Date of Award

9-16-2010

Document Type

Open Access Thesis

Degree Name

Medical Doctor (MD)

First Advisor

Walter N. Kernan, MD

Second Advisor

Hal Blumenfeld, MD, PhD

Third Advisor

Joseph Schindler, MD

Abstract

WHITE MATTER HYPERINTENSITY VOLUME AS A BIOMARKER OF OXIDATIVE STRESS IN ACUTE ISCHEMIC STROKE Zachary A. Corbin, Natalia S. Rost, MGH Stroke Service, Department of Neurology, Massachusetts General Hospital; Jeffrey B. Blumberg, Paul E. Milbury, Antioxidant Research Laboratory, Jean Mayer USDA Human Nutrition Research Center on Aging, Tufts University, Boston, MA; Michael K. Parides, Department of Health Evidence and Policy, Mount Sinai School of Medicine, New York, NY; and Karen L. Furie, MGH Stroke Service, Department of Neurology, Massachusetts General Hospital (Sponsored by Walter N. Kernan, Section of General Internal Medicine, Department of Internal Medicine, Yale University School of Medicine, New Haven, CT). Oxidative stress contributes to brain injury during ischemic stroke, but antioxidant clinical trials have been unable to demonstrate a benefit to date. The all comers approach to patient selection in these trials may have contributed to their lack of success. We hypothesize that white matter hyperintensity is a biomarker that can identify ischemic stroke patients with increased levels of oxidative stress and improve future trials. White matter hyperintensity represents chronic loss of cellular brain tissue and has been correlated with oxidative stress in humans and animal models. To test our hypothesis, we examined the correlation between white matter hyperintensity volume and molecular biomarkers of oxidative stress in patients with acute ischemic stroke. The patients for our study were a subset of participants in an ongoing prospective biomarker study at Massachusetts General Hospital and the Brigham and Womens Hospital. From all participants in that parent study, we selected patients if they had an analyzable MRI obtained within 72 hours of stroke onset. During the parent study, the plasma Oxygen Radical Absorbance Capacity and urinary 8-hydroxy-2-deoxy-guanosine levels were measured at baseline (between 0 and 9 hours after stroke onset) and plasma F2-isoprostane levels were measured at baseline and again at 48 hours after stroke onset. White matter hyperintensity volume was determined using a validated semi-automated analysis of brain MRI. Baseline characteristics we examined included demographic features, comorbid illness, and body mass index, and 3-month functional outcomes measured by the modified Rankin Scale score and Barthel Index of Activities of Daily Living. White matter hyperintensity volumes were adjusted for head size using intracranial area measurements and log-transformed prior to statistical analysis. Correlations were performed between the log of the normalized white matter hyperintensity volume and age, functional scores, and biomarkers of oxidative stress. Out of a projected 600 patient cohort in the parent study, an estimated 80% will be eligible for this substudy. At the time of this analysis, measurements had been completed for 158 patients. Mean age was 71±15 years; 56% were male; 71% had hypertension, 44% had hyperlipidemia, 32% had atrial fibrillation, and 20% had diabetes mellitus. Mean log of the normalized white matter hyperintensity volume was 1.38±1.32. Log of the normalized white matter hyperintensity volume was correlated with age (ρ=0.62, p<0.0001), modified Rankin Scale (ρ=0.20, p=0.04), and Barthel Index (ρ=-0.21, p=0.04). White matter hyperintensity volume did not correlate significantly with molecular biomarkers of oxidative stress. In conclusion, our analysis showed that that white matter hyperintensity volume does not correlate with systemic molecular biomarkers of oxidative stress measured at baseline or 48 hours. As expected, white matter hyperintensity volume does correlate with age and functional scores in patients with acute ischemic stroke.

Comments

This is an Open Access Thesis.

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