Making the invisible visible.

Hungry Messengers

When you fill your stomach with a piece of chocolate cake, your brain receives a signal for that fullness and tells your body to start metabolizing. Thankfully, this signalling isn’t the result of the sugars or fats from the cake flooding your brain; these molecules could do harm to your central nervous system, so the protective blood-brain barrier (BBB) prevents them from making that crossing. The signal for fullness is transmitted via specialized brain cells called tanycytes that cross the BBB and act as important messengers between the body and the brain.

Identifying the Cause

McGill University’s Dr. Masha Prager-Khoutorsky is an expert on tanycyte cells, studying their link to conditions such as obesity, high blood pressure, and diabetes. Using a 2019 Azrieli Future Leader in Canadian Brain Research Grant, Dr. Prager-Khoutorsky identified a strong influencer of tanycyte cells’ ability to communicate signals of fullness to the brain – circadian rhythm.

“The Future Leader Grant allowed me to develop this new direction in the lab. It’s a prestigious award that definitely helped me as a new investigator. The cohorts of Future Leaders are truly the future of neuroscience!”

Dr. Masha Prager-Khoutorsky

Missing Signals

As Dr. Prager-Khoutorsky explains, when tanycytes malfunction and can’t do their job, for example when they’re unable to sense leptin, the hormone that gets released into the blood when we eat, the brain doesn’t get the signal it needs to control metabolism. In other words, the brain doesn’t receive a signal of fullness from the body. In the case of obesity, the result is more calories being storedas fat.

Changes to our circadian rhythms may be one of the reasons behind increased rates of obesity.

Disrupted Rhythms

“Yes, we’re eating different foods and that plays a role. But we’ve also experienced significant changes to our circadian rhythms over the last many years. For example, we’re exposed to light for far longer periods of time, and this affects circadian rhythm, which thereby affects metabolism,” says Dr. Prager-Khoutorsky.

Communication Between Cells, and Nations

With an additional $1.5 million in funding through the competitive Joint Canada-Israel Health Research Program, Dr. Prager-Khoutorsky is building on her Brain Canada-funded work to explore yet another factor that influences the ability of tanycytes to communicate between the body and the brain – neuroinflammation caused by bacterial infections. This new project builds on an existing collaboration with Dr. Ruud Buijs based at Universidad Nacional Autónoma de México and includes a new collaborator in Dr. Yoav Livneh from the Weizmann Institute of Science in Israel.

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Interconnected Diseases

Cerebrovascular disease, specifically small vessel disease (SVD), is a prominent risk factor for Alzheimer’s and other dementias. It damages the cerebral white matter, and it contributes to shrinkage in certain areas of the brain. In turn, Alzheimer’s can cause SVD by contributing to the accumulation of a protein called beta-amyloid in the brain’s blood vessels. The damage caused by these brain conditions together affects overall brain function and cognitive decline in aging individuals.

Identifying treatment options targeted to individuals with cerebrovascular disease as an Alzheimer’s risk factor requires a better understanding of the biological processes involved.

Identifying the Genes

Tackling this challenge is precisely what Dr. Walter Swardfager from the University of Toronto and Sunnybrook Research Institute set out to accomplish with his International Research Grant Program (IRGP) Alzheimer’s Association Research Grant (AARG), co-funded by the Alzheimer’s Association and Brain Canada. With this funding support, Dr. Swardfager was able to identify genomic variants that, in the presence of SVD, increase shrinking of the brain.

Targeting a Rogue Enzyme

In their preliminary explorations, Dr. Swardfager and his team discovered that variations in a gene called EPHX2 were linked to damage to the brain’s white matter. Single nucleotide polymorphisms, or genetic variations, in the EPHX2 gene affected the volume of brain shrinkage in the presence of SVD across various neurodegenerative diagnoses. This discovery suggests that the enzyme produced by the EPHX2 gene might be targeted to protect against SVD-related brain changes and cognitive decline in individuals with or at risk for Alzheimer’s.

“We’re now submitting and receiving grants that build on the science in this area and may take us all the way to clinical trials. It’s been tremendous.”

Dr. Walter Swardfager

Because of this finding and with leveraged funding from his AARG, Dr. Swardfager’s team went on to show that the products of the EPHX2 enzyme were elevated in the blood of people with SVD. Based on this evidence, Dr. Swardfager prepares to soon test whether inhibiting the enzyme encoded by EPHX2 prevents SVD-related cognitive impairments clinically. He hopes that the approach might ultimately prevent or slow progression to dementia.

