A disease progression model to quantify the non-motor symptoms of Parkinson’s disease in participants with leucine-rich repeat kinase 2 mutation.

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Leucine-rich repeat kinase 2 (LRRK2) inhibitors are currently in clinical development as interventions to slow progression of Parkinson’s disease (PD). Understanding the rate of progression in PD as measured by both motor and non-motor features is particularly important in assessing the potential therapeutic effect of LRRK2 inhibitors in clinical development. Using standardized data from the Critical Path for Parkinson’s Unified Clinical Database, we quantified the rate of progression of the Movement Disorder Society-sponsored revision of the Unified Parkinson’s Disease Rating Scale (MDS-UPDRS) Part I (non-motor aspects of experiences of daily living) in 158 PD participants who were carriers and 598 PD participants who were non-carriers of at least one of three different LRRK2 gene mutations (G2019S, R1441C/G, R1628P). Age and disease duration were found to predict baseline disease severity, while presence of at least one of these three LRRK2 mutations was a predictor of the rate of MDS-UPDRS Part I progression. The estimated progression rate in MDS-UPDRS Part I was 0.648 (95% confidence interval: 0.544, 0.739) points per year in non-carriers of a LRRK2 mutation and 0.259 (95% confidence interval: 0.217, 0.295) points per year in carriers of a LRRK2 mutation. This analysis demonstrates that the rate of progression based on MDS-UPDRS Part I is approximately 60% lower in carriers as compared to non-carriers of LRRK2 gene mutations.

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Authors: Malidi Ahamadi, Nitin Mehrotra, Nathan Hanan, Ka Lai Yee, Ferdous Gheyas, Judith Anton, Massimo Bani, Babak Boroojerdi, Hans Smit, Jonas Weidemann, Sreeraj Macha, Vincent Thuillier, Chao Chen, Minhua Yang, Caroline H Williams-Gray, Glenn T Stebbins, Gennaro Pagano, Yaming Hang, Kenneth Marek, Charles S Venuto, Monica Javidnia, David Dexter, Anne Pedata, Bob Stafford, Mussie Akalu, Diane Stephenson, Klaus Romero, Vikram Sinha, Critical Path for Parkinson’s Consortium