By Claire Henchcliffe, MD, PhD

Associate Professor of Neurology and Neuroscience, Weill Cornell Medical College

Dr. Henchcliffe reports she is a consultant and on the speakers bureau for Acadia, Impax, and Allergan, and is a consultant for US WorldMeds and Gerson Lehrman Group.

SYNOPSIS: In this cross-sectional study, plasma alpha-synuclein levels were higher in individuals with Parkinson’s disease than controls, and correlated with cognitive decline.

SOURCE: Lin CH, Yang SY, Horng HE, et al. Plasma alpha-synuclein predicts cognitive decline in Parkinson’s disease. J Neurol Neurosurg Psychiatry 2017; May 26. doi:10.1136/jnnp-2016-314857. [Epub ahead of print].

Neuroimaging biomarkers, including single positron emission computerized tomography (SPECT) and positron emission tomography (PET) scans, are already in sporadic use to aid in diagnosis of Parkinson’s disease (PD), but the search is on for a fluid-based biomarker that would be simpler, cheaper, and more broadly accessible than sophisticated neuroimaging. In this study, plasma was collected at a tertiary referral center from 80 participants with PD and 34 controls for analysis of α-synuclein levels. The groups were well matched for gender and education level, but those with PD were significantly older than controls (mean age, 69.6 ± 12.3 years vs. 61.9 ± 9.5 years, respectively; P < 0.01). The immunoassay used by these investigators is highly innovative, making use of magnetic nanoparticles that have anti-α-synuclein monoclonal antibodies bound to them. Binding to plasma α-synuclein then is measured by a reduction in magnetic susceptibility, termed the immune-magnetic reduction (IMR) signal. Using this assay, α-synuclein plasma concentration was markedly higher in PD than control subjects at 1.96 pg/mL (95% confidence interval [CI], 1.02-1.98 pg/mL) compared with 0.02 pg/mL (95% CI, 0.01-0.03 pg/mL), respectively (P < 0.0001). No correlation with age was determined in control subjects, leading to the suggestion that the difference between PD and control groups was due to disease state and not the difference in age. PD participants were then divided by Hoehn and Yahr stage (range 1-4), in which higher stage denotes worse function. Although those with higher Hoehn and Yahr stages had increased α-synuclein plasma concentration, this association did not hold when using a multivariate linear regression model that included age, gender, and disease duration. However, higher α-synuclein plasma concentrations were found to be associated with more profound cognitive dysfunction, as assessed by the Mini-Mental Status Examination (MMSE). Median α-synuclein plasma concentration increased between groups from 0.42 pg/mL (95% CI, 0.25-0.93 pg/mL) for PD, to 1.29 pg/mL (95% CI, 0.76-1.93 pg/mL) for PD with mild cognitive impairment, to 4.09 (95% CI, 1.99-6.19) pg/mL for PD with dementia.

COMMENTARY

Although α-synuclein already is a leading candidate as a fluid-based PD biomarker, several issues remain to be addressed. The first is what samples would be best to test. The most robust results to date have measured α-synuclein in cerebrospinal fluid (CSF), finding a decrease in CSF α-synuclein in PD, as opposed to the increase in plasma α-synuclein determined in this study. Obtaining CSF from patients for analysis generally is straightforward, but a blood-, urine-, or saliva-based marker would be preferable given the relative speed and simplicity of collection of these biofluids compared with CSF. A second issue concerns the debate over what technique is best for measurement. A major problem is that α-synuclein is present at low concentration in plasma and is abundant in red blood cells. Therefore, difficulties associated with measuring low concentration of this specific protein are compounded by even a small degree of red blood cell contamination of the sample. This has led to varying results from previous studies, despite encouraging findings in CSF. However, Lin and colleagues presented robust data based on a novel detection technology, making use of antibodies immobilized onto magnetic nanoparticles, which they have used previously to investigate Alzheimer’s disease biomarkers. This has enabled them to measure in a range of 0.3 fg/mL to 310 pg/mL, according to their previous study. The major finding of this study is the association of increased plasma α-synuclein concentration with degree of cognitive decline, suggesting that this assay could be a predictive marker of cognitive decline. If this association holds, it could serve as a biomarker to detect effects of a clinical trial intervention. The findings need to be replicated in an independent cohort that includes more detailed cognitive testing, and, eventually, a longitudinal study will have to be undertaken. Nonetheless, this is an encouraging finding, and this study highlights a novel technology that could well be applied in other disorders.