Objective: Describe rates of phenoconversion and progression to functionally meaningful impairment in early Neuronal α-Synuclein Disease (NSD).

Background: There is increasing focus on testing disease modifying therapies (DMT) in individuals before they develop clinically defined diagnoses of PD or DLB (prodromal individuals). There is substantial body of data on the rate of phenoconversion in iRBD cohorts but minimal amount of data in biologically defined populations.

Method: Analyzed data on Parkinson´s Progression Markers Initiative PPMI participants who met criteria for NSD stage 2B, defined by positive biomarkers of a-synuclein pathology and dopaminergic dysfunction, clinical features of RBD and/or hyposmia but no functional impairement and no diagnosis of PD/DLB/MSA/dementia.  Progression was defined by either phenoconversion (investigator determined) to any of the above diagnoses or progression to NSD stage >3, defined by presence of participant reported functional impairement. Analysis was conducted for the overall NSD 2B cohort and by prodromal subgroups defined as: A1-participants with PSG confirmed RBD and hyposmia; A2-participants with PSG confirmed RBD and no hyposmia; B-participants with self reported dream enactment behavior and hyposmia; C-participants with hyposmia and no RBD features.

Results: 271 participants with NSD Stage 2B were included in analysis. Table 1 presents baseline demographic and key disease characteristics for the cohort and subgroups. Annual rate of phenoconversion for the overall cohort over 3 years was 4.4% (2.5-7.7% 95% CI), 10.3% (6.6-15.9%), 18.4% (11.8-28.0%) at year 1,2,3 respectively. Rate of progression to functional impairment was significantly higher: 21.4%(17.0-26.8%), 33.8%(27.6- 41.0%).43.0%(34.7-52.5%) at year 1,2,3 respectively (Fig 1). Analysis by prodromal subgroups demonstrated no significant differences for the phenoconversion rate but subgroups with RBD spectrum disorder achieved milestone of functional impairment significantly earlier (Fig 2).

Conclusion: Significant number of NSD 2B individuals demonstrate clinical progression over 1-3 years. Participant reported time to functional impairments appears to be a more sensitive milestone than phenoconversion. This data is essentially important for design of the DMT trials in early NSD population and for counseling potentially qualified participants regarding their risk of progression.

Table 1

Figure 1

Figure 2

References: Acknowledgements:
Data used in the preparation of this article was obtained from the Parkinson’s Progression Markers Initiative database (//www.ppmi-info.org/access-data-specimens/download-data), RRID:SCR_006431. For up-to-date information on the study, visit www.ppmi-info.org.

PPMI –a public-private partnership– is funded by the Michael J. Fox Foundation and funding partners, including Abbvie, Alamar Biosciences, Aligning Science Across Parkinson’s, Arrowhead Pharma, AskBio, BIAL, BioArctic, Biohaven, BlueRock Therapeutics, Bristol-MyersSquibb, Calico Labs, Capsida Biotherapeutics, Critical Path Institute, DaCapo Brainscience, Denali, Edmond J. Safra Foundation, Eli Lilly, Gain Therapeutics, GE HealthCare, Genentech, GSK, Insitro, Johnson & Johnson Innovative Medicine, Lundbeck, Merck, Neumora, Neuron23, Novartis, Regeneron, Roche, Sanofi, Tenvie, UCB, VanquaBio, Voyager Therapeutics, the Weston Family Foundation.

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MDS Abstracts - https://www.mdsabstracts.org/abstract/rates-of-phenoconvertion-and-progression-to-functionally-meaningful-impairment-in-nsd-stage-2b-participants-ppmi-cohort/