Animal Models May Help Researchers Understand the Biology of Delirium in Humans

Using animal models in research, especially rodents, to reveal the biology of delirium can serve as a valuable approach for understanding delirium in human patients, according to a new review paper published today in Alzheimer's & Dementia: The Journal of the Alzheimer's Association. The paper developed by the NIH-funded Network for Investigation of Delirium: Unifying Scientists (NIDUS) provides key recommendations to scientists studying delirium, which may serve to unify and guide the new and burgeoning field of delirium biology.

The first author of the paper, Preclinical and Translational Models for Delirium:  Recommendations for Future Research from the NIDUS Delirium Network, is Sarinnapha M. Vasunilashorn, Ph.D., Assistant Professor, Harvard Medical School, Harvard T.H. Chan School of Public Health, Division of General Medicine, Beth Israel Deaconess Medical Center, and a member of the Aging Brain Center Working Group at the Hinda and Arthur Marcus Institute for Aging Research at Hebrew SeniorLife.

“Delirium is a complex syndrome that requires careful study across multiple model systems (e.g., humans and animals) to understand what is happening at the cellular level of the brain and body,” said Dr. Vasunilashorn.  “There remains much room for growth in the field of delirium research. This research paper provides useful guidelines and suggestions to other scientists, with the overall goal of helping advance preclinical research for delirium,” she said.

Delirium is a clinical syndrome characterized by an acute decline in cognition, which can present as inattention, disorientation, lethargy or agitation, and perceptual disturbance. Delirium is common among older hospitalized patients, and can lead to poor outcomes, including prolonged hospital stays, deep psychological stress for patients and their families, functional decline, and Alzheimer’s and related dementias (ADRD).  In fact, a campaign to reduce delirium has been championed by this journal in the hope of reducing the burden of ADRD.  Delirium is also associated with death.  With in-hospital mortality rates for patients with delirium of 25–33 percent and annual health care costs in excess of $182 billion in the U.S. alone, delirium has garnered increasing attention as a worldwide public health and patient safety priority.

“This paper discusses the use of preclinical and translational animal models for delirium by addressing the current limitations in our understanding of the neurobiology of delirium. The authors discuss the promise (and limitations) of preclinical and translational models for delirium in advancing the current knowledge of delirium pathophysiology and informing the development of new prevention and treatment approaches,” said senior author Sharon K. Inouye, M.D., M.P.H., Director of the Aging Brain Center at the Marcus Institute and principal investigator of the NIDUS Delirium Network.    

Other key authors on this work include: Nadia Lunardi, M.D., Ph.D., University of Virginia (co-first author); Roderic Eckenhoff, M.D., Perelman School of Medicine at the University of Pennsylvania (co-senior author); Niccolo Terrando, Ph.D., Duke University (co-senior author); along with 13 interdisciplinary experts from institutions around the world.  

Funding is provided by National Institute on Aging: Grant No. R33AG071744 to the Network for Investigation of Delirium Unifying Scientists (NIDUS); K01AG057836 and Alzheimer’s Association: AARF-18-560786 and AARG-22-917342 to Dr. Vasunilashorn; and the International Society to Advance Alzheimer's Research and Treatment (ISTAART).

Additional Information  

In this paper, an expert panel of delirium researchers and animal model investigators outline key considerations in the development of preclinical and translational models for understanding delirium pathophysiology. This includes:

1. Given that delirium is a complex behavioral syndrome, it is impossible to adopt a single animal model that will perfectly mirror all aspects of human delirium. This paper makes the important distinction that animal models for (and not of) delirium should be the desired goal, achievable through using a set of cognitive and behavioral tests to identify features that resemble human delirium across several animal models (i.e., no single animal model for delirium will suffice).
2. From human studies, several promising biofluid, neurophysiologic, and electrophysiologic markers have emerged that point to the role of inflammation, as well as brain cellular stress and injury. To determine the directionality of the relationships of these markers with delirium, animal models can be used to validate and expand on the observations in human studies. 
3. As more knowledge of delirium is gained, animal models should become an integral part of a whole systems approach to investigating delirium neurobiology. Such approaches will combine multiple strategies across disciplines, providing that future advances in clinical medicine may become more readily available, and helping to improve the healthcare of older adults who experience delirium.

About The Aging Brain Center

The Aging Brain Center is dedicated to advancing medical knowledge about delirium and the interface between delirium and dementias, such as Alzheimer’s disease. Each year, more than 12 million older Americans develop delirium, an acute medical condition that presents as an abrupt confusion or a sudden change in cognitive abilities.  Long-term consequences of delirium include increased risks of death, dementia, and prolonged disability.  Delirium is especially common in patients with Alzheimer’s disease, and prevention of delirium in this group of patients is of critical importance.

About Hebrew SeniorLife  
Hebrew SeniorLife, an affiliate of Harvard Medical School, is a national senior services leader uniquely dedicated to rethinking, researching, and redefining the possibilities of aging. Hebrew SeniorLife cares for more than 3,000 seniors a day across six campuses throughout Greater Boston. Locations include: Hebrew Rehabilitation Center-Boston and Hebrew Rehabilitation Center-NewBridge in Dedham; NewBridge on the Charles, Dedham; Orchard Cove, Canton; Simon C. Fireman Community, Randolph; Center Communities of Brookline, Brookline; and Jack Satter House, Revere. Founded in 1903, Hebrew SeniorLife also conducts influential research into aging at the Hinda and Arthur Marcus Institute for Aging Research, which has a portfolio of more than $63 million, making it the largest gerontological research facility in the U.S. in a clinical setting. It also trains more than 1,000 geriatric care providers each year. For more information about Hebrew SeniorLife, visit our website or follow us on our blog, Facebook, Instagram, Twitter, and LinkedIn.