α-synuclein RT-QuIC in cerebrospinal fluid of LRRK2-linked Parkinson's disease

Abstract

Background: Leucine-rich kinase 2 (LRRK2)-linked Parkinson's disease (PD) is clinically indistinguishable from idiopathic PD (IPD). A pleiotropic neuropathology has been recognized but the majority of studies in LRRK2 p.G2019S patients reveal Lewy-type synucleinopathy as its principal histological substrate. To date no in vivo biomarkers of synucleinopathy have been found in LRRK2 mutation carriers.

Objectives: We used real-time quaking-induced conversion (RT-QuIC) technique to assess the presence of alpha-synuclein (a-syn) aggregates in cerebrospinal fluid (CSF) of LRRK2 p.G2019S carriers.

Methods: CSF samples of 51 subjects were analyzed: 15 LRRK2 p.G2019S PD, 10 IPD, 16 LRRK2 p.G2019S nonmanifesting carriers (NMC) and 10 healthy controls. The presence of parkinsonism and prodromal symptoms was assessed in all study subjects.

Results: Forty percent (n = 6) LRRK2-PD, and 18.8% (n = 3) LRRK2-NMC had a positive a-syn RT-QuIC response. RT-QuIC detected IPD with 90% sensitivity and 80% specificity. No clinical differences were detected between LRRK2-PD patients with positive and negative RT-QuIC. A positive RT-QuIC result in LRRK2-NMC occurred in a higher proportion of subjects meeting the Movement Disorder Society research criteria for prodromal PD.

Interpretation: RT-QuIC detects a-syn aggregation in CSF in a significant number of patients with LRRK2-PD, but less frequently than in IPD. A small percentage of LRRK2-NMC tested also positive. If appropriately validated in long-term studies with large number of mutation carriers, and hopefully, postmortem or in vivo confirmation of histopathology, RT-QuIC could contribute to the selection of candidates to receive disease modifying drugs, in particular treatments targeting a-syn deposition.

Figure 1

Final fluorescence values (A) and Lag‐phase (B) of positive a‐syn RT‐QuIC subjects in IPD, LRRK2‐PD, LRRK2‐NMC and healthy controls (HC). All but two of the IPD patients with positive RT‐QuIC had final fluorescence values of 65,000, with the remaining two patients having values of 54,801 and 45,792, respectively. The seven IPD that had final fluorescent values of 65,000 are represented by a single point on Figure 1A. Among the LRRK2‐PD patients with positive RT‐QuIC two patients had a final fluorescence value of 65000 and appear as a single point on Figure 1A. One LRRK2‐PD patient and one LRRK2‐NMC with positive RT‐QuIC had unmeasurable lag‐phases as the final fluorescence values were less than 44,000 in both duplicates and are not represented in Figure 1B.