Alpha-Synuclein Protofibrils in Cerebrospinal Fluid: A Potential Biomarker for Parkinson's Disease

Article type: Research Article

Authors: von Euler Chelpin, Marianne^a | Söderberg, Linda^b | Fälting, Johanna^b | Möller, Christer^b | Giorgetti, Marco^c | Constantinescu, Radu^d | Blennow, Kaj^{a; e} | Zetterberg, Henrik^{a; e; f; g} | Höglund, Kina^{a; e; *}

Affiliations: [a] Department of Psychiatry and Neurochemistry, Institute of Neuroscience and Physiology, the Sahlgrenska Academy at the University of Gothenburg, Mölndal, Sweden | [b] BioArctic AB, Stockholm, Sweden | [c] AbbVie Inc., North Chicago, IL, USA | [d] Department of Neurology, Sahlgrenska University Hospital, Göteborg, Sweden | [e] Clinical Neurochemistry Laboratory, Sahlgrenska University Hospital, Mölndal, Sweden | [f] Department of Neurodegenerative Disease, UCL Institute of Neurology, Queen Square, London, UK | [g] UK Dementia Research Institute at UCL, London, UK

Correspondence: [*] Correspondence to: Dr. Kina Höglund, Associate Professor, Department of Psychiatry and Neurochemistry, Institute of Neuroscience and Physiology, the Sahlgrenska Academy at the University of Gothenburg, House V3/SU, SE-431 80 Mölndal, Sweden. Tel.: +46 763074975; E-mail: kina.hoglund@vgregion.se.

Abstract: Background:Currently, there is no established biomarker for Parkinson's disease (PD) and easily accessible biomarkers are crucial for developing disease-modifying treatments. Objective:To develop a novel method to quantify cerebrospinal fluid (CSF) levels of α-synuclein protofibrils (α-syn PF) and apply it to clinical cohorts of patients with PD and atypical parkinsonian disorders. Methods:A cohort composed of 49 patients with PD, 12 with corticobasal degeneration (CBD), 22 with progressive supranuclear palsy, and 33 controls, that visited the memory clinic but had no biomarker signs of Alzheimer’s disease (AD, tau<350 pg/mL, amyloid-beta 42 (Aβ42)>530 pg/mL, and phosphorylated tau (p-tau)<60 pg/mL) was used in this study. The CSF samples were analyzed with the Single molecule array (Simoa) technology. Total α-synuclein (α-syn) levels were analyzed with a commercial ELISA-kit. Results:The assay is specific to α-syn PF, with no cross-reactivity to monomeric α-syn, or the β- and γ-synuclein variants. CSF α-syn PF levels were increased in PD compared with controls (62.1 and 40.4 pg/mL, respectively, p = 0.03), and CBD (62.1 and 34.2 pg/mL, respectively, p = 0.02). The accuracy of predicting PD using α-syn PF is significantly different from controls (area under the curve 0.68, p = 0.0097) with a sensitivity of 62.8% and specificity of 67.7%. Levels of total α-syn were significantly different between the PD and CBD groups (p = 0.04). Conclusion:The developed method specifically quantifies α-syn PF in human CSF with increased concentrations in PD, but with an overlap with asymptomatic elderly controls.

Keywords: Parkinson's disease, alpha-synuclein protofibrils, Simoa, biomarker, CSF, atypical parkinsonian disorders

DOI: 10.3233/JPD-202141

Journal: Journal of Parkinson's Disease, vol. 10, no. 4, pp. 1429-1442, 2020