The central hypothesis of this protocol is that it is possible, using First Degree Relatives (FDRs) of patients with Multiple Sclerosis (MS) and assessing a variety of both known and unknown risk factors for MS, to define a risk algorithm for earliest signs of development of MS. The plan will be to do an abbreviated brain Magnetic Resonance Imaging (MRI) scan in asymptomatic, young FDRs, analyze blood for a variety of immunological, genetic, neuroaxonal damage, metabolic, viral serology and other markers, and have FDRs fill out a detailed bioscreen questionnaire about lifestyle factors and perform a cognitive screening test. The investigators will then compare the results of the various blood/other studies in FDRs with and without an MRI showing signs signs concerning for MS, as well as age-and sex-matched NON-FDRs who will have blood drawn and fill out the questionnaire. With this preliminary cross-sectional study, the investigators hope to begin to identify a risk stratification model for those at highest risk of developing MS, ie FDRs, with a long-term goal of developing a longitudinal study to increase sensitivity and specificity of the risk model.
Specific Aims, among asymptomatic first degree relatives (FDRs), aged 18-30, of multiple sclerosis (MS) patients: 1. Determine the prevalence of brain MRI lesions disseminated in space (DIS), consistent with MS 2. Gather data on potential risk factors or early signs related to MS development, including markers for: genes, immunological function, environmental factors, neuroaxonal damage, Vitamin D levels, lipid metabolism, activity levels, mood abnormalities, and cognitive function. From this, develop a risk factor score, incorporating all relevant potential markers of increased risk of DIS. 3. To use this pilot, cross-sectional study as a base for development of a long-term, longitudinal, multi-center study to determine genetic and environmental risks for pre-symptomatic MS 4. To create and maintain a biobank of specimens for future analysis as other potential biomarkers become available. 5. Evaluate for potential dissemination in time (DIT) and dissemination in space (DIS) in asymptomatic FDRs through longitudinal assessment. Sequences to include 1. Whole brain T1-weighted images acquired using 3-Dimensional fast spoiled-gradient recalled acquisitions (T1-3D-FSPGR) with 1 mm slice thickness and isotropic voxel dimensions. 2. Whole brain 3-Dimensional Double Inversion Recovery (DIR) acquisition with 1.5 mm slice thickness. 3. Whole brain T2-weighted Fluid Attenuated Inversion Recovery (FLAIR ) images with 1 mm slice thickness and isotropic voxel dimensions will be combined with 4. Whole brain T2\*-weighted segmented echo-planar imaging (segEPI) images with \<=1 mm slice thickness and isotropic voxel dimensions to obtain FLAIR\* images. Blood analysis for: 1. Single Nucleotide Polymorphism analysis of greater than 200 known mutations associated with risk of MS, and do an human leukocyte antigen (HLA) analysis 2. CD20 on CD4+ cell analysis 3. B Cell Anergy analysis Lipid levels 4. Viral serologies (HSV, EBV, CMV, VZV) 5. Neurofilament Light 6. Vitamin D levels Bioscreen analysis based on that from the Diabetes Autoimmunity Study in the Young (DAISY); and to include the Godin Leisure-Time Exercise Questionnaire (GLTEQ), which has been validated in both adults and children and a validated dietary/food frequency questionnaire. In addition perform a cognitive screen with a Symbol Digit Modality test. Blood will also be stored for future potential analysis, including peripheral blood mononuclear cells, serum, and Ribonucleic acid (RNA).
Study Type
OBSERVATIONAL
Enrollment
300
Perform brain MRI; draw blood; fill out bioscreen questionnaire; perform SDMT
University of Colorado Anschutz Medical Campus
Aurora, Colorado, United States
RECRUITINGDiscovery of Lesions disseminated in space on brain MRI
Lesions disseminated in space on brain MRI. The presence or absence of these lesions will only be measured once at the initial visit.
Time frame: At the subject's Initial Visit
Define risk stratification algorithm for prediction of MS
The investigators will measure the prevalence of specific genetic markers including, single nucleotide polymorphism analysis of more than 200 known mutations and analysis of HLA-DRB1 variants, with the goal of defining an expanded risk stratification scheme.
