Differential role of CSF alpha-synuclein species, tau, and Aβ42 in Parkinson's Disease.

Lucilla Parnetti,Claudia De Carlo,Paolo Eusebi,Nicola Tambasco,David Giannandrea,Aroldo Rossi,Nour K Majbour,Davide Chiasserini,Nicola Salvadori,Paolo Calabresi,Lucia Farotti,Omar El-Agnaf,Viviana Lisetti

doi:10.3389/fnagi.2014.00053

Abstract

There is a great interest in developing cerebrospinal fluid (CSF) biomarkers for diagnosis and prognosis of Parkinson's disease (PD). CSF alpha synuclein (α-syn) species, namely total and oligomeric α-syn (t-α-syn and o-α-syn), have shown to be of help for PD diagnosis. Preliminary evidences show that the combination of CSF t-α-syn and classical Alzheimer's disease (AD) biomarkers—β-amyloid 1–42 (Aβ42), total tau (t-tau), phosphorylated tau (p-tau)—differentiate PD patients from controls, and that reduced levels of Aβ42 represent a predictive factor for development of cognitive deterioration in PD. In this prospective study carried out in 44 PD patients and 25 neurological controls we wanted to verify whether the combination of CSF α-synuclein species—t-α-syn and o-α-syn—and classical AD biomarkers may help in differentiating PD from neurological controls, and if these biomarkers may predict cognitive decline. The median of follow-up duration was 3 years (range: 2–6 years). Mini Mental State Examination (MMSE) and Montreal Cognitive Assessment (MoCA) were used for monitoring cognitive changes along time, being administered once a year. Oligo/total α-syn ratio (o/t-α-syn ratio) confirmed its diagnostic value, significantly contributing to the discrimination of PD from neurological controls. A greater diagnostic accuracy was reached when combining o/t-α-syn and Aβ42/tau ratios (Sens = 0.70, Spec = 0.84, AUC = 0.82; PPV = 0.89, NPV = 0.62, LR+ = 4.40, DOR = 12.52). Low CSF Aβ42 level was associated with a higher rate of MMSE and MoCA decline, confirming its role as independent predictive factor for cognitive decline in PD. None of the other biomarkers assessed (t-tau, p-tau, t-α-syn and o-α-syn) showed to have prognostic value. We conclude that combination of CSF o/t-α-syn and Aβ42/tau ratios improve the diagnostic accuracy of PD. PD patients showing low CSF Aβ42 levels at baseline are more prone to develop cognitive decline.

Highlights

Parkinson’s disease (PD) is a common neurodegenerative disorder evolving, in a substantial proportion of patients, to dementia
In this study we evaluated both the diagnostic accuracy and the capability in predicting cognitive decline of cerebrospinal fluid (CSF) Alzheimer’s disease (AD) biomarkers (Aβ42, t-tau, p-tau and Aβ42/t-tau ratio) and α-syn species (t-αsyn, o-α-syn and o/t-α-syn ratio) in PD patients and neurological controls with a median follow up duration of 3 years
With the aim to find the best predictors of PD to be included in the final model, we considered all the CSF enzyme activities which had already shown significant differences between other neurological conditions (OND) and PD groups after the univariate analysis

Summary

Introduction

Parkinson’s disease (PD) is a common neurodegenerative disorder evolving, in a substantial proportion of patients, to dementia. It is defined as a typical movement disorder and its diagnosis is mainly based on motor-related clinical criteria, other functional domains are involved. PD is a complex neurodegenerative disorder in which many different pathophysiological processes take place, such as protein aggregation, oxidative damage and lysosomal dysfunction (Parnetti et al, 2013). Concomitant pathologies (i.e., Alzheimer and Lewy bodies pathologies) resulting from the mutual interaction between Aβ42, tau and α-syn during the course of the disease have major role in the neuropathological processes underlying dementia in PD (Tsigelny et al, 2008; Ciaccioli et al, 2013). Α-syn causes aggregation and polymerization of tau, which induces the formation of intracellular amyloid-tau inclusions (Waxman and Giasson, 2011)

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