Precision Diagnostic Strategies for Atypical Parkinsonian Disorders

Atypical parkinsonian disorders—progressive supranuclear palsy (PSP), corticobasal degeneration (CBD), and multiple system atrophy (MSA)—are rare, rapidly progressive neurodegenerative syndromes with complex clinical presentations, distinct neuropathological signatures, and limited therapeutic options. Accurate diagnosis is challenging, particularly in early stages, due to overlap with Parkinson’s disease and among themselves, phenotypic heterogeneity, and the lack of reliable stand-alone biomarkers. Misclassification is a frequent occurrence, with significant consequences for prognosis, patient care, and the design of clinical trials. This review synthesizes current evidence on clinical, neuroimaging, and biomarker-based diagnosis of PSP, CBD, and MSA. We describe core and variant phenotypes, provide epidemiological updates, and present neuropathological correlates, along with structured diagnostic approaches. Advances in MRI morphometry, tau- and α–synuclein–sensitive PET, quantitative oculomotor and autonomic testing, and fluid biomarkers—particularly neurofilament light chain—are critically evaluated for their diagnostic value and limitations. We identify ten persistent challenges to early and accurate diagnosis, including phenotypic mimicry, non-specific imaging, limited biomarker specificity, and inequitable access to advanced diagnostics. We propose tiered, multimodal algorithms that integrate standardized clinical phenotyping with quantitative imaging, molecular diagnostics, and pathology-linked validation. This approach may reduce diagnostic delays, enhance trial enrichment, and facilitate earlier, personalized interventions in these disorders.