Abstract
Background and Objectives: Despite ongoing research and evolving diagnostic criteria, progressive supranuclear palsy (PSP) and corticobasal syndrome (CBS) remain notoriously difficult to differentiate, largely due to their overlapping clinical presentations and the absence of definitive biomarkers. Materials and Methods: We provide a comprehensive review of cerebrospinal fluid (CSF) biomarkers, which have proven valuable in the diagnosis of other neurodegenerative conditions, and their application to PSP and CBS. Results: The most promising results derive from a combination of biomarkers associated with Parkinson's disease, Alzheimer's disease, and neurofilament light chain. Furthermore, CSF proteomics analysis offers valuable insights into the pathogenesis of PSP and CBS and could also contribute to accurate diagnosis. Conclusions: CSF biomarkers hold significant potential for improving the differential diagnosis of PSP and CBS. A stepwise combination approach-starting with CSF α-synuclein and neurofilament light chain, followed by amyloid-β42 and total and phosphorylated tau-may provide clinicians with a practical framework for distinguishing PSP and CBS from other neurodegenerative disorders. To advance this field, future efforts should prioritize large-scale, multicenter studies employing standardized methodologies to enhance the validity and reproducibility of biomarker-based diagnostics. Importantly, considering the frequent pathological overlap between PSP and CBS, future studies would greatly benefit from pathology-confirmed cohorts to ensure diagnostic accuracy and to better delineate biomarker profiles across these challenging conditions.