Alpha-Synuclein Biomarkers Across Saliva, Skin, and CSF Show Diagnostic Promise for Parkinson's Disease

Alpha-synuclein (α-syn) biomarkers are emerging as promising tools for the biological diagnosis of Parkinson's disease (PD), with abnormal protein deposits detected in peripheral tissues including salivary glands, skin, and cerebrospinal fluid (CSF). Detection of misfolded α-synuclein in CSF by seed amplification assay (SAA) has demonstrated high sensitivity and specificity for detecting underlying synuclein pathology, including validation in more than 600 neuropathologically confirmed cases, with similar performance in clinically diagnosed PD.

In the salivary glands, α-syn appears to be most clinically relevant within nerve fibers rather than the saliva-producing acinar cells themselves. Studies have found abnormal α-syn deposits in peripheral tissues, including the submandibular and minor salivary glands. Beach and colleagues showed that submandibular gland tissue from patients with Parkinson's disease may contain this pathology, supporting the view that Parkinson's disease involves both the brain and the peripheral nervous system. Submandibular gland biopsies have been performed in living patients as part of PD biomarker studies, including multicenter research evaluating α-syn across saliva, blood, cerebrospinal fluid, skin, colon, and salivary gland tissue. In these studies, gland biopsy has shown diagnostic promise, but it has not yet become a routine clinical test because sensitivity, sampling technique, and tissue adequacy remain important limitations.

Because gland biopsy has limitations, researchers are also studying less invasive ways to detect PD-related protein changes in the mouth. Cells collected from the oral lining with a small brush have shown abnormal α-syn patterns in people with Parkinson's disease. This approach is similar in concept to Parkinson's skin biopsy testing because both look for abnormal α-syn outside the brain, using more accessible body sites as potential biomarkers. The difference is that skin biopsy examines small nerve fibers in the skin and is currently further along clinically, while oral mucosal testing examines cells from the lining of the mouth and remains earlier in development. Saliva is also being studied as a possible diagnostic fluid, with researchers measuring α-syn and other disease-related markers, including inflammatory proteins and markers linked to neurodegeneration. Recent reviews suggest that certain abnormal forms of α-syn in saliva may be more consistently associated with Parkinson's disease than total α-syn alone.

Multicenter studies have reported sensitivity exceeding 85–90% for clinically diagnosed PD, with high specificity among healthy controls and other neurodegenerative diseases. Particularly impactful were the initial findings in the Parkinson's Progression Markers Initiative (PPMI) cohort, which demonstrated αSyn-SAA positivity in 87.7% of PD participants and 86% of prodromal participants prior to evidence of dopaminergic deficit, suggesting that αSyn pathology, detectable by αSyn-SAA, may precede neurodegeneration detectable by conventional imaging. Recent advances in αSyn-SAA technology have demonstrated the ability to distinguish multiple system atrophy (MSA) from PD and other synucleinopathies, representing an important clinical advance given the rapid progression and poorer prognosis associated with MSA.

Clinicopathological studies report diagnostic accuracies of 70–85% for clinical PD diagnosis, with even lower accuracy in early disease and atypical parkinsonism. These findings have resulted in enthusiasm for moving toward a biologically defined framework for PD, similar to the biomarker-based framework adopted in Alzheimer's disease (AD). Recent research criteria increasingly incorporate αSyn-SAA as evidence of underlying synucleinopathy. However, translating a biomarker from research settings into clinical care requires more than diagnostic accuracy alone. While emerging SAAs have demonstrated clear clinical utility in distinguishing MSA from other synucleinopathies, the broader challenge of clinical implementation lies not in whether a biomarker can detect active disease, but in establishing clinical use guidelines and how these assays can best inform patient care across a range of presentations.

Most studies have focused on well-characterised research cohorts enriched for PD and related synucleinopathies. However, in routine neurology clinics, patients often present with overlapping symptoms, vascular disease, medication effects, or uncertain diagnoses. Moreover, increasing evidence suggests that synuclein pathology frequently coexists with other neurodegenerative diseases, including AD. As clinical adoption of αSyn-SAA expands, performance across broader patient populations, including individuals with nonspecific symptoms, atypical parkinsonism, and community-based cohorts, will further define the real-world utility of αSyn-SAA and refine evidence-based clinical use guidelines. Although current testing relies on CSF, continued advances in blood and skin-based assays may further improve accessibility.

Technical aspects of the assay require strong laboratory skills and close attention to detail. To ensure reproducible and reliable results, αSyn-SAA should be performed by trained professionals operating under an established quality management system using rigorously qualified SAA-competent materials sourced through standardised quality control processes. As for any in vitro diagnostic test, compliance with relevant regulatory standards is required for the use of αSyn-SAA as part of medical decision-making. In the USA, the test is currently offered to clinicians as a laboratory developed test, in compliance with Clinical Laboratory Improvement Amendments (CLIA) regulations, through a centralised commercial laboratory. In Europe, implementation must comply with the EU In Vitro Diagnostic Regulation (IVDR).