Fluid biomarkers in atypical Parkinsonism: current state and future perspectives.

Diagnosing Atypical Parkinsonian Syndromes (APS) may be challenging due to overlapping clinical features of Parkinson's disease (PD), and the lack of pathognomonic diagnostic tests. Fluid biomarkers can be useful tools that make it easier to identify and track different APS. Objectives: this narrative review aim to update the current state of fluid biomarker research in APS and their potential implications in clinical practice. A comprehensive literature search was conducted in PubMed and Scopus using the following terms: "Aβ42 amyloid beta with 42 amino acids'', " alpha-synuclein'', "Atypical Parkinsonian Syndromes'', "corticobasaldegeneration'', "C reactive protein'', "cerebrospinal fluid'', "dementia with Lewy bodies'', "multiple system atrophy'', "neurofilament light, oligomericαsyn, phosphorylated α -syn'', "tau phosphorylated at threonine 181'', "progressive supranuclear palsy'', "Seeding Amplification Assay'', "t-tau; total tau". The lack of high-affinity α-syn antibodies and ligands may contribute to α-syn's low efficacy as a diagnostic biomarker of APS. Cerebrospinal fluid (CSF) biomarkers reflecting Alzheimer pathology, axonal damage (neurofilament light chain) add valuable diagnostic and prognostic information in the neurochemical characterization of APS. Inflammatoryand microRNAs markers need to be further validated before their clinical use. Seeding Amplification Assays (SAA), despite their high sensitivity and specificity, are at this point used only as a research tool, and they are not quantitative or reflective of disease severity. Biomarker research for early identification and prognosis of APS patients requires multicenter collaboration, validation, and AI-based diagnostics, despite immature biological classification systems.