Systemic inflammation and delirium: important co-factors in the progression of dementia

Abstract

It is widely accepted that inflammation plays some role in the progression of chronic neurodegenerative diseases such as AD (Alzheimer's disease), but its precise role remains elusive. It has been known for many years that systemic inflammatory insults can signal to the brain to induce changes in CNS (central nervous system) function, typically grouped under the syndrome of sickness behaviour. These changes are mediated via systemic and CNS cytokine and prostaglandin synthesis. When patients with dementia suffer similar systemic inflammatory insults, delirium is a frequent consequence. This profound and acute exacerbation of cognitive dysfunction is associated with poor prognosis: accelerating cognitive decline and shortening time to permanent institutionalization and death. Therefore a better understanding of how delirium occurs during dementia and how these episodes impact on existing neurodegeneration are now important priorities. The current review summarizes the relationship between dementia, systemic inflammation and episodes of delirium and addresses the basic scientific approaches currently being pursued with respect to understanding acute cognitive dysfunction during aging and dementia. In addition, despite there being limited studies on this subject, it is becoming increasingly clear that infections and other systemic inflammatory conditions do increase the risk of AD and accelerate the progression of established dementia. These data suggest that systemic inflammation is a major contributor to the progression of dementia and constitutes an important clinical target.

Figure 1. Systemic inflammation, delirium and cognitive decline

a) It is well established that systemic inflammation in those with dementia frequently leads to delirium. b) It is also established that delirium in demented patients tends to exacerbate disease progression. c) Thus insults that often trigger delirium may accelerate disease, in the presence or absence of the delirious episode. However, little research has addressed this scenario.

Figure 2. Systemic inflammatory events may trigger delirium and contribute to pathological burden

a) Systemic inflammatory events trigger the release of inflammatory mediators by tissue macrophages and brain vascular endothelial cells. These mediators may impact on neuronal function directly, or via the activation of microglial cells that have become primed by neurodegenerative disease or aging. Inflammatory mediators may cause reversible disruption of neuronal function, perhaps resulting in delirium. These mediators may also induce acute neuronal synaptic or dendritic damage that may be reversible and contribute to delirium or may be irreversible and contribute to long-term cognitive decline. These inflammatory mediators can also bring about neuronal death acutely and these changes are obviously irreversible and contribute to the accumulating damage and neuropathological burden. Thus acute and long-term cognitive effects are likely to occur by both overlapping and distinct mechanisms. b) Successive systemic inflammatory insults induce acute dysfunction, which is progressively less reversible each time, but also contribute to the progression of permanent disability (adapted from Field et al., 2010 (ref 23)). Abbreviations: IL-1β: interleukin 1β; IL-1RI: interleukin 1 receptor type I; TNF-α: tumour necrosis factor α; TNFp55: TNF p55 receptor; IL-6: interleukin 6; GCs: glucocorticoids; GR: glucocorticoid receptor; NO: nitric oxide; PGE2: prostaglandin E2, EP1-4: prostaglandin receptors 1-4; PAMPs: pathogen associated molecular patterns; IFNα/β, interferons a and b; SIEs: systemic inflammatory events.