Inflammatory and lipid markers in clinical and pre-clinical Parkinson’s disease patients

Parkinson’s disease (PD) risk gene discoveries have implicated lipids and inflammation in pathology. However, most research to date has been protein-centric. Therefore, the extent of lipid involvement in PD and relationships between inflammatory and lipid pathways are unclear. Research into these areas may provide novel insights into PD pathology, therapeutic targets and biomarkers for an earlier diagnosis and monitoring disease progression in clinical trials. To investigate lipid dysregulation in PD and in mutation carriers of the PD risk gene LRRK2, untargeted mass spectrometry was performed using serum (N = 221) and cerebrospinal fluid (CSF, N = 88) from controls, pre-clinical and clinical PD LRRK2 G2019S carriers and sporadic PD patients. Findings were then validated in a second cohort (N = 315) using serum from the same groups. Significant lipid alterations were found in mutation carrier and PD patient serum and CSF. Altered lipids implicated sphingolipid metabolism and insulin signalling pathways in PD. Further, altered serum and CSF lipids correlated with cytokines involved in insulin/glucose signalling. Pre-clinical PD biofluid changes suggest that lipids are worthwhile candidates for longitudinal studies assessing whether baseline markers predict PD. Correlation analysis indicated that although serum lipids did not robustly associate with clinical severity, CSF lipids were associated. Finally, whether mutations in the lipid-related risk gene, GBA, affected inflammatory markers was assessed in plasma (N = 371) from clinical and pre-clinical GBA mutation carriers, sporadic PD patients and controls. Inflammatory markers were overall unchanged in GBA mutation carriers, suggesting these are not promising biomarker candidates. These findings strongly support a role for lipid dysregulation in PD. These results indicate that lipids are promising candidates to pursue for understanding PD aetiology, as well as potential novel biomarkers for genetic and sporadic PD