To examine alterations in the kynurenine (Kyn) and polyamine pathways in participants with PD via plasma and CSF metabolomics and to test for associations with presence of a pathogenic LRRK2 mutation.

Both Kyn and polyamine pathways have been implicated in PD pathophysiology. Their role in individuals with a pathogenic LRRK2 mutation is unknown.

Using liquid chromatography with mass spectrometry, we analysed plasma samples of 368 subjects from the LRRK2 Cohort Consortium (LCC) who were classified into four groups: iPD (n=70), PD with LRRK2+ (n=118), unaffected controls (UC) with LRRK2+ (n=115), and UC without LRRK2+ (n=65). Matched CSF samples were available in 68 subjects. Differences and pairwise comparisons between the levels of metabolites across four groups and the interaction between LRRK2 and PD status were examined using robust linear regression and ANCOVA models, adjusted by age, sex, and LCC repository. Data and biospecimens used in the analyses presented in this abstract were obtained from the MJFF-sponsored LRRK2 Cohort Consortium (LCC). For up-to-date information on the study, visit www.michaeljfox.org/lcc.

Comparing PD to UC, plasma Kyn, kynurenic acid (Kyna), Kyna/Kyn ratio, and Kyn/tryptophan ratio were reduced by 10% (p=0.003), 22% (p<0.001), 12% (p=0.007), and 11% (p<0.001), respectively. Plasma N-acetylputrescine (N-AcPut), N1-acetylspermidine, and N-AcPut/putrescine ratio were higher by 32% (p<0.001), 18% (p<0.001), and 36% (p<0.001), respectively. These associations did not depend on LRRK2 status, with similar results among both LRRK2+ carriers and non-carriers and no significant interactions between LRRK2 and PD status (p>0.1). Consistent results were found in the corresponding CSF samples.

Our findings provide additional evidence to support altered kynurenine and polyamine pathways in PD, independent of LRRK2 status. This suggests that the roles of these pathways may be generalized in PD pathogenesis, playing out after the unique neurodegenerative influence of pathogenic LRRK2 mutations converges with the pathophysiology common to all of PD.