Inflammatory Biomarkers and Neurotransmitter Perturbations in Delirium

Abstract

Delirium is an acute neuropsychiatric syndrome characterized by acute changes in cognition (e.g., perceptual distortions, impairment in abstract thinking, memory impairment, disorientation), psychomotor alterations (e.g., hyper- or hypoactivity), disturbances in the circadian sleep-wake cycle, emotional disturbance (e.g., irritability, anger, fear, anxiety, perplexity), and altered level of consciousness and attention (e.g., reduced ability to direct, focus, sustain, and shift attention). Delirium’s prevalence surpasses that of all other psychiatric syndromes in every medical unit in which it has been studied, from the general medical setting (between 15% and 60%), among the elderly admitted to a general hospital (between 6% and 46%), in the postoperative setting (between 10% and 74%), and in up to 87% of critically ill patients in the intensive care units. Delirium is a neurobehavioral syndrome caused by the transient disruption of normal neuronal activity secondary to systemic disturbances. Over the years, multiple theories have been proposed to explain the processes leading to the development of delirium. Most of these theories are complementary, rather than competing, as there is significant interdependence among most of them (see Fig. 10.1). It is likely that none of the previously postulated theories by itself explains the phenomena of delirium but rather that a multitude of them act together to lead to the biochemical derangement we know as delirium. The latest such theory is the Systems Integration Failure Hypothesis (SIFH) which proposes that individuals have varying degrees of non-modifiable factors, or substrates, and that this “load” will determine the basic frailty of the system in an inverse relationship with acute “precipitants and modifiable” factors (e.g., infection and inflammation, sleep deprivation, trauma, surgery, hypoxia, medication use, substances of abuse, organ failure, electrolyte imbalance, metabolic derangement). Ultimately, the SIFH proposes that the specific combination of neurotransmitter dysfunction and the variability in integration and appropriate processing of sensory information and motor responses, as well as the degree of breakdown in cerebral network connectivity, directly contributes to the various cognitive and behavioral changes and clinical motoric phenotype observed in delirium. There are a number of patient-specific physiological characteristics that serve as substrate to the development of delirium (Fig. 10.2). Of these, this article will focus on neuroinflammation as a substrate for delirium and its relationship to the development of specific neurotransmitter perturbations characteristic of the syndrome of delirium.