Objective: To compare clinical and biomarker features and rate of progression among LRRK2-associated parkinsonism cases with and without in vivo evidence of pathologic alpha-synuclein (asyn) in cerebrospinal fluid (CSF).

Background: Among LRRK2-associated parkinsonism cases with nigral degeneration, over two-thirds demonstrate evidence of abnormal asyn, but a substantial minority do not. Understanding the clinical phenotype and underlying biology in such individuals is critical for molecularly-targeted therapeutic development.

Method: Data used in this analysis are from the Parkinson’s Progression Markers Initiative (PPMI; www.ppmi-info.com). The sample includes LRRK2-associated parkinsonism, age and disease-duration frequency-matched sporadic PD, and healthy control groups. Presence of pathologic CSF asyn was assessed with the asyn seed amplification assay (SAA). A range of clinician- and patient- reported outcome assessments were administered. Olfaction was assessed with smell identification test and hyposmia defined as ≤15^th percentile expected for age and sex.  Biomarkers included dopamine transporter (DAT) scan, CSF amyloid-beta_1-42, total tau, phospho-tau, and neurofilament light chain. To investigate possible genetic modifiers, the groups were compared with polygenic risk score analysis and risk variant analysis.

Results: The sample included 148 LRRK2-parkinsonism cases (86% G2019S variant), 46 SAA- and 102 SAA+ cases. At baseline, compared to the SAA+ group, the SAA- group were older (median [IQR] 61.5 [55.6-66.9] vs 69.1 [65.2-72.2] years, p<0.0001), more likely to be female (43 (42%) vs 28 (61%), p=0.035), and less likely to be hyposmic (75 (77%) vs 13 (29%), p<0.0001). Compared to the SAA+ group, the SAA- group had significantly higher percent expected DAT binding in the putamen for their age and sex (median [IQR] 0.26 [0.22-0.37] vs 0.36 [0.29-0.45], p<0.0001). Genetic analysis did not reveal significant differences in the 2 groups. A comparison of CSF biomarkers and longitudinal progression among the groups is underway.

Conclusion: We found clinical and biomarker differences in LRRK2-parkinsonism cases with in vivo evidence of pathologic asyn compared to those without. The underlying biology in LRRK2-parkinsonism cases without asyn requires further investigation to inform therapeutic development.

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MDS Abstracts - https://www.mdsabstracts.org/abstract/lrrk2-associated-parkinsonism-with-and-without-in-vivo-evidence-of-pathologic-alpha-synuclein-clinical-and-biomarker-characterization/