on December 24, 2008
Published online before print December 24, 2008, doi: 10.1161/STROKEAHA.108.529214
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Submitted on June 19, 2008
From Academic Units of Pathology (J.E.S., O.H., S.B.W., M.S.F., G.F., C.E.L., P.G.I.) and Neurology (P.R.H., H.H., P.J.S.), University of Sheffield, Sheffield, UK; MRC Biostatistics Unit (F.M.), Institute of Public Health, Cambridge, UK; Institute for Health and Ageing (J.T.O., R.B., R.N.K.), University of Newcastle upon Tyne, UK; Department of Public Health and Primary Care (C.B.), University of Cambridge, Cambridge, UK. * To whom correspondence should be addressed. E-mail: P.G.Ince{at}sheffield.ac.uk.
Background and Purpose—White matter lesions (WML) in brain aging are linked to dementia and depression. Ischemia contributes to their pathogenesis but other mechanisms may contribute. We used RNA microarray analysis with functional pathway grouping as an unbiased approach to investigate evidence for additional pathogenetic mechanisms. Methods—WML were identified by MRI and pathology in brains donated to the Medical Research Council Cognitive Function and Ageing Study Cognitive Function and Aging Study. RNA was extracted to compare WML with nonlesional white matter samples from cases with lesions (WM[L]), and from cases with no lesions (WM[C]) using RNA microarray and pathway analysis. Functional pathways were validated for selected genes by quantitative real-time polymerase chain reaction and immunocytochemistry. Results—We identified 8 major pathways in which multiple genes showed altered RNA transcription (immune regulation, cell cycle, apoptosis, proteolysis, ion transport, cell structure, electron transport, metabolism) among 502 genes that were differentially expressed in WML compared to WM[C]. In WM[L], 409 genes were altered involving the same pathways. Genes selected to validate this microarray data all showed the expected changes in RNA levels and immunohistochemical expression of protein. Conclusion—WML represent areas with a complex molecular phenotype. From this and previous evidence, WML may arise through tissue ischemia but may also reflect the contribution of additional factors like blood–brain barrier dysfunction. Differential expression of genes in WM[L] compared to WM[C] indicate a "field effect" in the seemingly normal surrounding white matter.
Accepted on July 22, 2008
Microarray RNA Expression Analysis of Cerebral White Matter Lesions Reveals Changes in Multiple Functional Pathways
Julie E. Simpson PhD;
Key words: brain ischemia • gene microarray analysis • gene regulation • MRI • neuropathology • white matter disease