Objective: To assess: (a) effects of LRRK2 and GBA1 pathogenic variants on baseline urinary bis(monoacylglycerol) phosphate (BMP) levels in those with and without Parkinson’s disease (PD+, PD- respectively), (b) longitudinal changes in BMP levels in LRRK2 carriers and (c) whether baseline BMP levels predict disease progression.
Background: We have previously reported increases in urine BMP levels in LRRK2 G2019S mutation carriers in smaller cohorts. Additionally, LRRK2 kinase inhibitors reduce urinary BMP levels, underscoring its utility as a target engagement biomarker in therapeutic trials. However, the effects of the more pathogenic LRRK2 R1441G or GBA1 N409S variants on baseline BMP levels or prognostic utility of baseline BMP have not been examined in large, deeply phenotyped cohorts.
Method: Using quantitative assays, we determined urine BMP levels (di-18:1-BMP, di-22:6 BMP and 2,2’di-22:6-BMP) in the following PPMI cohorts: LRRK2 G2019S PD+ (N=134) and PD- (N=182), LRRK2 R1441G PD+ and PD- (N=15 each), GBA1 N409S PD+ (N=76) and PD- (N=178), sporadic PD+ (N=379) and compared them with healthy controls (HC) without the pathogenic variants (N=190). BMP levels were compared across variants and PD groups using nonparametric methods. Linear mixed models (LMMs) were used to assess longitudinal BMP levels between PD+ and PD-. LMMs and Tobit analyses were used to evaluate the effect of baseline BMP levels on longitudinal changes in DAT imaging, UPDRS-III OFF scores and MoCA.
Results: At baseline, LRRK2 G2019S and R1441G carriers had 3-7x higher BMP levels compared to HC, independent of the PD status. GBA1 N409S carriers PD+ and PD- also showed significant but smaller elevation (~30-40%) in BMP levels compared to HC. In LRRK2 PD+, urinary BMP levels did not change longitudinally over two years. Baseline BMP levels did not predict longitudinal (over 5 years) decline in striatal DAT, UPDRS-III OFF or MoCA in any of the cohorts.
Conclusion: Our data show elevation in baseline BMP levels in carriers of pathogenic variants in LRRK2 and GBA1 N409S and its stability over time in LRRK2 carriers PD+. These data would facilitate integration of BMP as a target engagement biomarker in therapeutic trials. However, baseline BMP does not appear to have prognostic utility for PD progression.
To cite this abstract in AMA style:
K. Merchant, T. Simuni, J. Fedler, M. Brumm, C. Caspell, E. Tangstrandt, F. Hsieh, K. Nudelman, T. Foroud, C. Coffey, A. Siderowf, C. Tanner, K. Marek, P. Investigators. Bis(monoacylglycerol) phosphate levels are elevated at baseline in carriers of pathogenic variants in LRRK2 and GBA1 and do not predict progression of PD in PPMI cohorts [abstract]. Mov Disord. 2022; 37 (suppl 2). https://www.mdsabstracts.org/abstract/bismonoacylglycerol-phosphate-levels-are-elevated-at-baseline-in-carriers-of-pathogenic-variants-in-lrrk2-and-gba1-and-do-not-predict-progression-of-pd-in-ppmi-cohorts/. Accessed November 21, 2024.« Back to 2022 International Congress
MDS Abstracts - https://www.mdsabstracts.org/abstract/bismonoacylglycerol-phosphate-levels-are-elevated-at-baseline-in-carriers-of-pathogenic-variants-in-lrrk2-and-gba1-and-do-not-predict-progression-of-pd-in-ppmi-cohorts/