Real-time study explores how the aging brain copes with stress

One morning last September, Debbie Stiles left her small town of Paso Robles – known for its vineyards and olive groves – in the quiet darkness before dawn and headed north toward Stanford Hospital. The three-hour drive took her from rural calm into the fast-paced world of Bay Area medicine, where she would begin a life-changing surgical and scientific journey.

The 69-year-old was about to undergo cardiac surgery to repair failing valves. Left untreated, she risked heart failure.

Stiles remembers being terrified – so much so that she asked her anesthesiologist to “knock her out before she saw the lights” of the operating room. Those lights, as bright as a film set, are designed to eliminate shadows. No shadows, less room for error.

That anesthesiologist was Igor Feinstein, a clinical assistant professor at Stanford Medicine. He would be the one to put her to sleep and monitor her vitals while the surgeons worked on her heart.

Feinstein would also accompany her in another way: as a clinician-scientist on the team behind the CARDIAC-PND Study, a research effort supported by the Knight Initiative for Brain Resilience at Stanford’s Wu Tsai Neurosciences Institute. Led by anesthesiology professor Martin Angst, the study is probing a fundamental question at the intersection of aging and neuroscience: Why do some people remain cognitively resilient, while others decline?

As Stiles drifted off into darkness again, Feinstein’s face was the last one she saw.

Why some brains resist time, trauma, and illness

Dementia is a slow, often devastating unraveling of memory, identity, and independence that touches nearly every family. Yet amid this grim reality, some people seem to defy the odds. They reach their eighties, nineties, or even surpass 100 with their minds remarkably intact.

Scientists call this capacity brain resilience: the ability to withstand age-related changes or disease without significant cognitive decline. With more than 10 million people worldwide developing dementia every year – a number expected to rise sharply as populations age – understanding brain resilience has become one of the most urgent challenges in neuroscience.

This is the mission of the Knight Initiative for Brain Resilience: to decode how the brain stays healthy over time and to turn those discoveries into tools that help people live cognitively vibrant lives as they age.

But studying brain resilience in real life – especially in humans – is uniquely difficult. After all, the living brain is largely inaccessible. Much of what is known comes from research in animals or postmortem brains, which don’t fully capture the biological complexity of aging in living people. Even when we assess cognitive performance in aging adults, we rarely see the biology behind the behavior.

That’s what makes the CARDIAC-PND Study (short for Cognitive Assessment and Resilience in the Aging Brain After Cardiac Surgery – Perioperative Neurodegeneration) so significant. By using surgery as a kind of biological stress test, researchers can track how the brain responds to injury – and how it recovers. It’s one of the first and largest efforts to track brain resilience in real time, in living people, over a meaningful stretch of their lives.

“[Surgery is] one of the only moments in medicine where we can observe human biology before, during, and after a challenge,” said Angst, the study’s principal investigator. “That gives us a unique chance to study resilience as it unfolds.”

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Photos courtesy Rhee Bevere

Stiles is one of the people helping make that possible.

Her mother was a nurse who had dedicated her life to caring for others. But it wasn’t just her mother’s career that inspired Stiles to participate in the CARDIAC-PND Study. She had also witnessed dementia slowly dismantle her mother’s identity. “She used to call me and say, ‘I feel goofy today. I hate it,’” Stiles recalled. The disease turned a woman who had always been sharp, confident and capable into someone who was frustrated with herself and diminished. “She was always the smartest person in the room. And not being that person anymore… it just broke her.”

Joining the study was a way to help unlock the secrets of brain resilience, and help others avoid what her mother went through. Why was her mother’s brain so susceptible? Could her decline have been predicted or even prevented?

When researchers approached her, she didn’t hesitate. “I hope I can help someone else,” she said.

Turning the operating room into a lab

The idea for the CARDIAC-PND Study can be traced back to a shift in perspective.

For years, Angst had studied the pharmacology of opioids, working to advance the field of pain medicine. But a decade ago, he found himself at a professional crossroad. As breakthroughs in genomics and data-driven biology began to transform how scientists studied the human body, he realized the methods he had relied on could only take his research so far. Rather than leaving academia behind, he chose to pivot. He wanted his research to make a more direct, meaningful difference in people’s lives. So he turned his focus to something deceptively simple: healing.

As an anesthesiologist, Angst realized he was observing profound biological stress every day. Surgery, especially in older adults, is a major insult to the body. “Surgery is an intentional injury,” he said. “It’s a real-time window into how the body responds to a challenge – biologically, behaviorally, cognitively.”

The operating room, he realized, could become a human lab.

Together with Stanford colleagues Brice Gaudillière and Nima Aghaeepour, and later with Feinstein, Angst built a translational research program around human resilience, using surgery to study how the body heals and adapts.

It was, in many ways, a return to a very old biological idea: Healing from injury is one of the most fundamental things we need to be able to do to survive. But now, with the tools of modern science, researchers could begin to ask new questions about healing at the molecular level, in real time.

With support from a Knight Initiative Translational Award, the CARDIAC-PND Study follows cognitively healthy older adults through every stage of their surgical journey: before anesthesia, in the operating room, and for years afterward. Along the way, the researchers collect blood and cerebrospinal fluid, perform cognitive testing, and analyze thousands of molecular signals to identify patterns of stress, injury, and resilience.

“It’s an extraordinary opportunity to study how the aging brain copes with stress in real time,” Angst said. “And it’s a chance to start asking how we might protect it.”

