The statistics associated with stroke are stark: of the 15 million people who experience one each year, approximately one-third die, and another third sustain permanent disability. For stroke survivors, post-stroke depression (PSD) is also a concern; approximately 30% of survivors develop the condition, with prevalence peaking at three months post-stroke. Individuals with PSD exhibit poorer outcomes and higher mortality rates, making prevention and treatment important goals.
To better understand the etiology of PSD, the research team of Nguyen et al. (2016) applied a data-driven discovery proteomics approach to identify and quantify peptides for the purpose of revealing biological mechanisms.1 The team also hoped to determine if the previous work of Zhan et al.,2 which used isobaric tags for relative and absolute quantitation on ethylenediaminetetraacetic acid anticoagulated blood samples and the DAVID bioinformatics tool to implicate the complement and coagulation cascade pathway in the development of PSD, was replicable using different methodology.
To this end, the researchers applied label-free quantitation to blood serum samples collected from 44 stroke survivors at three months post-stroke. After processing the samples, they analyzed the tryptic peptides via liquid chromatography–electrospray ionization–tandem mass spectrometry on an LTQ Orbitrap Elite mass spectrometer (Thermo Scientific). For the resultant 475 peptides, they selected the gene set enrichment analysis bioinformatics tool to interrogate multiple databases (Hallmark, GO, KEGG, BioCarta and Reactome).
The research team indicates that their most significant finding was the downregulation of coagulation and complement cascades in stroke patients with depressive symptoms. They report this as consistent over four of the five databases (excluding GO). Additionally, they found that the biological changes described here are also characterizable for patients with only mild depressive symptoms and generally positive recovery. They note that their sample size was necessarily small, comprising individuals who experienced only mild stroke, and that a few of the participants had prior history of depression. However, Monte Carlo modeling indicated no significant impact of prior history on the collected data.
Further, the researchers state that, while their findings bear some dissimilarities in terms of individual gene expression (almost certainly due to sample type, stroke timeline and study design), the data they present unambiguously support the coagulation and complement cascade pathway dysregulation posited by Zahn et al. They indicate that this confirmation is particularly robust considering that two divergent methods yielded complementary findings.
Nguyen et al. offer this study as evidence supporting peripheral immunodepression associated with unresolved inflammatory processes in the brain after a stroke event. They call for further research into blood proteins implicated in the pathophysiology of PSD—both here and in the previous study. They further suggest that this data could inform research involving other cerebrovascular diseases with comorbid anxiety.
1. Nguyen, V.A., et al. (2016) “A pathway proteomic profile of ischemic stroke survivors reveals innate immune dysfunction in association with mild symptoms of depression—a pilot study,” Frontiers in Neurology, 7(85), doi: 10.3389/fneur.2016.00085.
2. Zhan, Y., et al. (2014) “Plasma-based proteomics reveals lipid metabolic and immunoregulatory dysregulation in post-stroke depression,” European Psychiatry, 29(5) (p. 307–315), doi: 10.1016/j.eurpsy.2014.03.004.