Fostering a Talent Pipeline

“Establishing this dataset has increased the productivity of my lab and provided training opportunities to 18 undergraduate and graduate students,” says Dr. Swardfager. “We’re now submitting and receiving grants that build on the science in this area and may take us all the way to clinical trials. It’s been tremendous.”

Funded in 2017, two years into his assistant professorship in the Department of Pharmacology & Toxicology at the University of Toronto, this grant contributed significantly to growing Dr. Swardfager’s academic career and lab.

“Grants like the AARG that support early-career researchers, and seed funding from organizations like BrainCanada and the Alzheimer’s Association, are essential. This was the first international research grant I received. I cannot overstate the importance of this funding and the number of doors it has opened for my trainees and for me,” shares Dr. Swardfager, who is now a Canada Research Chair.

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Seeing More Clearly

Dr. Eric Smith from the University of Calgary and his team have identified blood and brain imaging markers to distinguish between Alzheimer’s disease and a lesser-known contributor to cognitive decline called cerebral amyloid angiopathy (CAA).

His research was made possible thanks to funding from Brain Canada, through a 2015 Multi-Investigator Research Initiative (MIRI) Team Grant.

Better Diagnosis for Better Treatment

“This funding from Brain Canada was critical in allowing us to identify brain imaging and blood markers for an understudied cause of cognitive decline called cerebral amyloid angiopathy,” says Dr. Smith. “It allowed us to shine a light on less common contributors to dementia that are now more important than ever to consider when we think about individualized treatment options.”

Helping Patients, and Family Doctors

Cerebral amyloid angiopathy, or CAA, accounts for 7% of dementia risk and 20% of all hemorrhagic strokes. It is considered a sister disease of Alzheimer’s disease (AD) but one that is not well known to the general public or family physicians as it is often difficult to distinguish from other causes of cognitive decline.

“I am grateful to Brain Canada for recognizing the need to look at complimentary and novel approaches to better understand cognitive decline in a way that allows us to look beyond Alzheimer’s disease in a silo.”

Dr. Eric Smith

To better understand the commonalities and distinctions between these two diseases, Dr. Smith and collaborators sought to identify markers for CAA in biofluids and brain images.

Pioneering a Whole New Technique

They discovered a new test that can detect beta-amyloid in the blood using white blood cells that ingest beta-amyloid in their journey through our bodies’ blood vessels.

Dr. Peter Stys from the University of Calgary, working with Dr. Smith and his colleagues, developed a technique called AmiraSpec™ that uses highly sensitive probes in blood samples to detect aggregates of beta-amyloid ingested by white blood cells. With leveraged funding from the Weston Brain Institute and a new collaboration with McGill University, Dr. Stys and Dr. Smith are expanding this work. The AmiraSpec™ technology, which has been patented, is now being developed for a broader range of other diseases that are characterized by misfolded proteins, including Parkinson’s disease and multiple sclerosis.

Discovery upon Discovery

Another discovery showed that measuring injury to the brain’s white matter, the reduced ability of brain regions to receive higher blood flow when needed, and brain shrinkage are important imaging markers of CAA in the brain. A recent study by Dr. Smith and colleagues showed that these markers account for 50% of the effect CAA has on cognition.

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First-of-its-kind Study

Brain imaging expert Dr. Catherine Lebel at the University of Calgary has published a first-of-its-kind study focused on youth at risk of serious mental illnesses, including schizophrenia, bipolar disorder, and major depressive disorder. The study is part of a larger 2014 Multi-Investigator Research Initiative (MIRI) led by psychiatrist Dr. Jean Addington at the University of Calgary and funded by Brain Canada and the Hotchkiss Brain Institute.

“We wanted to figure out – who’s going to need support? And can we get them that support early?” explains Dr. Lebel.

All Types of Young Brains

The first step of the project classified youth based on clinical assessments of their risk for serious mental illness and their symptoms. Groups included: healthy controls with no personal or family history of mental illness, people who were healthy but carried a familial risk, people with mild symptoms, people experiencing more significant symptoms but without a diagnosis, and people who received a diagnosis during the study.

The team then collected brain imaging data from these five distinct groups of youth at baseline and after one year todetermine whether the brain showed signs of transition to serious mental illness.

