Probing Links Between Post-Op Delirium, Sleep and Dementia

Research at Massachusetts General Hospital shines a light on the biological and neurophysiological basis of postoperative delirium and its connection to Alzheimer's disease and related dementias. Seun Johnson-Akeju, MD, anesthetist-in-chief of the Department of Anesthesia, Critical Care and Pain Medicine at Massachusetts General Hospital and the Henry Isaiah Dorr associate professor of Research and Teaching in Anaesthetics and Anaesthesia at Harvard Medical School, is leading the Minimizing ICU Neurological Dysfunction with Dexmedetomidine-induced Sleep (MINDDS) Trial, which aims to discover biomarkers for postoperative delirium and uncover pathophysiological mechanisms underlying dementia.

Subscribe to the latest updates from Geriatrics & Palliative Care Advances in Motion

Thank you for subscribing!

Error: Please enter a valid email address.

Email Address Submit

"We hope that findings from the MINDDS cohort will aid the discovery of minimally invasive and cost-effective blood biomarkers for postoperative delirium, transform clinical research by permitting low-cost screening of patients at most significant risk, advance clinical care by suggesting pharmacological treatments, and importantly, to advance our understanding of the pathophysiological mechanisms underlying Alzheimer's disease and related dementias," he says.

Post-Operative Delirium: Risk Factors and Prevalence

The first successful public demonstration of the use of ether for surgical anesthesia took place at Mass General in 1846. In the nearly two centuries since, the field of anesthesiology has been integral to the evolution of modern medicine. While some patients seem to sail through anesthesia without issue, others develop a sudden onset of changes in mental processes following surgery or critical illness. This cognitive storm, known as postoperative delirium (confused thinking and reduced awareness), can cause lasting problems for those who experience it.

"Postoperative delirium is associated with loss of independence, increased duration of hospitalization, long-term cognitive deficits, and increased mortality," Dr. Johnson-Akeju says. Those challenges are difficult for patients and families at an individual level and are also associated with a significant economic burden. "The estimated costs that have been ascribed to postoperative delirium are upwards of $30 billion per year," he adds.

There are various risk factors for postoperative delirium, including older age, frailty, depression, poor nutrition and preexisting cognitive impairment. Females are also more likely than males to experience postoperative delirium. "Depending on the patient population, postoperative delirium may affect 10% to as many as 50% of patients after surgery," Dr. Johnson-Akeju says.

Previous research has pointed toward ways to prevent postoperative delirium. "Many studies have demonstrated the benefits of multi-component approaches to minimize the incidence of delirium. They include factors such as addressing visual and hearing impairments, noise, poor sleep hygiene, immobility and dehydration," Dr. Johnson-Akeju says.

Yet while those multi-component approaches have been shown to reduce the burden of delirium, their impact on patients' long-term cognitive function remains unclear. "We do not have a magic pill that can treat or prevent delirium," he adds.

MINDDS Trial Explores the Sleep-Delirium Connection

In the MINDDS trial, Dr. Johnson-Akeju and his colleagues are zeroing in on the role of sleep. "Sleep is a natural state of decreased arousal that is likely important for various functions, including information processing and memory, clearing toxins from the brain, physical restoration, mood regulation, cardiovascular health, immune regulation and much more," he says.

There's also evidence that it affects delirium risk. In an analysis of more than 321,000 patients from the UK Biobank, Lei Gao, MBBS, a Mass General anesthesiologist and scientist, found that poor sleep in middle-aged and older adults was associated with an increased risk of postoperative delirium. Their study, published in The Journals of Gerontology: Series A, found those with moderately poor sleep were 18% more likely to develop delirium. In comparison, those with severely poor sleep burden were 57% more likely—a risk magnitude equivalent to two additional cardiovascular risks.

To better understand the role of sleep in postoperative delirium, participants in the MINDDS trial received a small dose of the intravenous medication dexmedetomidine, which has been shown to mimic the neurophysiology of natural sleep. "The premise of the MINDDS trial is to study whether biomimetic sleep can reduce the incidence of delirium," he says.

Approximately 400 patients were recruited for the trial, all adults over 60 who received elective major cardiac surgery at Mass General. The patients underwent cognitive assessments and donated various biological samples to further the study of postoperative delirium. While exploring a link between sleep and delirium was a primary goal, the researchers also examined the impact of surgery on pain, mood, sleep habits, physical function and cognition at 30, 90 and 180 days after surgery.

Associations Between Post-Operative Delirium and Dementia

The study also investigates the association between postoperative delirium and dementia, including Alzheimer's disease. Previous work has suggested that postoperative delirium is linked to accelerated cognitive decline. "We are trying to decipher whether this relationship is causal or whether postoperative delirium represents an unmasking of latent pathophysiology underlying Alzheimer's disease and related dementias," Dr. Johnson-Akeju says.

Clues may come from the study of tau proteins, which play a role in maintaining the stability of axonal microtubules. It's well known that Alzheimer's disease and related dementias are associated with hyperphosphorylated tau that aggregates into tangles in the brain. Researchers including Dr. Johnson-Akeju have found that postoperative delirium is also associated with increased levels of tau that can be detected in the blood, as he and his colleagues described in a study published in the British Journal of Anaesthesia.

"The findings suggest a mechanistic link between postoperative delirium and tau, upstream of tau hyperphosphorylation and cortical aggregation of these tau isoforms," he says. "We are currently using biological samples from the large, unique and deeply phenotyped MINDDS patient cohort to understand better the molecular mechanisms underlying postoperative delirium."

Dr. Johnson-Akeju and his colleagues recently completed collecting data from MINDDS study participants and are analyzing their findings. Meanwhile, his Neuroanesthesia Research Laboratory is continuing related lines of research to develop tools and strategies to optimize postoperative cognitive recovery.

Dr. Johnson-Akeju says Mass General and the Department of Anesthesia are marked by an intellectually rich environment and culture of excellence, which drew him to train and, later, to practice there. As anesthetist-in-chief since 2020, he hopes to continue to foster a culture of world-class research grounded in clinical care.

"Mass General is the ideal place to conduct this research, given our institutional focus on the brain health of our patients, especially older patients," he says. "These studies promise to lend fundamental new insights into how our brains function."

Learn more about the Department of Anesthesia, Critical Care and Pain Medicine

Explore research in the Neuroanesthesia Research Laboratory