Diagnostic biomarkers for α-synucleinopathies- state of the art and future developments: a systematic review

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. In this review, we describe in detail the most promising techniques to detect pathological α-syn in patient-derived 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. 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.