Older adults sometimes become suddenly confused after surgery, even when the operation itself goes well.
A new study from UVA Health may help explain why this condition, known as postoperative delirium, has been linked to a greater risk of later memory problems and dementia.
Delirium is different from dementia. It usually appears quickly and can cause confusion, poor attention, changes in awareness, disturbed sleep, unusual behavior or difficulty knowing where a person is.
Symptoms may come and go over hours or days. Although delirium can affect people of any age, older and frail patients are particularly vulnerable after major surgery or a stay in intensive care.
Doctors have long known that postoperative delirium can make recovery more difficult. Patients may remain in hospital longer, experience more complications and need additional care after discharge.
Researchers are especially concerned because people who experience delirium have a higher chance of later cognitive decline. Until now, however, scientists have not fully understood how a short period of delirium might be connected with longer-lasting changes in the brain.
A team led by Dr. Nadia Lunardi and Dr. Hari Prasad Osuru at UVA Health investigated this question using aged mice. The researchers exposed the animals to a combination of anesthesia, surgery and stress similar to aspects of intensive care.
They found that these experiences changed the activity of genes in the brain. Genes contain the instructions cells use to perform their jobs, but cells can increase or decrease the activity of particular genes depending on circumstances.
The researchers found changes in systems that help control memory and learning. They also found disruption in genes involved in the body’s internal clock, which helps regulate normal cycles of sleep and wakefulness.
This connection is important because sleep problems are common during delirium. Hospitals can be noisy and unfamiliar, and pain, medicines, illness and repeated nighttime checks may further disturb normal sleep.
In the aged mice, the combination of anesthesia, surgery and intensive care-like stress produced memory problems and disturbed sleep patterns. These changes resembled some features seen in older patients with postoperative delirium.
The scientists then tested whether they could reverse the underlying brain changes. They used vorinostat, a medicine already approved by the U.S. Food and Drug Administration for certain types of T-cell lymphoma.
Vorinostat is a cancer medicine, but it can also affect the way cells control gene activity. This made it useful for testing whether the gene changes identified in the study were fixed or potentially reversible.
Mice that received vorinostat before anesthesia, surgery and intensive care-related stress performed better on tests of thinking and memory. Their sleep patterns also improved, and they showed fewer behaviors resembling delirium.
The researchers also saw improvements in the structure of nerve cells. In addition, genes involved in memory and the body’s biological clock began functioning more normally.
These findings suggest that surgery and intensive care stress may leave a biological mark on the aging brain by changing how certain genes are controlled. Importantly, the mouse experiments indicate that at least some of these changes may be reversible.
The study focused on two processes that influence whether genes are more or less active without changing the genetic code itself. Scientists call these processes epigenetic changes, but they can be thought of simply as biological controls that help cells decide which instructions to use.
If these controls are disturbed in brain cells, memory, learning and sleep may be affected. Researchers believe this could provide one possible link between an episode of delirium and later cognitive problems.
However, the study does not show that vorinostat can prevent delirium or dementia in people. The experiments were conducted in mice, and a drug that improves symptoms in an animal model may behave very differently in older surgical patients.
Vorinostat is also a powerful cancer medicine with possible side effects. It would therefore be inappropriate for people to take it for delirium unless future clinical trials show that the benefits outweigh the risks.
The timing of treatment also matters. In this experiment, the drug was given before the animals experienced anesthesia, surgery and intensive care-related stress, so researchers still need to learn whether treatment after delirium begins would have similar effects.
Another question is whether the changes seen in mice accurately represent the many causes of delirium in humans. Older patients can develop delirium because of infections, medicines, pain, dehydration, organ problems and other medical stresses in addition to surgery and anesthesia.
Even so, the study provides researchers with a useful new direction. Rather than viewing delirium only as temporary confusion, scientists may need to consider whether it reflects deeper changes in vulnerable brain cells.
The UVA team is now studying individual types of brain cells to understand which ones respond most strongly to surgical and intensive care stress. The goal is to identify more precise treatments that could protect the brain without exposing patients to unnecessary risks.
Preventing delirium is already an important part of hospital care for older adults. Measures such as supporting normal sleep, keeping patients oriented, encouraging safe movement, treating pain carefully and addressing medical problems can help reduce risk in some patients.
The new research may eventually add biological treatments to those approaches. If scientists can identify the exact changes that make the aging brain vulnerable, it may become possible to prevent delirium and perhaps reduce the longer-term cognitive decline associated with it.
The study was conducted by researchers at UVA Health and the University of Virginia School of Medicine and was published in the journal Alzheimer’s & Dementia.
Overall, the work is promising because it identifies specific, reversible brain changes and shows that a drug can influence them in an animal model. But it remains early research, and the results should be viewed as a clue about how delirium may affect the brain rather than evidence for a new treatment in patients.
Source: University of Virginia.
