Cerebrospinal Fluid α-Synuclein Species in Cognitive and Movements Disorders

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.

Dopamine transporter SPECT imaging in corticobasal syndrome: A peak into the underlying pathology?

“…Classical AD CSF biomarkers (Aβ 42 , τ T , τ P‐181 ) were measured in duplicate by double sandwich, enzyme‐linked immunosorbent assay (ELISA) with commercially available kits (EUROIMMUN beta‐amyloid (1–42) ELISA; EUROIMMUN Total‐Tau ELISA; EUROIMMUN pTau(181) ELISA, respectively) according to manufacturer instructions. A protocol was implemented in order to control for pre‐analytical and analytical variability as described in detail elsewhere 22 . Cutoff values of the Neurochemistry and Biomarkers Unit of the National and Kapodistrian University of Athens were applied for τ T (UNL ≤400pg/ml), τ P‐181 (UNL ≤60pg/ml) and Aβ 42 (LNL ≥480pg/ml), as described elsewhere in detail 22 …”

“…A protocol was implemented in order to control for pre‐analytical and analytical variability as described in detail elsewhere 22 . Cutoff values of the Neurochemistry and Biomarkers Unit of the National and Kapodistrian University of Athens were applied for τ T (UNL ≤400pg/ml), τ P‐181 (UNL ≤60pg/ml) and Aβ 42 (LNL ≥480pg/ml), as described elsewhere in detail 22 …”

Classical Cerebrospinal Fluid Biomarkers in Dementia with Lewy Bodies

“…The form of quantitated α-syn may play some role, since synucleinopathies, such as DLB, may exhibit lower total α-syn and higher ratio of phosphorylated/total α-syn ratiο, as compared to other neurodegenerative diseases [ 28 ]. Furthermore, α-syn determination by Real-Time Quaking-Induced Conversion Assay (RT-QuIC) may prove a robust biomarker for prodromal DLB, as shown by a recent research team [ 29 ], but still, well-designed studies with a large number of participants need to be conducted.…”

Cerebrospinal Fluid Biomarkers for Alzheimer’s Disease in the Era of Disease-Modifying Treatments

“…Furthermore, normal levels of all three CSF classical biomarkers may be observed not only in normal aging, but also in psychiatric disorders which may present with cognitive complaints [67,68] and in some of the frontotemporal pathologies [69], which may enter in the differential diagnosis of psychiatric disorders. Assessment of α-synuclein may be of value in the presence of Lewy body pathology [70], but results are conflicting [71,72]. Another emerging biomarker is TAR DNA-binding protein 43 (TDP43), which may prove helpful in identifying TDP43-related frontotemporal pathologies, especially when combined with the classical biomarkers [73]; much work still has to be done.…”