Transcriptional vulnerability of brain regions in Alzheimer's disease and dementia.
This study determined (a) the association between stages of Alzheimer's disease (AD) and overall gene expression change, and (b) brain regions of greatest vulnerability to transcriptional change as the disease progressed. Fifteen cerebrocortical sites and the hippocampus were examined in persons with either no cognitive impairment or neuropathology, or with only AD-associated lesions. Cases were stratified into groups of 7-19 based on the degree of cognitive impairment (clinical dementia rating scale, CDR); neurofibrillary tangle distribution and severity (Braak staging) or density of cerebrocortical neuritic plaque (NP; grouping by NP density). Transcriptional change was assessed by Affymetrix U133 mRNA microarray analysis. The results suggested that (a) gene expression changes in the temporal and prefrontal cortices are more closely related to disease severity than other regions examined; (b) more genes are down-regulated at any given disease severity stage than up-regulated; (c) the degree of gene expression change in a given regions depends on the disease severity classification scheme used; and (d) the classification of cases by CDR provides a more orderly gradient of gene expression change in most brain regions than Braak staging or NP grouping.
Haroutunian
Vahram
V
Department of Psychiatry, The Mount Sinai School of Medicine, New York, NY 10029, USA. vahram.haroutunian@mssm.edu
Katsel
Pavel
P
Schmeidler
James
J
D000369:Aged, 80 and over; D000544:Alzheimer Disease / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D001921:Brain / Q000378:metabolism* / Q000473:pathology / Q000503:physiopathology; D015331:Cohort Studies; D003704:Dementia / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D015536:Down-Regulation / Q000235:genetics; D005260:Female; D020869:Gene Expression Profiling / Q000379:methods; D005786:Gene Expression Regulation / Q000235:genetics*; D005819:Genetic Markers / Q000235:genetics; D020022:Genetic Predisposition to Disease / Q000235:genetics*; D006801:Humans; D008297:Male; D016874:Neurofibrillary Tangles / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D011237:Predictive Value of Tests; D012333:RNA, Messenger / Q000032:analysis / Q000378:metabolism; D012720:Severity of Illness Index; D014158:Transcription, Genetic / Q000235:genetics*
D005819:Genetic Markers; D012333:RNA, Messenger