Journal
BRAIN PATHOLOGY
Volume 25, Issue 1, Pages 35-43Publisher
WILEY
DOI: 10.1111/bpa.12219
Keywords
aging; blood-brain barrier; dementia; small vessel disease; vascular; white matter lesions
Categories
Funding
- UK Medical Research Council
- MRC [MR/J004308/1]
- Alzheimer's Research UK (ARUK)
- Biotechnology and Biological Sciences Research Council (BBSRC)
- Department of Health
- Medical Research Council [MRC/G9901400, MRC U.1052.00.0013, MRC/G0900582/1]
- UKNIHR Biomedical Research Centre for Ageing and Age-related Disease
- NIHR Cambridge Biomedical Research Centre
- Cambridgeshire and Peterborough NIHR CLAHRC
- Nottingham University Hospitals NHS Trust
- University of Sheffield
- Sheffield Teaching Hospitals NHS Foundation Trust
- Alzheimers Research UK [ART-PG2010-5] Funding Source: researchfish
- Biotechnology and Biological Sciences Research Council [BB/K006711/1] Funding Source: researchfish
- Medical Research Council [MR/L016451/1, G0900652, G9901400, MR/J004308/1, G0502157, G0400074, G1100540, MR/L022656/1] Funding Source: researchfish
- National Institute for Health Research [NF-SI-0611-10084] Funding Source: researchfish
- BBSRC [BB/K006711/1] Funding Source: UKRI
- MRC [G9901400, MR/L016451/1, G0502157, G0900652, G1100540, MR/L022656/1, G0400074] Funding Source: UKRI
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Cerebral white matter lesions (WML) are common in the aging brain and are associated with dementia and depression. They are associated with vascular risk factors and small vessel disease, suggesting an ischemic origin, but recent pathology studies suggest a more complex pathogenesis. Studies using samples from the population-representative Medical Research Council Cognitive Function and Ageing Study neuropathology cohort used post-mortem magnetic resonance imaging to identify WML for further study. Expression of hypoxia-related molecules and other injury and protective cellular pathways in candidate immunohistochemical and gene expression microarray studies support a role for hypoxia/ischemia. However, these approaches also suggest that immune activation, blood-brain barrier dysfunction, altered cell metabolic pathways and glial cell injury contribute to pathogenesis. These abnormalities are not confined to WML, but are also found in apparently normal white matter in brains with lesions, suggesting a field effect of white matter abnormality within which lesions arise. WML are an active pathology with a complex pathogenesis that may potentially offer a number of primary and secondary intervention targets.
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