Abstract
BackgroundCurrently there are no effective treatments for many neurodegenerative diseases. Reliable biomarkers for identifying and stratifying these diseases will be important in the development of future novel therapies. Lewy Body Dementia (LBD) is considered an under diagnosed form of dementia for which markers are needed to discriminate LBD from other forms of dementia such as Alzheimer’s Disease (AD). This work describes a Label-Free proteomic profiling analysis of cerebral spinal fluid (CSF) from non-neurodegenerative controls and patients with LBD. Using this technology we identified several potential novel markers for LBD. These were then combined with other biomarkers from previously published studies, to create a 10 min multiplexed targeted and translational MRM-LC-MS/MS assay. This test was used to validate our new assay in a larger cohort of samples including controls and the other neurodegenerative conditions of Alzheimer’s and Parkinson’s disease (PD).ResultsThirty eight proteins showed significantly (p < 0.05) altered expression in LBD CSF by proteomic profiling. The targeted MRM-LC-MS/MS assay revealed 4 proteins that were specific for the identification of AD from LBD: ectonucleotide pyrophosphatase/phosphodiesterase 2 (p < 0.0001), lysosome-associated membrane protein 1 (p < 0.0001), pro-orexin (p < 0.0017) and transthyretin (p < 0.0001). Nineteen proteins were elevated significantly in both AD and LBD versus the control group of which 4 proteins are novel (malate dehydrogenase 1, serum amyloid A4, GM2−activator protein, and prosaposin). Protein-DJ1 was only elevated significantly in the PD group and not in either LBD or AD samples. Correlations with Alzheimer-associated amyloid β-42 levels, determined by ELISA, were observed for transthyretin, GM2 activator protein and IGF2 in the AD disease group (r2 ≥ 0.39, p ≤ 0.012). Cystatin C, ubiquitin and osteopontin showed a strong significant linear relationship (r2 ≥ 0.4, p ≤ 0.03) with phosphorylated–tau levels in all groups, whilst malate dehydrogenase and apolipoprotein E demonstrated a linear relationship with phosphorylated-tau and total-tau levels in only AD and LBD disease groups.ConclusionsUsing proteomics we have identified several potential and novel markers of neurodegeneration and subsequently validated them using a rapid, multiplexed mass spectral test. This targeted proteomic platform can measure common markers of neurodegeneration that correlate with existing diagnostic makers as well as some that have potential to show changes between AD from LBD.Electronic supplementary materialThe online version of this article (doi:10.1186/s13024-015-0059-y) contains supplementary material, which is available to authorized users.
Highlights
There are no effective treatments for many neurodegenerative diseases
This targeted proteomic platform can measure common markers of neurodegeneration that correlate with existing diagnostic makers as well as some that have potential to show changes between Alzheimer’s Disease (AD) from Lewy Body Dementia (LBD)
Analysis of the LBD cerebral spinal fluid (CSF) proteome demonstrated 40 proteins were significantly altered with 22 proteins by a factor of 2-fold or more when compared to the control group (Additional file 1: Table S1)
Summary
There are no effective treatments for many neurodegenerative diseases. Reliable biomarkers for identifying and stratifying these diseases will be important in the development of future novel therapies. This work describes a Label-Free proteomic profiling analysis of cerebral spinal fluid (CSF) from non-neurodegenerative controls and patients with LBD Using this technology we identified several potential novel markers for LBD. These were combined with other biomarkers from previously published studies, to create a 10 min multiplexed targeted and translational MRM-LC-MS/MS assay This test was used to validate our new assay in a larger cohort of samples including controls and the other neurodegenerative conditions of Alzheimer’s and Parkinson’s disease (PD). The global impact of dementia is increasing rapidly with 150 million people estimated to be affected worldwide by 2015 This is largely due to neurodegenerative disorders such as Alzheimer’s disease (AD) and Lewy body dementia (LBD) [1]. This work set out to i) perform an in-depth biomarker discovery experiment to identify potentially unique CSF protein signatures for neurodegenerative conditions with the focus on LBD ii) combine these new biomarkers, with conventional biomarkers and potential biomarkers described previously in the literature [5,6,7,8,9,10,11,12,13,14], into a rapid, high-throughput and multiplexed test iii) validate these new markers alongside previously described biomarkers in a larger multicentre cohort of samples from patients with AD, PD and LBD
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