Plasma-based proteomics reveals lipid metabolic and immunoregulatory dysregulation in post-stroke depression

Abstract Background: Post-stroke depression (PSD) is the most common psychiatric complication facing stroke survivors and has been associated with increased distress, physical disability, poor rehabilitation, and suicidal ideation. However, the pathophysiological mechanisms underlying PSD remain unknown, and no objective laboratory-based test is available to aid PSD diagnosis or monitor progression. Methods: Here, an isobaric tags for relative and absolute quantitation (iTRAQ)-based quantitative proteomic approach was performed to identify differentially expressed proteins in plasma samples obtained from PSD, stroke, and healthy control subjects. Results: The significantly differentiated proteins were primarily involved in lipid metabolism and immunoregulation. Six proteins associated with these processes – apolipoprotein A-IV (ApoA-IV), apolipoprotein C-II (ApoC-II), C-reactive protein (CRP), gelsolin, haptoglobin, and leucine-rich alpha-2-glycoprotein (LRG) – were selected for Western blotting validation. ApoA-IV expression was significantly upregulated in PSD as compared to stroke subjects. ApoC-II, LRG, and CRP expression were significantly downregulated in both PSD and HC subjects relative to stroke subjects. Gelsolin and haptoglobin expression were significantly dysregulated across all three groups with the following expression profiles: gelsolin, healthy control > PSD > stroke subjects; haptoglobin, stroke > PSD > healthy control. Conclusions: Early perturbation of lipid metabolism and immunoregulation may be involved in the pathophysiology of PSD. The combination of increased gelsolin levels accompanied by decreased haptoglobin levels shows promise as a plasma-based diagnostic biomarker panel for detecting increased PSD risk in post-stroke patients.

[1]  D. Kwiatkowski,et al.  Gelsolin in Complex with Phosphatidylinositol 4,5-Bisphosphate Inhibits Caspase-3 and -9 to Retard Apoptotic Progression* , 2000, The Journal of Biological Chemistry.

[2]  L. Ramos,et al.  Association of the apolipoprotein A‐IV: 360 gln/his polymorphism with cerebrovascular disease, obesity, and depression in a Brazilian elderly population , 2005, American journal of medical genetics. Part B, Neuropsychiatric genetics : the official publication of the International Society of Psychiatric Genetics.

[3]  R. Robinson,et al.  Post-stroke depression and lesion location. , 1988, Stroke.

[4]  Lippincott Williams Wilkins,et al.  Stroke--1989. Recommendations on stroke prevention, diagnosis, and therapy. Report of the WHO Task Force on Stroke and other Cerebrovascular Disorders. , 1989, Stroke.

[5]  I. Holme,et al.  Haptoglobin and risk of myocardial infarction, stroke, and congestive heart failure in 342,125 men and women in the Apolipoprotein MOrtality RISk study (AMORIS) , 2009, Annals of medicine.

[6]  R. Calabró,et al.  Cerebrovascular Diseases: Post-stroke Depression and Anhedonia , 2014 .

[7]  C. Kluft,et al.  The association between inflammation markers, coronary artery disease and smoking. , 2002, Vascular pharmacology.

[8]  J. W. Sanger,et al.  Angiopathic consequences of saturating the plasma scavenger system for actin. , 1990, Proceedings of the National Academy of Sciences of the United States of America.

[9]  D. Oxley,et al.  Disease Biomarkers in Cerebrospinal Fluid of Patients with First-Onset Psychosis , 2006, PLoS medicine.

[10]  Maarten Uyttenboogaart,et al.  Optimizing Cutoff Scores for the Barthel Index and the Modified Rankin Scale for Defining Outcome in Acute Stroke Trials , 2005, Stroke.

[11]  C. Turck,et al.  Gelsolin Binding and Cellular Presentation of Lysophosphatidic Acid* , 2000, The Journal of Biological Chemistry.

[12]  N. Meader,et al.  Screening for poststroke major depression: a meta-analysis of diagnostic validity studies , 2013, Journal of Neurology, Neurosurgery & Psychiatry.

