Brain Peripheral Benzodiazepine Receptors in Patients With Multiple Sclerosis
Condition: Multiple Sclerosis
MeSH terms: Multiple Sclerosis; Sclerosis
Study type: Interventional
Phase: Phase 1

Summary: 
      This study will use positron emission tomography (PET) to measure a brain protein called
      peripheral benzodiazepine receptor (PBR) in patients with multiple sclerosis. PBR is created
      during the inflammation process, and brain inflammation is a key feature of multiple
      sclerosis (MS). PBR usually affects one type of brain cell, but it can also cause damage to
      surrounding areas of the brain in patients with MS. PET studies of PBRs and brain
      inflammation may help elucidate the role of these brain cells in patients with MS.

      Healthy normal volunteers and patients with MS between 18 and 70 years of age may be eligible
      for this study. Patients with MS must have had onset of disease between 18 and 40 years of
      age.

      Patients with MS undergo the following procedures:

      Visit 1: Medical history, physical examination, blood tests and magnetic resonance imaging
      (MRI).

      Visit 2: Blood tests and PET scan.

      Visits 3 and 4: MRI and physical examination.

      Visit 5: PET scan and blood tests.

      Visit 6: MRI and physical examination.

      Healthy volunteers undergo the following:

      Visit 1: Medical history, physical examination, blood tests.

      Visits 2 and 3: PET and blood tests.

      Magnetic Resonance Imaging

      MRI uses a magnetic field and radio waves to produce images of body tissues and organs. For
      this procedure, the subject lies on a table that can slide in and out of the scanner (a metal
      cylinder), wearing earplugs to muffle loud knocking noises that occur during the scanning
      process. The procedure lasts about 90 minutes; the patient is asked to lie still for up to 25
      minutes at a time. The subject can communicate with the MRI staff at all times during the
      scan. During part of the scan a contrast agent is administered through a catheter (plastic
      tube) placed in an arm vein to enhance the images.

      Positron Emission Tomography (PET)

      The PET scan gives information on brain and body chemistry and function. The subject lies on
      a bed that slides in and out of the doughnut-shaped scanner. A catheter is placed in a vein
      in the arm and another is placed in an artery in the wrist or elbow area. The catheter in the
      arm is used for injecting a radioactive material that the scanner detects, and the other is
      used to collect blood samples. A custom-molded plastic mask is used to support the head and
      prevent it from moving during the procedure. The subject may be asked to perform various
      tasks during the PET scan or to lie quietly. The scan lasts about 2.5 hours.
    

Detailed description: 
      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.
    

Intervention name(s): [(11)C]PBR28
Intervention type(s): Radiation
Intervention description(s): PET Ligand
Intervention model: Single Group Assignment
Masking: None (Open Label)
Primary purpose: Basic Science
Keywords: Inflammation; Neuroimmunology; Multiple Sclerosis; MS; Healthy Volunteer; HV