The Diagnostic Use of Skin Biopsy in Parkinson’s Disease and other Synucleinopathies: Background, Supporting Evidence, and Controversies
The idea of using skin biopsy for diagnosing Parkinson’s disease (PD) and related synucleinopathies, including multiple system atrophy (MSA), dementia with Lewy bodies (DLB), and pure autonomic failure (PAF), originated from the key pathological role played in these disorders by the abnormal accumulation of misfolded α-synuclein in neurons. Traditionally, definitive PD diagnosis has been based on post-mortem evidence of abnormal brain aggregates of α-synuclein (Lewy Bodies), but growing data suggests that α-synuclein pathology may also affect peripheral nerves, including those in the skin.
The development of methods to detect phosphorylated α-synuclein (P-Syn) in skin biopsies was pioneered by researchers at the University of Würzburg in Germany in the early 2010s. Their work, along with ensuing research in multiple laboratories, demonstrated that skin biopsies could reliably identify P-Syn in cutaneous nerves of PD patients and other synucleinopathies. This discovery paved the way for further investigations into the diagnostic and prognostic value of skin biopsy, resulting in a rapidly expanding number of studies that are providing increasing confirmatory evidence, although standardization and validation remain ongoing challenges in clinical practice.
Key Evidence Supporting the Diagnostic Use of Skin Biopsies
1. High Diagnostic Accuracy. A recent multicenter study demonstrated that skin biopsies could identify individuals with synucleinopathies with high sensitivity and specificity. The detection of P-Syn in cutaneous nerve fibers distinguished patients with PD, DLB, MSA, and PAF from healthy controls, suggesting its potential as a reliable diagnostic biomarker. The percentage of skin biopsies with abnormal P-Syn was close to 93% in PD patients, and even higher in other synucleinopathies, reaching 96.0% in DLB 98% in MSA, and 100% in PAF. Conversely, only about 3% healthy controls had abnormal cutaneous P-Syn. This and other studies showed that abnormal P-Syn is virtually absent in skin nerves of healthy people, including those who are very elderly.
2. Ability to distinguish different synucleinopathies. Research indicates that skin biopsy can differentiate between some subtypes of synucleinopathy. For example, the pattern and distribution of skin P-Syn deposits may help distinguish PD from MSA, providing more accurate clinical diagnoses. Patients with MSA had greater and more widespread P-Syn distribution than patients with PD, with high sensitivity and specificity in distinguishing between the two synucleinopathies. In addition, patients with PD had reduced nerve fiber densities compared with patients with MSA, providing further elements of differential diagnosis between two conditions often difficult to tease apart purely on clinical grounds. Detection of P-Syn deposits can also distinguish PD from atypical parkinsonisms due to tauopathies, like progressive supranuclear palsy (PSP).
3. Correlation with Disease Severity. Some studies have found a correlation between the amount of P-Syn in skin biopsies and the severity of autonomic dysfunction in PD patients, suggesting that skin biopsy findings could not only assist in diagnosis but also in monitoring disease progression. However, commercially available skin biopsies do not currently provide precise quantitative measures of P-Syn deposition.
4. Prodromal stages of synucleinopathy. P-Syn in skin biopsies can be also abnormal in individuals with clinical features associated with prodromal PD, including rapid eye movement sleep behavior disorder (RBD) and hyposmia. A positive skin biopsy for P-Syn in these subjects may provide useful prognostic implications, predicting time of phenoconversion, and present opportunities for targeted disease modifying trials.
5. Feasibility and Reproducibility: The procedure for obtaining skin biopsies is minimally invasive and can be performed in outpatient settings. Standardization of biopsy sites and immunohistochemical techniques has improved the reproducibility of results across different clinical centers.
Image courtesy of CND Life Sciences
Controversies and Challenges
Despite the promising findings summarized above, several challenges and controversies hinder its widespread clinical adoption:
1.Variability in Detection Methods and Interpretation. One major challenge is the variability in detection methods and interpretation of results across different laboratories. Varying sensitivity and specificity rates for detecting P-SYN in skin biopsies have been reported, raising concerns about the reliability of the technique. This inconsistency may stem from differences in biopsy techniques, anatomical sites sampled, and immunohistochemical methods used. For instance, in one study some PD patients had P-Syn detected in one biopsy site, while other had all three sites positive, underscoring variability in deposition and need for multiple sampling sites to improve diagnostic accuracy.
