Vascular Disease Risk Factors and MS Progression: A Study of Brain Metabolism

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 DESCRIPTION: Recent studies suggest that presence of vascular disease risk factors (VDRF) such as diabetes, hypertension, hyperlipidemia, peripheral vascular disease and heart disease can significantly increase the risk of disability progression in multiple sclerosis (MS). There appears to be a dose-response relationship between VDRF and MS disability with the presence of a single VDRF increasing the risk of early gait disability by 51% and the presence of 2 of these conditions increasing the risk to 228%. Among Veterans, VDRF are highly prevalent. In the last two years, among the 19,282 Veterans with MS who received care within the VA system, ~9300 had hyperlipidemia, ~9200 suffered from hypertension and ~3500 had diabetes mellitus. Approximately 5900 MS Veterans had both hypertension and hyperlipidemia. Increasingly, evidence indicates mitochondrial dysfunction and resultant deficiencies in ATP and other high energy phosphorus metabolites contribute to neurodegeneration in MS. Our collaborator Dr. William Rooney at the Oregon Health & Science University Advanced Imaging Research Center has developed techniques to measure high energy phosphorus (HEP) metabolites and cerebral blood flow using a 7 Tesla (T) magnetic resonance imaging (MRI) instrument and demonstrated that people with MS have gray matter deficiencies in HEP metabolites as well as cerebral blood flow abnormalities. The purpose of this research is to determine if VDRF are associated with increased abnormalities in cerebral blood flow and metabolism in people with MS as assessed with high-field brain MRI and if these abnormalities contribute to brain atrophy and clinical disease progression in MS. The overriding hypothesis of this project is that vascular risk factors in MS increase the rate of disease progression and do so by decreasing gray matter metabolism and blood flow and worsening brain atrophy. To address this hypothesis the following aims will be achieved: Specific Aim 1: Using matched cohorts, determine whether Veterans with MS with VDRF in comparison with those without VDRF have decreased cerebral blood flow and volume detected by MRI and high energy phosphate metabolites in cerebral gray matter assessed by 31P magnetic resonance spectroscopic imaging (MRSI). Specific Aim 2: Determine if brain atrophy progresses faster in Veterans with MS and VDRF than those without VDRF and whether 31P MRSI and cerebral blood flow deficits are associated with an increased rate of brain atrophy. Specific Aim 3: Determine if clinical impairment, disability and quality of life deteriorates faster in Veterans with MS and VDRF than those without VDRF and whether 31P MRSI and cerebral blood flow deficits are associated with an increased rate of disease progression. Research Design and Methods: We propose a longitudinal, quantitative MRI study using 31P MRSI assessing mitochondrial function and perfusion measurements to quantify blood volume and flow to investigate whether MS Veterans with VDRF in comparison with those without VDRF have reduced cerebral blood flow and volume, reduced high energy phosphorus metabolites, and accelerated brain atrophy, clinical impairment and disability. This will be a 3-year long controlled study with a single-site, mixed design (cross sectional and longitudinal) with two arms. MRI data will be collected at baseline, 12, 24 and 36 months. We will enroll a total of 60 MS subjects with goal to have 30 subjects in each arm: 1) MS subjects with VDRF; 2) MS subjects without VDRF. MS Subjects aged 40-65 years will be included and may or may not be on disease modifying therapy. The results of these studies will provide the basis for designing a clinical trial to study if interventions aimed at improving VDRF can reduce the risk of disease progression among MS Veterans.