[13]  Alan J. Thomas,et al.  Long-term incidence of depression and predictors of depressive symptoms in older stroke survivors , 2013, British Journal of Psychiatry.

[14]  P. Ridker,et al.  Complement factor H Y402H gene polymorphism, C-reactive protein, and risk of incident myocardial infarction, ischaemic stroke, and venous thromboembolism: a nested case-control study. , 2006, Atherosclerosis.

[15]  D. Kwiatkowski,et al.  Pulmonary vascular permeability and ischemic injury in gelsolin-deficient mice. , 2003, American journal of respiratory cell and molecular biology.

[16]  P. Schnohr,et al.  A common mutation in lipoprotein lipase confers a 2-fold increase in risk of ischemic cerebrovascular disease in women but not in men. , 2000, Circulation.

[17]  M. Mattson,et al.  The Actin-Severing Protein Gelsolin Modulates Calcium Channel and NMDA Receptor Activities and Vulnerability to Excitotoxicity in Hippocampal Neurons , 1997, The Journal of Neuroscience.

[18]  J. Fleiss,et al.  Hamilton Depression Rating Scale. Extracted from Regular and Change Versions of the Schedule for Affective Disorders and Schizophrenia. , 1981, Archives of general psychiatry.

[19]  M. Moskowitz,et al.  Neuroprotective effects of gelsolin during murine stroke. , 1999, The Journal of clinical investigation.

[20]  J. Ribalta,et al.  Antioxidative and Antiatherosclerotic Effects of Human Apolipoprotein A-IV in Apolipoprotein E-Deficient Mice , 2001, Arteriosclerosis, thrombosis, and vascular biology.

[21]  Jung-Fu Chen,et al.  Correlation between serum lipid, lipoprotein concentrations and anxious state, depressive state or major depressive disorder , 2003, Psychiatry Research.

[22]  C. Caltagirone,et al.  The etiology of poststroke depression: a review of the literature and a new hypothesis involving inflammatory cytokines , 2006, Molecular Psychiatry.

[23]  J. Forteza,et al.  Usefulness of haptoglobin and serum amyloid A proteins as biomarkers for atherothrombotic ischemic stroke diagnosis confirmation. , 2009, Atherosclerosis.

[24]  H. Hampel,et al.  Blood‐Cerebrospinal Fluid Barrier Dysfunction for High Molecular Weight Proteins in Alzheimer Disease and Major Depression: Indication for Disease Subsets , 1997, Alzheimer disease and associated disorders.

[25]  A. Gautier,et al.  C-reactive protein , 2005 .

[26]  S. Crewther,et al.  Meta-analyses indicate associations between neuroendocrine activation, deactivation in neurotrophic and neuroimaging markers in depression after stroke. , 2013, Journal of stroke and cerebrovascular diseases : the official journal of National Stroke Association.

[27]  D. B. Smith,et al.  Role of plasma gelsolin and the vitamin D-binding protein in clearing actin from the circulation. , 1986, The Journal of clinical investigation.

[28]  R. Lahesmaa,et al.  Quantitative Proteomics Analysis of the Nuclear Fraction of Human CD4+ Cells in the Early Phases of IL-4-induced Th2 Differentiation , 2010, Molecular & Cellular Proteomics.

[29]  R. Burns,et al.  Increase of medical hospital length of stay by depression in stroke and amputation patients: a pilot study. , 1992, Psychotherapy and psychosomatics.

[30]  R G Robinson,et al.  The impact of poststroke depression on recovery in activities of daily living over a 2-year follow-up. , 1990, Archives of neurology.

[31]  T. Stossel,et al.  Plasma gelsolin is a marker and therapeutic agent in animal sepsis* , 2007, Critical care medicine.

[32]  S. Kasner,et al.  Clinical Usefulness of a Biomarker-Based Diagnostic Test for Acute Stroke: The Biomarker Rapid Assessment in Ischemic Injury (BRAIN) Study , 2009, Stroke.

[33]  C. Molina,et al.  Etiologic Diagnosis of Ischemic Stroke Subtypes With Plasma Biomarkers , 2008, Stroke.