2. Specificity Concerns. While P-Syn aggregation is a hallmark of synucleinopathies, its presence in skin biopsies raises questions about specificity. Some studies suggest that P-Syn can be detected in other conditions, including post-infectious immune and inflammatory processes, potentially leading to false-positive results. This overlap necessitates further research to delineate the specificity of skin biopsy findings for synucleinopathies.
3. Procedural Considerations: Although minimally invasive, skin biopsies are still invasive procedures that require technical expertise. The detection of P-Syn is both time-consuming and costly, which may limit its routine use in clinical settings. Additionally, continuous monitoring through repeated biopsies poses practical challenges over time.
4. Clinical Utility and Decision-Making. While skin biopsy detection of P-Syn has shown promise in differentiating synucleinopathies, its impact on clinical decision-making remains unclear. In one study, skin P-Syn deposition was detected in 55.2% (32 of 58) individuals with unknown diagnosis before biopsy. A study from the same group reported changes in diagnosis and treatment plans in over 50% of cases, highlighting its potential utility. However, further research is needed to validate these findings and assess long-term outcomes.
5. Access and ethical issues. Skin biopsies require clinical expertise and laboratory resources that are not yet widely available, raising concerns around equitable access. In addition, screening subjects ‘at risk’ of synucleinopathy may pose serious ethical questions regarding psychological consequences in virtually asymptomatic subjects.
Conclusion
While skin biopsy presents an exciting avenue for improving the diagnosis of PD and other synucleinopathies, further research is needed to establish standardized methodologies and confirm its clinical utility. If validated, it could offer a minimally invasive and earlier diagnostic tool, potentially improving patient care, refine selection of participants for clinical trials with a precision medicine approach to specific therapies and possibly facilitate the development of disease-modifying treatments. However, until consensus is reached on standardization, accuracy and specificity, its role in routine clinical practice remains an open question.
Further reading
Doppler K, Ebert S, Üçeyler N, Trenkwalder C, Ebentheuer J, Volkmann J, Sommer C. Cutaneous neuropathy in Parkinson’s disease: a window into brain pathology. Acta neuropathologica. 2014 Jul;128:99-109.
Gibbons C, Wang N, Rajan S, Kern D, Palma JA, Kaufmann H, Freeman R. Cutaneous α-synuclein signatures in patients with multiple system atrophy and Parkinson disease. Neurology. 2023 Apr 11;100(15):e1529-39.
Donadio V, Fadda L, Incensi A, Furia A, Parisini S, Colaci F, Defazio G, Liguori R. Skin nerve phosphorylated α-synuclein in the elderly. Journal of Neuropathology & Experimental Neurology. 2024 Apr 1;83(4):245-50.
Gibbons CH, Levine T, Adler C, Bellaire B, Wang N, Stohl J, Agarwal P, Aldridge GM, Barboi A, Evidente VG, Galasko D. Skin biopsy detection of phosphorylated α-synuclein in patients with synucleinopathies. Jama. 2024 Apr 16;331(15):1298-306.
Isonaka R, Sullivan P, Goldstein DS. Pathophysiological Significance of α-Synuclein in Sympathetic Nerves: In Vivo Observations. Neurology. 2025 Feb 11;104(3):e210215.
Dietiker C, Tanner C. Evolving Perspectives on α-Synuclein Testing. JAMA neurology. 2025.
Michele Tagliati, MD, FAAN is a Professor of Neurology and Director of the Division of Movement Disorders at the Cedars-Sinai Medical Center in Los Angeles. He has spoken and presented scientific posters at past World Parkinson Congresses.
𝕏: @mtagliati960
Ideas and opinions expressed in this post reflect that of the author(s) solely. They do not necessarily reflect the opinions or positions of the World Parkinson Coalition®