The Promise and Pitfalls of Biomarkers for Differential Diagnosis in Parkinson’s Disease and Atypical Parkinsonism

Parkinson’s disease (PD) and atypical parkinsonian syndromes (APSs) present diagnostic challenges due to overlapping clinical features. Misdiagnosis rates exceed 25% for PD and 50% for APS, highlighting the need for improved diagnostic methods. To review current diagnostic approaches and explore the potential of plasma biomarkers in differentiating PD from APS. A comprehensive literature review was conducted to assess diagnostic methods, including clinical assessment, neuroimaging, and biomarkers. Current diagnostic methods rely on clinical assessment and neuroimaging, which lack sensitivity in early disease stages. Cerebrospinal fluid biomarkers show promise but are invasive. Plasma biomarkers, including α‐synuclein species, neurofilament light chain, and DJ‐1, offer a minimally invasive alternative. However, challenges such as preanalytical variability and lack of standardized assays hinder clinical implementation. Advances in proteomics, metabolomics, and machine learning may enhance diagnostic accuracy. Early and precise differentiation between PD and APS is critical for optimal treatment and prognosis. Plasma biomarkers have the potential to revolutionize differential diagnosis, but further research is needed. Future studies should focus on biomarker validation in prodromal cohorts, assay standardization, and integration into clinical trials. Ethical considerations, including psychosocial impacts and healthcare disparities, must also be addressed. Improved diagnostic accuracy could lead to more targeted therapies, reduced healthcare costs, and better patient outcomes. Standardization of biomarker assays and addressing ethical concerns are crucial for successful clinical implementation.