Delirium and Alzheimer disease: A proposed model for shared pathophysiology

Delirium and Alzheimer’s disease (AD) are frequent causes of cognitive impairment among older adults and share a complex relationship in that delirium and AD can occur independently, concurrently, and interactively – for example, delirium can alter the course of an underlying AD. Whether delirium is a marker of vulnerability to AD, unmasks unrecognized AD, accelerates preclinical AD, or itself can cause permanent neuronal damage and lead to AD is poorly understood, and addressing these issues is a high-priority focus in aging research1. In this paper, we propose a novel conceptual model (Figure 1) illustrating how biomarker studies might advance our understanding of the interrelationship of delirium and AD due to neuronal injury. We cite examples of potential neuronal injury biomarkers, their temporal trends, and how they fit within the framework of our model. Open in a separate window Figure 1. Conceptual model for the interrelationship between delirium and AD. Grey boxes indicate the baseline brain status (far left panel, BASELINE) delirium “state” (middle panels, ACUTE and CONVALESCENT), or outcome (far right panel, OUTCOME); white boxes indicate corresponding (hypothesized) biomarker level. Solid arrows indicate hypothesized pathways for development of delirium (gray),complicated delirium (black), or no delirium (white); dashed arrows indicate where exceptions can occur. 1This figure is intended to represent the most likely pathways for outcomes but there are exceptions. For example, a patient with a resilient brain (upper box, far left panel) could develop a severe delirium, if the delirium trigger was sufficiently noxious (lower box, second panel from left) and ultimately develop long-term cognitive decline or ADRD; likewise someone with a vulnerable brain (lower box, far left) who is resilient to the delirium trigger because of high cognitive reserve might develop a mild delirium (middle box, second panel from left) and go on to recover (upper box, far right panel) 1 Delirium can be triggered by a range of insultsincluding surgery, infections, hypoxia, metabolic abnormalities, stroke, drugs, or anesthetics, and these insults can vary in severity and duration 2 Abnormal risk biomarkers (at baseline) of a vulnerable brain might reflect inflammation, oxidative stress, or chronic neurodegeneration present at basal level 3 Abnormal biomarkers triggered by delirium mightreflect inflammation, alterations in neurotransmitter function, neuronal or microglial dysfunction, or neuronal death, or acceleration of underlying chronic processes. As biomarkers become increasingly abnormal, deliriumseverity may increase as well. 4 Abnormal end product (i.e., neuronal injury/cell death) biomarkers emerge in the convalescent phase when disease processes are sufficient during the acute phase to trigger neuronal injury. Note: This model will accommodate multiple putative biomarkers. For example, anemia can still be integrated into our conceptual model, as a risk or disease marker that is contributory along the pathway to neuronal injury. abbreviations: AD=Alzheimer’s disease; ADRD=Alzheimer’s disease and relateddementias; LTCD=long-term cognitive decline; MCI=mild cognitive impairment