With no cure for the disease, scientists around the world are conducting research that is leading to breakthroughs in the diagnosis, progression and prevention of Alzheimer’s. Dr. Julie Ottoy, scientist in the Hurvitz Brain Sciences Program, is one of the many researchers at Sunnybrook Research Institute, studying the pathophysiology of Alzheimer’s and what impacts it has on patient outcomes.

Dr. Ottoy’s interest in researching the causes and progression of Alzheimer’s disease started from her personal experiences. Like many Canadians, she has seen firsthand how the disease can impact the lives of family members and friends. Her experiences with her own loved ones and conversations with individuals with lived experience have played a pivotal part in shaping her work.

They remind me time and again that the research we do is about people, their families and their futures.

Dr. Ottoy’s research is working to answer some of the most fundamental questions surrounding Alzheimer’s. Who is most likely to develop Alzheimer’s? In what cases does the disease progress faster? Can we detect changes in the brain before symptoms appear?

Her work specifically focuses on better understanding mixed dementia. This is when Alzheimer’s disease occurs alongside vascular brain damage, which occurs when the blood vessels in our brain are affected and the blood flow to the brain is disrupted. Although mixed dementia is common, it’s not fully understood, making diagnosis and treatment challenging.

Using advanced neuroimaging techniques, like PET and MRI scans, blood-based biological markers, computational biology and AI-based analysis tools, Dr. Ottoy’s research focuses on two overarching themes:

• Mechanisms: To better understand how changes in our blood vessels and immune system contribute to brain changes seen in Alzheimer’s and mixed dementia.
• Biomarkers: To investigate novel biological markers that can aid researchers and clinicians in predicting the progression of these disorders in their early stages.

Her research looks for signs of vascular damage on brain scans, patterns of inflammation and the presence of toxic proteins that form into amyloid plaques and tau tangles. By combining this information, researchers can group patients into more specific subgroups based on the biological changes driving their disease, in turn driving more targeted intervention.

Photo illustration. Kevin Van Paassen/Sunnybrook Health Sciences Centre.

“Alzheimer’s is a very heterogeneous disease, meaning there is a number of different contributing factors and causes for the disease,” explains Dr. Ottoy. “By identifying different subgroups of patients using biomarkers, we are a step closer to creating more tailored treatments that match the individual needs of each patient more closely.”

Another area of her research investigates how well different brain regions connect with one another. The abnormal buildup of tau, one of the toxic proteins in Alzheimer’s disease, leads to cognitive decline in Alzheimer’s disease. Some studies suggest the way brain regions connect with each other is a key mechanism for the spreading of tau. Dr. Ottoy’s work studies these highly-connected regions and tau epicentres, to predict where the tau will build up next.

By studying the interface between the vascular system, immune cells and the spread of Alzheimer’s-specific toxic proteins throughout the brain, scientists can identify novel treatment targets, determine the best time and approach for disease intervention and develop new biomarkers that can inform future clinical trials and potential treatments. Understanding immuno-vascular contributions to dementia is important because both vascular and immune factors are modifiable.

With the advent of disease-modifying treatments, we are closer than ever in meaningfully slowing the progression of Alzheimer’s disease.

Today’s research lays the groundwork for larger-scale initiatives, including multi-site collaborations, like Toronto’s first 7-Tesla MRI, housed at Sunnybrook and part of the Toronto Neuro-Immunology/Imaging Consortium (TONIIC), a multi-site collaborative research initiative focused on neuroimmunology and neuroimaging for diseases such as Alzheimer’s. These research efforts will deepen understanding of disease mechanisms and aid in identifying new biomarkers and therapies.

“My hope is that these advancements will drive the development of combination treatment strategies that reach the clinic and accelerate progress toward precision medicine for neurodegenerative diseases.”

Dr. Ottoy’s research in immune-vascular contributions to dementia is funded by the Alzheimer’s Association and BrightFocus.