[34]  X. Su,et al.  Proteomic analysis of serum proteins in acute ischemic stroke patients treated with acupuncture , 2011, Experimental biology and medicine.

[35]  M. Endres,et al.  Inhibition of histone deacetylation protects wildtype but not gelsolin-deficient mice from ischemic brain injury , 2008, Experimental Neurology.

[36]  M. Rosengart,et al.  The Actin Cytoskeleton: An Essential Component for Enhanced TNF&agr; Production by Adherent Monocytes , 2002, Shock.

[37]  Andrew H. Miller,et al.  CYTOKINE TARGETS IN THE BRAIN: IMPACT ON NEUROTRANSMITTERS AND NEUROCIRCUITS , 2013, Depression and anxiety.

[38]  Y. Itoh,et al.  Degradation of cross-linked fibrin by matrix metalloproteinase 3 (stromelysin 1): hydrolysis of the gamma Gly 404-Ala 405 peptide bond. , 1996, Biochemistry.

[39]  C. Meisinger,et al.  Association between different domains of physical activity and markers of inflammation. , 2009, Medicine and science in sports and exercise.

[40]  Tiao-Lai Huang.  Serum lipid profiles in major depression with clinical subtypes, suicide attempts and episodes. , 2005, Journal of affective disorders.

[41]  P. Janmey,et al.  Capacity of human serum to depolymerize actin filaments. , 1987, Blood.

[42]  J. Attia,et al.  Predictors of depression and anxiety in community dwelling stroke survivors: a cohort study , 2014, Disability and rehabilitation.

[43]  Y. Tsujimoto,et al.  Inhibition of apoptosis by the actin‐regulatory protein gelsolin , 1997, The EMBO journal.

[44]  E. Domenici,et al.  Early-life stress and antidepressants modulate peripheral biomarkers in a gene–environment rat model of depression , 2010, Progress in Neuro-Psychopharmacology and Biological Psychiatry.

[45]  P. Xie,et al.  Comparative proteomic analysis of plasma from major depressive patients: identification of proteins associated with lipid metabolism and immunoregulation. , 2012, The international journal of neuropsychopharmacology.

[46]  G. Utermann,et al.  Activation of lecithin: cholesterol acyltransferase by human apolipoprotein A-IV. , 1985, The Journal of biological chemistry.

[47]  B. Tavitian,et al.  In Vivo Evidence That the Increase in Matrix Metalloproteinase Activity Occurs Early after Cerebral Ischemia , 2012, Molecular imaging.

[48]  T. G. Clark,et al.  Fibrinogen Concentration and Risk of Ischemic Stroke and Acute Coronary Events in 5113 Patients With Transient Ischemic Attack and Minor Ischemic Stroke , 2004, Stroke.

[49]  D. Kardassis,et al.  Synergism between nuclear receptors bound to specific hormone response elements of the hepatic control region-1 and the proximal apolipoprotein C-II promoter mediate apolipoprotein C-II gene regulation by bile acids and retinoids. , 2003, The Biochemical journal.

[50]  G. Ferretti,et al.  Effect of human Apo AIV against lipid peroxidation of very low density lipoproteins. , 2002, Chemistry and physics of lipids.

[51]  D. Clair,et al.  Detection of complement factor B in the cerebrospinal fluid of patients with cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy disease using two-dimensional gel electrophoresis and mass spectrometry , 2000, Neuroscience Letters.

[52]  R. Hales,et al.  J Neuropsychiatry Clin Neurosci , 1992 .

[53]  J. Marler,et al.  Measurements of acute cerebral infarction: a clinical examination scale. , 1989, Stroke.

[54]  S. Yusuf,et al.  Risk factors for ischaemic and intracerebral haemorrhagic stroke in 22 countries (the INTERSTROKE study): a case-control study , 2010, The Lancet.

[55]  Temporal evolution of average apparent diffusion coefficient threshold to define ischemic abnormalities in a rat permanent occlusion model , 2000 .

