Atypical Alpha-Synucleinopathy Presenting as Clinical Progressive Supranuclear Palsy: A Multidisciplinary Single-Case Study

Background: Progressive supranuclear palsy (PSP) is a neurodegenerative disease characterized by the predominant deposition of 4R-tau in both neuronal and glial inclusions, leading to progressive and significant motor and cognitive impairments (Dickson et al., 2007). While PSP is generally characterized by the abnormal accumulation of aggregated tau protein in the brain, previous studies have reported atypical presentations with no detectable tau pathology or even the co-occurrence of other proteinopathies, like alpha-synucleinopathy (Martínez-Maldonado et al., 2023; Mori et al., 2002; Pansuwan et al., 2021; Uchikado et al., 2006). Objectives: This thesis aims to investigate the clinical, neuropsychological, imaging, and neuropathological features of a patient with the clinical diagnosis of PSP. Methods: A single-case study was conducted, including detailed neurological-motor and neuropsychological evaluations, structural MRI and FDG-PET scans, and postmortem neuropathological examination methods. Results: Despite initial clinical and imaging findings consistent with PSP, postmortem analysis revealed an atypical alpha-synucleinopathy. The patient exhibited hallmark PSP motor symptoms and neuropsychiatric alterations (mainly impulsivity) but not a cognitive profile (intact, with atypical executive dysfunctions). Conclusion: This case illustrates the difficulties of accurately diagnosing neurodegenerative diseases, even in patients with seemingly typical presentations. Despite the initial clinical and imaging findings consistent with PSP, postmortem analysis showed an atypical type of alpha-synucleinopathy. The contradicting results emphasize the necessity for thorough assessments as well as the discovery of in vivo biomarkers that would lead to precise diagnosis and customized patient care. This approach could help design more effective disease-modifying therapies and palliative care programs.