Researchers have identified a key biological link between postoperative delirium and long-term dementia, and they have found that an existing cancer drug may reverse the harmful brain changes involved. The discovery offers a potential path to protecting older patients from cognitive decline after major surgery.
In studies on aged mice, scientists found that the combined stress of anesthesia, surgery, and intensive care altered gene activity in the brain. These changes disrupted memory formation and the internal biological clock, producing cognitive impairment and sleep disturbances closely resembling postoperative delirium in humans. The condition affects an estimated 7 million hospitalized Americans each year and is linked to up to $152 billion in healthcare costs, according to the American Delirium Society.
The key breakthrough came when researchers administered vorinostat, an FDA-approved drug already used for certain T-cell lymphomas, before exposing the mice to surgical stress. Treated mice showed improved neuronal structure, better memory performance, and restored function in genes tied to learning and circadian rhythm. They also experienced fewer delirium-like symptoms and more normal sleep patterns compared to untreated mice.
The study, published in the journal Alzheimer's & Dementia, identified two “epigenetic” mechanisms that control whether genes are switched on or off. The stress of surgery left a molecular imprint on the brain through these pathways, impairing its ability to form new memories and regulate healthy sleep. This helps explain why postoperative delirium is a strong risk factor for later dementia, a connection that had previously remained unclear.
“Postoperative delirium affects millions of older adults worldwide and is associated with longer hospital stays, increased complications and a greater risk of subsequent cognitive decline,” said Dr. Nadia Lunardi, chief of neuroanesthesia at UVA Health and a senior author of the study. “By identifying reversible biological changes associated with surgery and intensive care, we hope this work will pave the way for new strategies to prevent the condition and reduce the risk of long-term cognitive decline in vulnerable older patients.”
While delirium can strike at any age, it is most common in older and frail patients. The team’s findings suggest that targeting these epigenetic pathways could offer both preventive and therapeutic benefits. The fact that vorinostat reversed the harmful changes in mice is particularly promising, as the drug is already approved for human use, which could accelerate the path to clinical trials.
The researchers are now using advanced single-cell technologies to determine how specific brain cell populations respond to perioperative stress. “These studies will help us identify the precise cell-specific mechanisms driving postoperative delirium and guide the development of more targeted therapeutic strategies,” said Dr. Hari Prasad Osuru, a research scientist involved in the study. “Ultimately, our goal is to translate these discoveries into interventions that prevent postoperative delirium, improve recovery after surgery, preserve long-term brain health and reduce the risk of cognitive decline in vulnerable older patients.”
The research was supported by the National Institutes of Health, and the team plans to continue investigating whether vorinostat or similar drugs could one day be used to safeguard brain health in human patients facing major surgery.