Peripheral Biomarkers of Parkinson’s Disease: focus on the Nrf2 Pathway, Oxidative Stress and Neuroinflammation

Parkinson’s disease (PD) is a progressive neurodegenerative disorder characterized by interconnected pathogenic mechanisms, including α-synuclein misfolding and aggregation, neuroinflammation, and oxidative stress. This thesis investigated potential peripheral biomarkers associated with these pathogenic processes in patients with sporadic Parkinson's disease across different disease stages, with particular attention to sex-related differences. Nrf2, SOD1, HO-1 and α-synuclein were evaluated in peripheral blood mononuclear cells (PBMCs), while NfL and other inflammatory markers, including TREM2, IL-6 and TNF-α, were assessed in plasma samples. Nrf2, SOD1 and α-synuclein did not clearly distinguish PD patients from healthy controls, while HO-1 levels were reduced in PD patients, particularly in de novo and intermediate-stage patients. Plasma NfL was significantly increased in PD and was associated with more advanced disease stages. Most inflammatory markers showed no significant differences, although TNF-α was reduced in PD patients compared to healthy controls. Sex-related differences were observed for selected inflammatory markers, with higher TREM2 levels and lower IL-6 levels in females compared with male PD patients. Overall, these preliminary findings do not support Nrf2, SOD1 or α-synuclein as reliable peripheral biomarkers of sporadic PD. Conversely, HO-1 may represent a candidate for further investigation, while NfL emerged as the marker most clearly associated with neuroaxonal damage and disease severity. Larger cohorts will be required to validate these findings.