Using Peripheral Blood Mononuclear Cells to Determine a Gene Expression Profile of Acute Ischemic Stroke A Pilot Investigation
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 microar...
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| Published in | Circulation (New York, N.Y.) Vol. 111; no. 2; pp. 212 - 221 |
|---|---|
| Main Authors | , , , , , , , , , , , |
| Format | Journal Article |
| Language | English |
| Published |
Hagerstown, MD
Lippincott Williams & Wilkins
18.01.2005
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| Subjects | |
| Online Access | Get full text |
| ISSN | 0009-7322 1524-4539 1524-4539 |
| DOI | 10.1161/01.CIR.0000152105.79665.C6 |
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| Abstract | 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. |
|---|---|
| AbstractList | 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. 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. METHOD:S: 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 ( similar to 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. 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.BACKGROUNDDirect 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.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 (approximately 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.METHODS AND RESULTSUsing 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 (approximately 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.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.CONCLUSIONSThis 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. 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. 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 (approximately 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. 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. |
| Author | Zudaire, Enrique Wright, Violet Moore, David F. Li, Hong Gelderman, Monique P. Yu, Hua Cooper, Ronald A. Goldin, Ehud Baird, Alison E. Jeffries, Neal Blevins, Gregg Elkahloun, Abdel |
| Author_xml | – sequence: 1 givenname: David F. surname: Moore fullname: Moore, David F. organization: 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 – sequence: 2 givenname: Hong surname: Li fullname: Li, Hong organization: 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 – sequence: 3 givenname: Neal surname: Jeffries fullname: Jeffries, Neal organization: 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 – sequence: 4 givenname: Violet surname: Wright fullname: Wright, Violet organization: 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 – sequence: 5 givenname: Ronald A. surname: Cooper fullname: Cooper, Ronald A. organization: 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 – sequence: 6 givenname: Abdel surname: Elkahloun fullname: Elkahloun, Abdel organization: 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 – sequence: 7 givenname: Monique P. surname: Gelderman fullname: Gelderman, Monique P. organization: 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 – sequence: 8 givenname: Enrique surname: Zudaire fullname: Zudaire, Enrique organization: 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 – sequence: 9 givenname: Gregg surname: Blevins fullname: Blevins, Gregg organization: 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 – sequence: 10 givenname: Hua surname: Yu fullname: Yu, Hua organization: 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 – sequence: 11 givenname: Ehud surname: Goldin fullname: Goldin, Ehud organization: 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 – sequence: 12 givenname: Alison E. surname: Baird fullname: Baird, Alison E. organization: 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 |
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| Keywords | Vascular disease Cerebral infarction Nervous system diseases Stroke Mononuclear cell Ischemia genes Central nervous system disease Cardiovascular disease Gene expression Cerebrovascular disease Cerebral disorder |
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| Snippet | Background—
Direct brain biopsy is rarely indicated during acute stroke. This study uses peripheral blood mononuclear cells (PBMCs) to determine whether a... Direct brain biopsy is rarely indicated during acute stroke. This study uses peripheral blood mononuclear cells (PBMCs) to determine whether a systemic gene... BACKGROUND: Direct brain biopsy is rarely indicated during acute stroke. This study uses peripheral blood mononuclear cells (PBMCs) to determine whether a... |
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| SubjectTerms | Acute Disease Adaptation, Physiological - genetics Aged Aged, 80 and over Biological and medical sciences Blood and lymphatic vessels Blood vessels and receptors Brain Ischemia - blood Brain Ischemia - genetics Cardiology. Vascular system Cohort Studies Computer Systems Diseases of the peripheral vessels. Diseases of the vena cava. Miscellaneous Female Fundamental and applied biological sciences. Psychology Gene Expression Profiling Gene Expression Regulation Humans Leukocytes, Mononuclear - metabolism Male Medical sciences Middle Aged Neurology Oligonucleotide Array Sequence Analysis Pilot Projects Predictive Value of Tests Prospective Studies Reverse Transcriptase Polymerase Chain Reaction Vascular diseases and vascular malformations of the nervous system Vertebrates: cardiovascular system |
| Subtitle | A Pilot Investigation |
| Title | Using Peripheral Blood Mononuclear Cells to Determine a Gene Expression Profile of Acute Ischemic Stroke |
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