Effect of Ocrelizumab on Neuroinflammation in Multiple Sclerosis as Measured by 11C-PBR28 MR-PET Imaging of Microglia Activation

Effect of Ocrelizumab on Neuroinflammation in Multiple Sclerosis as Measured by 11C-PBR28 MR-PET Imaging of Microglia Activation

Effect of Ocrelizumab on Neuroinflammation in Multiple Sclerosis as Measured by 11C-PBR28 MR-PET Imaging of Microglia Activation

Using magnetic resonance-PET (MR-PET) imaging with [11C]PBR28, a second-generation 18kDa translocator protein (TSPO) radiotracer, we have previously demonstrated abnormally high TSPO expression, indicative of microglia activation, across different brain tissue compartments of multiple sclerosis (MS) patients1. In this study, we propose to study the efficacy of ocrelizumab, a humanized monoclonal antibody that has been shown to decrease neuroinflammation in relapsing-remitting multiple sclerosis (RRMS) and progressive multiple sclerosis (MS) patients. We will test these effects by studying a cohort of 24 MS patients (12 RRMS, 12 progressive MS). Participants will be studied before (within 3 months prior to initiating treatment) and after treatment with ocrelizumab (~12 month follow up), a therapeutic drug that will be part of their standard medical care. We will use [11C]PBR28 to help determine changes in neuroinflammation. The purpose of this study is to determine the effects of ocrelizumab treatment on neuroinflammation by analyzing the uptake and distribution of [11C]PBR28 in individuals with multiple sclerosis. The specific aims of the current study are: To assess whether treatment with ocrelizumab in subjects with either relapsing-remitting MS or progressive MS is associated with decreased [11C]PBR28 binding in the cortex and white matter (lesions and normal appearing white matter), suggesting reduced neuroinflammation. To assess whether changes in neuroinflammation under ocrelizumab treatment, as measured by [11C]PBR28 uptake at 12-month follow up relative to baseline, are associated with changes in structural MR metrics of brain tissue damage including white matter lesion load, cortical atrophy, and demyelination in the cortex and in the normal-appearing white matter as measured by magnetization transfer ratio (MTR). To explore whether changes in functional and structural imaging metrics under ocrelizumab are associated with changes in clinical outcome measures.

Multiple sclerosis patients will be evaluated with 11C-PBR28 MR-PET at baseline before and at 12 month follow up after Ocrelizumab therapy.

This study will evaluate, serially, functional and structural tissue changes in the cortex and WM of subjects with RRMS and progressive disease under Ocrelizumab using 11C-PBR28 MR-PET imaging at baseline and at approximately 12-month follow up.

To measure changes in 11C-PBR28 uptake in the brain of multiple sclerosis patients under Ocrelizumab therapy

To assess whether changes in neuroinflammation under Ocrelizumab treatment relate to changes in structural MR metrics of brain tissue damage

To measure changes in 11C-PBR28 uptake in the brain of multiple sclerosis patients under Ccrelizumab therapy correlate with changes in WM lesion load, cortical atrophy and demyelination in the cortex and in the NAWM as measured by magnetization transfer ratio (MTR)

To explore whether changes in functional and structural imaging metrics under Ocrelizumab are associated with changes in clinical outcomes measures

To measure whether changes in 11C-PBR28 uptake or in structural imaging metrics correlate with measures of neurological disability and cognition

Inclusion Criteria: Signed informed consent RRMS and/or PMS subtype EDSS between 0 and 7.0 Express at least one high-affinity (Ala147) allele of the TSPO receptor for PBR28 Initiating Ocrelizumab treatment within the next 3 months Exclusion Criteria: Hypersensitivity to trial medications History of life-threatening reaction to Ocrelizumab Acute or uncontrolled chronic medical condition Impaired hearing Claustrophobia 300 lbs of greater (weight limit of MRI table) Pregnancy or breastfeeding Sensitivity to imaging agents Contraindications to MRI Use of benzodiazepines, topiramate, doxycycline, mynocicline