A Pathway Proteomic Profile of Ischemic Stroke Survivors Reveals Innate Immune Dysfunction in Association with Mild Symptoms of Depression – A Pilot Study

Abstract

Depression after stroke is a common occurrence, raising questions as to whether depression could be a long-term biological and immunological sequela of stroke. Early explanations for post-stroke depression (PSD) focused on the neuropsychological/psychosocial effects of stroke on mobility and quality of life. However, recent investigations have revealed imbalances of inflammatory cytokine levels in association with PSD, though to date, there is only one published proteomic pathway analysis testing this hypothesis. Thus, we examined the serum proteome of stroke patients (n = 44, mean age = 63.62 years) and correlated these with the Montgomery–Åsberg Depression Rating Scale (MADRS) scores at 3 months post-stroke. Overall, the patients presented with mild depression symptoms on the MADRS, M = 6.40 (SD = 7.42). A discovery approach utilizing label-free relative quantification was employed utilizing an LC-ESI–MS/MS coupled to a LTQ-Orbitrap Elite (Thermo-Scientific). Identified peptides were analyzed using the gene set enrichment approach on several different genomic databases that all indicated significant downregulation of the complement and coagulation systems with increasing MADRS scores. Complement and coagulation systems are traditionally thought to play a key role in the innate immune system and are established precursors to the adaptive immune system through pro-inflammatory cytokine signaling. Both systems are known to be globally affected after ischemic or hemorrhagic stroke. Thus, our results suggest that lowered complement expression in the periphery in conjunction with depressive symptoms post-stroke may be a biomarker for incomplete recovery of brain metabolic needs, homeostasis, and inflammation following ischemic stroke damage. Further proteomic investigations are now required to construct the temporal profile, leading from acute lesion damage to manifestation of depressive symptoms. Overall, the findings provide support for the involvement of inflammatory and immune mechanisms in PSD symptoms and further demonstrate the value and feasibility of the proteomic approach in stroke research.

Proteomic identification of galectin-11 and 14 ligands fromHaemonchus contortus

“…Data were collected on an Orbitrap Elite (Thermo-Fisher Scientific, Waltham, MA, USA) in a data-dependent acquisition mode using m/z 300–1,500 as MS scan range, CID MS/MS spectra and were collected for the 20 most intense ions. Dynamic exclusion parameters were set as described previously ( Nguyen et al, 2016 ). The Orbitrap Elite was operated in dual analyser mode, with the Orbitrap analyser being used for MS and the linear trap being used for MS/MS.…”

Neuro-Immune Hemostasis: Homeostasis and Diseases in the Central Nervous System

“…In schizophrenic patients, in comparison to bipolar patients and healthy subjects, the C3 and C4 serum concentrations and their hemolytic properties were decreased ( Spivak et al, 1993 ). A pathway proteomic profile of ischemic stroke survivors with mild depression showed that both lectin and the classical pathway of complement activation are downregulated and the phenomenon is associated with depressive symptoms ( Nguyen et al, 2016 ). C3 is pivotal for the entire process; it is required for both lectin and classical activation of complement and for immune system regulation.…”

Proteomic-Based Approaches for the Study of Ischemic Stroke

“…Among 60 proteins showing > 1.5-fold change, vWF, ADAMTS13, S100A7, and DLG4 were further investigated in serum by ELISA. Nguyen et al examined the serum proteome of stroke patients (n = 44) by utilizing label-free relative quantification and correlated these with the depression rating scale scores at 3 months post-stroke [13]. The results indicated that downregulation of complement expression in the periphery in conjunction with increasing MADRS scores post-stroke may be a biomarker for incomplete recovery of brain metabolic needs, homeostasis, and inflammation following ischemic stroke damage.…”