“If you can predict who will transition and develop serious mental illness, you can intervene earlier and maybe prevent it in the ideal circumstance.”

Dr. Catherine Lebel

Seeing Brain Connections

Dr. Lebel and her team used the imaging data to generate “connectomes”, which are essentially maps that illustrate how the brain is functioning as a network. The connectomes map the imaging data for both structural connectivity, which is how white matter is connected within the brain, and functional connectivity, which is how different areas of the brain work together. Using a machine learning model, the team then sought to confirm whether any brain features were distinct across the five categories of youth.

“We looked at the question in a number of ways and we didn’t find any major brain differences between youth who do and youth who don’t yet have – but are at risk for – a serious mental illness,” explains Dr. Lebel. “Maybe there are no differences to be found. But there is still a lot to be learned from an experiment like this.”

Full Spectrum Approach

This approach could serve as a new framework for future studies seeking to predict serious mental illness. Studies of this kind often look at one illness at a time, but Dr. Lebel and her team looked at the full spectrum of mental illness. This choice reflects increasing consensus in the scientific community that in their early stages, serious mental illnesses are often indistinguishable from one another.

Helping Youth and Parents

Dr. Lebel is the recipient of a Bell Let’s Talk-Brain Canada Mental Health Research Program grant where she leads a project focused on improving mental health and parenting through app-based intervention. She is also the recipient of the prestigious 2022 Steacie Prize, awarded annually to a young investigator for outstanding scientific research carried out in Canada.

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Some Genes Put Kids at Higher Risk

Dr. Sébastien Jacquemont was awarded a 2015 Brain Canada Multi-Investigator Research Initiative (MIRI) Team Grant. A medical geneticist and researcher, Dr. Jacquemont seeks to understand why certain genetic profiles put children at a higher risk for autism, schizophrenia, or other neuropsychiatric conditions. This knowledge is key to establishing early interventions and developing tailored therapies.

Creating a Better Test Group

Dr. Jacquemont observed that existing datasets of cognitive, behavioural, and brain measures lacked children with mutations associated with a high risk for neurodevelopmental conditions, who he was often seeing in the clinic. He wanted to develop a cohort of families carrying different genetic mutations associated with these conditions so he could test whether different mutations affecting the same biological function would lead to similar neuropsychiatric symptoms.

Go Big. Go Bold.

Dr. Jacquemont and his team saw value in studying the whole array of mutations at once to assess their influence on the brain and behaviour characteristics. A decade ago, this was a very bold idea. “’Why would you do that?’ I was asked. ‘It’s not going to work. Why not continue to study one mutation at a time?’,” recounts Dr. Jacquemont.

Brain Canada Gets It

Dr. Jacquemont asserts that most funding agencies would not have supported this project. But Brain Canada saw value in Dr. Jacquemont’s approach, and in the team that he assembled to pursue it, including autism expert Dr. Mayada Elsabbagh, neuropsychologist Dr. Sarah Lippé, and neuroimaging expert Dr. Alan Evans, to name a few. The team recruited 400 families to participate in their Brain Canada-funded study and after four years, was able to demonstrate significant correlations between certain genetic mutations and functional connectivity in the brain.

“With many of these same co-investigators, we’ve now turned our Team Grant into a much larger project – Q1K (Québec 1000 Families), which is the largest clinically integrated autism research project in the province of Quebec and one of the largest in the world,” explains Dr. Jacquemont. Q1K received $10 million in philanthropic funding from Fondation Marcelle et Jean Coutu.

“Thanks to Brain Canada investment, we’re officially liberated from the idea of studying one gene at a time.”

Dr. Sébastien Jacquemont

Research Momentum Is Growing

Dr. Jacquemont was also recently awarded a $2.5 million grant from the National Institutes of Health (NIH) to continue his bold approach of studying ecosystems of genes based on their contributions to brain function and behaviour in neuropsychiatric conditions. “There’s no way we would have been able to get the NIH grant if it wasn’t for the preliminary findings of our Brain Canada Team Grant – the hypothesis might have been interesting, but without the preliminary data it simply would not have been funded,” says Dr. Jacquemont.

Data from Dr. Jacquemont’s project is now shared through the Enhancing NeuroImaging Genetics through Meta-Analysis (ENIGMA) Consortium, a network of more than 2,500 scientists from around the world.

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