Risk Factors in Early Multiple Sclerosis

Risk Factors in Early Multiple Sclerosis

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).

Inclusion Criteria:

• FDR Inclusion Criteria

  1. Male and female
  2. All races and ethnicities
  3. Ages 18-30
  4. Must have a parent, sibling or child with MS fulfilling McDonald 2017 criteria
  5. No symptoms suggestive of MS on formal screen
  6. Ability to undergo a non-contrast MRI and venipuncture, and perform an environmental screen, mood screen and cognitive test

• Non-FDR Inclusion Criteria

  1. Male and female
  2. All races and ethnicities
  3. Ages 18-30
  4. Must NOT have a FDR (parent, sibling, child) or second degree relative (grandparent, aunt or uncle) with MS fulfilling McDonald 2017 criteria
  5. No symptoms suggestive of MS on formal screen
  6. Ability to undergo venipuncture and perform an environmental screen.

Exclusion Criteria:

• FDR Exclusion Criteria

  1. Symptoms suggestive of MS on formal screen
  2. Prior diagnosis of autoimmune disease that may be associated with CNS dysfunction and MRI lesions, e.g. Sjogren's

• Non-FDR Exclusion Criteria

  1. Symptoms suggestive of MS on formal screen
  2. Prior diagnosis of autoimmune disease that may be associated with CNS dysfunction and MRI lesions, e.g. Sjogren's