Objective: To examine 2-year longitudinal change in clinical, dopamine transporter (DAT) imaging and biofluid biomarkers in non-manifesting carriers (NMCs) of LRRK2 G2019S versus healthy controls (HCs) in PPMI.

Background: We previously reported the presence of subtle motor and non-motor signs of PD in LRRK2 NMCs at baseline, independent of DAT deficits.

Method: We analyzed baseline, 1- and 2-year longitudinal data from the PPMI LRRK2 G2019S NMC (N=176) and HC (N=185) cohorts. All participants are assessed annually with comprehensive motor and non-motor scales, DAT imaging and biofluid biomarkers. The latter included cerebrospinal fluid (CSF)Abeta, total tau and phospho-tau; serum urate and neurofilament light chain (NfL); and urine bis(monoacylglycerol) phosphate (BMP). The dataset was downloaded June 30, 2020.

Results: At baseline, LRRK2 NMCs had a mean (SD) age of 62 (7.7) years and were 56% female. 7 % of NMCs had DAT deficit (defined as <65 % of age/sex-expected lowest putamen SBR) and 7% had hyposmia (defined as ≤10th percentile). Although compared to HCs, LRRK2 NMCs at baseline scored significantly worse on numerous clinical scales, there was no significant longitudinal change in any of these measures over 2 years. There also was no significant longitudinal decline in caudate or putamen DAT binding. There were no longitudinal differences in CSF and serum biomarkers between LRRK2 NMCs and HCs. Urinary BMP was significantly elevated in NMCs at all time points but there was no significant longitudinal change. There was no association between baseline CSF, serum or DAT biomarkers with 2-year change in clinical outcomes. Baseline urine BMP levels correlated with baseline DAT binding but not with 2-year change in DAT. 5/176 NMCs developed PD during the follow up.

Conclusion: We present a comprehensive clinical and biomarker longitudinal characterization of in LRRK2 G2019S NMCs. Our data highlight challenges in identifying clinical and/or biological characteristics that predict progression to clinically defined neurodegenerative disease over a time period feasible for therapeutic trials of disease prevention and highlight the need for biomarker-based enrichment approaches. PPMI is now testing DAT imaging as an enrichment strategy for NMC recruitment. Longitudinal clinical and biomarker data may help identify risk factors and trajectory for progression to PD.

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MDS Abstracts - https://www.mdsabstracts.org/abstract/longitudinal-clinical-and-biomarkers-characteristics-of-non-manifest-lrrk2-g2019s-carriers-the-ppmi-cohort/