Exploring the Pathophysiology of Delirium: An Overview of Biomarker Studies, Animal Models, and Tissue-Engineered Models

Abstract

Delirium is an acute brain disorder associated with disorganized thinking, difficulty focusing, and confusion that commonly follows major surgery, severe infection, and illness. Older patients are at high risk for developing delirium during hospitalization, which may contribute to increased morbidity, longer hospitalization, and increased risk of institutionalization following discharge. The pathophysiology underlying delirium remains poorly studied. This review delves into the findings from biomarker studies and animal models, and highlights the potential for tissue-engineered models of the brain in studying this condition. The aim is to bring together the existing knowledge in the field and provide insight into the future direction of delirium research.

Figure 1.

General methodology proposed for studying delirium starting from a human clinical population to downstream mechanistic studies using in vitro and in vivo models. (Abbreviations: Alzheimer’s Disease and Related-Dementias (ADRD); clustered regularly interspaced short palindromic repeats/CRISPR-associated protein 9 (CRISPR-Cas9); electroencephalography (EEG); induced-pluripotent stem cell (iPSC); small interfering RNA (siRNA).

Figure 2.

In vitro models to study cellular mechanisms involved in delirium. (A) Derivation of disease-specific neural cell types via reprogramming of somatic cells to induced pluripotent stem cell (iPSC) intermediates or directly via transdifferentiation to generate cortical neurons, astrocytes, and microglial cells. Schematics partly derived from Servier Medical Art, provided by Servier, licensed under a Creative Commons attribution license. (B) Neural organoids derived from iPSCs and formed embryoid bodies (EB). Image re-produced from under a Creative Commons attribution license. (C) Microfluidic blood-brain barrier model generated with a chip design and human brain vascular pericytes (hBVPs), human astrocytes (hAs), and human brain microvascular endothelial cells (hBMECs). Image re-produced from under a Creative Commons attribution license.