A Milestone-Based Approach to Monitoring Disease Progression in Parkinson’s Disease Michael C. Brumm,1 Andrew Siderowf,2 Tanya Simuni,3 Elliot Burghardt,1 Chelsea Caspell-Garcia,1 Arthur W. Toga,4 Douglas Galasko,5 Brit Mollenhauer,6,7 Lana M. Chahine,8 Tatiana Foroud,9 Vanessa Arnedo,10 Mark Frasier,10 Alyssa Reimer,10 Caroline Tanner,11 Kathleen Poston,12 Daniel Weintraub,2,13 Samantha J. Hutten,10 Karl Kieburtz,14 Kenneth Marek,15 and Christopher S. Coffey1 1University of Iowa, Iowa City, IA, USA; 2University of Pennsylvania, Philadelphia, PA, USA; 3Northwestern University, Chicago, IL, USA; 4University of Southern California, Los Angeles, CA, USA; 5University of California, San Diego, CA, USA; 6University Medical Center Goettingen, Goettingen, Germany; 7Paracelsus-Elena-Klinik, Kassel, Germany; 8University of Pittsburgh, Pittsburgh, PA, USA; 9Indiana University, Indianapolis, IN, USA; 10The Michael J. Fox Foundation for Parkinson’s Research, New York, NY, USA; 11University of California, San Francisco, CA, USA; 12Stanford University, Stanford, CA, USA; 13Philadelphia Veterans Affairs Medical Center, Philadelphia, PA, USA; 14University of Rochester, Rochester, NY, USA; 15Institute for Neurodegenerative Disorders, New Haven, CT, USA OBJECTIVE RESULTS DESIGN/METHODS Clinical features at baseline that predicted reaching at least one milestone included increasing age (p<0.0001), greater MDS-UPDRS total score (p<0.0001) and greater depression score on the GDS-15 (p=0.0341). Biomarker predictors of reaching a milestone included decreasing DAT SPECT binding (p=0.0043) and CSF lower total alpha-synuclein (p=0.0033). Dopaminergic treatment was not significantly associated with the endpoint (p=0.1639). To assess the frequency of progression to clinically meaningful disease milestones and examine baseline predictors of reaching these milestones in early Parkinson’s disease (PD) using Parkinson Progression Marker Initiative (PPMI) data. CONCLUSIONS Clinically relevant milestones occur frequently within five years of follow-up even in early PD, and are associated with baseline clinical and biological markers, but not significantly associated with dopaminergic treatment. The results of this analysis are relevant for patient selection and outcome assessment in clinical trials. Funding agencies: PPMI – a public-private partnership – is funded by the Michael J. Fox Foundation for Parkinson’s Research funding partners 4D Pharma, Abbvie, Acurex Therapeutics, Allergan, Amathus Therapeutics, ASAP, Avid Radiopharmaceuticals, Bial Biotech, Biogen, BioLegend, Bristol-Myers Squibb, Calico, Celgene, Dacapo Brain Science, Denali, The Edmond J. Safra Foundaiton, GE Healthcare, Genentech, GlaxoSmithKline, Golub Capital, Handl Therapeutics, Insitro, Janssen Neuroscience, Lilly, Lundbeck, Merck, Meso Scale Discovery, Neurocrine Biosciences, Pfizer, Piramal, Prevail, Roche, Sanofi Genzyme, Servier, Takeda, Teva, UCB, Verily, and Voyager Therapeutics. BACKGROUND  Assessment of time to clinically relevant milestones could serve as a composite endpoint in clinical trials and be implemented in trials including patients receiving dopaminergic treatment. We measured 25 milestones across six domains: “walking and balance”; “motor complications”; “cognitive”; “autonomic”; “functional independence”; and “activities of daily living.” Milestones reflected severe manifestations of a given problem (e.g., a score ≥ 3 on relevant MDS-UPDRS items). Progression Milestone Assessment(s) Criteria Walking and Balance Domain Walking and Balance MDS-UPDRS Item 2.12 Response ≥ 3 Freezing MDS-UPDRS Item 2.13 Response ≥ 3 Gait MDS-UPDRS Item 3.10 Response ≥ 3 (ON or OFF) Freezing of Gait MDS-UPDRS Item 3.11 Response = 4 (ON or OFF) Postural Stability MDS-UPDRS Item 3.12 Response ≥ 3 (ON or OFF) Hoehn and Yahr Stage Hoehn and Yahr Stage Response ≥ 4 (ON or OFF) Motor Complications Domain Dyskinesias MDS-UPDRS Items 4.1 and 4.2 Response ≥ 3 (on BOTH) Fluctuations (Functiona