Objective: To describe and assess biological congruency, defined as expected biological profile based on abnormal CSF α-synuclein Seed Amplification Assays (CSFaSynSAA) and dopamine transporter SPECT scan (DAT).

Background: Phenoconversion to clinically diagnosed Parkinson’s disease (PD) or dementia with Lewy bodies (DLB) remains the clinical and regulatory gold standard and relies on established diagnostic criteria. Biomarkers of α-synuclein pathology and dopaminergic dysfunction imaging offer an opportunity to revisit phenoconversion and investigate its congruency with biological characteristics.

Method: Descriptive analysis of Parkinson´s Progression Markers Initiative participants who phenoconverted to PD, DLB, multiple system atrophy (MSA) and Alzheimer’s disease (AD) from prodromal cohorts (isolated REM sleep behavior disorder (iRBD) and hyposmia), non-manifesting genetic carrier cohorts (GBA and LRRK2), and healthy controls (HC). Phenoconversion was determined by the site investigator and confirmed at the last observation. Participants with Neuronal alpha-Synuclein Disease (NSD) were functionally staged using the Integrated Staging System (ISS). Analysis included participants with ≥ 1 follow-up visit and available CSFaSynSAA or DAT biomarkers within ± 2 years of phenoconversion.

Results: A total of 121 participants phenoconverted, with biological data available for 103 phenoconverters (92 PD, 7 DLB, 2 MSA, 2 AD). Annual phenoconversion rates varied across cohorts: iRBD 7.9%, hyposmia 4.2%, GBA 0.3%, LRRK2 1.3%, LRRK2+GBA 0.9%, and HC 0.5%. We found the expected profile (CSFaSynSAA+/DAT+) for clinically diagnosed synucleinopathy in 74 (71.8%) participants. Hyposmics showed the highest biological alignment (87%), followed by iRBDs (72%). CSFaSynSAA negativity was higher than expected among LRRK2 phenoconverters (67%), who also were more likely to be normosmics (83%). Phenoconversion sometimes occurred after functional impairment, with 31.9% of iRBD and 18.4% of hyposmic participants already at NSD-ISS stage ≥4 at time of phenoconversion.

Conclusion: Clinical phenoconversion might not align with biological evidence of synucleinopathy or dopaminergic loss and may occur after meaningful functional impairment. These findings warrant revisiting phenoconversion as an endpoint and favour biologically anchored staging frameworks integrating biomarkers and functional impairment.

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MDS Abstracts - https://www.mdsabstracts.org/abstract/synuclein-and-dopamine-transporter-biomarkers-among-phenoconverters-to-parkinsonian-disorders/