The study is also a reflection of its Stanford environment. “The sheer scope and boldness of the Knight Initiative is most striking,” Angst said. “Where else could we do this? The effort spans from top-notch basic science to patient-centered research, driven by a belief that innovation should serve humanity.”

More than 100 patients have already enrolled in the study. With sustained support, the team aims to reach 500 participants and follow them for decades – essentially for the rest of their lives. That kind of long-term commitment is rare in clinical research, but it could yield an unusually detailed view of how brains age, recover, and decline.

The hidden toll of surgery

Stiles had survived cancer in her thirties, but the treatment left its mark. Decades later, it was her heart that needed repair. She anticipated a long and physically demanding recovery. What she didn’t know – what few patients do – is that surgery would challenge her brain, too.

Cardiac surgery, in particular, pushes the body to its limits. The procedure requires a bypass machine that temporarily takes over the work of the heart and lungs, circulating blood through two hoses – each about the diameter of a boba straw. One pulls blood out of the body, the other returns it, replenished with oxygen. The process triggers a massive inflammatory response throughout the body.

“We do all these highly invasive things to our patients, and then we expect all their organs to work the same,” said Feinstein. “That assumption never sat right with me.”

Trained in neuroscience and deeply involved in both the clinical and research aspects of the study, Feinstein has been working alongside Angst, his longtime mentor, to probe how surgical stress affects brain health.

As medical director of the study, he meets with each participant before surgery, follows them through recovery, and provides cognitive feedback at follow-up visits – building the kind of rapport that’s essential for long-term engagement and meaningful data.

In 2021, the two published a small study which found that major surgery can trigger the massive release of molecules associated with cognitive decline in some people – a finding that helped inspire the larger effort now underway.

Research suggests that 40-60% of patients experience cognitive impairment after major surgery, though for most, it is temporary. For others – up to 10% – the changes can persist for months or become permanent, affecting their ability to think, remember, and navigate daily life.

These changes often aren’t obvious to clinicians. They emerge gradually, at home, as patients struggle to follow routines, keep appointments, or return to work. At Stanford, where patients are often older and undergoing some of the most complex surgeries available, these risks are even more pressing.

“These patterns echo what patients report anecdotally, but we still have no way to predict who’s vulnerable,” said Feinstein. “And when you’re pushing the envelope with what’s surgically possible, addressing that uncertainty becomes even more important.”

That’s what the CARDIAC-PND Study hopes to change. It’s not just about gathering data – it’s about decoding how the aging brain responds to surgical stress, and identifying molecular signals that might predict resilience or decline before symptoms appear.

Because the real toll of surgery isn’t always what happens in the operating room. Sometimes, it’s what happens afterward.

Signs of stress and resilience

Nine months after surgery, Stiles is building up her strength and stamina through cardiac rehabilitation. Cognitively, she said she feels great: “Thankfully, I haven’t noticed any changes in my memory or focus.”

She may turn out to be one of the fortunate people whose brains are naturally resilient to stress in ways scientists are just beginning to understand.

Early results from the first 40 participants, which Feinstein recently presented at a conference in Hawaii, demonstrated that studying brain resilience in this way is both feasible and deeply revealing. The findings are also providing biological clues that may explain why some brains recover while others falter.

Though all participants appeared cognitively healthy before surgery, nearly half showed signs of Alzheimer’s-related changes in their blood – suggesting that many were already biologically vulnerable, even if they didn’t show any signs of the disease. (Some people with Alzheimer’s biomarkers never go on to develop clinical symptoms, but these signals can still indicate increased risk.)

“When I saw the data, I was shocked,” said Feinstein. “It’s highly worrisome that we’re taking vulnerable brains and subjecting them to these very invasive procedures.”

The researchers also observed a consistent sequence of events unfolding over time: Levels of a protein called phosphorylated tau 181, an indicator of neuronal stress, surged during surgery. Then, a few days later, levels of neurofilament light – a sign of neuronal death – began to climb, peaking about a week after surgery.

“The timing is new here,” said Angst. “The injury to the brain doesn’t seem to happen all at once. It unfolds over a week, which is what you would expect as stressed neurons begin to die. Another finding is that the extent of injury seems to vary dramatically from patient to patient.”

In fact, the more vulnerable a patient appeared at baseline, the more stress and damage their brain showed afterward. Vulnerable patients also performed worse on cognitive tests three months later – particularly in memory, echoing what many patients report anecdotally.

For Feinstein and Angst, these patterns are both sobering and promising. They confirm what patients often report – that something feels off with their memory after surgery. But they also open new avenues for prevention.

By studying the most resilient patients, the team hopes to uncover biological pathways – especially those linked to inflammation and immune function – that help protect the brain during surgery and support recovery. The goal is to use those insights to predict outcomes and, eventually, shift the odds toward resilience.

And if physicians can identify vulnerable patients ahead of time, they may be able to take action: Choose a less invasive approach, delay surgery, or intervene beforehand. One such strategy – known as prehabilitation – aims to reduce inflammation and boost physical capacity before the first incision is ever made. That might include exercise, nutritional support, cognitive training, or stress management in the weeks leading up to surgery.

Saying yes

Stiles continues her recovery at home, easing back into everyday routines with a new appreciation for what her body – and brain – have been through. She’s proud to be part of research that could help others age with confidence.

“I hope they learn something from me,” she said. “Even just a little.”

Before surgery, the last person Stiles saw was Feinstein – a steady presence at an uncertain moment. That image stays with them both. For Feinstein, it’s a reminder that every insight into brain resilience starts with a person who said yes – to surgery and to science.