Increased Neuroinflammation in Asymptomatic LRRK2 Mutation Carriers: A Pilot PET Imaging Study (P4.321)

Objective: To investigate if subjects that carry LRRK2 mutations, a known risk factor for Parkinson’s disease (PD), exhibit increased neuroinflammation compared to age matched healthy controls. Background: LRRK2 is known to play a role in the regulation of the innate immune system and response to inflammation. Similarly, neuroinflammation is hypothesized to be a likely contributor to PD origin and its progression. Thus, we investigated if increased neuroinflammation could be a mechanism by which LRRK2 mutations increase the risk of PD. Methods: In this pilot study we imaged 4 Healthy Controls (HC) (age 44 ± 16, mean, std; range 24-63) and 3 age matched unaffected LRRK2 G2019S mutation carriers (UC)(age 51 ± 12, mean, std; range 37-61) with 11C-PBR28, a second generation TSPO binding PET ligand. All subjects were mixed affinity binders (MAB). 38 MRI guided regions of interest were placed on the PET images. The primary outcome measures were standard uptake values (SUV), previously cross-validated with the total distribution values in a subset of the data. Mean SUV values across ROI were compared between groups using a t-test. Results: Mean SUV values were highly significantly elevated in the LRRK2 mutation carriers (SUVHC = 0.52 ±0.04, SUVUC = 0.83 ±0.13, p< 0.0001). Values were elevated in every region and no age dependence in the values was observed. Conclusions: These data suggest increased neuroinflammation is present in asymptomatic LRRK2 mutation carriers well before the expected age of disease onset and may indeed contribute to increase susceptibility to PD. While this was a very limited sample, the separation in the SUV values between groups was statistically highly significant. Extension to a larger sample including LRRK2-associated and sporadic PD will provide further information on the role of neuroinflammation in PD pathogenesis. Disclosure: Dr. Sossi has nothing to disclose. Dr. Mabrouk has nothing to disclose. Dr. Walker has nothing to disclose. Dr. Shahinfard has nothing to disclose. Dr. Vafai has nothing to disclose. Dr. Fu has nothing to disclose. Dr. Heffernan has nothing to disclose. Dr. McKenzie has nothing to disclose. Dr. Farrer has received license fee or contractual rights payments from Athena Diagnostics and Lundbeck. Dr. Zhang has nothing to disclose. Dr. Wszolek has received personal compensation in an editorial capacity for Parkinsonism & Related Disorders and the European Journal of Neurology. Dr. Wszolek has received royalty payments for the discovery of LRRK2 gene mutations. Dr. Aasly has nothing to disclose. Dr. Stoessl has received personal compensation for activities with Teva, Fujimoto, AbbVie, and UCB Pharma as a speaker/advisory board member/consultant.