Measuring Active Microglia in Progressive Multiple Sclerosis
Condition: Secondary Progressive Multiple Sclerosis
MeSH terms: Multiple Sclerosis; Multiple Sclerosis, Chronic Progressive; Sclerosis
Study type: Observational

Summary: 
      This is pilot study designed to quantifying the innate immune inflammatory burden in a cohort
      of secondary progressive multiple sclerosis subjects. Innate immunity is recognized as a
      major cause of tissue injury in central nervous system (CNS) disease. Our hypothesis is that
      the innate immune response is heightened in SPMS as compared to healthy controls (HC's) and
      this activity increases over time and correlates with ongoing neuronal loss and disability.
      The investigators will test this hypothesis by using highly specific molecular imaging
      techniques, specifically PET, in conjunction with high field MRI. The investigators will
      utilize the PET radioligand [11C]PK11195 which will be used as a marker of activated
      macrophages/microglia. The investigators will correlate [11C]PK11195 uptake with conventional
      measures of inflammation and neuronal integrity on high-resolution MRI.

      SPMS subjects will have two baseline [11C]PK-11195 PET scans (separated by 24 to 72 hours,
      test-retest) and subsequent scans at 6, 12 and 24 months. SPMS Subjects will have brain MRI's
      at baseline, 6, 12 and 24 months.

      Healthy Controls will have 2 baseline PET scans and one MRI.
    

Detailed description: 
      This is pilot study designed to determine the baseline and longitudinal regional-specific
      change in uptake of [11C]PK-11195 in subjects with secondary progressive multiple sclerosis
      (SPMS). Eighteen subjects with SPMS will be enrolled in the two-year study. Given low sample
      size, a stable treatment regimen is required to control for potential treatment effect. In
      addition, subjects must have been on current therapy for at least 6 months to ensure the
      measurement is reflective of true disease activity and not treatment effect. Thirteen
      age-matched healthy controls (HC) will be enrolled. The role of HC is to establish the
      variability or "noise" associated with the instrument (test-retest), which will ensure that
      PK uptake measured at any time point in MS is biologically relevant.

      This proposal also includes a sub-study to validate a non-invasive quantification methodology
      for PK-PET. The most rigorous method, or gold standard, for quantifying PET data is based
      upon measuring the arterial input function. Measuring radioactivity within the arterial
      circulation requires arterial cannulation. Arterial cannulation is considered safe; however,
      is labor-intensive and often discourages subjects from participation. Image-derived input
      function (IDIF) is a method to calculate the input function without cannulation of the artery
      using the imaging data. Studies in human research volunteers are still required to compare
      the results obtained with classical arterial sampling and the IDIF. The current study will
      validate IDIF as a substitute for arterial sampling in this context. All healthy controls
      will undergo this validation process, which will include arterial and venous sampling. This
      validation is also required within subjects. Subjects will be given the option to participate
      in this validation stage.

      Absolute Quantification of PK-PET (gold standard arterial sampling): Catheters will be placed
      in the radial artery for characterizing the plasma input function. This will make it possible
      to use a two tissue reversible plasma input (2T4k) model. Blood sampling will be acquired
      using both an online continuous blood sampling device as well as manually at discrete times
      (5, 10, 15, 20, 30, 40, 50 and 60 minutes post injection). The continuous sampling will be
      used to measure the activity concentrations of the whole blood, while the discrete manual
      sampling will be used to calculate the plasma concentration, and estimate the fraction of
      radioactive metabolites using HPLC. The total blood loss is estimated to be 8-10 tablespoons
      (120-150 mL, or about one third of the amount that volunteers donate to the Red Cross when
      giving blood). To generate the plasma input functions, the ratio of the plasma data to whole
      blood will be calculated for each manual blood sample and fitted through these points to a
      model with a one- or two-exponential function. Metabolite correction will be accomplished by
      multiplying the plasma curve with a function obtainable from a fit to the measured parent
      fraction. Venous blood will be similarly obtained for IDIF metabolic correction and utilized
      for validation against classic arterial sampling. The investigators will acquire up to 6
      venous samples of 3 mL each with a 2 mL purge prior to each sample, for a total blood loss of
      30 mL (one fluid ounce, or about 6.67% of the amount that volunteers donate to the Red Cross
      when giving blood).

      Dynamic PET acquisition and processing: The data will be acquired in list mode to facilitate
      processing at any dynamic framing rate.

