Cerebrospinal fluid α-synuclein in neurodegenerative disorders—A marker of synapse loss?

Abstract

The association of α-synuclein (α-syn) neuropathology with Parkinson's disease (PD) and several related disorders has led to an intense research effort to develop cerebrospinal fluid (CSF)- or blood-based α-syn biomarkers for these types of diseases. Recent studies show that α-syn is present in CSF and possible to measure using enzyme-linked immunosorbent assay (ELISA). Here, we describe a novel ELISA that allows for quantification of α-syn in CSF down to 50 pg/mL. The diagnostic value of the test was assessed using CSF samples from 66 Alzheimer's disease (AD) patients, 15 PD patients, 15 patients with dementia with Lewy bodies (DLB) and 55 cognitively normal controls. PD and DLB patients and controls displayed similar CSF α-syn levels. AD patients had significantly lower α-syn levels than controls (median [inter-quartile range] 296 [234–372] and 395 [298–452], respectively, p < 0.001). Moreover, AD patients with mini-mental state examination (MMSE) scores below 20 had significantly lower α-syn than AD patients with MMSE scores of 20 or higher ( p = 0.02). There was also a tendency towards a negative correlation between α-syn levels and disease duration in the AD group ( r = −0.247, p = 0.06). Altogether, our results speak against CSF α-syn as a reliable biomarker for PD and DLB. The lower α-syn levels in AD, as well as the association of α-syn reduction with AD severity, approximated by MMSE, suggests that it may be a general marker of synapse loss, a hypothesis that warrants further investigation.