Role of Microglial Activation and Norepinephrine Transporter Abnormalities in Pathogenesis of MS-related Fatigue

Design: This is a single center, cross-sectional study of patients with multiple sclerosis, who will each, undergo both, [C-11]MRB-PET (norepinephrine transporter binding) and [F-18]PBR06-PET (microglial activation), in addition to 7 Tesla brain MRIs. Patients will also undergo cross-sectional estimations of blood markers.

Genotype Testing:

Blood sample drawn on the initial screening visit will be used to obtain genomic DNA for genotyping for polymorphism within the TSPO gene on chromosome 22q13.2, using a Taqman assay. High affinity and medium affinity binders will be included while the low affinity binders will be excluded from the study.

PET Scanning:

During the PET scan visits, all women subjects of child bearing age will undergo a stat quantitative serum hCG pregnancy test and only women with a negative test will undergo the radiopharmaceutical injection. The radiotracers will be produced using standardized procedures. At the time of imaging, the subjects will be positioned in the gantry of a high-resolution PET/CT camera. Head alignment will be made, relative to the canthomeatal line, using projected laser lines whose positions are known with respect to the slice positions of the scanner. A head support apparatus will be used to minimize head motion.Dynamic data over 120 minutes for PET quantification will be acquired, according to previously described methods for both tracers.

MRI Scanning:

High resolution MRI scanning will be performed using the 7T Siemens MAGNETOM Terra MRI unit at Brigham & Women's Hospital (BWH).

Serum assays:

Serum measurements for inflammatory markers and relevant neurochemicals will be performed according to established procedures.

Clinical Data

The following non-imaging, clinical data will be obtained:

Modified fatigue Impact Scale (MFIS) Fatigue Severity Status Scale (FSSS) Expanded Disability Status Scale (EDSS) Timed 25-feet walk (T25W) MS Functional Composite (MSFC) Symbol digit modalities test (SDMT) MSQOL-54 scale (QOL) Pittsburgh Sleep Quality Index (PSQI) Beck's Depression Inventory (BDI) Center for Epidemiological Studies-Depression Scale (CES-D) Hospital Anxiety and Depression Scale (HADS)

Inclusion criteria

• Subjects meeting the definition for RRMS or SPMS by International Panel (2017 McDonald) Criteria.
• We will recruit patients with RRMS, recently diagnosed in the last 2 years. There will be no disease modifying therapy restrictions for RRMS or SPMS patients.
• Male and female subjects age 18 to 60 years.
• Patients able to withhold medication that may interfere with C-11[MRB] radiotracer uptake for 24 hours before the scan.

Exclusion criteria

• Relapse/Corticosteroid treatment in the past 4 weeks to avoid transient effects on imaging
• Individuals with a known alternate neurologic disorder, previous head injury, or substance abuse.
• Individuals with bipolar disease and schizophrenia
• Concurrent medical conditions that contraindicate study procedures.
• Women who are pregnant or nursing. Also, any woman who is seeking to become pregnant or suspects she is pregnant will be excluded from enrollment.
• Claustrophobia
• Non-MRI compatible implanted devices
• Low affinity binders