Regional microglial activation in the substantia nigra is linked with fatigue in MS

Tarun Singhal; Steven Cicero; Hong Pan; Kelsey Carter; Shipra Dubey; Renxin Chu; Bonnie Glanz; Shelley Hurwitz; Shahamat Tauhid; Mi-Ae Park; Marie Kijewski; Emily Stern; Rohit Bakshi; David Silbersweig; Howard L Weiner

doi:10.1212/NXI.0000000000000854

Regional microglial activation in the substantia nigra is linked with fatigue in MS

Neurol Neuroimmunol Neuroinflamm. 2020 Aug 7;7(5):e854. doi: 10.1212/NXI.0000000000000854. Print 2020 Sep 3.

Authors

Affiliations

¹ From 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. [email protected].
² From 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.

Abstract

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.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Acetanilides
Adult
Fatigue* / diagnostic imaging
Fatigue* / etiology
Fatigue* / immunology
Fatigue* / physiopathology
Female
Humans
Magnetic Resonance Imaging
Male
Microglia* / immunology
Middle Aged
Multiple Sclerosis* / complications
Multiple Sclerosis* / diagnostic imaging
Multiple Sclerosis* / immunology
Multiple Sclerosis* / physiopathology
Positron-Emission Tomography
Substantia Nigra* / diagnostic imaging
Substantia Nigra* / immunology

Substances

Acetanilides
N-fluoroacetyl-N-(2,5-dimethoxybenzyl)-2-phenoxyaniline