      Innate immunity is recognized as a major cause of tissue injury in central nervous system
      (CNS) disease. In this study the investigators will specifically quantify the innate immune
      inflammatory burden in a cohort of secondary progressive multiple sclerosis (SPMS) subjects.
      Our hypothesis is that the innate immune response is heightened in SPMS as compared to
      healthy controls (HC's) and this activity increases over time and correlates with ongoing
      neuronal loss and disability. The investigators will test this hypothesis by using highly
      specific molecular imaging techniques, specifically PET, in conjunction with high field MRI.
      The investigators will utilize the PET radioligand [11C]1533; PK11195 which binds to the
      translocator protein 18 kDa (TSPO) on activated macrophages/microglia. The investigators will
      correlate [11C]PK11195 uptake with conventional measures of inflammation and neuronal
      integrity on high-resolution MRI.

      MS is a chronic inflammatory disease of central nervous system characterized by focal T cell
      and macrophage infiltrates associated with demyelination. The primary innate immune cells in
      MS consist of infiltrating macrophages/monocytes and resident microglia. Cells of the innate
      immune system are effector cells that function to cause CNS injury both through direct
      effects on neighboring cells, such as oligodendrocytes, and through generation of soluble
      proinflammatory mediators that have distant effects on cells, such as neurons. The innate
      immune inflammatory is thus sufficient to explain focal injury and diffuse injury. In the
      majority of subjects, MS begins as a relapsing-remitting course but eventually evolves to a
      state of progressive decline in disability. Focal inflammatory demyelinating lesions are the
      predominant pathological findings in the subjects with relapsing disease whereas diffuse
      axonal injury with microglial activation has been found to be the hallmark of progressive
      disease.1 Microglial activation itself occurs either as a response to CNS injury for example
      as in Wallerian degeneration, or in response to signals from other inflammatory cells
      including macrophages and lymphocytes.

      Activated microglia and infiltrating macrophages express TSPO (previously referred to as the
      peripheral benzodiazepine receptor) which can be detected with radioligand [11C]PK-111952.

      Determination of the significance of any [11C]PK-11195 uptake within a cohort of MS subjects
      would require a correlation with HC¿s to ensure the observation is a valid measurement of
      disease activity.

      The MS subjects will also have two baseline [11C]PK-11195 PET scans (separated by 24 to 72
      hours, test-retest) to measure disease related intra-individual variability and will have
      subsequent scans at 6, 12 and 24 months. Baseline test-retest [11C]PK-11195 PET uptake
      between MS subjects and HC's will be compared to ensure minimal disease-related variability
      and to ensure our baseline and subsequent longitudinal measurements in MS subjects have met a
      level of biological significance. One baseline brain MRI is required for HC and MS subjects.
      Subjects will have brain MRI's at 6, 12 and 24 months.

      Objective: Aim 1: To quantify level of activity and dynamic change in the innate immune
      inflammatory burden over the course of two years in a cohort of SPMS subjects.

      Primary objective: Measure the level of baseline and change of whole brain uptake of
      [11C]PK-11195 at 6, 12 and 24 months in SPMS subjects.

      Objectives:

        -  To correlate the change in T2-hyperintense lesion volume at 6,12 and 24 months of with
           whole brain uptake of [11C]PK-11195 on PET (at the 6,12 and 24 months) in SPMS subjects.

        -  To correlate the change of conventional MRI measures of neuronal integrity (Gray Matter
           Fraction, White Matter Fraction, whole brain volume, T1-hypointense lesion volume) at
           6,12 and 24 months with whole brain PET uptake of [11C]PK-11195 (at the 6,12 and 24
           months) in SPMS subjects.

        -  To correlate the change in whole brain PET uptake of [11C]PK-11195 (at the 6,12 and 24
           months) and level in disability, as measured by a change in EDSS at 6, 12, and 24 months
           in SPMS subjects.
    

Intervention name(s): [C11]PK-1195 PET scan
Intervention type(s): Drug
Intervention description(s): PET scan with tracer [C11]PK-1195
Observational model: Cohort
Time perspective: Prospective
Sampling method: Non-Probability Sample
Study population: 
        Approximately 36 subjects (with SPMS and controls) including screen failures will be
        enrolled regardless of gender
      
Keywords: SPMS; Myelin Water Fraction; activated microglia