Objective: To investigate differences in baseline α-synuclein seed amplification assay (SAA) metrics and longitudinal clinical subtypes of Parkinson’s disease (PD) between the two biological sexes.

Background: PD is a heterogeneous neurodegenerative disorder with notable variations in clinical presentation and progression. The role of biological sex in PD heterogeneity remains unclear.

Method: Data on 421 individuals (276 men, 145 women) with PD was retrieved from Parkinson’s Progression Markers Initiative (PPMI) [1] cohort including extensive longitudinal data on clinical manifestations, and biomarkers. The CSF αSyn-SAA positivity and amplification parameters (time-to-threshold [TTT], time-to-50% Fmax [T50], area under the curve [AUC], slope) from a 150-hours protocol were compared between males and females. Using a multi-domain subtyping method, we classified PD population into three subtypes: “mild motor-predominant”, “Intermediate” and “Diffuse malignant” [2] at baseline, year-5 and year-10 of follow-up. Multinomial logistic regression adjusted for baseline age were used to evaluate the interaction between biological sex and SAA parameters in association with clinical subtypes.

Results: There was no difference in the age of onset (60.2 vs 61.6 yrs, p=0.187), and αSyn-SAA positivity (93.3% vs 93.6%, p=0.914) between men and women. At baseline, females demonstrated significantly shorter TTT (63.1 vs 66.7, p=0.004) and T50 values (69.2 vs 72.1, p=0.018), lower slope (30.4 vs 34.3, p=0.002) but larger AUC (p=0.011) than males. After 5- and 10-years of follow-up, more males manifested as a diffuse malignant subtype than females (year-5: 25.8% vs 9.7%, p=0.003; year-10: 32.2% vs 13.2%, p=0.007). Multinomial logistic regression revealed than biological sex is an independent predictor of longitudinal clinical subtype, as males have 4.0 times (95% CI 1.3-12.2, p=0.014) higher odds of developing a diffuse malignant subtype after 10-years regardless of age and baseline αSyn-SAA metrics.

Conclusion: We demonstrated significant sex differences in baseline αSyn-SAA parameters and clinical subtypes of PD after 10-years of disease diagnosis. Biologically male individuals are more likely to manifest as ‘diffuse malignant’ subtype, with a higher burden of non-motor features 10-years after diagnosis. These clinical differences are independent of baseline sex-related variations in αSyn-SAA parameters.

Figure 1.

References: 1. Marek K., Jennings D., Lasch S., Siderowf A., Tanner C., Simuni T. The Parkinson progression marker initiative (PPMI) Prog Neurobiol 2011; 95: 629–635.
2. Fereshtehnejad SM, Zeighami Y, Dagher A, Postuma RB. Clinical criteria for subtyping Parkinson’s disease: biomarkers and longitudinal progression. Brain 2017; 140(7): 1959-1976.

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MDS Abstracts - https://www.mdsabstracts.org/abstract/sex-differences-in-%ce%b1-synuclein-seed-amplification-assay-parameters-and-longitudinal-clinical-subtypes-of-parkinsons-disease/