Clarifying the overlapping pathology of delirium and dementia

Project Summary Dementia is a leading cause of death in the United States and is associated with loss of quality of life and independence; it cannot be prevented, or cured. Delirium is a sudden state of confusion that is associated with increased morbidity and mortality and impaired long-term cognition. Both delirium and dementia are bereft of therapies, largely due to the limited understanding of their pathogeneses. The vulnerability of people with dementia to experience delirium offers a unique opportunity to understand their overlapping pathology and to identify new therapies. It has long been thought that changes in the neurotransmitter acetylcholine cause delirium, because drugs that inhibit acetylcholine can cause a state of confusion that resembles delirium. In Aim 1, we will measure electrical activity in the brain that is affected by acetylcholine. Demonstrating that changes in this electrical activity correspond with the onset and resolution of delirium would strengthen the cholinergic deficiency theory of delirium. However, changes in acetylcholine alone do not explain the various symptoms caused by delirium or why different people develop different symptoms. In Aim 2, we will determine whether changes in the neurotransmitter noradrenaline explain these differences, clarifying the overlapping pathology of delirium and dementia. Alzheimer’s disease and related dementias accumulate abnormal tau proteins in a small region of the brain called the locus coeruleus early in the disease. The locus coeruleus controls noradrenaline signaling throughout the brain, and plays important roles in arousal and attention. When severe inflammation stresses the body, damage to the locus coeruleus may lessen the release of noradrenaline and predispose the person to hypoactive delirium. On the other hand, in the absence of early dementia pathology a robust release of noradrenaline may predispose towards hyperactive delirium. Understanding the role of noradrenaline in these different types of delirium could guide new targeted therapies. Further, noradrenaline regulates metabolism in the brain by stimulating the release of lactate from astrocytes to support nearby neurons. Some regions of the brain are less able to respond to the effects of noradrenaline, potentially making them vulnerable to metabolic insufficiency. In Aim 2, we will determine whether these brain regions are vulnerable to delirium by measuring the location and severity of slow wave electrical activity across the brain. In Aim 3, we will determine whether these brain regions are vulnerable to injury and long-term damage following surgery. Again, understanding whether metabolic insufficiency contributes to delirium and long-term injury could guide targeted preventative therapies in vulnerable patients.