Objective:
To examine longitudinal change in the clinical characteristics of non-manifesting LRRK2 mutation carriers (NMCs) compared to healthy controls (HC) in the Parkinson’s Progression Markers Initiative (PPMI) cohort.

Background:
LRRK2 NMCs are an important target population for future disease modifying interventions. We have previously reported that LRRK2 NMCs have significant differences in a number of clinical characteristics compared to HC. Defining the trajectory of change in the clinical and biologic characteristics is essential to select the LRRK2 cohort at highest risk of phenoconversion.

Method:
We examined longitudinal change in a spectrum of clinical characteristics of LRRK2 NMCs versus HC who had at least a year of longitudinal follow up. We modeled the change between the baseline score and the average follow-up score. All models were adjusted for age and gender.

Results:
189 LRRK2 (92% G2019S) and 186 HC were included in the analysis. NMCs were mean age 61.6 (SD 7.4) and HC 61.1 (1.2) . At baseline 12% of NMCs had abnormal dopamine transporter scan versus 6% of HC. At baseline NMCs had lower smell test scores (p= 0.0066), higher MDS-UPDRS total, Part I, II and III scores, lower MOCA scores, higher depression ( GDS), autonomic dysfunction ( SCOPA- AUT), state and trait anxiety, and impulse control disorders score. Longitudinally LRRK2 NMCs had a significant change only in MDS-UPDRS Part II (p=0.012). Group × time interaction (the difference between groups in the rate of change over time) was significant only for MOCA (p<0.001) which actually declined in HC compared to LRRK2s and a trend for MDS- UPDRS Part II (p=0.045) in LRRK2s.

Conclusion:
While NMCs have a number of PD motor and non-motor signs at baseline, there is no significant short-term longitudinal change in this cohort with predominantly normal baseline DAT imaging. In order to identify participants at highest risk of phenoconvertion, cohorts will have to be enriched by DAT imaging and other biomarkers (still to be defined) demonstrating early phases of neurodegeneration. Soon to be launched PPMI 2.0 study will continue to follow NMCs longitudinally and will recruit a large cohort of other prodromal individuals (hyposmic and RBD) to address these questions.

References: Abstract submitted on behalf of the PPMI Investigators

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