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This contributes to frequent misdiagnoses, as shown by autopsy findings, and to improper patient selection in clinical trials, hindering disease-modifying therapy development. 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Molecular Neurodegeneration (2026) 21:1 Molecular Neurodegeneration  \n[https://doi.org/10.1186/s13024-025-00914-0](https://doi.org/10.1186/s13024-025-00914-0)  \nREVIEW Open Access  \nDiagnostic biomarkers  \nfor α-synucleinopathies-state of the art and future developments: a systematic review  \nV. Donadio 1,2*†, M. Ingelsson3,4,5†, G. Rizzo 1, A. Furia 1, A. Incensi 1, C. Del prete 1, M. Pinho6, R. Liguori 1,2† and  \nS. Pritzkow6*†  \nAbstract  \nBackground Alpha-synucleinopathies are common disorders that are expected to become increasingly prevalent in the future along with the longer life expectancy. However, their diagnosis is problematic as they are mainly based on clinical criteria without the support of disease-specific biomarkers. This leads to frequent misdiagnoses, as underlined by autopsy studies, and an imprecise selection of patients for clinical trials, preventing progress in the development of disease-modifying treatments. In recent years important advances have been made regarding the development of specific biomarkers for the detection of pathological α-synuclein (α-syn), which may improve the diagnosis of patients affected by α-synucleinopathies.  \nResults In this review, we describe in detail the most promising techniques to detect pathological α-syn in patientderived samples. In particular, we describe the diagnostic accuracy of each individual cerebrospinal fluid (CSF), plasma and skin α-syn biomarker in differentiating α-synucleinopathies from controls, from other neurodegenerative disorders and between different α-synucleinopathies. Furthermore, we underline the main advantages and limitations of these techniques for clinical practice. Finally, we provide our suggestions for further development considering both technical aspects and large-scale standardization.  \nConclusions and Relevance We conclude that immunofluorescence on biopsied skin tissue and the seed amplification assay on CSF show the best diagnostic accuracy and reliability in the studies that have been performed to date. We discuss the opportunities of these techniques as well as the main current limitations and technical problems that need to be considered before they can be adopted for clinical use.  \nKeywords Biomarkers, α-synucleinopathies, Skin biopsy, Immunofluorescence, Seed amplification assay  \n†Donadio V, Ingelsson M, Liguori R and Pritzkow S. contributed equally to the work.  \n*Correspondence:  \nV. Donadio [vincenzo.donadio@unibo.it](vincenzo.donadio@unibo.it)  \nS. Pritzkow [Sandra.Pritzkow@uth.tmc.edu](Sandra.Pritzkow@uth.tmc.edu)  \nFull list of author information is available at the end of the article  \n© The Author(s) 2025. Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit [http://creativecommons.org/l](http://creativecommons.org/l)icenses/by/4.0/. The Creative Commons Public Domain Dedication waiver ([http://creativecommons.org/publicdomain/zero/1.0/](http://creativecommons.org/publicdomain/zero/1.0/)) applies to the data made available in this article, unless otherwise stated in a credit line to the data.  \nDonadio et al. Molecular Neurodegeneration (2026) 21:1 Page 2 of 14  \nGraphical Abstract  \nBackground  \nAlpha-synucleinopathies are neurodegenerative disorders character","cbCaian6icOgcX47","https://ap.wps.com/l/cbCaian6icOgcX47","pdf",2019686,14,"English","# Abstract\n## Background\n## Results\n## Conclusions and Relevance\n# Graphical Abstract\n## Background","[{\"question\":\"Why are diagnostic biomarkers needed for α-synucleinopathies?\",\"answer\":\"Diagnosis is difficult because it mainly depends on clinical criteria without disease-specific biomarkers, leading to misdiagnosis and poor selection of patients for clinical trials. This slows progress toward disease-modifying treatments.\"},{\"question\":\"Which sample types and techniques are reviewed for detecting pathological α-syn?\",\"answer\":\"The review describes techniques to detect pathological α-syn in patient-derived samples, focusing on cerebrospinal fluid (CSF), plasma, and skin biomarkers. It also compares diagnostic accuracy across these sources and among different α-synucleinopathies.\"},{\"question\":\"What do the authors conclude about the most reliable diagnostic methods?\",\"answer\":\"They conclude that immunofluorescence on biopsied skin tissue and the seed amplification assay on CSF show the best diagnostic accuracy and reliability in studies to date. The paper also discusses limitations and technical issues before clinical adoption.\"}]","Diagnostic biomarkers for α-synucleinopathies - state of the art and future developments: a systematic review | PDF",1790754135,35]