Objective: To examine sex differences in cardiovascular risk, white matter hyperintensities (WMH), and neurodegeneration, and to determine their relationship with clinical progression in progressive supranuclear palsy Richardson syndrome (PSP-RS).

Background: Studies examining the roles of vascular burden and neurodegeneration in PSP-RS are scarce. Patients with PSP-RS present a characteristic profile of comorbidities, particularly cardiovascular disease. WMH burden has shown limited association with clinical progression in PSP. However, the contribution of vascular and neurodegenerative processes may differ between male and female patients.

Method: We analyzed data from 121 individuals with PSP-RS enrolled in the Tilavonemab (ABBV-8E12) clinical trial. A cardiovascular risk (CVR) score was derived from age, sex, systolic blood pressure, body mass index, smoking status, diabetes, and antihypertensive medication use. Disease severity and progression were assessed using the Progressive Supranuclear Palsy Rating Scale (PSPRS), with change calculated between baseline and 24 weeks. Baseline plasma neurofilament light chain (NfL) levels were used as a marker of neurodegeneration. WMH burden was quantified at baseline from FLAIR MRI using the lesion segmentation toolbox in MATLAB. Multiple regression models were used to examine sex differences and interaction effects.

Results: The cohort included 72 males (59.5%) and 49 females (40.5%). Males were older (M: 69.7 ± 7.2 years vs. F: 67.2 ± 6.3 years; p = 0.05) and had higher CVR scores (M: 18.1 ± 3.7 vs. F: 16.7 ± 4.5; p = 0.05). At baseline, females presented greater PSPRS scores (F: 35.5 ± 10.6 vs. M: 31.5 ± 10.7; p = 0.03). In females, WMH burden was associated with age and NfL, whereas in males WMH burden was associated with CVR. When examining disease progression (change in the PSPRS)_, both WMH burden and plasma NfL levels presented a significant interaction with sex, with a stronger association in females than in males.

Conclusion: These findings suggest sex-specific relationships between vascular burden and neurodegeneration in PSP-RS. WMH burden appears to reflect vascular risk in males, while neurodegeneration measured by NfL is a stronger predictor of clinical progression in females.

This study used AbbVie data accessed via Vivli; Vivli had no role in the study.

References: Tepedino MF, Diana F, Avallone AR, Pellecchia MT, Cuoco S, Aiello M, Manara R, Barone P, Picillo M. Investigating the impact of white matter hyperintensities on longitudinal progression in progressive supranuclear palsy. Neurol Sci. 2025 Dec;46(12):6933-6937. doi: 10.1007/s10072-025-08547-3. Epub 2025 Oct 18. PMID: 41107578.
Greten S, Wegner F, Jensen I, Krey L, Rogozinski S, Fehring M, Heine J, Doll-Lee J, Pötter-Nerger M, Zeitzschel M, Hagena K, Pedrosa DJ, Eggers C, Bürk K, Trenkwalder C, Claus I, Warnecke T, Süß P, Winkler J, Gruber D, Gandor F, Berg D, Paschen S, Classen J, Pinkhardt EH, Kassubek J, Jost WH, Tönges L, Kühn AA, Schwarz J, Peters O, Dashti E, Priller J, Spruth EJ, Krause P, Spottke A, Schneider A, Beyle A, Kimmich O, Donix M, Haussmann R, Brandt M, Dinter E, Wiltfang J, Schott BH, Zerr I, Bähr M, Buerger K, Janowitz D, Perneczky R, Rauchmann BS, Weidinger E, Levin J, Katzdobler S, Düzel E, Glanz W, Teipel S, Kilimann I, Prudlo J, Gasser T, Brockmann K, Hoffmann DC, Klockgether T, Krause O, Heck J, Höglinger GU, Klietz M. The comorbidity and co-medication profile of patients with progressive supranuclear palsy. J Neurol. 2024 Feb;271(2):782-793. doi: 10.1007/s00415-023-12006-4. Epub 2023 Oct 6. PMID: 37803149; PMCID: PMC10827866.

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MDS Abstracts - https://www.mdsabstracts.org/abstract/sex-differences-in-vascular-burden-neurodegeneration-and-clinical-progression-in-progressive-supranuclear-palsy-richardson-syndrome/