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When Janice* began to have trouble with her short-term memory, she and her husband became concerned.

“My dad had been diagnosed with Alzheimer’s disease in his early 60’s, so I had a pretty good view of what it looked like,” says Janice. “I spoke to my family doctor and was later referred to Sunnybrook.”

Janice, who is now in her mid-seventies, was then assessed by Dr. Sandra Black, renowned cognitive neurologist and Scientific Director of the Dr. Sandra Black Centre for Brain Resilience and Recovery at Sunnybrook Research Institute.

After a series of tests, Janice was diagnosed with Mild Cognitive Impairment. The condition is defined when there is a memory problem or other cognitive complaints by the person or their family, but the person is still able to carry out all activities of daily living. MCI can include problems with memory, word finding or way finding, concentration, problem solving insight and judgment.

Dr. Black’s team, which embeds research into care, offered Janice participation in an observational study called the Brain Eye Amyloid Memory (BEAM) study, which provided a detailed eye exam, cognitive testing, mood and daily function questionnaires, and a quantitative brain scan using Magnetic Resonance Imaging (MRI) and Positron Emission Tomography (PET). After participating in BEAM, Janice was found to have amyloid deposits in her brain, and diagnosed with MCI due to early-stage Alzheimer’s disease.

Living with early-stage Alzheimer’s disease

For Janice, living with early-stage Alzheimer’s disease means she now relies more heavily on her husband for support, and spends a lot of her time doing whatever she can to slow down the disease.

“We eat a Mediterranean diet, have switched to non-alcoholic wine, and spend time walking outdoors and exercising in our home gym,” says Janice. Previous research suggests that physical activity and exercise have the potential to lessen amyloid buildup in the brain, while also decreasing inflammation. “We also aim to get 7-8 hours of sleep each night.”

Janice knows the importance of staying engaged with friends and keeping her brain stimulated, using apps like Duolingo and Wordle regularly.

“We’re planning a trip to Paris shortly, so I’ve been practicing my French every day.”

Joining a clinical trial

Janice and her husband with Dr. Sandra Black, cognitive neurologist and Scientific Director of the Dr. Sandra Black Centre for Brain Resilience and Recovery at Sunnybrook Research Institute.

As part of her efforts to potentially slow down the disease, Janice enrolled in a pharmaceutical clinical trial at Sunnybrook investigating a potential new antibody therapy aimed at blocking the tau tangle formation that co-occurs with amyloid plaques in Alzheimer’s disease. At the Dr. Sandra Black Centre for Brain Resilience and Recovery, researchers are actively involved in several trials testing biomarkers (including in the blood and eyes), as well as new potentially disease-modifying treatments for Alzheimer’s disease and other dementias.

The trial Janice is participating in is a double-blinded randomized control trial, meaning that she and the research team are unaware if she is receiving a placebo or the experimental therapy, which is currently being tested for efficacy and safety.

“My hope is potential therapies like these will slow down the disease for me or others. You can’t be unrealistic, but you can be hopeful.”

She visits Sunnybrook with her husband each month for an infusion, and is closely monitored by the clinical trials team, which sometimes includes assessments like cognitive testing, brain imaging, EKGs, and blood work as well.

Although she doesn’t know if the infusions are helping her, she remains positive. “If things don’t get too much worse, we could handle it. We’re doing everything we can.”

Janice’s advice for other people facing a similar situation?

“As soon as you notice something is off, try to save yourself and your family by doing everything you can. Don’t try to hide it. [This disease] is not going to go easy on you, but there is a lot you can do — don’t give up.”

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Alzheimer’s disease is a brain disorder that affects memory and behaviour and interferes with everyday life. As the disease progresses, individuals experience more cognitive difficulties, and can lose their ability to read, walk or recognize loved ones. Some risk factors include age, genetics and sex, however anyone can get it in their lifetime. People with dementia have different experiences, but the effects of the disease are felt by many – patients, family members and friends alike.