[56]  I. Goldberg,et al.  Lipoprotein ApoC-II activation of lipoprotein lipase. Modulation by apolipoprotein A-IV. , 1990, The Journal of biological chemistry.

[57]  S. Orkin,et al.  Plasma and cytoplasmic gelsolins are encoded by a single gene and contain a duplicated actin-binding domain , 1986, Nature.

[58]  H. Koo,et al.  Refolding of the catalytic and hinge domains of human MT1-mMP expressed in Escherichia coli and its characterization. , 2002, Molecules and cells.

[59]  Jun Ma,et al.  The peripheral blood transcriptome dynamically reflects system wide biology: a potential diagnostic tool. , 2006, The Journal of laboratory and clinical medicine.

[60]  D. Kwiatkowski,et al.  Muscle is the major source of plasma gelsolin. , 1988, The Journal of biological chemistry.

[61]  Brad T. Sherman,et al.  DAVID: Database for Annotation, Visualization, and Integrated Discovery , 2003, Genome Biology.

[62]  P. Nawroth,et al.  Stress Mediators and Immune Dysfunction in Patients with Acute Cerebrovascular Diseases , 2013, PloS one.

[63]  D. Horrobin,et al.  Depression and bipolar disorder: relationships to impaired fatty acid and phospholipid metabolism and to diabetes, cardiovascular disease, immunological abnormalities, cancer, ageing and osteoporosis. Possible candidate genes. , 1999, Prostaglandins, leukotrienes, and essential fatty acids.

[64]  K. Mounzer,et al.  Relationship of admission plasma gelsolin levels to clinical outcomes in patients after major trauma. , 1999, American journal of respiratory and critical care medicine.

[65]  Edward T. Bullmore,et al.  Plasma Protein Biomarkers for Depression and Schizophrenia by Multi Analyte Profiling of Case-Control Collections , 2010, PloS one.

[66]  J. Vandekerckhove,et al.  Gelsolin and functionally similar actin‐binding proteins are regulated by lysophosphatidic acid , 1998, The EMBO journal.

[67]  M. King,et al.  The protective effects of plasma gelsolin on stroke outcome in rats , 2011, Experimental & Translational Stroke Medicine.

[68]  Jian-An Su,et al.  Cytokine changes in the pathophysiology of poststroke depression. , 2012, General hospital psychiatry.

[69]  R. Sacco.  Newer risk factors for stroke , 2001, Neurology.

[70]  K. Kobak,et al.  Hamilton Depression Rating Scale , 2010 .

[71]  P. Janmey,et al.  Inactivation of endotoxin by human plasma gelsolin. , 2005, Biochemistry.

[72]  M. Sentí,et al.  Lipoprotein and Apolipoprotein Profile in Men With Ischemic Stroke: Role of Lipoprotein (a), Triglyceride‐Rich Lipoproteins, and Apolipoprotein E Polymorphism , 1992, Stroke.

[73]  Jouko Lönnqvist,et al.  Assessment of Depression After Stroke: A Comparison of Different Screening Instruments , 2009, Stroke.

[74]  P. Tso,et al.  Apolipoprotein AIV: a potent endogenous inhibitor of lipid oxidation. , 1998, American journal of physiology. Heart and circulatory physiology.

[75]  B. Luo,et al.  Plasma gelsolin levels and 1-year mortality after first-ever ischemic stroke. , 2011, Journal of critical care.

[76]  C. Caltagirone,et al.  Neuropsychiatric symptoms and interleukin-6 serum levels in acute stroke. , 2013, The Journal of neuropsychiatry and clinical neurosciences.

[77]  M. Dinubile,et al.  Temporal association between serum gelsolin levels and clinical events in a patient with severe falciparum malaria. , 1997, Clinical infectious diseases : an official publication of the Infectious Diseases Society of America.

[78]  S. Crewther,et al.  Sustained inflammation 1.5 years post-stroke is not associated with depression in elderly stroke survivors , 2013, Clinical Interventions in Aging.

[79]  Peng Xie,et al.  Plasma metabonomics as a novel diagnostic approach for major depressive disorder. , 2012, Journal of proteome research.