Recent advances in establishing fluid biomarkers for the diagnosis and differentiation of alpha-synucleinopathies - a mini review.

The clinical differentiation between multiple system atrophy (MSA), Parkinson's disease (PD), dementia with Lewy bodies (DLB), as well as the distinction between these synucleinopathies from other neurodegenerative disorders can be challenging, particularly at early disease stages or when the presentation is atypical. That is also true for predicting the fate of patients with limited or prodromal forms of synucleinopathies such as pure autonomic failure (PAF) or idiopathic REM-sleep behavior disorder (iRBD) which are known to be at risk of developing MSA, PD, or DLB. After discussing current classification concepts of the synucleinopathies, this invited mini-review reflects on two recently described and validated spinal fluid biomarkers, namely neurofilament light chain (NfL) and α-synuclein oligomers detected by protein aggregation assays, that have shown great promise not only as markers differentiating MSA from the Lewy-body synucleinopathies but also as markers that predict future phenoconversion to MSA among patients with PAF. Discussed are the strengths and limitations of these markers, and how they appear to complement each other nicely as a biomarker panel, enhancing the specificity of one of these markers, yet adding further robustness and simplicity to a marker that is technically rather challenging. The review concludes with thoughts on potential next steps in the development of fluid biomarkers in this rapidly emerging field.