Cholinergic deficiency hypothesis in delirium: a synthesis of current evidence

Tammy T Hshieh, Tamara G Fong, Edward R Marcantonio, Sharon K Inouye, Tammy T Hshieh, Tamara G Fong, Edward R Marcantonio, Sharon K Inouye

Abstract

Deficits in cholinergic function have been postulated to cause delirium and cognitive decline. This review examines current understanding of the cholinergic deficiency hypothesis in delirium by synthesizing evidence on potential pathophysiological pathways. Acetylcholine synthesis involves various precursors, enzymes, and receptors, and dysfunction in these components can lead to delirium. Insults to the brain, like ischemia and immunological stressors, can precipitously alter acetylcholine levels. Imbalances between cholinergic and other neurotransmitter pathways may result in delirium. Furthermore, genetic, enzymatic, and immunological overlaps exist between delirium and dementia related to the cholinergic pathway. Important areas for future research include identifying biomarkers, determining genetic contributions, and evaluating response to cholinergic drugs in delirium. Understanding how the cholinergic pathway relates to delirium may yield innovative approaches in the diagnosis, prevention, and treatment of this common, costly, and morbid condition.

Figures

Figure 1
Figure 1
Central cholinergic pathways overlap with locations of neuroimaging abnormalities in delirium brain studies. Positron emission tomography (PET) and single photon emission computed tomography (SPECT) studies on patients with delirium from hepatic encephalopathy, cardiotomy, and traumatic brain injury demonstrate abnormal perfusion in the same cortical, subcortical regions as cholinergic pathways. Cholinergic pathways are indicated by black arrows, locations of abnormal neuroimaging are shaded, brain regions involved in attention are textured.
Figure 2
Figure 2
Potential pathophysiological mechanisms for delirium. AD = Alzheimer’s disease; ApoE = apolipoprotein E; βA = β-amyloid; APP = amyloid precursor protein; Ach = acetylcholine; ChAT = choline acetyltransferase; AChE = acetylcholinesterase; IL-1 = interleukin-1; TNF-α = tumor necrosis factor-α; IGF-1 = insulin-like growth factor-1; CoA = coenzyme A; NAD+= nicotinamide adenine dinucleotide; NADP = nicotinamide adenine dinucleotide phosphate; CAC = citric acid cycle; GPCR = G-protein coupled receptor; Ca+2 = calcium; 5-HT = serotonin.
Figure 3
Figure 3
Relationship of stroke, traumatic brain injury, and diverse stressors to delirium. Schematic demonstration of potential pathophysiologic pathways linking stroke, traumatic brain injury and environmental, medical stressors with delirium. Ach = acetylcholine; ChAT = choline acetyltransferase; IGF-1 = insulin-like growth factor 1; CNS = central nervous system. *Represents one potential pathophysiologic pathway to delirium; other mechanisms exist.
Figure 4
Figure 4
Interactions between acetylcholine and other neurotransmitters in delirium. Schematic demonstration of how decreased acetylcholine levels in delirium alter levels of other neurotransmitters.

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