Novel Assessment of Synaptic Density in Progressive MS

The investigators propose to use the novel SV2a-PET ligand, [F-18]SDM-8 to assess synaptic density in progressive MS (including primary progressive multiple sclerosis (PPMS) and secondary progressive multiple sclerosis (SPMS)) as compared to relapsing-remitting multiple sclerosis (RRMS) patients and healthy controls, given its improved imaging characteristics and potential for large scale applicability. The specific aims of the study are: Aim 1: To compare the cortical and subcortical grey matter synaptic density in progressive MS patients, patients with relapsing-remitting MS, and healthy subjects, using a novel [F-18] labeled synaptic density PET ligand, [F-18]SDM8, also known as [F-18]SynvesT-1. Aim 2: To compare the relationship of synaptic density PET and standard 3T MRI measures including global and regional brain atrophy and lesion load with clinical measures of physical disability, cognitive impairment, fatigue and depression in MS patients. Aim 3: To assess the relationship of synaptic density PET with serum neurofilament light chain (NfL) and with serum measurements of inflammatory markers, IL-1β, TNF-α, IL-6, MCP-1 (Monocyte Chemoattractant Protein-1) and MIF-1 (Macrophage Migration Inhibitory Factor-1).

I. Subject Selection Subjects will be recruited at the Partners MS Center, 60 Fenwood Road, Boston, MA during routine clinical appointments by their physician or one of the other co-investigators listed on the protocol. II. Study Procedures Subjects will be required to come for 3 visits for this study. Initial Visit: During the first visit, subjects will be administered the screening questionnaire (if that has not already been done over telephone). Subjects will review and eventually sign the consent form. They will be administered standardized questionnaires for cognitive testing and/or other co-morbidities. PET Visit: All subjects will undergo at least one visit for PET scan. During the PET scan visits, all women subjects of child bearing age will undergo a stat quantitative serum hCG pregnancy test and only women with a negative test will undergo the radiopharmaceutical injection. PET imaging procedures PET scanning session will be conducted at MGH Gordon Center PET scanning facility, 55 Fruit Street, Boston, MA. For PET scanning, an intra-arterial catheter will be inserted into the [F-18] SynVest-1 for metabolite blood sampling by a trained anesthesiologist. Allen's test will be performed prior to insertion of the intra-arterial catheter. In the event that an arterial line cannot be established to obtain metabolite samples, a venous line will be placed. In addition, an intravenous (IV) catheter will be inserted into the radial antecubital or other arm or hand vein for injection of tracer. Radiopharmaceutical will be injected as a bolus (approximately 5mCi for [F-18]SynVest-1 followed by 5 mL of saline). The whole PET session will last up to 120 min. At the time of imaging, the subjects will be positioned in the gantry of a PET camera. Head alignment will be made, relative to the canthomeatal line, using projected laser lines whose positions are known with respect to the slice positions of the scanner. A head support apparatus will be used to minimize head motion. Brain PET data acquisition will begin at the moment of radiotracer injection. Images will be acquired using a high-resolution PET/CT scanner. MRI Visit: All subjects will undergo a 3T Brain MRI during an MRI visit that may precede or follow the PET scan visit. Pregnancy screening prior to MRI: All women will be queried about their pregnancy status, use of contraception and last menstrual period. If they are reliably using contraception, can state the timing of their last menstrual period, and do not believe they could be pregnant, the investigators will proceed with the MRI scan without pregnancy testing. If they cannot do this, then they will undergo a urine pregnancy test. If a woman is seeking pregnancy and not using contraception, she will undergo a urine pregnancy test. MRI imaging procedures MRI scanning session will be performed at BWH MRI facility at 60 Fenwood Road, Boston, MA. Several pulse sequences will be performed to image the brain. There will be no intravenous contrast used for any of the MRIs. The MRI scan session will take approximately 1 hour. Imaging Data The following data will be collected on all subjects during scanning sessions: During PET scanning, brain images will be acquired in 3-D mode, and dynamic acquisition scans will continue for up to 120 minutes. A non-diagnostic CT scan will be performed for attenuation correction of PET transmission data at the time of initiation of scanning. Blood samples will be collected via an arterial line for radiotracer analysis via the cannula other than the one used for radiotracer injection. Non Imaging Data MS subjects Expanded Disability Severity Scale (EDSS) Timed 25-feet walk (T25W) Modified Fatigue impact Scale Hamilton Depression Rating Scale Wechsler Logical Memory paragraph recall Healthy Controls Folstein Mini Mental Status Examination Hamilton Depression Rating Scale Wechsler Logical Memory paragraph recall

Primary Progressive Multiple Sclerosis, Secondary Progressive Multiple Sclerosis, Relapsing Multiple Sclerosis, Multiple Sclerosis

Subjects will be administered standardized questionnaires for cognitive testing/other co-morbidities. They will undergo PET Scan and 3T Brain MRI. For PET Scan, an intra-arterial catheter will be inserted into the radial artery for [F-18]SDM-8 metabolite blood sampling by a trained anesthesiologist. Allen's test will be performed prior to insertion of the intra-arterial catheter. If arterial line can't be established to obtain metabolite samples, a venous line will be placed. In addition, an intravenous (IV) catheter will be inserted into the radial antecubital or other arm or hand vein for injection of tracer. Radiopharmaceutical will be injected as a bolus (approximately 5mCi for [F-18]SDM-8 followed by 5 mL of saline). The PET session will last up to 120 min. A head support apparatus will be used to minimize head motion. Brain PET data acquisition will begin at the moment of radiotracer injection. For MRI, several pulse sequences will be performed, no IV contrast will be used.

This will be calculated over whole brain, within white matter, within grey matter, and within MRI-visible lesions.

Inclusion Criteria: Subjects meeting the definition for MS (including PPMS, RRMS or SPMS) by International Panel (2017 McDonald) Criteria. Age and sex-matched healthy controls will also be recruited. Subjects willing to undergo PET and MRI imaging Subjects willing and able to give informed consent Exclusion Criteria: Individuals with a known alternate neurologic disorder, previous head injury, or substance abuse. Individuals with bipolar disease and schizophrenia Concurrent medical conditions that contraindicate study procedures. Women who are pregnant or nursing. Also, any woman who is seeking to become pregnant or suspects she is pregnant will be excluded from enrollment. Claustrophobia Non-MRI compatible implanted devices Corticosteroid treatment in the past four weeks