Sex-driven variability in TSPO-expressing microglia in MS patients and healthy individuals.

Background: Males with multiple sclerosis (MS) have a higher risk for disability progression than females, but the reasons for this are unclear.
Objective: We hypothesized that potential differences in TSPO-expressing microglia between female and male MS patients could contribute to sex differences in clinical disease progression.
Methods: The study cohort consisted of 102 MS patients (mean (SD) age 45.3 (9.7) years, median (IQR) disease duration 12.1 (7.0-17.2) years, 72% females, 74% relapsing-remitting MS) and 76 age- and sex-matched healthy controls. TSPO-expressing microglia were measured using the TSPO-binding radioligand [ ¹¹ C](R)-PK11195 and brain positron emission tomography (PET). TSPO-binding was quantified as distribution volume ratio (DVR) in normal-appearing white matter (NAWM), thalamus, whole brain and cortical gray matter (cGM).
Results: Male MS patients had higher DVRs compared to female patients in the whole brain [1.22 (0.04) vs. 1.20 (0.02), p  = 0.002], NAWM [1.24 (0.06) vs. 1.21 (0.05), p  = 0.006], thalamus [1.37 (0.08) vs. 1.32 (0.02), p  = 0.008] and cGM [1.25 (0.04) vs. 1.23 (0.04), p  = 0.028]. Similarly, healthy men had higher DVRs compared to healthy women except for cGM. Of the studied subgroups, secondary progressive male MS patients had the highest DVRs in all regions, while female controls had the lowest DVRs.
Conclusion: We observed higher TSPO-binding in males compared to females among people with MS and in healthy individuals. This sex-driven inherent variability in TSPO-expressing microglia may predispose male MS patients to greater likelihood of disease progression.
Competing Interests: SL has received travel Honoria from Roche, and research support from the Turunmaa Duodecim society, Finnish Brain Foundation, Turku Doctoral Programme in Clinical Research and Finnish Governmental Research Funding (VTR) for Turku University Hospital. MN has received research support from the Finnish MS Foundation, Maire Taponen Foundation, the Finnish Cultural Foundation, Drug Research Doctoral Programme of University of Turku and the Research Council of Finland’s Flagship InFLAMES. AS was supported by the Emil Aaltonen foundation, the Paulo Foundation, the Orion Research Foundation sr, Finnish Governmental Research Funding (VTR) for Turku University Hospital and Research Council of Finland (#341059). JR serves as a neurology consultant for Clinical Research Services Turku (CSRT Oy). LA has received honoraria from Biogen, Roche, Genzyme, Merck Serono and Novartis, and institutional research grant support from the Research Council of Finland, Sanofi-Genzyme and Merck Serono. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.
(Copyright © 2024 Laaksonen, Saraste, Nylund, Hinz, Snellman, Rinne, Matilainen and Airas.)