Abstract
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; n = 13), multiple system atrophy (MSA; n = 9), progressive supranuclear palsy (PSP; n = 13), corticobasal degeneration (CBD; n = 9), Alzheimer’s disease (AD; n = 51), frontotemporal degeneration (FTD; n = 26) and vascular dementia patients (VD; n = 14). PD patients exhibited higher pS129-α-syn/α-syn ratios compared to FTD (p = 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 α-syn levels compared to CBD (p = 0.024). Patients with a synucleinopathy (PD and MSA) exhibited lower t-α-syn levels (p = 0.002; cut-off value: ≤865 pg/mL; sensitivity: 95%, specificity: 69%) and higher pS129-/t-α-syn ratios (p = 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.
Highlights
Diagnostic accuracy of cognitive and movement disorders based on established clinical diagnostic criteria is suboptimal, even among experts [1,2,3,4]
Biomarkers that provide in vivo information of the underlying pathology in patients with cognitive and movement disorders are needed in order to improve diagnostic accuracy
Cerebrospinal fluid (CSF) biomarkers have already been incorporated in the NIA/AA and IWG-2 diagnostic criteria for Alzheimer’s disease (AD) [5,6]
Summary
Diagnostic accuracy of cognitive and movement disorders based on established clinical diagnostic criteria is suboptimal, even among experts [1,2,3,4] This is due to the clinical variability of most neurodegenerative diseases, which, not uncommonly, manifest with atypical phenotypes. CSF biomarkers have already been incorporated in the NIA/AA and IWG-2 diagnostic criteria for Alzheimer’s disease (AD) [5,6]. These include amyloid beta with 42 amino acids (Aβ42), a marker of amyloid pathology (plaque formation); total tau protein (τT), a nonspecific marker of neurodegeneration; phosphorylated tau protein at threonine 181 (τP-181), a marker of tau pathology (tangle formation). AD is characterized by a decrease in Aβ42 and an increase in τT and τP-181, which results in elevated biomarker indices such as τT/Aβ42 and τP-181/τT ratios
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