Can we stop memory loss?
By Lauren Vogel
Forgetful. Distracted. Dazed. Struggling to find words. Trapped in a constant state of déjà vu. A brain in slow motion. A head stuffed with rags.
People with brain fog vividly describe a common constellation of debilitating impairments in memory and executive function — the basic mental processes required to prioritize, focus, and follow through on thoughts and tasks. But brain fog isn’t a clinical diagnosis as much as a colloquial catch-all for the cognitive difficulties that cut across a wide range of conditions — from cancer to long COVID. And despite growing recognition, these cognitive difficulties can be poorly understood by clinicians who lack adequate testing or treatments to tackle the problem.
“In patients with breathlessness, we might look to the lungs, or with a painful calf to blood clotting,” writes Laura McWhirter, a consultant neuropsychiatrist and clinical research fellow at the University of Edinburgh, in a 2023 study. “But where in the brain might we look for the source of a fog?”
Research at the Temerty Faculty of Medicine is cutting through the haze — from pioneering work tracing the cognitive fallout of anesthesia and chemotherapy to the hunt for treatments for Alzheimer’s disease and long COVID.
Beverley Orser (PGME ’87, PhD ’95), like many of her peers in anesthesiology, initially struggled to believe that the same miracle drugs that block the pain of surgery could have lasting cognitive impacts on patients.
“For decades and decades, we’ve known that sometimes our patients weren’t quite right after surgery,” says Orser, the chair of Temerty Medicine’s Department of Anesthesiology & Pain Medicine. Yet, it was widely assumed that any effects of anesthesia cleared once the drugs left the body. Perioperative neurocognitive disorders — ranging from short-term delirium to lasting cognitive decline — affect roughly one in four surgical patients one week after surgery, and one in 10 patients up to three months later.
Orser’s own mother struggled to remember visitors and manage her medications for weeks after a hip replacement, despite showing all appearances of an exemplary recovery. “Subsequently, she developed major cognitive decline,” Orser recalls. “It became apparent to me that even someone who is seemingly doing well can have quite a major change in brain function after anesthesia and surgery.”
After a series of studies in the early 2000s revealed that the anesthetic ketamine could improve symptoms of depression long after the drug left the body, Orser refocused her lab at the University of Toronto to better understand the mechanisms at work. “We were surprised to find that anesthesia triggered an overexpression of memory—blocking receptors in the brain in animal models,” Orser says.
Changes in either the number or function of these α5-GABAA receptors cause profound learning and memory deficits, she explains. “Later, we found that inflammatory factors also drive an overexpression of these receptors, while drugs that inhibit them improve cognitive behaviours,” she says.
These findings led to the development of a new class of drugs for restoring memory loss after surgery and pointed to a new “druggable” target for the treatment for other cognitive disorders. “We’ve looked at traumatic brain injury, and there’s some evidence that overactivity of α5-GABAA likely contributes to changes in plasticity that underly memory deficits,” Orser says. Other labs have found similar links with stroke, depression and Alzheimer’s disease.
Like anesthesia, cancer treatments are linked with a wide range of cognitive deficits commonly known as “chemo brain.”
“It affects memory, attention, ability to focus, your processing speed — all things that make you feel like you’re not quite yourself,” says Melanie Sekeres (PhD ’12), an assistant professor in the University of Ottawa’s School of Psychology. As many as three in four chemotherapy patients experience these deficits that in some cases can last for decades. While earning a PhD at U of T, Sekeres collaborated with Gordon Winocur, then a professor in Temerty Medicine’s Department of Psychiatry. They worked on one of the first studies to shed light on how cancer and chemotherapy cause cognitive impairment in animal models.
They found three distinct brain changes at play. The first is an immune reaction to the cancer itself that triggers inflammation, affecting brain function. Then, chemotherapy causes a reduction in the generation of new neurons in the hippocampus, a brain structure critical to forming and recalling memories.
Finally, both chemotherapy and tumour growth cause significant shrinking of both the hippocampus and the frontal lobes, another structure involved in memory.
Sekeres notes that the problems with focus and other executive functions reported by patients receiving chemo appear similar to the frontal lobe dysfunction seen in aging adults and those with dementia.