Time frame: Within 4 months of the Initial Visit
Define risk stratification algorithm for prediction of MS
The investigators will measure the prevalence of immunological markers including, CD4, CD8, CD40, CD19 and CD20 with the goal of defining an expanded risk stratification scheme.
Time frame: Within 4 months of the Initial Visit
Define risk stratification algorithm for prediction of MS
The investigators will measure the prevalence of vitamin D deficiencies, with the goal of defining an expanded risk stratification scheme.
Time frame: Within 4 months of the Initial Visit
Define risk stratification algorithm for prediction of MS
The investigators will measure the prevalence of lipid markers including, total cholesterol, high and low density lipoproteins, and triglycerides, with the goal of defining an expanded risk stratification scheme.
Time frame: Within 4 months of the Initial Visit
Define risk stratification algorithm for prediction of MS
The investigators will measure the presence of the viral infection Epstein-Barr virus, with the goal of defining an expanded risk stratification scheme.
Time frame: Within 4 months of the Initial Visit
Define risk stratification algorithm for prediction of MS
The investigators will measure the presence of the viral infection Cytomegalovirus, with the goal of defining an expanded risk stratification scheme.
Time frame: Within 4 months of the Initial Visit
Define risk stratification algorithm for prediction of MS
The investigators will measure the presence of the viral infection Herpes Simplex I, with the goal of defining an expanded risk stratification scheme.
Time frame: Within 4 months of the Initial Visit
Define risk stratification algorithm for prediction of MS
The investigators will measure the presence of the viral infection Herpes Simplex II, with the goal of defining an expanded risk stratification scheme.
Time frame: Within 4 months of the Initial Visit
Define risk stratification algorithm for prediction of MS
The investigators will measure the presence of the viral infection Varicella zoster virus, with the goal of defining an expanded risk stratification scheme.
Time frame: Within 4 months of the Initial Visit
Define risk stratification algorithm for prediction of MS
The investigators will measure the prevalence of CNS damage marker Neurofillament light, with the goal of defining an expanded risk stratification scheme.
Time frame: Within 4 months of the Initial Visit
Define risk stratification algorithm for prediction of MS
The investigators will measure activity level, using the Godin Leisure-time Exercise questionnaire, with the goal of defining an expanded risk stratification scheme. Weekly frequencies of strenuous, moderate, and light activities (i.e. number of times per week an individual performs these activities) are multiplied by nine, five, and three, respectively. Total weekly leisure activity is calculated in arbitrary units by summing the products of the separate components, as shown in the following formula: Weekly leisure activity score = (9 × Strenuous) + (5 × Moderate) + (3 × Light). As there is no limit for the number of times a participant can perform an exercise per week, the maximum score is boundless. While, a sedentary individual may exhibit the minimum score of 0.
Time frame: Within 4 months of the Initial Visit
Define risk stratification algorithm for prediction of MS
The investigators will evaluate cognitive functions using the Perceived Stress Scale, with the goal of defining an expanded risk stratification scheme. This will be used to evaluate stress domains. Individual scores on the Perceived Stress Scale can range from 0 to 40 with higher scores indicating higher perceived stress. Scores ranging from 0-13 would be considered low stress. Scores ranging from 14-26 would be considered moderate stress. Scores ranging from 27-40 would be considered high perceived stress.
Time frame: Within 4 months of the Initial Visit
Define risk stratification algorithm for prediction of MS
The investigators will evaluate cognitive functions using University of Colorado's NeuroQol Depression Scale, with the goal of defining an expanded risk stratification scheme. This assessment will be used to evaluate depression domains. The minimum raw score is 8, which represents better (desirable) self-reported health, and the maximum score is 40, which represents worse (undesirable) self-reported health. These raw scores will be converted to T-scores, with 36.9 being the minimum and 75.0 being the maximum T-score.
Time frame: Within 4 months of the Initial Visit
Define risk stratification algorithm for prediction of MS
The investigators will evaluate cognitive functions using University of Colorado's NeuroQol Anxiety Scale, with the goal of defining an expanded risk stratification scheme. This assessment will be used to measure anxiety domains, with the highest raw score of 40 representing worse (undesirable) self-reported anxiety, and a raw score of 8 representing better (desirable) self-reported anxiety. These raw scores will be converted to T-scores, with 36.4 being the minimum and 76.8 being the maximum T-score.
Time frame: Within 4 months of the Initial Visit
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