Under normal circumstances inflammation is a natural, protective immune response to injury, infections, and oxidative stress that serves to facilitate healing. Yet, if left uncontrolled, inflammation can cause severe damage throughout the body, including in the central nervous system.
Inflammation is regulated by a range of mediators, including cytokines, which can be either pro-inflammatory, such as the interleukins 1 (IL-1), 2 (IL-2) and 6 (IL-6), tumour necrosis factor alpha (TNF-alpha), and interferon gamma (IFN- gamma), or anti-inflammatory, for example IL-4, IL-5 and IL-10.[1,2] Cytokines, together with a few selected inflammatory markers, such as C-reactive protein (CRP), are clinically used as biomarkers for inflammatory disease.
The role of altered cytokine profiles in psychiatric disorders, such as cognitive decline and depression, is supported in several lines of evidence.
Inflammation and cognitive decline
Ageing is naturally associated with decreases in cognitive function and a growing body of evidence suggests that age-related inflammation may contribute to these changes. Only one in 1000 older adults exhibit no evidence of cognitive deterioration.
While research has been conflicting regarding which inflammatory markers are most predictive of cognitive decline, findings have been generally consistent that overall inflammation and immune function are closely tied to cognitive function and may contribute to increased risk of cognitive decline and dementia.
In a longitudinal examination of inflammatory markers and global cognitive decline, participants in the highest tertile of IL-6 or CRP serum concentrations performed significantly worse at baseline and follow-up testing, with a 24% increased risk of cognitive decline over a two year period in comparison to those participants in the lowest tertile. A significant inverse relationship between executive function and visuospatial ability has also been related to serum CRP levels.
Moreover, researchers have demonstrated that older adults with lower levels of IL-6 and CRP are more likely to maintain their baseline levels of cognitive function (as opposed to decline) over an eight year follow-up period.
Oxidation, inflammation, and Nrf2
Like inflammation, oxidative stress has been increasingly recognised as a contributing factor in ageing and in various forms of pathophysiology generally associated with ageing.
Transcription factor Nrf2 (nuclear factor erythroid 2-related factor 2) plays a central role in the induction of cytoprotective genes in response to oxidative stress. Once activated, Nrf2 becomes a part of the Antioxidant Response Element (ARE) which is the master regulator of the antioxidant response. Nrf2 modulates the expression of hundreds of genes, including antioxidant enzymes (such as glutathione and superoxide dismutase) and phase 2 detoxification enzymes, as well as genes that control disparate processes such as immune and inflammatory responses.[6,8] Thus, the Nrf2-mediated signalling pathway provides a pivotal line of defence to counteract environmental insults and endogenous stressors.
A study on institutionalised older adults demonstrated pronounced oxidative stress, reduced antioxidant status, and high levels of pro-inflammatory cytokines. The elevated levels of inflammatory markers were correlated with increased oxidative stress, and both were associated with low cognitive performance.
Many studies have shown Nrf2 to be a promising target for the prevention of chronic inflammatory disorders, including cardiovascular disease, neurodegenerative diseases and carcinogenesis.
Who is at risk?
Given the strong association between cognitive decline and inflammation, it is important to identify those patients who are at increased risk of inflammation. While elevated inflammatory profiles occur with ageing even in the absence of disease, there are several factors that may increase inflammation levels beyond senescence.
For example, those with metabolic syndrome, diabetes, or obesity, are at heightened risk for innate and chronic inflammation.
Lifestyle factors such as poor diet, lack of physical exercise, inadequate sleep, and smoking can also increase systemic inflammation. An inflammatory dietary pattern characterised by higher intake of red meat, processed meat, peas and legumes, and fried foods, and lower intake of wholegrains correlates with elevated IL-6 levels. Researchers who followed more than 5000 participants between years 1991-2009 found that inflammatory eating habits are linked with faster cognitive decline after multivariable adjustment.
Other research shows that obesity and high fat feeding leads to systemic inflammation and is associated with a range of comorbidities, including cognitive dysfunction. Greater body mass has been indirectly associated with declines in memory and executive functioning via elevated levels of CRP.
Psychological stress is another important risk factor for cognitive loss. Stress can activate the immune response via the hypothalamic-pituitary-adrenal (HPA) axis, leading to the release of the stress hormone cortisol. High levels of cortisol may lead to memory deficits in healthy older adults. The pro-inflammatory cytokines IL-1 and TNF-alpha also stimulate the HPA axis, further contributing to stress-induced cognitive decline. Thus, it appears feasible that inflammation may mediate the effects of stress on cognitive function.
Psychological distress is also linked to inflammation. Findings from studies suggest that depressive symptoms are associated with increased pro-inflammatory cytokine profiles and that the level of cytokines corresponds to the severity of symptoms. Depression may also adversely influence cognitive function by affecting working memory, executive function, and processing speed.
