Microarray RNA expression analysis of cerebral white matter lesions reveals changes in multiple functional pathways.
OBJECTIVE
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.


CONCLUSIONS
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.
Simpson
Julie E
JE
Academic Units of Pathology, University of Sheffield, Sheffield, UK.
Hosny
Ola
O
Wharton
Stephen B
SB
Heath
Paul R
PR
Holden
Hazel
H
Fernando
Malee S
MS
Matthews
Fiona
F
Forster
Gill
G
O'Brien
John T
JT
Barber
Robert
R
Kalaria
Raj N
RN
Brayne
Carol
C
Shaw
Pamela J
PJ
Lewis
Claire E
CE
Ince
Paul G
PG
D000368:Aged; D000369:Aged, 80 and over; D000375:Aging / Q000473:pathology; D053898:Biosynthetic Pathways / Q000235:genetics*; D001921:Brain / Q000254:growth & development / Q000473:pathology*; D001923:Brain Chemistry / Q000235:genetics; D001927:Brain Diseases / Q000235:genetics* / Q000473:pathology*; D005260:Female; D006801:Humans; D007150:Immunohistochemistry; D008279:Magnetic Resonance Imaging; D008297:Male; D009419:Nerve Tissue Proteins / Q000235:genetics; D020411:Oligonucleotide Array Sequence Analysis; D012313:RNA / Q000032:analysis / Q000096:biosynthesis* / Q000235:genetics; D018075:RNA, Complementary / Q000096:biosynthesis / Q000235:genetics; D015203:Reproducibility of Results; D020133:Reverse Transcriptase Polymerase Chain Reaction
D009419:Nerve Tissue Proteins; D018075:RNA, Complementary; D012313:RNA