Abstract
Currently the longitudinal proteomic profile of post-ischemic stroke recovery is relatively unknown with few well-accepted biomarkers or understanding of the biological systems that underpin recovery. We aimed to characterize plasma derived biological pathways associated with recovery during the first year post event using a discovery proteomics workflow coupled with a topological pathway systems biology approach. Blood samples (n = 180, ethylenediaminetetraacetic acid plasma) were collected from a subgroup of 60 first episode stroke survivors from the Australian START study at 3 timepoints: 3–7 days (T1), 3-months (T2) and 12-months (T3) post-stroke. Samples were analyzed by liquid chromatography mass spectrometry using label-free quantification (data available at ProteomeXchange with identifier PXD015006). Differential expression analysis revealed that 29 proteins between T1 and T2, and 33 proteins between T1 and T3 were significantly different, with 18 proteins commonly differentially expressed across the two time periods. Pathway analysis was conducted using Gene Graph Enrichment Analysis on both the Kyoto Encyclopedia of Genes and Genomes and Reactome databases. Pathway analysis revealed that the significantly differentiated proteins between T1 and T2 were consistently found to belong to the complement pathway. Further correlational analyses utilized to examine the changes in regulatory effects of proteins over time identified significant inhibitory regulation of clusterin on complement component 9. Longitudinal post-stroke blood proteomics profiles suggest that the alternative pathway of complement activation remains in a state of higher activation from 3-7 days to 3 months post-stroke, while simultaneously being regulated by clusterin and vitronectin. These findings also suggest that post-stroke induced sterile inflammation and immunosuppression could inhibit recovery within the 3-month window post-stroke.
Highlights
Ischemic stroke covers a variety of cerebrovascular events that affect up to 800,000 people in the United States every year, with 133,000 deaths reported in 2017 (16.74%) [1]
The results indicated that proteins involved in the complement but not the coagulation pathway of the immune system are likely to be associated with post-stroke depressive symptoms [14]
The biology of post-stroke recovery is not well-understood, with patients exhibiting varying profiles based on factors such as their age, location of lesion, and degree of stroke damage [72]
Summary
Ischemic stroke covers a variety of cerebrovascular events that affect up to 800,000 people in the United States every year, with 133,000 deaths reported in 2017 (16.74%) [1]. Evidence from stroke rehabilitation studies suggest the greatest efficacy for motor-based rehabilitation is within this 3 month time window [4], though recovery may continue at a slower rate over subsequent months and years. We aimed to investigate the changes in the molecular profile of proteins in plasma samples via a mass spectrometry (MS) based discovery proteomics approach [6]. Mass spectrometry and nuclear magnetic resonance (NMR) based techniques examining protein expression are among the most versatile techniques for protein identification and quantification, with the ability to address a wide range of biological samples, especially plasma, and serum [7, 8]. Proteomics utilizes the advantage of systems biology techniques to quantify a large number of analytes in an exploratory fashion, with a computational bioinformatics approach to further categorize biomarkers into biosystems [9]
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