Combined analysis of skin morphometry (reduced α-syn–positive fibers, increased collagen IV staining and α-syn–positive melanocytes) plus salivary α-syn oligomers discriminates Parkinson's patients from controls and correlates with clinical scores.

Offers minimally invasive, α-syn–related biomarkers that can improve diagnostic accuracy and patient stratification and serve as complementary endpoints for PD therapeutic development and trials.

Oligomeric species of alpha-synuclein (α-syn) in saliva and phosphorylated α-syn deposits in the skin are established molecular biomarkers for Parkinson's disease (PD). However, existing research has yet to fully explore the diagnostic potential of non-phosphorylated α-syn and other cutaneous morphometric parameters, such as variations in collagen type IV within the dermis and epidermis or α-syn expression in melanocytes. This study aims to evaluate and compare the diagnostic utility of these skin morphometric parameters in differentiating 32 PD patients from 19 healthy subjects (HSs), while also examining their correlation with salivary α-syn oligomer levels. Skin biopsies were analyzed via immunofluorescence and confocal microscopy, while salivary oligomeric α-syn was quantified through competitive ELISA. Results revealed a significant reduction in α-syn-positive fibres in PD patients compared to HSs (0.91; <0.0001). Conversely, the collagen staining area and the number of α-syn-positive melanocytes were significantly increased in the skin of PD patients. Specifically, the collagen type IV staining area was significantly higher in the dermis and surrounding the sweat glands of PD patients, demonstrating optimal diagnostic power (0.9448; <0.0001). Similarly, the increase in α-syn-positive melanocytes in PD patients showed robust diagnostic potential (0.84; <0.001). Salivary α-syn oligomers accurately discriminated between PD and HS groups. Furthermore, significant correlations were found between collagen type IV and melanocyte morphometric parameters and various clinical scores in PD. Our findings highlight how multimodal morphometric analysis of the skin can enhance diagnostic accuracy in PD, supporting the use of salivary and cutaneous biomarkers as complementary tools that may reflect distinct aspects of PD pathology.