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Updated: Dec 12, 2025
Comprehensive Autopsy Program for Individuals with Multiple Sclerosis
Published on: July 19, 2019
Regional microglial activation in the substantia nigra is linked with fatigue in MS
Tarun Singhal1, Steven Cicero2, Hong Pan2
1From the Partners MS Center (T.S., S.C., K.C., B.G., R.B., H.L.W.), Ann Romney Center for Neurological Diseases, Department of Neurology, Brigham and Women's Hospital, Harvard Medical School, Boston, MA; PET Imaging Program in Neurologic Diseases (T.S., S.C., K.C.), Ann Romney Center for Neurological Diseases, Department of Neurology, Brigham and Women's Hospital, Harvard Medical School, Boston, MA; Functional Neuroimaging Laboratory (H.P., R.B., D.S.), Department of Psychiatry, Brigham and Women's Hospital, Harvard Medical School, Boston, MA; Division of Nuclear Medicine and Molecular Imaging (S.D., M.-A.P., M.K.), Department of Radiology, Brigham and Women's Hospital, Harvard Medical School, Boston, MA; Laboratory for Neuroimaging Research (R.C., S.T.), Ann Romney Center for Neurological Diseases, Department of Neurology, Brigham and Women's Hospital, Harvard Medical School, Boston, MA; Department of Medicine (S.H.), Brigham and Women's Hospital, Harvard Medical School, Boston, MA; Ceretype Neuromedicine (E.S.)Department of Radiology (R.B.), Brigham and Women's Hospital, Harvard Medical School, Boston, MA. tsinghal@bwh.harvard.edu.
Objective:
The goal of our study is to assess the role of microglial activation in MS-associated fatigue (MSAF) using [F-18]PBR06-PET.
Methods:
Fatigue severity was measured using the Modified Fatigue Impact Scale (MFIS) in 12 subjects with MS (7 relapsing-remitting and 5 secondary progressive) and 10 healthy control participants who underwent [F-18]PBR06-PET. The MFIS provides a total fatigue score as well as physical, cognitive, and psychosocial fatigue subscale scores. Standardized Uptake Value (SUV) 60-90 minute frame PET maps were coregistered to 3T MRI. Voxel-by-voxel analysis using Statistical Parametric Mapping and atlas-based regional analyses were performed. SUV ratios (SUVRs) were global brain normalized.
Results:
Peak voxel-based level of significance for correlation between total fatigue score and PET uptake was localized to the right substantia nigra (T-score 4.67, p = 0.001). Similarly, SUVRs derived from atlas-based segmentation of the substantia nigra showed significant correlation with MFIS (r = 0.76, p = 0.004). On multiple regression, the right substantia nigra was an independent predictor of total MFIS (p = 0.02) and cognitive MFIS subscale values (p = 0.007), after adjustment for age, disability, and depression. Several additional areas of significant correlations with fatigue scores were identified, including the right parahippocampal gyrus, right precuneus, and juxtacortical white matter (all p < 0.05). There was no correlation between fatigue scores and brain atrophy and lesion load in patients with MS.
Conclusion:
Substantia nigra microglial activation is linked to fatigue in MS. Microglial activation across key brain regions may represent a unifying mechanism for MSAF, and further evaluation of neuroimmunologic basis of MSAF is warranted.
Insights
Microglial activation in the substantia nigra is linked to fatigue in multiple sclerosis (MS). This finding suggests neuroinflammation may be a key factor in MS-associated fatigue (MSAF).
Area of Science:
- Neuroscience
- Immunology
- Radiology
Background:
- Multiple Sclerosis (MS) is a chronic neurological disease.
- MS-associated fatigue (MSAF) significantly impacts patient quality of life.
- The underlying mechanisms of MSAF, particularly the role of neuroinflammation, are not fully understood.
Purpose of the Study:
- To investigate the association between microglial activation and fatigue in MS patients.
- To utilize [F-18]PBR06-PET imaging to quantify neuroinflammation.
- To explore the relationship between specific brain regions and fatigue severity.
Main Methods:
- 12 MS patients and 10 healthy controls underwent [F-18]PBR06-PET scans.
- Fatigue severity was assessed using the Modified Fatigue Impact Scale (MFIS).
- PET data were analyzed using voxel-based and atlas-based methods, coregistered with MRI.
Main Results:
- A significant correlation was found between microglial activation in the right substantia nigra and total MFIS scores.
- The right substantia nigra independently predicted total and cognitive MFIS scores.
- Additional correlations were observed in the parahippocampal gyrus, precuneus, and white matter.
Conclusions:
- Microglial activation in the substantia nigra is a key factor in MS-associated fatigue.
- Neuroinflammation in specific brain regions may underlie MSAF.
- Further research into the neuroimmunological basis of MSAF is warranted.
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