Inflammation in mood disorders and depression
Patients with major depressive disorder (MDD) exhibit all of the fundamental features of an inflammatory response, including increased expression of pro-inflammatory cytokines. Meta-analyses of the literature suggest that peripheral blood IL-1 beta, IL-6, TNF-alpha and CRP are the most reliable biomarkers of increased inflammation in patients with anxiety and depression.[13,14] Other factors that support the role of inflammation in depression include:
- a large percentage of individuals with inflammatory illnesses struggle with depression
- elevated inflammatory markers are associated with MDD
- pro-inflammatory cytokines initiate a cascade of reactions that lower serotonin levels (via activation of the extrahepatic enzyme IDO, which degrades tryptophan, a precursor to serotonin)
- anti-inflammatory agents such as cyclooxygenase-2 (COX-2) inhibitors, aspirin, and TNF receptor antagonists can enhance depression treatments
- blockade of cytokines, such as TNF, or inflammatory pathway components, such as COX-2, has been shown to reduce depressive symptoms in patients with rheumatoid arthritis, psoriasis, cancer and MDD
- inhibition of inflammatory pathways can improve mood.
There also appears to exist a relationship between inflammation and treatment-resistant depression (TRD), which occurs in about one third of patients. Those who do not respond to standard antidepressant therapy tend to show an increased level of inflammatory markers. Patients with other neuropsychiatric disorders, including anxiety and schizophrenia, also present with elevated markers of inflammation.
Curcumin is derived from the rhizome of Curcuma longa (turmeric), a member of the ginger family. Curcumin is known to exhibit various therapeutic properties, including antioxidant and anti-inflammatory, which suggest a potential neuroprotective nature of this compound. The protective activity of curcumin may be mediated via several mechanisms, including:[16,17]
- modulation of pro-inflammatory cytokines, including TNF-alpha, IL-1 and IL-6
- inhibition of nuclear factor-kappa B (NF-kB), a major regulator of inflammatory mediators
- inhibition of lipoxygenase (LOX), COX-2, and iNOS expression, leading to decreased levels of prostaglandin E2 (PGE2) and nitric oxide
- induction of phase 2 antioxidant enzymes via activation of Nrf2 signalling.
Curcumin has been shown to exhibit activity against various neurological diseases, including age-associated neurodegeneration and depression, as well as Alzheimer’s disease, multiple sclerosis, schizophrenia, neuropathic pain, and cerebral injury. Even though clinical data is limited, epidemiological evidence from curcumin-consuming populations such as India shows that long term consumption of curcumin is slinked with a remarkably lower incidence rate of neurodegenerative cases.
Omega-3 fatty acids (krill and fish oils)
The healthy brain is highly enriched with the long-chain omega-3 fatty acids eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) and their derivatives, which serve to regulate several biochemical processes, including cell survival, neurotransmission, cell survival and neuroinflammation. Omega-3 fatty acids may provide a range of neurobiological activities via modulation of neurotransmitters, inflammation, oxidation and neuroplasticity.20 A body of evidence has implicated dietary deficiency in EPA/DHA in the aetiology and pathophysiology of numerous psychiatric disorders.
The anti-inflammatory effects of omega-3 fatty acids include:
- Inhibitory effects on arachidonic acid (AA) metabolism (competitive inhibition of COX and LOX favours the synthesis of anti-inflammatory prostaglandins (PGE3) and leukotrienes (LTB5) rather than their pro-inflammatory counterparts PGE2 and LTB4).
- Inhibitory effect on NFkB activation and pro-inflammatory cytokines, including TNF-alpha, IL-1beta, IL-6.
- Decreased CRP.
Omega-3 fatty acids in mood disorders
The antidepressant effect of fatty acids has been reported in a number of clinical trials. Insufficient DHA is associated with dysfunctional neuronal membrane stability and transmission of serotonin, noradrenalin and dopamine, which may contribute to the aetiology of mood and cognitive dysfunction of depression. In addition, the omega-3 fatty acids may be used as an adjunct to enhance the efficacy of standard treatment.
When omega-3 fatty acids were administered as a combination therapy with citalopram, a significantly greater improvement in Hamilton Depression Rating scale score was noted, suggesting that there may be an advantage to combining omega-3 fatty acids with a selective serotonin uptake inhibitors in the treatment of individuals with MDD.
Another study comparing the therapeutic effects of EPA (1000mg/day), fluoxetine and a combination of both in MDD, found that the combination was significantly better than either therapy alone. Interestingly, when taken alone, fluoxetine and EPA were similarly effective in controlling depressive symptoms; response rates were 50%, 56% and 81% in the fluoxetine, EPA and combination groups, respectively.
Omega-3 fatty acids support cognitive function
Higher intakes of essential fatty acids have been found beneficial for the ageing brain and may provide a novel strategy to maintain cognitive function into old age.[26-28]
It has been suggested that krill oil may be a superior source of omega-3 fatty acids in this cohort as its fatty acids are incorporated into phospholipids, leading to enhanced absorption and bioavailability, rather than fish oil in which the omega-3’s are present as triglycerides. However the difference in effect on cognitive function between phospholipid and triglyceride omega-3 storage has not been elucidated.
