Brain Peripheral Benzodiazepine Receptors in Patients With Multiple Sclerosis

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.

- SUBJECTS WITH MULTIPLE SCLEROSIS - INCLUSION CRITERIA:

- Ages between 18 and 70, inclusive.

- Diagnosis of definite MS according to published criteria.

- The presence of at least one gadolinium-enhancing lesion on the screening brain
magnetic resonance image (MRI), and T2 lesion load volume greater than 5 cc.

- Subjects must be able to provide written, informed consent prior to any testing under
this protocol, including screening and baseline investigations that are not considered
part of routine patient care.

SUBJECTS WITH MULTIPLE SCLEROSIS - EXCLUSION CRITERIA:

- Prior participation in other research protocols or clinical care in the last year such
that radiation exposure would exceed the annual guidelines.

- Homozyous for the low- affinity binding form of TSPO by TSPO genotype analysis (
Ala147Thr polymorphism in rs6971 SNP in exon 4 of the TSPO gene).

- Pregnancy and breast-feeding.

- Presence of ferromagnetic metal in the body or heart pacemaker.

- ECG with clinically significant abnormalities.

- Positive HIV test.

- Positive pregnancy test.

- Concurrent medical conditions including hepatic cirrhosis, end-stage renal disease or
any acute and severe decompensation of disease that in the opinion of the investigator
would compromise the safety of the patient.

- Subjects with cognitive impairment who are unable to provide written, informed
consent.

- Subjects who have received immunomodulatory/disease-modifying therapy, including
investigational MS therapy, within 12 weeks prior to PET imaging or who have received
corticosteroids within 6 weeks prior to PET imaging.

HEALTHY VOLUNTEERS - INCLUSION CRITERIA:

All subjects must be healthy and aged 18-70 years.

HEALTHY VOLUNTEERS - EXCLUSION CRITERIA:

Homozyous for the low- affinity binding form of TSPO by TSPO genotype analysis ( Ala147Thr
polymorphism in rs6971 SNP in exon 4 of the TSPO gene).

Current psychiatric illness, substance abuse or severe systemic disease based on history
and physical exam.

ECG with clinically significant abnormalities. Any existing physical exam and ECG within
one year will be reviewed and if none already exists in the chart, these will be obtained
and reviewed.

Laboratory tests with clinically significant abnormalities.

Prior participation in other research protocols in the last year such that radiation
exposure would exceed the annual guidelines.

Pregnancy and breast-feeding.

Positive pregnancy test.

Claustrophobia.

Presence of ferromagnetic metal in the body or heart pacemaker.

Positive HIV test.

A history of brain disease.