Association between cerebrospinal fluid LRRK2 and incident orthostatic hypotension differs by genetic background in Parkinson's disease.

BACKGROUND: Orthostatic hypotension (OH) is an important manifestation of cardiovascular autonomic dysfunction in Parkinson's disease (PD), but biomarkers associated with incident OH have not been well established. Cerebrospinal fluid (CSF) LRRK2 provides a measurable marker of LRRK2-related biology, but its association with incident OH is unknown. OBJECTIVE: To determine whether baseline CSF LRRK2 is associated with incident OH and whether this association differs between sporadic PD and LRRK2-PD. METHODS: We analyzed longitudinal Parkinson's Progression Markers Initiative (PPMI) data from 190 participants with PD, including 159 participants free of OH at baseline with follow-up orthostatic assessments. Cox proportional hazards models evaluated the association between standardized ln-transformed baseline CSF LRRK2 and time to incident OH, including a CSF LRRK2-by-genetic-group interaction and adjustment for age, sex, disease duration, and baseline systolic blood pressure change after standing. RESULTS: During follow-up, 52 of 159 participants developed OH. Higher baseline CSF LRRK2 was associated with a higher hazard of incident OH in sporadic PD (HR 10.50 per 1-SD higher ln-transformed CSF LRRK2, 95% CI 2.95-37.35; p < 0.001), whereas no clear association was observed in LRRK2-PD (HR 1.74, 95% CI 0.63-4.79; p = 0.284). The CSF LRRK2-by-genetic-group interaction was significant (interaction HR 0.166, 95% CI 0.083-0.331; p < 0.001) and remained consistent across sensitivity analyses. CONCLUSIONS: The association between baseline CSF LRRK2 and incident OH differed by genetic background. Baseline CSF LRRK2 was associated with incident OH in sporadic PD, whereas no clear association was observed in LRRK2-PD. Independent replication is required.