Cerebrospinal Fluid Total and Phosphorylated α-Synuclein in Patients with Creutzfeldt–Jakob Disease and Synucleinopathy

Abstract

High levels of total α-synuclein (t-α-synuclein) in the cerebrospinal fluid (CSF) were reported in sporadic Creutzfeldt-Jakob disease (sCJD). The potential use of t-α-synuclein in the discrimination of Lewy body dementias (i.e., Parkinson's disease dementia (PDD) and dementia with Lewy bodies (DLB)) is still under investigation. In addition, phospho-serine-129 α-synuclein (p-α-synuclein) has been described to be slightly increased in the CSF of synucleinopathies. Here, we analyzed t-α-synuclein and p-α-synuclein concentrations and their ratio in the context of differential diagnosis of neurodegenerative diseases. We quantified the levels of CSF t-α-synuclein and p-α-synuclein in a cohort of samples composed of neurological controls (NC), sCJD, PDD, and DLB by means of newly developed specific enzyme-linked immunosorbent assays. T-α-synuclein and p-α-synuclein were specifically elevated in sCJD compared to other disease groups. The area under the curve (AUC) values for t-α-synuclein were higher for the discrimination of sCJD from dementias associated to Lewy bodies as compared to the use of p-α-synuclein. A combination of both markers even increased the diagnostic accuracy. An inverse correlation was observed in CSF between t-α-synuclein and p-α-synuclein, especially in the DLB group, indicating a disease-relevant association between both markers. In conclusion, our data confirm t-α-synuclein and p-α-synuclein as robust biomarkers for sCJD and indicate the potential use of colorimetric t-α-synuclein ELISAs for differential diagnosis of dementia types.

Measurement of CSF α‐synuclein improves early differential diagnosis of mild cognitive impairment due to Alzheimer’s disease

“…Specific assays that discriminate oligomers and phosphorylated forms of α‐syn are needed to test this possibility, to interpret longitudinal changes in CSF α‐syn, and to ascertain the specificity for discrimination of LBD from other non‐AD‐disorders. Interestingly, a recent report indicates an inverse correlation between CSF levels of total α‐syn and phospho‐serine‐129 α‐syn in LBD, indicating a disease‐relevant association between both markers (Schmitz et al ).…”

Longitudinal analyses of cerebrospinal fluid α‐Synuclein in prodromal and early Parkinson's disease

“…How α‐syn gets into CSF is incompletely understood, although a recent study indicates that neuronal activity, particularly at excitatory synapses, is a major contributor to its release . In contrast to PD, levels of α‐syn are markedly increased in CSF in Creutzfeldt‐Jakob disease, where rapid and progressive neuronal death occurs …”

“…33 In contrast to PD, levels of α-syn are markedly increased in CSF in Creutzfeldt-Jakob disease, where rapid and progressive neuronal death occurs. 34 The reasons for CSF α-syn variability remain to be determined. One explanation could be partly attributed to misdiagnoses that are not excluded in this cohort and that are reported to be a problem among de novo PD subjects.…”

Diagnostic Accuracy of Prion Disease Biomarkers in Iatrogenic Creutzfeldt-Jakob Disease

“…The addition to p-tau in the form of p-tau/t-tau ratio (n = 19) increased the sensitivity achieved by t-tau alone up to 94.7%, with only one case below the p-tau/t-tau cut-off (<0.075, [25]). Mean p-tau/t-tau ratio was 0.018. a-syn (n = 21) displayed a sensitivity of 90.5% based on the sCJD cut-off of 3300 pg/mL [26] with a mean concentration of 13,346 pg/mL. Nfl (n = 21) displayed a sensitivity of 85.7% using a cut-off of 7000 pg/mL [27] with a mean concentration of 12,986 pg/mL.…”