While there is currently no cure for Alzheimer’s disease, efforts are being made worldwide to manage the disease. At Sunnybrook, scientists are driving the innovation and treatment of brain health and creating hope for the future.

Improving diagnosis and treatment

Much of the international criteria we have now for Alzheimer’s disease and other dementias is thanks in part to contributions from The Sunnybrook Dementia Study, a 25-year observational study measuring and monitoring changes in patients with dementias, vascular disease and other neurodegenerative diseases. Led by Dr. Sandra Black, cognitive neurologist and senior scientist at Sunnybrook, this study began in 1995 and is applying advanced MRI, genetic testing and cognitive and functional assessments at yearly intervals to measure and monitor changes in patients with neurodegenerative diseases.

The study has been a success thanks to its multidisciplinary team and importantly, the more than 1600 patient participants explains Dr. Black. “We learn from our patients, engage them in a partnership — it’s research embedded in care.”

Some of these patients may go on to participate in one of the many Alzheimer’s clinical trials at Sunnybrook. There are currently participants in several pharmaceutical studies that are working toward potentially modifying the disease by testing antibody therapies that can remove amyloid plaques in the brain. One example is the AHEAD study, which is exploring whether an investigational treatment can slow or stop the earliest brain changes due to Alzheimer’s disease. Researchers can detect changes in the brain of those with Alzheimer’s disease up to 20 years before symptoms begin. The goal of the AHEAD study is to prevent the development of memory loss and other symptoms, before the plaques cause too much damage to the brain.

While not yet approved in Canada, researchers and clinicians are also excited about new blood tests, available through research trials, that are being used for screening those at higher risk of developing Alzheimer’s disease. In addition to this screening process, amyloid PET scans are done using Sunnybrook’s Cyclotron facility, Health Canada’s only approved tracer for detecting amyloid deposits in the brain.

“Thanks to rapidly advancing precision medicine technologies, Alzheimer’s disease may soon become a preventable and treatable condition,” says Dr. Black. “This is a very exciting time in research, given the increasing prevalence of Alzheimer’s disease in Canada’s aging population.”

Addressing changing dementia demographics

In the past 20 years, Canada’s population has changed, but much of our scientific understanding of dementia risk factors is based on populations of European descent. As the population profile of dementia patients is projected to change, more research is needed to address the unique needs and experiences of diverse communities. The Canadian Multi-Ethnic Research on Aging (CAMERA) study aims to understand the risk factors of Alzheimer’s disease in diverse ethnic groups in Canada.

The study, led by Dr. Jenny Rabin, scientist in the Hurvitz Brain Sciences Research Program at Sunnybrook Research Institute, is following 300 participants, free from significant cognitive impairment, across three different ethnic groups: individuals from European, South Asian and Chinese descent. The study will allow researchers to study the earliest changes associated with Alzheimer’s disease and other cognitive disorders. CAMERA is the first study in Canada that brings together brain imaging and cognitive measures to investigate risk factors for dementia in a multi-ethnic cohort.

“This knowledge will ultimately allow us to develop more effective dementia prevention and intervention strategies for Canada’s diverse communities,” says Dr. Rabin.

Changing the course of the disease

The biggest risk factor for Alzheimer’s disease is age. Most individuals diagnosed with dementia are over the age of 65, however about one per cent of people with Alzheimer’s will have the genetic form known formally as autosomal dominant Alzheimer’s disease (ADAD). Also referred to as early-onset familial Alzheimer’s disease, the condition is genetically inherited or passed down through families. Individuals will begin to experience cognitive decline as early as their 30s. In Canada, there are more than 25,000 people under the age of 65 living with dementia.

“In the prime of your life, you’ll begin to experience memory loss, then develop changes in behaviour, such as trouble controlling emotions. You may lose your inhibitions. Eventually, you will lose the ability to communicate,” says Dr. Mario Masellis, neurologist and associate scientist at Sunnybrook.

