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Cytokines and mental status at icu

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presented in the 25th Cognitive Neuroscience Congress

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Cytokines and mental status at icu

  1. 1. CYTOKINES AND MENTAL STATUS AT ICU REZA NEJAT, M. D., ANESTHESIOLOGIST, FCCM, FORMER ASSISTANT PROFESSOR, SBMU, BAZARGANAN HOSPITAL, TEHRAN, IRAN
  2. 2. CYTOKINES AND MENTAL STATUS AT ICU •Inflammation: •An essential evolutionary conserved physiological surviving process against infection and injury which helps to preserve and restore tissue homeostasis.
  3. 3. CYTOKINES AND MENTAL STATUS AT ICU •Inflammation has been figured out to be the common mechanism in many disorders: • Cardiac, Cancer, DM,… •Neuropsychiatric disorders: • Neurodegenerative • Mood and anxiety • Schizophrenia
  4. 4. CYTOKINES AND MENTAL STATUS AT ICU Inflammation is associated with a range of depression symptoms: tiredness, lack of energy, sleep problems, changes in appetite cognitive and emotional symptoms anhedonia, depressed mood, feelings of self-worth, concentration problem, suicidal ideation
  5. 5. CYTOKINES AND MENTAL STATUS AT ICU Patients with sepsis may acquire neurological damage during hospitalization through: Cerebral ischemia, Metabolic derangements, Neuro-inflammation Sepsis: an independent risk factor of stress disorders after critical illness
  6. 6. CYTOKINES AND MENTAL STATUS AT ICU •Inflammatory signaling: • a contributor to the short- and long term modulation of mood and cognition
  7. 7. CYTOKINES AND MENTAL STATUS AT ICU •Inflammatory response (innate): •Production of signaling molecules: • Cytokines, chemokines, •Release of acute phase reactants and more signaling molecules
  8. 8. CYTOKINES AND MENTAL STATUS AT ICU CNS dysfunction during systemic infection: sickness behavior, Delirium, septic encephalopathy, Pathogenesis, the key element: the systemic production of pro-inflammatory cytokines: TNF-a and IL-1β, BBB cytokine transport systems; likely to play a role in the passage of these signals
  9. 9. CYTOKINES AND MENTAL STATUS AT ICU Cytokines
  10. 10. CYTOKINES AND MENTAL STATUS AT ICU • Cytokines: • Not small (60-70kDa), non-structural secreted proteins or small glycoprotein (<200 AA) released by many tissues, as well as brain parenchymal and endothelial cells, • Contribute to many intercellular pathways, regulating inflammatory and immunological responses through mediating complex interactions between: • hematopoietic cells, • lymphoid cell, • pro-inflammatory and anti-inflammatory cells
  11. 11. CYTOKINES AND MENTAL STATUS AT ICU In health, cytokines: Make the brain alert of eruption of immune responses to peripheral inflammatory processes: infection, injury, diseases by signaling an immuno- neuropsychiatric (INP) cascade of events.
  12. 12. CYTOKINES AND MENTAL STATUS AT ICU • Cytokines participate in the modulation of the Central Nervous System (CNS) physiology and behavior: • cognition • memory modulation • temperature regulation, • appetite, • drinking, • analgesia, • release of hormones from the hypothalamus, • locomotor activity
  13. 13. CYTOKINES AND MENTAL STATUS AT ICU three different groups of Cytokines: Pro-inflammatory: those that help launch the immune response (IL-1, IL-6, and TNF); Anti-inflammatory: those that block or dampen the immune response (IL-4, IL-10, and IL-3); Hematopoietic: those involved in stimulating the differentiation of hematologic progenitor cells into red and white blood cells (IL-3, IL-5, and G-CSF)
  14. 14. CYTOKINES AND MENTAL STATUS AT ICU •Activating inflammatory response may provoke neuropsychiatric disorders: • IFN-α (in hepatitis C and cancer) • Depression and anxiety, • ameliorated with SSRI. • Administration of endotoxin or typhoid vaccination to healthy volunteers: • symptoms of depression and anxiety
  15. 15. CYTOKINES AND MENTAL STATUS AT ICU •a subpopulation of patients with major depression exhibit features of: • ⇈ inflammatory cytokines: • Blood and CSF: • (IL-6, TNF-α, CRP, among the others) • ⇈ blood level of : • Acute phase reactant, • Chemokines • Adhesion molecules
  16. 16. CYTOKINES AND MENTAL STATUS AT ICU •⇈ inflammatory mediators was shown in: •PTSD (NF-κB) •Panic attacks •Obsessive-compulsive disorders •Anxiety-related personality dimensions
  17. 17. CYTOKINES AND MENTAL STATUS AT ICU • Inhibition of inflammatory cytokines ameliorates depression and anxiety: • Etanercept (anti-cytokine) • improvement of depressive symptoms • Infliximab (anti-cytokine) • Reducing depression and anxiety in patients with high CRP • acetylsalicylic acid (anti-inflammatory agents) • antidepressant efficacy
  18. 18. CYTOKINES AND MENTAL STATUS AT ICU • CNS cytokines: • regulate the production of other cytokines, • alter the BBB, • recruit inflammatory cells, • influence neurotransmitter metabolism • monoamines, serotonin, dopamine and glutamate
  19. 19. CYTOKINES AND MENTAL STATUS AT ICU •IL-1β, IL-6 and TNFα (after manipulations in the periphery or brain): • strongly expressed in the hippocampus • well placed to modulate memory
