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

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.

Figure 1. SPM analysis

(A) Statistical Parametric Mapping (SPM)-based, voxel-by-voxel maps of correlation between Modified Fatigue Impact Scale (MFIS) and PET uptake. The strongest positive correlation was seen in the right substantia nigra (cross-bars). Additional regions of significant correlations were seen in the left substantia nigra, periaqueductal gray, pons, medulla, precuneus, midcingulate, cerebellar vermis, and insular cortex regions. (B) SPM-based, voxel-by-voxel maps demonstrate widespread positive correlation in juxtacortical white matter between MFIS scores and PET uptake.

Figure 2. Correlational analysis between regional PET SUVR and fatigue scores

Correlations between (A) average substantia nigra (SN) SUVR and total MFIS, (B) right SN SUVR and total MFIS, (C) average SN SUVR and cognitive MFIS, (D) average SN SUVR and physical MFIS, and (E) right SN SUVR and psychosocial MFIS. MFIS = Modified Fatigue Impact Scale.

Figure 3. Comparison of substantia nigra PET uptake between subjects with MS with fatigue and subjects with MS without fatigue and healthy participants

(A) Individualized z-score maps showing increased [F-18]PBR06 PET uptake in the bilateral substantia nigra in a patient with MS with fatigue with a high total MFIS score (total MFIS score = 64) compared with a patient with MS without fatigue with a comparable EDSS score (3.5 vs 4) and a low total MFIS score (MFIS score = 33). For the latter patient, the ROIs for the substantia nigra are delineated but do not demonstrate an increased z-score of >2 compared with a healthy control group. (B) Increased average substantia nigra SUVR in patients with MS with fatigue compared with patients with MS without fatigue and healthy participants. (C) Increased right substantia nigra SUVR in patients with MS with fatigue compared with patients with MS without fatigue and healthy participants. (D) Increased left substantia nigra SUVR in patients with MS with fatigue compared with healthy controls. MFIS = Modified Fatigue Impact Scale. *p < 0.05; **p < 0.01.