A medication already used for cancer treatment has helped scientists uncover a potential reason why some seniors experience severe confusion after surgery. In studies with older mice, this drug reversed several brain changes associated with memory issues and disrupted sleep patterns.
This research could eventually lead to a better understanding of postoperative delirium, a sudden confusion that often occurs following surgical procedures. Delirium is common in hospitals and particularly affects older adults.
Patients with delirium might suddenly struggle to focus or understand their surroundings. They may become unusually drowsy, agitated, scared, or confused, with symptoms that can fluctuate significantly within a single day. Unlike most types of dementia, which tend to develop gradually over months or years, delirium develops rapidly—often as the brain responds to illness, medication, surgery, or physical stress.
While many recover from delirium, the condition isn’t always harmless once symptoms subside. Studies have shown links between delirium and prolonged hospital stays, increased complications, and a higher risk of long-term declines in memory and cognitive abilities. Researchers have long debated whether delirium simply reveals pre-existing brain vulnerabilities or if the experience itself causes lasting damage.
To explore this, scientists at UVA Health focused on aged mice. Led by Dr. Nadia Lunardi, chief of neuroanesthesia, and research scientist Dr. Hari Prasad Osuru, they simulated the effects of anesthesia, surgery, and stress—trying to mimic conditions experienced in intensive care. They then analyzed changes within the mice’s brains.
The combination of these factors altered how many genes were expressed, not by changing the DNA itself, but by affecting the epigenetic controls that regulate gene activity. Some of these genes are vital for memory, learning, and regulating the body’s internal clock—impacting sleep and wakefulness.
Following the stressful medical scenario, the older mice exhibited memory deficits and sleep disturbances, comparable to key features of postoperative delirium seen in humans. The researchers then tested vorinostat, a drug already approved in the U.S. for treating certain lymphomas involving immune cells. Vorinostat influences how genes are regulated without altering DNA directly.
Encouraging results emerged: mice given vorinostat before the stressful procedure performed better on memory and cognitive tests, and their sleep patterns normalized. Brain tissue analyses revealed fewer behaviors associated with delirium and improvements in the structure of neurons involved in communication and memory. Most notably, gene activity related to memory and circadian rhythms shifted back toward normalcy, suggesting some of the brain changes caused by stress might be reversible.
These findings shed light on a biological pathway connecting delirium with long-term cognitive decline. Major medical events may disturb gene regulation in the aging brain, impacting memory and sleep, and hampering recovery. Persistent disruptions might also explain why some individuals face ongoing cognitive challenges after delirium.
This process—epigenetics—involves chemical and structural modifications that influence gene activity without changing the underlying DNA sequence. Because some epigenetic changes can be modified by drugs, targeting this pathway holds promise for future treatments, supported by the success seen with vorinostat in mice.
However, caution is essential. Vorinostat has not been proven to prevent delirium or memory decline in humans. The mice received the drug before surgical stress, but real patients often present with multiple health problems and are prescribed various medications, complicating safety considerations. Additionally, vorinostat is a cancer drug with possible side effects, so any application in older surgical patients requires thorough testing.
The study also cannot confirm that delirium directly causes dementia, as both share risk factors such as advanced age, frailty, and pre-existing brain changes. Nonetheless, understanding these processes is crucial—they highlight how targeting gene regulation might help protect vulnerable individuals.
Researchers at UVA plan to delve deeper by examining individual brain cells to identify which types are most affected and how different areas respond to surgery. This knowledge could eventually lead to more precise therapies—drugs that specifically address the molecular changes contributing to delirium.
Until then, hospitals prioritize preventive measures and supportive care: maintaining sleep, orientation, and mobility; managing medical issues promptly; and minimizing exposure to stressors known to trigger delirium.
This research was conducted by scientists from UVA Health and the University of Virginia School of Medicine and published in Alzheimer’s & Dementia. It advances understanding beyond the mere association between delirium and dementia, providing insights into how acute medical stress might lead to long-term brain vulnerability. While the evidence is primarily biological and based on animal models, the hope is that these findings will pave the way for safer, more targeted interventions in the future.