Inflammation, Depression and Dementia: Are they Connected?

Department of Psychiatry and Neuropsychology, Brain and Behaviour Research Institute, University of Maastricht, Maastricht, The Netherlands.
Neurochemical Research (Impact Factor: 2.59). 11/2007; 32(10):1749-56. DOI: 10.1007/s11064-007-9385-y
Source: PubMed


Chronic inflammation is now considered to be central to the pathogenesis not only of such medical disorders as cardiovascular disease, multiple sclerosis, diabetes and cancer but also of major depression. If chronic inflammatory changes are a common feature of depression, this could predispose depressed patients to neurodegenerative changes in later life. Indeed there is now clinical evidence that depression is a common antecedent of Alzheimer's disease and may be an early manifestation of dementia before the cognitive declines becomes apparent. This review summarises the evidence that links chronic low grade inflammation with changes in brain structure that could precipitate neurodegenerative changes associated with Alzheimer's disease and other dementias. For example, neuronal loss is a common feature of major depression and dementia. It is hypothesised that the progress from depression to dementia could result from the activation of macrophages in the blood, and microglia in the brain, that release pro-inflammatory cytokines. Such cytokines stimulate a cascade of inflammatory changes (such as an increase in prostaglandin E2, nitric oxide in addition to more pro-inflammatory cytokines) and a hypersecretion of cortisol. The latter steroid inhibits protein synthesis thereby reducing the synthesis of neurotrophic factors and preventing reairto damages neuronal networks. In addition, neurotoxic end products of the tryptophan-kynurenine pathway, such as quinolinic acid, accumulate in astrocytes and neurons in both depression and dementia. Thus increased neurodegeneration, reduced neuroprotection and neuronal repair are common pathological features of major depression and dementia. Such changes may help to explain why major depression is a frequent prelude to dementia in later life.

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    • "Collectively, such overlap suggests shared factor(s) which may contribute to common MDD and AD pathogeneses[3]. For example, mounting evidence suggests that neuroinflammation-induced dysfunction of neurotransmission, neuronal apoptosis and/or reduction of neurogenesis may be potential shared risk factors for both diseases[3]. In line with this, proinflammatory cytokine IL-1β plays a critical role in both MDD and AD[27], and its genetic variance can increase the risk of clinical AD onset[28]. "
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    • "In short, what is the difference between a statistically significant and a biologically significant concentration? These aspects have been briefly discussed elsewhere (Leonard, 2007a). "
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    ABSTRACT: Cytokines are pleiotropic molecules with important roles in inflammatory responses. Pro-inflammatory cytokines and neuroinflammation are important not only in inflammatory responses but also in neurogenesis and neuroprotection. Sustained stress and the subsequent release of pro-inflammatory cytokines lead to chronic neuroinflammation,which contributes to depression. Hippocampal glucocorticoid receptors (GRs) and the associated hypothalamus–pituitary–adrenal (HPA) axis have close interactionswith pro-inflammatory cytokines and neuroinflammation. Elevated pro-inflammatory cytokine levels and GR functional resistance are among the most widely investigated factors in the pathophysiology of depression. These two major components create a vicious cycle. In brief, chronic neuroinflammation inhibits GR function, which in turn exacerbates pro-inflammatory cytokine activity and aggravates chronic neuroinflammation. On the other hand, neuroinflammation causes an imbalance between oxidative stress and the anti-oxidant system, which is also associated with depression. Although current evidence strongly suggests that cytokines and GRs have important roles in depression, they are essential components of a whole system of inflammatory and endocrine interactions, rather than playing independent parts. Despite the evidence that a dysfunctional immune and endocrine system contributes to the pathophysiology of depression, much research remains to be undertaken to clarify the cause and effect relationship between depression and neuroinflammation.
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    • "Cognitive reserve is the concept that was first proposed to account for observed individual differences in levels of neuropathology and corresponding cognitive functioning, and is thought to be the consequence of engagement in cognitively stimulating activities across the lifespan (for reviews see Nucci et al. 2011; Richards and Deary 2005; Richards and Sacker 2003; Sánchez Rodríguez et al. 2011; Stern 2009; Tucker and Stern 2011; Whalley et al. 2006). As several researchers have proposed that there may be a shared underlying mechanism for both dementia and depression in later life (Byers and Yaffe 2011; Korczyn and Halperin 2009; Leonard 2007), cognitive reserve may also help to protect against the experience of depressive symptoms and depressive thoughts. In Paulson et al. (2014), a higher level of education was protective against the negative effects of cerebrovascular burden on levels of depressive symptoms at baseline. "
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