In Alzheimer’s diagnosis and treatment, time is of the essence – the Dominantly Inherited Alzheimer Network Trials Unit (DIAN-TU) drug trial, is working toward slowing down, even potentially stopping, dementia symptoms in those predisposed to the Alzheimer’s gene. Dr. Masellis is leading the trial at Sunnybrook, one of the few Canadian sites taking part in the global study. The trial is testing two drugs that aim to lower the levels of the substance that causes amyloid plaques in the brain, which play a central role in Alzheimer’s disease.

Because early-onset dementia makes up a small number of dementia cases, there are fewer support systems for those patients, who may begin to experience cognitive decline while they’re still raising a family or growing their career. Research from the DIAN-TU trial can lead to the development of early intervention and prevention therapies to help people with early-onset Alzheimer’s disease.

The Garry Hurvitz Brain Sciences Centre

Sunnybrook’s new Garry Hurvitz Brain Sciences Centre, currently under construction, is a collaborative, state-of-the-art facility that will bring together clinical and research spaces to continue to advance Alzheimer’s diagnosis and care.

There may not be a cure yet, but the future of Alzheimer’s treatment is promising, thanks to the work of dedicated scientists and healthcare professionals at Sunnybrook and around the world.

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In a recently published preclinical study, Dr. Isabelle Aubert, senior scientist at Sunnybrook Research Institute and postdoctoral researcher Dr. Kristiana Xhima successfully used focused ultrasound to non-invasively deliver a therapeutic in the brain, targeting brain cells affected by Alzheimer’s disease and improving cognition.

The study has been published in the journal BRAIN.

This is the first study to demonstrate that repeated focused ultrasound blood-brain barrier modulation in the basal forebrain is safe in the presence of Alzheimer’s pathology, and when combined with a growth factor-related therapeutic, can lead to therapeutic effects. Focused ultrasound harnesses the power of sound waves to transiently open the blood-brain barrier, a protective barrier that prevents toxins or potentially helpful therapeutics in the bloodstream from entering the brain.

This promising research comes at an urgent time. It is estimated that more than 600,000 Canadians are currently living with dementia. According to a recent report from the Alzheimer’s Society of Canada, rates of dementia, including Alzheimer’s disease, are projected to rise to nearly 1 million people in Canada by 2030. Below, Drs. Aubert and Xhima discuss how their breakthrough research is an important advancement on the road to developing effective therapeutic approaches for the disease.

Dr. Aubert and Dr. Xhima

What was the impetus behind your study?

Dr. Aubert: This preclinical study was a follow-up to our previous proof-of-concept study that used MRI-guided focused ultrasound to non-invasively deliver a type of growth factor-related therapeutic (D3) to brain cells called cholinergic neurons, which are important for learning and memory and most vulnerable in Alzheimer’s disease. D3 stimulates important signaling mechanisms in brain cells that are related to the tropomyosin receptor kinase A (TrkA) pathway. The TrkA pathway is critical for neuroprotection, plasticity and survival of cholinergic neurons; engaging it with D3 promotes the resilience of brain cells against Alzheimer’s pathology.

In our first proof-of-concept study, we had found that D3 combined with focused ultrasound efficiently stimulated key survival and neuroprotective pathways, and in the short-term, helped to restore brain cell communication (also known as neurotransmission). Yet for clinical translation and impact, it was critical for us to study whether focused ultrasound combined with D3 could rescue cognitive function – the rationale and goal of the current study.

What did your current study find?

Dr. Xhima: In this preclinical study, we demonstrated the therapeutic potential of D3 in a preclinical model of Alzheimer’s and showed its impact on learning, memory and cognitive flexibility. The D3 therapeutic agent, like many promising therapeutics, does not have the properties required to efficiently cross the blood-brain barrier (BBB) and reach its targets deep in the brain. To overcome this challenge, we coupled the intravenous administration of the therapeutic drug D3 with MR-guided focused ultrasound to non-invasively, locally and transiently increase BBB permeability in key brain regions for the effective delivery of D3 from the blood to the brain.