  20. 20. CYTOKINES AND MENTAL STATUS AT ICU • IL-1β: • is required for hippocampal dependent plasticity and learning • chronic overexpression in the hippocampus: • leads to impairments of spatial memory and context fear conditioning! (age dependent) • application: (age dependent) • impairs induction and maintenance of LTP • induces deficit in hippocampal memory processes.
  21. 21. CYTOKINES AND MENTAL STATUS AT ICU • TNF-α: • overexpression in neurons or glial cells impairs: • passive avoidance memory, • synaptic plasticity, • cerebellar learning • mediates memory deficits after chronic LPS administration
  22. 22. CYTOKINES AND MENTAL STATUS AT ICU • TNF-α: • Controls the glial regulatory pathway: • cognitive circuits and function are modulated by gliotransmitters released by astrocytes. • exerts additional controls at hippocampal synapses, such as on trafficking of AMPA and GABA Habbas et al. Cell. 2015; 163: 1730–1741
  23. 23. CYTOKINES AND MENTAL STATUS AT ICU • IL-6: • Shows similar effects like TNF-α in learning and plasticity; • limits the plasticity during memory formation even in the absence of inflammation • Overexpression or application cause: • cognitive dysfunction, • broad memory impairments, • diminished LTP; learning • In stroke, plays role in the onset of: • apathetic-amotivational and loss of appetite and sleep disorders.
  24. 24. CYTOKINES AND MENTAL STATUS AT ICU activation individual cytokines vs activation a network of cytokines
  25. 25. CYTOKINES AND MENTAL STATUS AT ICU •IL-1β, TNF-α, and IL-6: • play a role in the modulation of memory • sometimes in a contradictory manner: • IL-1β both enhances and impairs context fear conditioning!!
  26. 26. CYTOKINES AND MENTAL STATUS AT ICU •IL-1β, TNF-α, and IL-6: • exert their effects directly and at the same time indirectly via network of inflammatory signaling: • IL-1β: • does not increase in isolation, • leads to increases in TNFα, IL-6, IL-1 family proteins, and cytokine receptors across multiple brain regions • TNF-α or IL-6 may change the expression of other inflammatory cytokines
  27. 27. CYTOKINES AND MENTAL STATUS AT ICU • Cytokines in pregnancy and neurocognitive disorder: • higher TNF-α and lower IL-8 throughout 2nd and 3rd trimesters were associated with poorer age 7 neurocognitive functioning: • Higher TNF-α: • lower IQ, poorer cognitive performance, and higher problem scores related to visual-motor maturity, • Lower levels of IL-8: • poorer scores for cognitive performance and motor function.
  28. 28. CYTOKINES AND MENTAL STATUS AT ICU • cytokines in the brain are not limited to: • IL-1β, TNF-α, and IL-6 • these may regulate the expression of others: • IL-4, IL-10 • Chemokines: • macrophage inflammatory protein (MIP-2, CXCL2), • monocyte chemotactic protein (MCP-1, CCL2), • karatinocyte derived cytokine (KC; CXCL1) • growth factors: • NGF, BDNF
  29. 29. CYTOKINES AND MENTAL STATUS AT ICU • IL-4 and IL-10: • alleviate the deleterious impact of inflammatory processes on memory and plasticity • can abrogate learning and memory deficits in inflammatory models of Alzheimer’s disease
  30. 30. CYTOKINES AND MENTAL STATUS AT ICU Cytokines and Delirium
  31. 31. CYTOKINES AND MENTAL STATUS AT ICU • Delirium and cytokines: • The cytokines, along with producing symptoms of fever, weakness, and lethargy, cause: • impaired concentration, • sleep disturbances, • agitation, • some of the cardinal symptoms of delirium.
  32. 32. CYTOKINES AND MENTAL STATUS AT ICU • Delirium and cytokines: • In the elderly: • microglia show a more reactive phenotype; release increased quantities of cytokines in the brain after peripheral stimulation. • microglial response may be less well- regulated due to reduced cholinergic feedback
  33. 33. CYTOKINES AND MENTAL STATUS AT ICU • Delirium and cytokines: • Acetylcholine may inhibit the release of pro- inflammatory cytokine IL-6 • depleted acetylcholine stores may predispose to delirium
  34. 34. CYTOKINES AND MENTAL STATUS AT ICU • Delirium and cytokines: • cytokines may induce a reduction in cholinergic activity; • repetitive cycle of inadequate regulation of inflammation due to cholinergic depletion
  35. 35. CYTOKINES AND MENTAL STATUS AT ICU •Cytokines: • play a role in symptoms of dementia, • are dysregulated in: • dementia, • psychiatric disorders in the cognitively normal population.
  36. 36. CYTOKINES AND MENTAL STATUS AT ICU • Cytokines: • are either neuroprotective or destructive, • display feed back loops: • either inhibit or stimulate their own release or that of other cytokines, • exerted effects is dependent upon the particular tissue or situation • This complexity explains the complexities that neuroimmunological research encounters.
  37. 37. CYTOKINES AND MENTAL STATUS AT ICU
  38. 38. CYTOKINES AND MENTAL STATUS AT ICU • ANY QUESTION? • rezanejat.com • icuaticu.com • 2icuedu.com • rezanejat@yahoo.com
  39. 39. CYTOKINES AND MENTAL STATUS AT ICU

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