Risk Factors in Early Multiple Sclerosis

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.

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