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Background   LRRK2  mutations are a common cause of dominantly inherited PD. Previous studies showed decreases in urine levels of didocohexaenoyl (22:6) bis(monoacylglycerol)phosphate in  LRRK2 ‐knockout mice and in non‐human primates treated with LRRK2 kinase inhibitors. We hypothesized that urine levels of bis(monoacylglycerol)phosphate isoforms will be higher in individuals with a PD‐causing gain‐of‐kinase function mutation,  LRRK2  G2019S. The objective of this study was to investigate alterations in urinary phospholipids as biomarkers of  LRRK2  mutations and Parkinson's disease status/phenotypes.    Methods  Ultra‐performance liquid chromatography–tandem mass spectrometry (UPLC‐MS/MS) was used to assess 54 bioactive phospholipids in urine from the  LRRK2  Cohort Consortium (n = 80). To confirm and extend the findings, urine from an independent  LRRK2  cohort from Columbia University Irving Medical Center (n = 116) was used. Both cohorts were composed of  LRRK2  G2019S carriers and non‐carriers with and without PD.    Results  In each cohort, 4 bis(monoacylglycerol)phosphate isoforms (di‐18:1‐bis[monoacylglycerol]phosphate, didocohexaenoyl [22:6] bis[monoacylglycerol] phosphate, 2,2′‐di‐22:6‐bis[monoacylglycerol]phosphate, and 2,2′‐di‐18:1‐bis[monoacylglycerol]phosphate) were significantly higher (2.5‐ to 4.3‐fold) in G2019S carriers compared with non‐carriers. Interestingly, 2,2′‐di‐18:1‐bis(monoacylglycerol)phosphate levels were marginally higher in  LRRK2  carriers with PD than in those without PD ( P  = 0.045). Moreover, increased 2,2′ and total di‐22:6‐bis(monoacylglycerol)phosphate were associated with worse cognitive status assessed by the Montreal Cognitive Assessment ( P  = 0.0033 and 0.0144, respectively).    Conclusions  The observed association of bis(monoacylglycerol)phosphate isoforms with  LRRK2  G2019S mutation, PD status among G2019S carriers, and correlation with cognitive decline suggest the potential use of urinary bis(monoacylglycerol)phosphate isoforms as biomarkers for clinical trials of  LRRK2 ‐targeted therapies. © 2019 The Authors.  Movement Disorders  published by Wiley Periodicals, Inc. on behalf of International Parkinson and Movement Disorder Society.

Higher Urine bis(Monoacylglycerol)Phosphate Levels in LRRK2 G2019S Mutation Carriers: Implications for Therapeutic Development