Dopaminergic nigrostriatal vulnerability in Parkinson's Disease with diabetes: evidence from severity-matched cohorts.

Abstract

Diabetes Mellitus (DM) has been recognized as a potential risk factor and disease-modifier in Parkinson's Disease (PD), being associated with worse motor and cognitive outcomes, and altered susceptibility of neural pathways. This study investigated the impact of DM on nigrostriatal dopaminergic vulnerability independently of disease severity in drug-naïve PD patients. This study analyzed two independent cohorts of PD patients (multi-center PPMI n = 174, single-center UniBS n = 95). Patients with and without DM were first compared and then matched for age, sex, and clinical severity. All patients underwent baseline ¹²³I-FP-CIT imaging to quantify dopamine transporter binding. Dopaminergic binding, neural reserve index and molecular connectivity patterns were compared between severity-matched groups. Patients with DM were older, predominantly male, and exhibited worse non-motor and cognitive symptoms. After severity matching, PD-DM exhibited more preserved nigrostriatal dopamine uptake compared to PD-n. PD-DM also showed fewer nigrostriatal dopaminergic connectivity alterations (10% vs. 21%) and reduced neural reserve index in the left putamen and - only in the single-center cohort- whole striatum. In drug-naïve PD patients, comorbid diabetes is associated with comparable clinical severity despite milder dopaminergic loss. This suggests an increased dopamine system vulnerability linked to DM, reducing the efficiency and compensatory mechanisms of nigrostriatal dopaminergic networks in PD.