Detection of disease-associated Î±-synuclein in the cerebrospinal fluid: a feasibility study

Ursula Unterberger,Uta Wagner,Armand Perret-Liaudet,Ingolf Lachmann,Walter Pirker,Till Voigtländer,Aline Geneste,Gabor G Kovacs,Katharina Flach,Anna S Berghoff

doi:10.5414/np300796

Abstract

With the aim to evaluate the significance and reliability of detecting disease-specific α-synuclein in the cerebrospinal fluid (CSF) we developed an ELISA and bead-assay. We used a commercial antibody (5G4) that does not bind to the physiological monomeric form of α-synuclein, but is highly specific for the disease-associated forms, including high molecular weight fraction of β-sheet rich oligomers. We applied both tests in CSF from a series of neuropathologically confirmed α-synucleinopathy cases, including Parkinson’s disease dementia (PDD) and dementia with Lewy bodies (DLB) (n = 7), as well as Alzheimer’s disease (n = 6), and control patients without neurodegenerative pathologies (n = 9). Disease-specific α-synuclein was detectable in the CSF in a subset of patients with α-synuclein pathology in the brain. When combined with the analysis of total α-synuclein, the bead-assay for disease-specific α-synuclein was highly specific for PDD/DLB. Detection of disease-associated α-synuclein combined with the total levels of α-synuclein is a promising tool for the in-vivo diagnosis of α-synucleinopathies, including PDD and LBD.

Highlights

Neurodegenerative disorders are characterized by the formation and deposition of abnormal isoforms of physiologically occurring proteins primarily in the brain of affected individuals [1]
Neither cerebrospinal fluid (CSF) protein levels and storage time, nor contamination with erythrocytes
We addressed the question whether d-α-syn can be detected in the CSF in patients with proven Lewy body pathology-related dementias

Summary

Introduction

Neurodegenerative disorders are characterized by the formation and deposition of abnormal isoforms of physiologically occurring proteins primarily in the brain of affected individuals [1]. Lewy-bodies (DLB) [2], this is α-synuclein, a presynaptic protein, which under pathological conditions is deposited in neurons and neuronal processes in the form of Lewy bodies and Lewy neurites [3]. Α-Synuclein is an extremely useful marker for the neuropathological diagnosis and staging of the aforementioned disorders. It is most desirable to make use of it in autopsies, and for early clinical diagnosis, while the patient could still potentially benefit from the result. The in-vivo detection of disease-associated α-synuclein (d-α-syn) has important clinical implications. Pathology, it is crucial to differentiate it from pure AD forms. This has significant therapeutic relevance, since patients with the former are sensitive to treatment with neuroleptics

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Conclusion