Diabetes impact on nigrostriatal vulnerability in Parkinson’s Disease

Mechanisms underlying the role of diabetes mellitus (DM) as modulator of severity in Parkinson’s Disease (PD) remain unclear. Aim of this study was to investigate the impact of DM on nigrostriatal dopaminergic vulnerability considering two independent cohorts of drug-naïve PD patients (PPMI and DNA studies). Patients with and without DM were first compared and then matched for age, sex, symptoms severity. Differences in ¹²³ I-FP-CIT binding and molecular connectivity alterations were tested in PD with and without DM within the nigrostriatal pathway. 269 drug-naïve patients were enrolled (PPMI, n=174; DNA, n=95). In both cohorts, patients with DM were older, predominantly male, and exhibited worse non-motor and cognitive symptoms. After severity-matching, patients with DM were found to exhibit more preserved dopamine binding in striatal regions compared to those without DM, together with a lower neural reserve. Patients with DM showed significant dopaminergic connectivity alterations (20%), primarily due to a loss of connectivity (98%). In contrast, patients without DM had more widespread connectivity changes (33%), characterized by both loss (84%) and gained connections (16%). These findings suggest that diabetes directly affects the nigrostriatal network, resulting in less deficits despite similar disease severity, perhaps decreasing the effect of reserve on dopaminergic neurons loss.