Inflammation, Delirium, Dementia and Ageing Brain Phenotypes: A Short Review and the Need for New Approaches to Explore Immune System Complexity

Ageing is associated with persisting systemic inflammation, both in chronic form and as delayed resolution after acute inflammatory illnesses. The clearest markers of this are raised blood concentrations of pro-inflammatory cytokines and other chemokines that are involved in mediating an inflammatory state, and C-reactive protein as general indicator of inflammation. This condition of “inflammaging” is linked causally in a complex and reciprocal manner with several diseases that are prevalent in older people including a tendency to develop delirium during acute perturbations of brain function, and to a predisposition to dementia and other age-associated neurodegenerative conditions. There is evidence of a key role of cytokines both in the aetiologies of such diseases and in the immune modulation processes that reduce inflammation, and evidence that interleukin-6 has a particularly complex effect depending on physiological and metabolic context. It is probable that the influence of cytokines on the central nervous system is directly mediated via receptors on neurons, microglial cells and astrocytes, rather than through secondary metabolic effects. The epigenetic mechanisms involved are starting to be understood. Though the descriptive phenomenology of inflammation has produced a large amount of information it is obviously, like the biochemistry of all living organisms, an extremely complex environment that cannot be described adequately using linear pathways, or even 3-dimensional models. To deal with the complexity, fluidity, stability, responses and fluctuations of immune chemistry it is proposed that a better grasp of immune system regulation, its responses to perturbation and its relationship with disease states and aging, including neuropathology, might be better progressed by using a multifactorial conditional logic approach, such as Boolean analysis. Such work will require an iterative collaboration between clinicians, molecular biologists, mathematicians and software engineers.