| Summary: | Total CSF α-synuclein (t-α-syn), phosphorylated α-syn (pS129-α-syn) and α-syn oligomers (o-α-syn) have been studied as candidate biomarkers for synucleinopathies, with suboptimal specificity and sensitivity in the differentiation from healthy controls. Studies of α-syn species in patients with other underlying pathologies are lacking. The aim of this study was to investigate possible alterations in CSF α-syn species in a cohort of patients with diverse underlying pathologies. A total of 135 patients were included, comprising Parkinson’s disease (PD; <i>n</i> = 13), multiple system atrophy (MSA; <i>n</i> = 9), progressive supranuclear palsy (PSP; <i>n</i> = 13), corticobasal degeneration (CBD; <i>n</i> = 9), Alzheimer’s disease (AD; <i>n</i> = 51), frontotemporal degeneration (FTD; <i>n</i> = 26) and vascular dementia patients (VD; <i>n</i> = 14). PD patients exhibited higher pS129-α-syn/α-syn ratios compared to FTD (<i>p</i> = 0.045), after exclusion of samples with CSF blood contamination. When comparing movement disorders (i.e., MSA vs. PD vs. PSP vs. CBD), MSA patients had lower <i>α-</i>syn levels compared to CBD (<i>p</i> = 0.024). Patients with a synucleinopathy (PD and MSA) exhibited lower t-<i>α-</i>syn levels (<i>p</i> = 0.002; cut-off value: ≤865 pg/mL; sensitivity: 95%, specificity: 69%) and higher <i>pS129-</i>/t-<i>α-</i>syn ratios (<i>p</i> = 0.020; cut-off value: ≥0.122; sensitivity: 71%, specificity: 77%) compared to patients with tauopathies (PSP and CBD). There are no significant α-syn species alterations in non-synucleinopathies.
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