Objective: To determine whether presence of synucleinopathy and dopaminergic biomarkers, either alone or in combination, predict phenoconversion to Parkinson’s disease (PD) differentially in GBA versus LRRK2 non-manifesting carriers (NMCs).

Background: PD diagnosis often follows a long prodromal period, with neurobiological changes preceding motor diagnosis by years.¹ NMCs of GBA and LRRK2 variants represent distinct at-risk populations with differing neurobiologic profiles and clinical course once diagnosed with PD.² CSF α-Synuclein seed amplification assay (αSyn-SAA) and SPECT dopamine transporter neuroimaging (DaTscan) are established prodromal PD biomarkers, though the hypothesized sequential relationship is not universally conserved, particularly in LRRK2, where dopaminergic loss can occur without obvious synucleinopathy and Lewy body pathology.³

Method: Data were drawn from the Parkinson’s Progression Markers Initiative (PPMI), an ongoing longitudinal multicenter observational study, and included three cohorts: GBA NMCs (N=138), LRRK2 NMCs (N=163), and healthy controls (HCs; N=235). Prodromal biomarker status was assessed at baseline via cerebrospinal fluid CSF αSyn-SAA and dopamine transporter imaging (DaTscan), both interpreted using qualitative reads as positive or negative. Clinical outcomes, including MDS-UPDRS Parts I, II, and III, MoCA, SCOPA-AUT, and phenoconversion to PD, were assessed at baseline and annually for up to nine years.

Results: αSyn-SAA positivity rates at enrollment were low and did not differ significantly across groups (p = .319): 7.2% in HCs, 7.4% in LRRK2 NMCs, and 5.1% in GBA NMCs. In contrast, DaTscan results revealed between-group differences (p < .001), with dopaminergic deficit present in 19.6% of LRRK2 NMCs, 3.6% of GBA NMCs and 4.3% of HCs.

Conclusion: Synucleinopathy and dopaminergic dysfunction are uncommon in GBA and LRRK2 NMCs at baseline in PPMI, suggesting that most participants are not close to phenoconversion. PPMI provides relatively large, well-characterized cohorts of GBA and LRRK2 NMCs and HCs with long-term follow-up, and analyses examining clinical progression over a decade, including phenoconversion to PD, will be presented at the IPMDS meeting.

References: 1. Serebryany-Piavsky V, Egulsky L, Manoim-Wolkovitz JE, et al. The modifying effect of mutant LRRK2 on mutant GBA1-associated Parkinson disease. Human Molecular Genetics. 2025;34(14):1184-1203. doi:https://doi.org/10.1093/hmg/ddaf062
2. Chahine LM, Lafontant DE, Choi SH, et al. LRRK2-associated parkinsonism with and without in vivo evidence of alpha-synuclein aggregates: longitudinal clinical and biomarker characterization. Brain Communications. 2025;7(2):fcaf103-fcaf103. doi:https://doi.org/10.1093/braincomms/fcaf103
3. Kopal J, Vo A, Tao Q, et al. Carriers of LRRK2 pathogenic variants show a milder, anatomically distinct brain signature of Parkinson’s disease. Communications Medicine. 2026;6(1). doi:https://doi.org/10.1038/s43856-025-01330-7

« Back to 2026 International Congress

MDS Abstracts - https://www.mdsabstracts.org/abstract/predictors-of-clinical-progression-over-a-decade-in-gba1-versus-lrrk2-non-manifesting-carriers/