Update on alpha-synuclein-based biomarker approaches in the skin, submandibular gland, gastrointestinal tract, and biofluids

There is a need for objective diagnostic and prognostic biomarkers in Parkinson's disease (PD), partly given the expected increase in clinical trials aimed at demonstrating a disease-modifying effect in early disease. Alpha-synuclein (α-syn) plays a decisive role in the pathogenesis of PD. Here, we review recent publications exploring established and novel methodologies to detect α-syn species in tissues and biofluids.Using immunohistochemistry (IHC), recent studies have focused on the detection of phosphorylated α-syn (p-α-syn) in cutaneous nerve fibers, reporting varying sensitivity and high specificity for the diagnosis of PD. A predilection for p-α-syn depositions in cutaneous autonomic nerve fibers has emerged, possibly contrasting with other synucleinopathies.Novel studies utilizing the seeding propensity of pathological α-syn have generated encouraging results with regard to diagnostic performance in both tissues and biofluids including skin, submandibular gland, and cerebrospinal fluid.Detection of neuronal p-α-syn in skin punch biopsies remains a promising minimally invasive diagnostic tool in PD. Seeding assays have emerged as a new method with its diagnostic potential warranting replication in further studies from various tissues and biofluids. Longitudinal studies employing both IHC and seeding assays are needed to identify possible biomarkers of disease progression.