A drug already used to treat cancer has helped scientists uncover a possible reason some older people develop serious confusion after surgery.
In experiments with aged mice, the medicine reversed several brain changes linked to memory problems and disturbed sleep.
The research could eventually help scientists understand postoperative delirium, a sudden state of confusion that can occur after surgery. The condition is common enough to be a major concern in hospitals, especially among older adults.
A person with delirium may suddenly have trouble paying attention or understanding what is happening around them. They may become unusually sleepy, restless, frightened or confused, and their symptoms can change dramatically during the same day.
This is different from most forms of dementia, which usually develop slowly over months or years. Delirium appears rapidly, often because the brain is reacting to illness, surgery, medicines or other physical stress.
Many patients recover from delirium, but the condition is not always harmless once the confusion disappears. Studies have linked it with longer hospital stays, more medical complications and a higher risk of later decline in memory and thinking.
Researchers have struggled to explain that long-term connection. Does delirium simply identify people whose brains were already vulnerable, or can the experience surrounding surgery produce changes that contribute to later problems?
Scientists at UVA Health explored this question in aged mice. The team was led by Dr. Nadia Lunardi, chief of neuroanesthesia at UVA Health, and research scientist Dr. Hari Prasad Osuru.
The researchers created an experimental situation involving anesthesia, surgery and stress designed to reproduce some features of intensive care. They then examined what happened inside the animals’ brains.
The combination changed the way many genes were being used. Although an animal’s DNA itself did not need to change, the biological controls that determine whether certain genes are switched up or down were altered.
Some of the affected genes are important for memory and learning. Others help control the body’s biological clock, the internal timing system that influences when we sleep, wake and carry out many daily body functions.
The aged mice developed problems with memory and sleep after the stressful medical experience. Researchers said these changes resembled important features of postoperative delirium seen in people.
The team then turned to a surprising medicine called vorinostat. It is already approved in the United States to treat certain T-cell lymphomas, a group of cancers involving immune cells.
Vorinostat can change how cells regulate gene activity. The scientists wanted to see whether using the drug could correct the abnormal gene patterns caused by anesthesia, surgery and intensive care-like stress.
The results were encouraging. Mice treated with vorinostat before the medical stress showed better performance on tests of memory and thinking than untreated mice.
Their sleep patterns also became more normal. Researchers found fewer delirium-like behaviors and improvements in the structure of brain cells involved in communication and memory.
Perhaps most importantly, activity in genes involved in memory and the internal body clock moved back toward normal. This suggested that some of the brain changes caused by the stressful experience were not permanent.
The discovery offers a possible biological explanation for why delirium and later cognitive decline may be connected. A major medical event could disrupt the systems controlling gene activity in an already vulnerable aging brain.
If those disruptions interfere with memory and sleep, they could potentially make recovery more difficult. Persistent changes might also help explain why some patients experience longer-term problems after an episode of delirium.
Scientists describe these gene-control processes as epigenetic. In simple terms, they are chemical and structural changes that influence which genetic instructions a cell reads without rewriting the DNA itself.
Epigenetic changes are especially interesting as treatment targets because some can be altered by medicines. The success of vorinostat in mice supports the idea that these pathways deserve further investigation.
But there is a major reason for caution. Vorinostat has not been proven to prevent postoperative delirium, memory loss or dementia in humans.
The animals received the drug before exposure to anesthesia, surgery and intensive care-like stress. Real patients are more complicated, and doctors may not always know in advance who will develop delirium.
Older surgical patients may also have heart disease, kidney disease, infections or many other conditions. They often take several medicines, making the safety of any new treatment particularly important.
Vorinostat itself is a cancer drug and can cause side effects. Even if the biological idea behind the treatment is correct, researchers may eventually find that another medicine acting on the same pathway is safer for older surgical patients.
The study also cannot prove that postoperative delirium directly causes dementia. Delirium and dementia share several risk factors, including older age, frailty and existing changes in the brain.
Still, understanding what happens during delirium could help doctors protect people who are especially vulnerable. The new findings suggest that memory systems and the body’s sleep clock may be important parts of that story.
The UVA researchers are now using advanced methods to examine individual brain cells. They want to discover exactly which cell types are most affected and how different areas of the brain respond to surgical stress.
This could eventually lead to treatments that are more targeted than vorinostat. Instead of broadly changing gene activity, future drugs might correct only the processes that contribute most strongly to delirium.
Until such treatments are proven, hospitals rely mainly on prevention and supportive care. Protecting sleep, helping patients remain oriented, encouraging safe movement and quickly treating medical problems are among the strategies used to reduce delirium risk.
The research was carried out by scientists at UVA Health and the University of Virginia School of Medicine. Their findings were published in the scientific journal Alzheimer’s & Dementia.
The study is important because it moves beyond showing that delirium and dementia are associated and offers a possible mechanism connecting acute hospital stress with longer-term brain vulnerability. Its strongest evidence comes from detailed biological experiments, but its biggest limitation is equally clear: the work was done in mice rather than patients.
Vorinostat therefore should not be viewed as a ready treatment for older adults having surgery. The more significant finding is that some harmful brain changes after major medical stress may be reversible, giving researchers a promising path toward safer and more precise ways to protect the aging brain.
Source: University of Virginia
