Observational review of phenoconversion rates and biomarker alignment in Parkinson's disease genetic cohorts

Background: Phenoconversion to Parkinson's disease (PD) or dementia with Lewy bodies (DLB) currently relies on established clinical diagnostic criteria. Availability of in vivo biomarkers--CSF -synuclein seed amplification assay (CSFaSynSAA) and dopamine transporter (DAT) imaging--offer the opportunity to investigate congruency between clinical phenoconversion and biologically defined disease. Methods: We analyzed Parkinson's Progression Markers Initiative participants who phenoconverted to PD, DLB, multiple system atrophy (MSA), Alzheimer's disease (AD) or other dementias from prodromal and non-manifesting genetic carrier (NMC) groups and controls. Site investigators determined phenoconversion based on established diagnostic criteria. All phenoconverters with [≥]1 annual follow-up visit, with available biomarkers and persistent clinically defined diagnosis at last observation were included. Neuronal alpha-Synuclein Disease Integrated Staging System (NSD-SS) staging was applied. Results: Among 121 phenoconverters, 103 had evaluable CSFaSynSAA and DAT data and were included in analysis: 92 PD, 7 DLB, 2 MSA, 2 AD/other dementias. Phenoconversion annual rates varied widely across groups: iRBD 7.9%, hyposmia 4.2%, GBA1 0.3%, LRRK2 1.3%, LRRK2+GBA1 0.9%, and controls 0.5%. Median time from baseline to phenoconversion ranged from 13-14 months in iRBD and hyposmia to 36-85 months in NMCs. The expected biomarker profile (CSFaSynSAA+/DAT+) for clinically-diagnosed synucleinopathy occurred in 74 (71.8%) participants. Biological alignment (CSFaSynSAA+/DAT+) was present in 87% hyposmics and 72% iRBD phenoconverters. CSFaSynSAA negativity was high among LRRK2 phenoconverters (67%), who also were more likely to have a preserved sense of smell (83%). Phenoconversion occurred later than onset of functional impairment: 15/47 (31.9%) iRBDs and 7/38 (18.4%) hyposmics were already NSD-ISS stage [≥]4 at time of phenoconversion. Conclusions: Clinical phenoconversion did not necessarily align with biological evidence of synucleinopathy or dopaminergic loss and can be delayed compared to onset of meaningful functional impairment. Longitudinal follow up on converters without biological evidence of PD is required to confirm conversion diagnosis and evaluate for a later occurrence of biomarker positivity.