Multiple Sclerosis
Conditions
Brief summary
The overarching aim is to assess the role of microglial activation and norepinephrine transporter binding in pathogenesis of MS-related fatigue, using novel Positron Emission Tomography (PET) radiotracers, \[F-18\]PBR06 and \[C-11\]MRB. Specific Aims: Specific Aim 1: To determine the relationship of cerebral microglial activation, as assessed by \[F-18\]PBR06 PET, with MS-related fatigue. Specific Aim 2: To determine the relationship of norepinephrine transporter (NET) binding, as assessed by \[C-11\]MRB PET, with MS-related fatigue. Specific Aim 3: To determine the relationship of microglial activation and NET binding, with grey matter pathology (lesion load and brain atrophy) assessed using 7T MRI, and evaluate their independent contribution in development of MS-related fatigue.
Detailed description
Design: This is a single center, cross-sectional study of patients with multiple sclerosis, who will each, undergo both, \[C-11\]MRB-PET (norepinephrine transporter binding) and \[F-18\]PBR06-PET (microglial activation), in addition to 7 Tesla brain MRIs. Patients will also undergo cross-sectional estimations of blood markers. Genotype Testing: Blood sample drawn on the initial screening visit will be used to obtain genomic DNA for genotyping for polymorphism within the TSPO gene on chromosome 22q13.2, using a Taqman assay. High affinity and medium affinity binders will be included while the low affinity binders will be excluded from the study. PET Scanning: 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. The radiotracers will be produced using standardized procedures. At the time of imaging, the subjects will be positioned in the gantry of a high-resolution PET/CT 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.Dynamic data over 120 minutes for PET quantification will be acquired, according to previously described methods for both tracers. MRI Scanning: High resolution MRI scanning will be performed using the 7T Siemens MAGNETOM Terra MRI unit at Brigham & Women's Hospital (BWH). Serum assays: Serum measurements for inflammatory markers and relevant neurochemicals will be performed according to established procedures. Clinical Data The following non-imaging, clinical data will be obtained: Modified fatigue Impact Scale (MFIS) Fatigue Severity Status Scale (FSSS) Expanded Disability Status Scale (EDSS) Timed 25-feet walk (T25W) MS Functional Composite (MSFC) Symbol digit modalities test (SDMT) MSQOL-54 scale (QOL) Pittsburgh Sleep Quality Index (PSQI) Beck's Depression Inventory (BDI) Center for Epidemiological Studies-Depression Scale (CES-D) Hospital Anxiety and Depression Scale (HADS)
Interventions
DRUG[F-18]PBR06
PET radiopharmaceutical. Subjects will undergo \[F-18\]PBR06-PET (microglial activation).
PET radiopharmaceutical. Subjects will undergo \[C-11\]MRB-PET (norepinephrine transporter binding).
Sponsors
Brigham and Women's Hospital
U.S. Army Medical Research Acquisition Activity
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
DIAGNOSTIC
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to 60 Years
Healthy volunteers
No
Inclusion criteria
* Subjects meeting the definition for RRMS or SPMS by International Panel (2017 McDonald) Criteria. * We will recruit patients with RRMS, recently diagnosed in the last 2 years. There will be no disease modifying therapy restrictions for RRMS or SPMS patients. * Male and female subjects age 18 to 60 years. * Patients able to withhold medication that may interfere with C-11\[MRB\] radiotracer uptake for 24 hours before the scan.
Exclusion criteria
* Relapse/Corticosteroid treatment in the past 4 weeks to avoid transient effects on imaging * 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 * Low affinity binders
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Standardized Uptake Value Ratio (SUVR) | Baseline | PET outcome measure for \[F-18\]PBR06 radioligand used to quantify microglial activation. |
| Area Under the Curve Ratio (AUCR) | Baseline | PET outcome measure for \[C-11\]MeNer radioligand used to quantify norepinephrine transporter binding in brain regions of interest (e.g, putaminal, pallidal, and white matter). |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Correlations Between Modified Fatigue Impact Scale (MFIS) and PET Outcome Measures | Baseline | MFIS is a fatigue rating scale. Scores range from 0-84. Higher values indicate worse fatigue. |
| Correlations Between Expanded Disability Status Scale (EDSS) and PET Outcome Measures | Baseline | EDSS is a disability rating scale. Scores range from 0-10. Higher values indicate worse clinical function. |
Countries
United States
Contacts
PRINCIPAL_INVESTIGATORTarun Singhal, MD
Brigham and Women's Hospital
Participant flow
Pre-assignment details
There is no random assignment.
Baseline characteristics
| Characteristic | — |
|---|---|
| Age, Continuous | 47.00 years STANDARD_DEVIATION 8.98 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 0 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 10 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants |
| Expanded Disability Status Scale | 3.8 Score on the EDSS (0-10) STANDARD_DEVIATION 2.1 |
| Modified Fatigue Impact Scale | 34.3 Score on the MFIS (0-84) STANDARD_DEVIATION 25.9 |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants |
| Race (NIH/OMB) Asian | 0 Participants |
| Race (NIH/OMB) Black or African American | 0 Participants |
| Race (NIH/OMB) More than one race | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants |
| Race (NIH/OMB) White | 10 Participants |
| Region of Enrollment United States | 10 Participants |
| Sex: Female, Male Female | 8 Participants |
| Sex: Female, Male Male | 2 Participants |
| Timed 25-Foot Walk | 11.6 Time in Seconds STANDARD_DEVIATION 14.6 |
Adverse events
| Event type | EG000 affected / at risk |
|---|---|
| deaths Total, all-cause mortality | 0 / 10 |
| other Total, other adverse events | 4 / 10 |
| serious Total, serious adverse events | 0 / 10 |
Outcome results
None listed