Microglial Activation Positron Emission Tomography (PET) Brain Imaging in Multiple Sclerosis and Alzheimer's Disease
Microglial Activation Positron Emission Tomography (PET) Brain Imaging in Multiple Sclerosis and Alzheimer's Disease
The specific aims of the study are:

 Primary: To determine the presence and regional distribution of microglial activation, as
 assessed by Fluorine-18 (18F) labeled "Peripheral Benzodiazepine Receptor 06" (PBR06) -PET,
 in subjects with active Relapsing Remitting Multiple Sclerosis (RRMS), Secondary Progressive
 Multiple Sclerosis (SPMS), and Alzheimer's Disease (AD) as compared to healthy controls

 Secondary:

 1. To assess the relationship between microglial activation and clinical variables
 including disease severity and comorbidities (such as pain, fatigue and/or depression),
 as well as clinical MRI findings (such as lesions and atrophy)

 2. A pilot substudy aims to establish the non-inferiority of [F-18]PBR06 as compared with
 Carbon-11 [C-11] labeled "Peripheral Benzodiazepine Receptor 28" (PBR28) PET in patients
 with RRMS.

 Hypothesis: The working hypothesis is that there is microglial activation in multiple
 sclerosis and Alzheimer's disease as compared to healthy controls and that the pattern/
 regional distribution of microglial activation is different in Multiple Sclerosis (MS) versus
 AD and correlates with disease severity and comorbidities.

 In addition, the investigators hypothesize that [F-18]PBR06-PET scans will be at least as
 good as [C-11]PBR28-PET scans, the current gold standard.
Four groups of subjects will be recruited:

 1. Subjects meeting the definition for RRMS by the International Panel Criteria, who are
 active, as defined by at least one MS relapse in the past 12 months, or at least one
 gadolinium enhancing lesion on Magnetic Resonance Imaging (MRI) within 3 months of
 enrollment.

 2. Subjects meeting the definition for SPMS by International Panel Criteria and who have
 demonstrated deterioration in Expanded Disability Status Scale (EDSS) score in last 1
 year

 3. Subjects meeting the definition for probable AD based on National Institute of
 Neurological and Communicable Diseases-Alzheimer's Disease and Related Disorders
 Association (NINCDS-ADRDA) criteria. In terms of severity of disease, we will select
 subjects with mild AD, as defined by Mini-Mental Status Examination (MMSE) score of
 20-26.

 4. Healthy Controls

 The study will be performed in two phases. In the early pilot phase, 8 subjects with RRMS
 will undergo both [C-11]PBR28 PET scan and [F-18]PBR06 PET scan. At the end of this phase, a
 formal interim analysis will be performed and if imaging characteristics of [F-18]PBR06 are
 found non-inferior to or better than [C-11]PBR28, rest of the study will be completed using
 [F-18]PBR06. All subjects will also undergo 3-Tesla (3T) MRI of the brain.

 The goal sample size is 30 subjects including 6 healthy controls, 8 subjects with relapsing
 remitting MS, 8 subjects with secondary progressive MS (SPMS), and 8 subjects with AD.

 Subjects will be recruited by the PI, one of the other co-investigators, or a staff member
 listed on the protocol at the Partners MS Center and the Behavioral Neurology Clinic of
 Brigham and Women's Hospital.

 Side Effects Monitoring:

 No side effects from the radiopharmaceuticals are expected. The dose of radiopharmaceutical
 being administered in this study is below that at which we would expect any effect, including
 physical dependence and addiction. Subjects will be exposed to a small amount of radiation.
 The radiotracer will be prepared in such a way as to ensure that it is sterile and pyrogen
 free, and its radiochemical purity (RCP) will be determined using Silica Gel-Instant Thin
 Layer Chromatography and/or high pressure liquid chromatography (HPLC). In addition, because
 both [F-18]PBR06 and [C-11]PBR28 are non-FDA approved radioligands, their use for this study
 will be reviewed by Radioactive Drugs Research Committee.

 Subject Safety:

 Subject monitoring during MRI and PET scans will be performed using a 2-way intercom system
 between the scanner operator and subject and by visual monitoring of the subject through the
 window into the scan room (the subject is visible to the operator at all times).

