Postoperative delirium has long been recognized as one of the most troubling complications of major surgery, particularly among older and medically frail patients. The condition can appear suddenly, leaving patients confused, disoriented, inattentive or unable to distinguish dreams from reality. Although delirium may resolve within days, physicians have observed that an acute episode can be followed by persistent memory problems and a heightened risk of dementia. Researchers at UVA Health have now identified molecular changes in the aging brain that may help explain this connection—and have shown in mice that an existing cancer drug can reverse many of those changes.
The study, led by Nadia Lunardi, MD, PhD, chief of UVA Health’s neuroanesthesia division, and Hari Prasad Osuru, PhD, examined how anesthesia, surgery and the physiological strain associated with intensive care affect the brains of aged mice. Together, the researchers refer to these exposures as anesthesia, surgery and intensive-care stress, or ASI. The experimental model was designed to reproduce several features of the perioperative experience that can challenge an older brain, including anesthesia exposure, tissue injury, inflammation and the disruption of normal sleep and daily routines that often occurs in critical care.
The team found that ASI produced a broad molecular imprint in the brains of the older animals. Rather than simply causing temporary changes in neuronal activity, the combined stressors altered gene regulation through epigenetic mechanisms. Epigenetics describes a layer of biological control that determines how strongly genes are expressed without changing the underlying DNA sequence. Chemical modifications to DNA-associated proteins can loosen or tighten chromatin, the complex structure that packages genetic material, making particular genes more or less accessible to the cellular machinery that reads them.
In the aged mice, these epigenetic changes affected genes involved in memory formation, neuronal structure and the circadian system—the internal biological clock that helps coordinate sleep, wakefulness, hormone release and other daily functions. The disruption was associated with impaired learning and memory, altered sleep patterns and behavioral abnormalities resembling aspects of postoperative delirium. The findings suggest that perioperative stress may interfere with the brain’s ability to adapt to new information at precisely the time when older neurons are already less resilient.
Memory formation depends on tightly coordinated changes in neuronal connections. When an animal learns, networks of neurons modify the strength and structure of their synapses, allowing information to be encoded and later retrieved. The UVA researchers observed evidence that ASI compromised this structural and functional plasticity. At the same time, genes that help synchronize the circadian rhythm were disturbed. Because sleep supports memory consolidation, waste clearance and metabolic recovery in the brain, a breakdown in the biological clock could amplify cognitive injury rather than merely accompany it.
The investigators then tested vorinostat, an FDA-approved drug currently used to treat certain types of T-cell lymphoma. Vorinostat belongs to a class of compounds known as histone deacetylase inhibitors. Histone deacetylases remove chemical groups from histone proteins, which help package DNA, and can thereby influence whether genes are active or silent. By inhibiting these enzymes, vorinostat can reshape chromatin accessibility and restore expression of genes that have been suppressed. The drug is not approved as a treatment for delirium or dementia, and its effects in this study should not be interpreted as evidence that patients should take it around the time of surgery.
In the mouse experiments, animals given vorinostat before exposure to anesthesia, surgery and intensive-care-related stress showed healthier neuronal structure and performed better on cognitive tests than untreated animals exposed to the same stressors. The drug also restored activity in gene networks associated with memory and circadian regulation. Their sleep patterns improved, and they displayed fewer behavioral features interpreted by the researchers as delirium-like symptoms. These results indicate that at least some of the brain changes induced by perioperative stress are not permanent. Instead, they may represent reversible alterations in gene regulation that can be targeted pharmacologically.
The discovery offers a possible biological explanation for why delirium and later cognitive decline can be linked without proving that delirium directly causes dementia in every patient. An episode of delirium may reveal an underlying vulnerability in the aging brain, while the molecular disruptions produced by surgery and critical illness could further reduce cognitive reserve. Epigenetic changes affecting synaptic plasticity and circadian control provide a plausible bridge between a short-term disturbance in attention and longer-lasting impairment in memory. The study also supports the idea that preventing or promptly correcting delirium-related biological changes could reduce the risk of prolonged cognitive problems.
Postoperative delirium affects millions of older adults worldwide and is associated with longer hospital stays, more complications and increased healthcare costs. The American Delirium Society estimates that approximately 7 million hospitalized Americans experience the condition each year, with annual costs reaching as high as $152 billion. Yet treatment remains largely supportive, relying on measures such as reorientation, sleep protection, early movement, careful medication management and correction of pain or metabolic abnormalities. A therapy designed to modify the molecular consequences of perioperative stress would represent a fundamentally different approach, although substantial testing would be required before vorinostat or related drugs could be considered for human prevention.
Lunardi and Osuru emphasize that the work is an early-stage discovery from an aged-animal model, not a clinical trial. Vorinostat can produce serious side effects, including blood abnormalities, gastrointestinal problems and effects on the heart, making indiscriminate use inappropriate. The researchers are now applying single-cell technologies and spatial transcriptomics to determine which brain cell populations respond most strongly to perioperative stress. These methods can reveal whether neurons, astrocytes, microglia or other cells drive the epigenetic changes, and where in the brain the molecular disruptions are concentrated. Such information could guide safer, more precise treatments aimed at preserving cognition after surgery.
The findings, published in Alzheimer’s & Dementia, identify epigenetic regulation as a promising target in the effort to understand postoperative delirium and its possible relationship to dementia. If future studies confirm the mechanism and establish a safe therapeutic window, drugs that selectively normalize gene activity could one day complement non-drug strategies for protecting vulnerable patients. For now, the results provide an important shift in perspective: the confusion that follows surgery may not be only a transient reaction to anesthesia or hospitalization, but a measurable biological event that leaves the aging brain temporarily—and potentially treatably—reprogrammed.
Subject of Research: Postoperative delirium, perioperative stress, epigenetic regulation, cognitive decline and dementia risk in aging brains.
Web References: https://doi.org/10.1002/alz.71556
References: Lunardi N, Osuru HP and colleagues, findings published in Alzheimer’s & Dementia, DOI: 10.1002/alz.71556.
Keywords: Postoperative delirium, dementia, cognitive decline, aging brain, anesthesia, surgery, intensive care, epigenetics, vorinostat, histone deacetylase inhibitors, memory, circadian rhythm, sleep disruption, neuroanesthesiology.