Improved cognitive performance has also been reported in healthy adults following supplementation with DHA, and a higher Omega-3 Index score has been associated with better information processing speeds and fewer errors of omission in healthy adolescent students. In children, increases in erythrocyte omega-3 fatty acids, specifically DHA, may improve literacy and behaviour in those with attention deficit hyperactivity disorder.
- Turner MD, Nedjai B, Hurst T, et al. Cytokines and chemokines: At the crossroads of cell signalling and inflammatory disease. Biochim Biophys Acta 2014;1843(11):2563-2582.
- Najjar S, Pearlman DM, Alper K, et al. Neuroinflammation and psychiatric illness. Journal of Neuroinflammation 2013;10(43).
- Simen AA, Bordner KA, Martin MP, et al. Cognitive dysfunction with aging and the role of inflammation. Ther Adv Chronic Dis 2011;2(3):175-195.
- Sartori AC, Vance DE, Slater LZ, et al. The impact of inflammation on cognitive function in older adults: Implications for health care practice and research. J Neurosci Nurs 2012;44(4):206-217.
- Yaffe K, Fiocco AJ, Lindquist K, et al. Predictors of maintaining cognitive function in older adults: the Health ABC Study. Neurology 2009;72(23):2029-2035.
- Hybertson BM, Gao B, Bose SK, et al. Oxidative stress in health and disease: The therapeutic potential of Nrf2 activation. Mol Asp Med 2011;32(4-6):234-246.
- Haschek WM, Rousseaux CG, Wallig MA (Eds). Haschek and Rousseaux’s handbook of toxicologic pathology, 3rd ed. Academic Press, 2013.
- Huang Y, Li W, Su Z-Y, et al. The complexity of the Nrf2 pathway: Beyond the antioxidant response. J Nutr Biochem 2015;26(12):1401-1413.
- Baierle M, Nascimento SN, Moro AM, et al. Relationship between inflammation and oxidative stress and cognitive decline in the institutionalized elderly. Oxid Med Cell Longev 2015;2015:804198.
- Ozawa M, Shipley M, Kivimaki M, et al. Dietary pattern, inflammation and cognitive decline: The Whitehall II prospective cohort study. Clin Nutr 2016. pii: S0261-5614(16)00035-2
- Miller AA, Spencer SJ. Obesity and neuroinflammation: a pathway to cognitive impairment. Brain Behav Immun 2014;42:10-21.
- Bourassa K, Sbarra DA. Body mass and cognitive decline are indirectly associated via inflammation among aging adults. Brain Behav Immun 2017;60:63-70.
- Miller AH, Raison CL. The role of inflammation in depression: from evolutionary imperative to modern treatment target. Nat Rev Immunol 2016:16;22-34.
- Friedrich MJ. Research on psychiatric disorders targets inflammation. JAMA 2014;312(5):474-476.
- Almond M. Depression and inflammation: Examining the link. Current Psychiatry 2013;12(6):24-32.
- Aggarwal BB, Harikumar KB. Potential therapeutic effects of curcumin, the anti-inflammatory agent, against neurodegenerative, cardiovascular, pulmonary, metabolic, autoimmune and neoplastic diseases. Int J Biochem Cell Biol 2009;41(1):40-59.
- Venigalla M, Gyengesi E, Munch G. Curcumin and apigenin – novel and promising therapeutics against chronic neuroinflammation in Alzheimer’s disease. Neural Regen Res 2015;10(8):1181-1185.
- Das L, Vinayak M. Long term effect of curcumin in restoration of tumour suppressor p53 and phase-II antioxidant enzymes via activation of nrf2 signalling and modulation of inflammation in prevention of cancer. PLoS One 2015;10(4):e0124000.
- Lee WH, Loo CY, Bebawy M, et al. Curcumin and its derivatives: their application in neuropharmacology and neuroscience in the 21st century. Curr Neuropharmacol 2013;11(4):338-378.
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- Gertsik L, Poland RE, Bresee C, et al. Omega-3 fatty acid augmentation of citalopram treatment for patients with major depressive disorder. J Clin Psychopharmacol 2012;32(1):61-64.
- Jazayeri S, Tehrani-Doost M, Keshavarz SA, et al. Comparison of therapeutic effects of omega-3 fatty acid eicosapentaenoic acid and fluoxetine, separately and in combination, in major depressive disorder. Aust N Z J Psychiatry 2008;42(3):192-198.
- Witte AV, Kerti L, Hermannstadter HM, et al. Long-chain omega-3 fatty acids improve brain function and structure in older adults. Cereb Cortex 2014;24(11):3059-3068.
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- Stonehouse W, Conlon CA, Podd J, et al. DHA supplementation improved both memory and reaction time in healthy young adults: a randomized controlled trial. Am J Clin Nutr 2013;97(5):1134-1143.
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