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(Circulation. 2005;111:212-221.)
© 2005 American Heart Association, Inc.

Stroke

Using Peripheral Blood Mononuclear Cells to Determine a Gene Expression Profile of Acute Ischemic Stroke

A Pilot Investigation

David F. Moore, MD, PhD, DIC; Hong Li, MD; Neal Jeffries, PhD; Violet Wright, RN, DNSc; Ronald A. Cooper, Jr, BA; Abdel Elkahloun, PhD; Monique P. Gelderman, PhD; Enrique Zudaire, PhD; Gregg Blevins, MD; Hua Yu, MD; Ehud Goldin, PhD; Alison E. Baird, FRACP, PhD

From the Section of Neurology, University of Manitoba, Winnipeg, Manitoba, Canada (D.F.M.); Stroke Neuroscience Unit (H.L., V.W., H.Y., A.E.B.), Biostatistics Branch (N.J.), Micro-Array Core Facility (R.A.C., A.E.), Neuroimmunology Branch (G.B.), and Developmental and Metabolic Neurology Branch (E.G.), National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, Md; Laboratory of Cellular Hematology, CBER, FDA, Rockville, Md (M.P.G.); and Cell and Cancer Biology Branch, National Cancer Institute, NIH, Bethesda, Md (E.Z.).

Correspondence to Alison E. Baird, FRACP, PhD, Stroke Neuroscience Unit, NINDS/NIH, 10 Center Dr, MSC1294, Room 3N258, Bethesda, MD 20892-1294. E-mail bairda{at}ninds.nih.gov

Received May 26, 2004; revision received September 11, 2004; accepted October 20, 2004.

Background— Direct brain biopsy is rarely indicated during acute stroke. This study uses peripheral blood mononuclear cells (PBMCs) to determine whether a systemic gene expression profile could be demonstrated in patients with acute ischemic stroke.

Methods and Results— Using oligonucleotide microarrays, we compared the gene expression profile of an index cohort of 20 patients with confirmed ischemic stroke on neuroimaging studies with that of 20 referent subjects. Validation studies used quantitative real-time polymerase chain reaction to measure the levels of 9 upregulated genes in the index cohort, and an independent cohort of 9 patients and 10 referent subjects was prospectively studied to determine the accuracy of the Prediction Analysis for Microarrays list to classify stroke. After correction for multiple comparisons with the Bonferroni technique, 190 genes were significantly different between the stroke and referent groups. Broad classes of genes included white blood cell activation and differentiation (60%), genes associated with hypoxia and vascular repair, and genes potentially associated with an altered cerebral microenvironment. Real-time polymerase chain reaction confirmed increased mRNA expression in 9 of 9 upregulated stroke-associated genes in the index cohort. A panel of 22 genes derived from the Prediction Analysis for Microarrays algorithm in the index cohort classified stroke in the validation cohort with a sensitivity of 78% and a specificity of 80%. Control for the Framingham stroke risk score revealed only a partial dependence of the stroke gene expression profile in PBMCs on vascular risk.

Conclusions— This study demonstrated an altered gene expression profile in PBMCs during acute ischemic stroke. Some genes with altered expression were consistent with an adaptive response to central nervous system ischemia.

Key Words: cerebral infarction • genes • ischemia • stroke

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