“It’s likely that some or many of the same cellular mechanisms, for example neuroinflammation leading to cellular dysfunction, are co-occurring in many of these conditions,” she says. Sekeres is now studying chemo brain in breast cancer survivors, hoping to untangle potential variables that may affect a person’s vulnerability. Among other factors, she’s asking patients about their stress, sleep quality and exercise level.
“A lot of these psychosocial and environmental factors may predispose or protect them,” she says.
Recent dementia research highlights the potential for using biomarkers to pinpoint treatments for cognitive symptoms. One of the most distressing of these symptoms is agitation, which can include physical and verbal aggression, and affects up to 88 per cent of people with Alzheimer’s disease. Doctors often prescribe antipsychotics to manage agitation, but these drugs carry serious risks of falls, heart problems, stroke and even death.
Krista Lanctôt (MSc ’89, PhD ’98), a professor in Temerty Medicine’s Department of Psychiatry and Department of Pharmacology and Toxicology, sought a safer alternative treatment in nabilone, a synthetic version of the tetrahydrocannabinol found in cannabis. “Our brains are already wired with cannabinoid receptors, and the brain makes cannabinoids that help with inflammation and oxidative stress,” explains Lanctôt, the Bernick Chair in Geriatric Psychopharmacology.
However, she says that, “as the brain deteriorates in Alzheimer disease, there’s a theory that changes to this endocannabinoid system contribute to cell death.” In addition to potentially providing a calming effect, nabilone may also take advantage of this natural system for fighting inflammation and oxidative stress.
In a small randomized controlled trial, Lanctôt and her team found that nabilone was much better than a placebo in decreasing agitation. They also looked at biomarkers in patients’ blood to determine who might benefit the most from the treatment. They found that a higher level of inflammation and oxidative stress were linked with more severe agitation. Patients with a higher level of inflammation were more likely to respond to treatment with nabilone, and their inflammation decreased with treatment.
The findings point to a new way to tackle agitation by targeting underlying inflammation, says Myuri Ruthirakuhan (PhD ’19), a postdoctoral fellow at the Sunnybrook Research Institute who led the biomarkers portion of the study as part of her doctoral work at Temerty Medicine. “We were able to show there is not only a clinical benefit, there’s a biological benefit as well,” Ruthirakuhan says.
Lanctôt and her colleagues are now undertaking a larger trial of 200 people to confirm the results.
Inflammation is also a likely culprit in long COVID. As many as 10 to 30 per cent of people infected with SARS-CoV-2 report ongoing symptoms after their initial illness.
Brain fog and fatigue are among the most common and disabling of these symptoms, says Roger McIntyre (PGME ’98), a professor in Temerty Medicine’s Department of Psychiatry and Department of Pharmacology and Toxicology. “These cognitive deficits may be related to so-called ‘friendly fire,’ where the immune system takes care of the virus but leaves collateral damage or prolonged inflammation, which we know can impact brain function,” says McIntyre, the head of the Mood Disorders Psychopharmacology Unit at University Health Network.
At the same time, the virus may attack the brain directly by killing cells and indirectly by damaging blood vessels, compromising the brain’s energy and oxygen supplies. The potential role of inflammation in long COVID prompted McIntyre to investigate the widely available antidepressant vortioxetine as a possible treatment. Previous studies have shown that vortioxetine can improve cognition regardless of whether a person has depression, McIntyre explains.
“There is a rich science showing this drug is potentially anti-inflammatory,” he says. In a recent trial of 200 people with long COVID, McIntyre initially didn’t see any difference in cognition between those who received vortioxetine for eight weeks and those who received a placebo.
However, on a closer look, those receiving the antidepressant reported significant improvements in their quality of life. Also, participants with an elevated marker of inflammation showed significant improvements in their cognition while taking the drug. McIntyre says his findings, which are not yet published, add to evidence supporting the role of inflammation in long COVID.
“Whatever this brain fog is, it is amenable to therapeutic intervention,” he says. “There’s a lead here and it will have to be replicated. But what this tells me is that maybe having long COVID is not a lifetime curse.”