presented in the 25th Cognitive Neuroscience Congress

1. CYTOKINES AND MENTAL
STATUS AT ICU
REZA NEJAT, M. D.,
ANESTHESIOLOGIST, FCCM,
FORMER ASSISTANT PROFESSOR, SBMU,
BAZARGANAN HOSPITAL,
TEHRAN, IRAN

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. 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. 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. 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. CYTOKINES AND MENTAL STATUS AT ICU
•Inflammatory signaling:
• a contributor to the short-
and long term modulation of
mood and cognition

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. 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. CYTOKINES AND MENTAL STATUS AT ICU
Cytokines

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. 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. 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. 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. 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. 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. CYTOKINES AND MENTAL STATUS AT ICU
•⇈ inflammatory mediators was shown in:
•PTSD (NF-κB)
•Panic attacks
•Obsessive-compulsive disorders
•Anxiety-related personality
dimensions

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. 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. 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. 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. 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. 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. 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. CYTOKINES AND MENTAL STATUS AT ICU
activation individual
cytokines
vs
activation a network of
cytokines

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. 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. 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. 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. 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. CYTOKINES AND MENTAL STATUS AT ICU
Cytokines
and
Delirium

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. 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. 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. 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. 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. 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. CYTOKINES AND MENTAL STATUS AT ICU

38. CYTOKINES AND MENTAL STATUS AT ICU
• ANY QUESTION?
• rezanejat.com
• icuaticu.com
• 2icuedu.com
• rezanejat@yahoo.com

39. CYTOKINES AND MENTAL STATUS AT ICU