 Subjects will need to lie still in the PET camera for period of 120 min, and subjects may
 find it uncomfortable to remain still over this time. Therefore, as mentioned above, subjects
 will be given the opportunity to take a break for up to 20 minutes after 70 minutes of PET
 scanning, following which the last 30 minutes of scanning will be completed. A standard
 head-support device will be used to make the subjects comfortable during the scanning.

 If subjects find an intravenous catheter or duration of scanning too uncomfortable, they are
 free to withdraw from the study at any time.

 The MRI scans take place in a confined space that makes some people claustrophobic.
 Claustrophobic individuals will be excluded from the study. Also during the scan the subject
 will hear loud banging noises and will therefore wear ear plugs to reduce this noise.

 Recruitment Process:

 Physicians at the Partners MS Center and the Brigham and Women's Hospital (BWH) Behavioral
 Neurology clinic may present the study to a subject during a regular scheduled clinic visit.
 If the subject is interested in the study, a copy of the consent form will be given. At the
 time of the subject's initial screening visit, a licensed physician investigator will answer
 any questions the subject may have regarding the study and subsequently obtain informed
 consent. In accordance with NIH guidelines, efforts will be made to attain a mix of study
 participants, in terms of gender and racial/ethnic representation.

 Consent Process:

 Informed consent will be obtained from the subjects by a licensed physician investigator on
 the study protocol. If the investigator is a clinician from the MS Center or Behavioral
 Neurology clinic, they will not be allowed to obtain consent from their own patients.
 Existing MS Center or Behavioral Neurology clinic subjects may be sent a letter describing
 the study and a copy of the consent document. Interested subjects are directed to contact
 research staff via a telephone number provided in the letter inviting participation in the
 study to set up a screening visit. They will have the opportunity to discuss the study with
 research study staff prior to giving consent as outlined above. Subjects approached for
 participation in the study during a routine clinical visit will have the opportunity to
 participate in the study at that time or they may choose to return for participation at
 another time in the future. All subjects will be informed that they are free to withdraw
 consent from the study at any time without affecting the quality or type of care that they
 receive at BWH. Subjects will be informed that they may not qualify for the study if their
 genetic analysis reveals that they are low affinity binders for translocator protein (TSPO).

 Monitoring and Quality Assurance:

 During the study period, subjects will be followed by their clinical neurologists for adverse
 events and disease progression. If problems are reported to their physicians, they will
 receive care as is normally performed. In addition, the Principal Investigator (PI) will
 review all laboratory results of tests undergone by the subjects during the study period and
 help co-ordinate any necessary care with patient's primary providers.
Inclusion Criteria:

 1. Male and female subjects age 18 to 70 years. For Alzheimer's Disease patients and
 healthy controls, the age range is going to be 18 to 85 years.

 2. For RRMS, it needs to be active, which is defined as at least one relapse in the past
 12 months, at least one gadolinium enhancing lesion on MRI within 12 months of
 enrollment or at least one new FLAIR bright lesion on MRI within 6 months of
 enrollment.

 3. For SPMS, deterioration in EDSS score in the last year is required.

 4. For the subjects in the Ocrelizumab arm, only the subjects who have already been
 prescribed Ocrelizumab by their treating MS neurologist but have not yet started the
 first infusion, will be included.

 5. AD subjects with MMSE score of 20-26.

 6. Subjects willing to undergo PET and MRI imaging

 7. Subjects willing and able to give informed consent

 Exclusion Criteria:

 1. Individuals with a known alternate neurologic disorder, previous head injury, or
 substance abuse.

 2. Individuals with bipolar disease and schizophrenia

 3. Concurrent medical conditions that contraindicate study procedures.

 4. 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.

 5. Claustrophobia

 6. Non-MRI compatible implanted devices

 7. For the Ocrelizumab arm, subjects already on Ocrelizumab will be excluded. For the
 Alemtuzumab arm, subjects already on Alemtuzumab will be excluded.

 8. For the Ocrelizumab arm and the Alemtuzumab arm, subjects with abnormal serum
 creatinine will be excluded.