Background: Dopaminergic responsiveness is a defining feature of Parkinson's disease (PD). However, there is limited information on how this evolves over time. Objectives: To examine serial dopaminergic responses, if there are distinct patterns, and which factors predict these. Methods: We analyzed data from the Parkinson's Progression Markers Initiative on repeated dopaminergic challenge tests (≥ 24.5% defined as a definite response). Growth-mixture modeling evaluated for different response patterns and multinomial logistic regression tested for predictors of these clusters. Results: There were 1,525 dopaminergic challenge tests from 336 patients. At enrolment, mean age was 61.2 years (SD 9.6), 66.4% were male and disease duration was 0.5 years (SD 0.5). 1 to 2 years after diagnosis, 48.0% of tests showed a definite response, but this proportion increased with longer duration (51.1-74.3%). We identified 3 response groups: 'Striking' (n = 29, 8.7%); 'Excellent' (n = 110; 32.7%) and 'Modest' (n = 197, 58.6%). Significant differences were as follows: striking responders commenced treatment earlier (P = 0.02), were less likely to be on dopamine agonist monotherapy (P = 0.01), and had better cognition (P < 0.01) and activities of daily living (P = 0.01). Excellent responders had higher challenge doses (P = 0.03) and were more likely to be on combination therapy (P < 0.01). Conclusion: Three distinct patterns of the dopaminergic response were observed. The proportion of PD cases with definite dopa responsiveness increased over time, so the initial treatment response may be an unreliable diagnostic aid.

Funding Sources and Conflict of Interest: MAL received consultancy fees for advising on a secondary analysis of an RCT sponsored by North Bristol NHS trust. VM has received honoraria from BIAL Pharma, AbbVie and Britannia Pharmaceuticals. KAG has received consultancy fees from Parkinson's UK. YBS has received consultancy payments from Human Centric DD Ltd and Parkinson's UK. DGG has received honoraria from BIAL Pharma, Britannia Pharmaceuticals, and UCB Pharma, consultancy fees from the Glasgow Memory Clinic, and grant support from Parkinson's UK. SEG: none; AN: none.

Funding: PPMI - a public-private partnership - is funded by the Michael J. Fox Foundation for Parkinson's Research and funding partners, including 4D Pharma, Abbvie, AcureX, Allergan, Amathus Therapeutics, Aligning Science Across Parkinson's, AskBio, Avid Radiopharmaceuticals, BIAL, Biogen, Biohaven, BioLegend, BlueRock Therapeutics, Bristol-Myers Squibb, Calico Labs, Celgene, Cerevel Therapeutics, Coave Therapeutics, DaCapo Brainscience, Denali, Edmond J. Safra Foundation, Eli Lilly, Gain Therapeutics, GE HealthCare, Genentech, GSK, Golub Capital, Handl Therapeutics, Insitro, Janssen Neuroscience, Lundbeck, Merck, Meso Scale Discovery, Mission Therapeutics, Neurocrine Biosciences, Pfizer, Piramal, Prevail Therapeutics, Roche, Sanofi, Servier, Sun Pharma Advanced Research Company, Takeda, Teva, UCB, Vanqua Bio, Verily, Voyager Therapeutics, the Weston Family Foundation and Yumanity Therapeutics.

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This study used publicly available data from the Parkinson's Progression Markers Initiative (PPMI) study, accessed in November 2022 at https://www.ppmi-info.org/15.

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