Measuring Active Microglia in Progressive Multiple Sclerosis

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.