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.

The study, spearheaded by Boutalbi, Dahan, Rozalen, and their colleagues, focuses on two blood-based biomarkers: neuron-specific enolase (NSE) and S100 calcium-binding protein B (S100B). Both molecules have long been associated with brain injury and neuroinflammation in adult populations, but their prognostic role in neonatal populations, especially those undergoing cardiac surgery with cardiopulmonary bypass (CPB), has remained largely unexplored until now. This research offers a pioneering investigation into how these biomarkers correlate with motor development at four months, a critical window when many infants with CCHD begin to manifest overt delays.

Complex congenital heart disease affects approximately 1% of live births worldwide, making it among the most prevalent birth defects. Despite advances in cardiac surgery and neonatal intensive care, children with CCHD remain vulnerable to neurodevelopmental impairments due to a confluence of factors including hypoxia, ischemia during surgery, and systemic inflammation. The use of CPB, while lifesaving, can induce a cascade of events that exacerbate brain vulnerability. Add to this the immature neonatal brain’s susceptibility to injury, and the challenge becomes evident: how can clinicians predict which infants will suffer neurodevelopmental setbacks, especially in the motor domain, which often sets the stage for more global impairments?

Neuron-specific enolase (NSE) is an enzyme found predominantly within neurons and neuroendocrine cells, released into the bloodstream following neuronal injury. Elevated levels of NSE thus serve as a proxy for neuronal damage. Similarly, S100B, a protein expressed mainly by astrocytes in the central nervous system, increases in serum when the blood-brain barrier integrity is compromised or astrocytic injury occurs. These characteristics render NSE and S100B prime candidates for non-invasive biomarkers capable of monitoring brain health in critically ill neonates.

In this study, the researchers enrolled newborns with confirmed CCHD who required surgical intervention involving CPB. Blood samples were obtained intraoperatively at predefined intervals to measure serum concentrations of NSE and S100B. Subsequently, these infants underwent standardized neurodevelopmental evaluations at four months of age, with a particular focus on motor function. The assessments employed validated scales designed to detect subtle signs of neuromotor delay, such as muscle tone abnormalities, reflex development, and milestone attainment.

The results revealed a striking association: elevated perioperative serum levels of NSE and S100B predicted poorer motor outcomes at the four-month mark. Infants exhibiting higher biomarker concentrations demonstrated significant delays in motor milestones compared to their counterparts with lower levels. This correlation persisted even after adjusting for confounding variables such as gestational age, birth weight, and the complexity of cardiac surgery. These findings underscore the potential of NSE and S100B as early, objective indicators of brain injury severity and developmental prognosis in this vulnerable population.

One of the study’s most compelling implications lies in its potential to refine postoperative neurodevelopmental surveillance. Currently, early identification of at-risk infants relies heavily on clinical observation and imaging studies, which may not capture subtle injuries or predict long-term outcomes with high fidelity. The integration of biomarker measurement could supplement traditional methods, offering a dynamic and quantifiable tool to flag infants likely to benefit from early neurorehabilitative therapies.

Moreover, the temporal profile of NSE and S100B release offers insights into the pathophysiological processes at play during and immediately following heart surgery. Notably, the elevation of these biomarkers reflects a period of heightened vulnerability marked by neuronal stress, blood-brain barrier disruption, and inflammatory cascades. Understanding these mechanisms opens avenues for therapeutic modulation—perhaps through neuroprotective agents aimed at reducing biomarker release or mitigating their underlying causes.

The study also raises intriguing questions about the universality of NSE and S100B as neurodevelopmental markers beyond the context of CCHD. Could these proteins serve as early warning signals following other neonatal insults, such as hypoxic-ischemic encephalopathy or preterm birth-related brain injury? The applicability of these biomarkers may extend far beyond cardiac surgery, heralding a new paradigm in neonatology where molecular surveillance complements clinical care to optimize outcomes.

It is important to note that while the findings are robust, the authors emphasize the need for longitudinal follow-up and larger sample sizes. Four months is a relatively short interval in neurodevelopmental trajectories, and longer-term studies are essential to fully elucidate how early biomarker elevations translate into functional outcomes during later infancy and childhood. Indeed, integrating biomarker data with advanced neuroimaging and genetic profiling could further enhance predictive accuracy and individualize patient care.

Nevertheless, this work situates NSE and S100B at the forefront of neonatal neuromonitoring strategies, setting a new standard for precision medicine in a challenging clinical arena. It exemplifies the power of translational research by bridging basic neurobiology with clinical practice to address a pressing unmet need in pediatric cardiology and neurology.

The trajectory from birth to early infancy represents a narrow but critical window when interventions tailored to emerging delays can dramatically improve long-term quality of life. Conventional approaches often miss this window, with neuromotor deficits only becoming apparent after substantial developmental impairment has occurred. By leveraging biomarkers like NSE and S100B, clinicians may soon have the ability to act preemptively, offering neuroprotective therapies, personalized physical and occupational therapy, or novel interventions designed to harness neuroplasticity at its peak.

In a broader context, these findings contribute to evolving understandings of how systemic illnesses affect brain development, emphasizing the intersection between organ-specific pathologies and central nervous system outcomes. Infants with CCHD embody a highly complex clinical scenario where cardiac function, cerebral perfusion, inflammatory mediators, and surgical stress intricately interplay to shape neurodevelopmental destiny.

To harness the full potential of these insights, multidisciplinary collaboration between neonatologists, cardiac surgeons, neurologists, and developmental therapists will be essential. Such teamwork can facilitate integrated care pathways that incorporate biomarker screening into routine postoperative management, optimize timing and dosing of interventions, and improve family counseling regarding prognosis and expectations.

In conclusion, this seminal study by Boutalbi and colleagues heralds a new era in early neurodevelopmental prognostication for infants with complex congenital heart disease. By identifying NSE and S100B as reliable early biomarkers of motor outcome, the research not only highlights a critical diagnostic advance but also sparks hope for more targeted, timely, and effective interventions. As science continues to unravel the molecular underpinnings of brain injury in these delicate patients, the prospect of improving lifelong developmental trajectories comes into clearer focus, promising a brighter future for children born with CCHD.

Subject of Research: The prognostic role of neuron-specific enolase (NSE) and S100B biomarkers in predicting early motor outcomes in infants with complex congenital heart disease undergoing surgery with cardiopulmonary bypass.

Article Title: Early motor outcomes in infants with complex congenital heart disease: the predictive role of NSE and S100B.

Article References:
Boutalbi, N., Dahan, S., Rozalen, W. et al. Early motor outcomes in infants with complex congenital heart disease: the predictive role of NSE and S100B. Pediatr Res (2025). https://doi.org/10.1038/s41390-025-04437-8

Image Credits: AI Generated

DOI: https://doi.org/10.1038/s41390-025-04437-8