hyperhomocysteinemia in human autopsy brain tissue |
| title_full_unstemmed | Genetic expression changes and pathologic findings associated with hyperhomocysteinemia in human autopsy brain tissue |
| title_short | Genetic expression changes and pathologic findings associated with hyperhomocysteinemia in human autopsy brain tissue |
| title_sort | genetic expression changes and pathologic findings associated with hyperhomocysteinemia in human autopsy brain tissue |
| topic | Alzheimer's disease astrocytes atherosclerosis hyperhomocysteinemia microglia microhemorrhages |
| url | https://doi.org/10.1002/trc2.12368 |
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