Brain Peripheral Benzodiazepine Receptors in Patients With Multiple Sclerosis

OBJECTIVE: The primary objective of this study is to measure brain peripheral benzodiazepine receptor (PBR) expression as a marker of neuroinflammation in subjects with MS using \[(11)C\]PBR28 PET imaging. Inflammation in the central nervous system (CNS) is a prominent feature of multiple sclerosis (MS), the leading cause of neurological disability in young adults. A complex sequence of inflammatory events leads to the formation of new lesions. The disruption of blood-brain barrier that occurs during this inflammatory cascade is the basis of Gadolinium-DTPA (Gd-DTPA) enhancing lesion on magnetic resonance imaging (MRI), currently the most widely utilized marker of neuroinflammation in MS. Although Gd-DTPA enhancement correlates with acute clinical relapses, its limitation as a biomarker of disease activity includes the relative insensitivity to mild degrees of inflammation and the lack of correlation to long-term disability. An alternative marker of neuroinflammation may, therefore, be informative. Activated microglia and macrophage constitute the secondary effector cells of CNS inflammation in MS. Recent studies investigating the expression of the peripheral benzodiazepine receptor (PBR) in the CNS have shown that the increased expression of PBR is a marker of activated microglia/macrophage. Specific ligands for PBR have allowed the study of activated microglia/macrophage in vivo through positron emission tomography (PET) imaging in a number of settings including inflammatory, ischemic and toxic injury to the CNS. The availability of a novel PBR ligand \[(11)C\]PBR28 developed by the Molecular Imaging Branch, NIMH, that demonstrated greater specific signal for PBR than the previously available ligands affords a unique opportunity to investigate a cell-type specific marker of neuroinflammation in MS. STUDY POPULATION: Subjects with definite MS (McDonald criteria) with evidence of brain inflammatory activity indicated by presence of Gd-DTPA enhancing lesions on MRI and a control group consisting of age-matched healthy volunteers. DESIGN: Up to 32 subjects with MS will undergo screening TSPO genotype analysis by PCR to accrue up to 16 MS subjects with confirmed high- or mixed- affinity binding genotype (HL or HH genotype) who will undergo a brain \[(11)C\]PBR28 PET and MRI imaging. Subjects with MS will undergo follow-up brain \[(11)C\]PBR28 PET and MRI at approximately 4-month interval. Subjects will undergo clinical examination at each PET imaging time point to assess clinical measures of disability and impairment. Up to an equal number of age-matched healthy volunteers will undergo screening TSPO genotype analysis by PCR. Up to 16 healthy volunteers with confirmed high- or mixed- affinity binding genotype (HL or HH genotype)undergo test retest brain \[(11)C\]PBR28 PET studies to determine the reproducibility of \[(11)C\]PBR28 PET in a healthy population compared to MS. OUTCOME MEASURES: The study seeks to test PBR expression measured by \[(11)C\]PBR28 PET imaging as a marker of neuroinflammation in patients with MS. Primary outcome measures include 1) correlation between increased PBR expression and gadolinium-enhancing lesions on MRI, and 2) correlation between increased PBR expression and previously and/or persistently gadolinium-enhancing lesions on MRI, 3) PBR expression in subjects with multiple sclerosis compared to that in healthy volunteers.