Following brain delivery of the therapeutic agent with focused ultrasound, performance in cognitive tasks was improved. The treatment of focused ultrasound with the therapeutic D3 led to enhanced neurotransmission in cholinergic neurons, which are highly vulnerable to injury in Alzheimer’s disease. We also observed beneficial effects on brain regeneration – new brain cells were formed in the hippocampus, an area of the brain that plays a major role in learning and memory, and amyloid plaques, common in Alzheimer’s, were reduced in targeted brain areas.

What could these results mean for patients and clinicians in the future?

Dr. Aubert: Although still early-stage, this work is an important and fundamental step in the development of potential treatments for the disease. The results also open the door for many other regenerative agents, that normally do not cross the BBB, to be tested and delivered using this drug-delivery platform. This is the first study to demonstrate that a growth-factor related agent delivered to the basal forebrain and associated cortical and hippocampal areas repeatedly using focused ultrasound BBB modulation is safe and can lead to therapeutic effects in the presence of Alzheimer’s pathology. These results provide a major step forward in terms of drug delivery that can be very promising for clinical translation.

Dr. Xhima: Another key feature of this preclinical research is that we tested focused ultrasound delivery of a TrkA-stimulating agent in the presence of established Alzheimer’s pathology. In contrast to many previous studies, here we showed that this therapeutic approach rescued cognition and improved Alzheimer’s related pathologies once they were already established, similar to how patients would present in the clinic. The beneficial effects of the treatment were also broad with respect to several key systems affected in Alzheimer’s disease. This makes us very hopeful about this therapeutic approach because it certainly represents an important step forward for potential clinical development.

What’s the next step in this work?

Dr. Xhima: The improvements in cognitive function we saw in the preclinical models studied lasted for several weeks, which raises the question: how often will treatment need to be repeated for therapeutic effects that can last over months and years?

Dr. Aubert: In addition to this, we’re interested in taking an exploratory approach to look at other molecular pathways in the brain that could also be affected by this treatment, since our results went beyond what was expected with target engagement on cholinergic neurons alone.

It’s important to note that this research is still at an early stage and has not yet moved to clinical trials. We are hopeful that this fundamental research will translate into the clinic in the near future, as we continue to explore therapeutic options to stop degeneration and promote regeneration in Alzheimer’s disease and dementia.

Hear Dr. Aubert and Dr. Xhima discuss their findings in further scientific detail on the BRAIN podcast, the official podcast of Brain and Brain Communications.

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Despite the statistics, innovative research is underway at Sunnybrook to help bring hope to the fight against Alzheimer’s and dementia.

“We may be entering a new era with possible effective treatments for this disorder which affects whole families and is increasingly prevalent with populations aging,” says Dr. Sandra Black, director of the Dr. Sandra Black Centre for Brain Resilience and Recovery. “Continued research is critical as we aim to develop and discover meaningful treatments and prevention strategies for Alzheimer’s and dementia.”

Here are just some of the innovative ways that Sunnybrook clinicians and researchers are on the leading edge of research in the detection, prevention, and treatment of Alzheimer’s and dementia.

Apathy and Agitation in Alzheimer’s

At Sunnybrook, clinical studies are underway on apathy and agitation in Alzheimer’s patients, where researchers are exploring ways to help decrease apathy in patients. This can help increase their interest in activities and their emotional responsiveness, which may help improve their quality of life, as well as their caregivers’.

Early on-set dementia

In a world-first study, a team of Sunnybrook scientists are trying to identify biomarkers, or biological clues in the brain, such as blood flow, that could demonstrate an early-onset frontotemporal dementia in people who have a genetic predisposition to the disease.

 

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Innovative technology

Researchers are also looking for innovative ways to deliver medicine or therapeutics directly to the areas of the brain involved in Alzheimer’s disease.

Preclinical research is exploring the delivery of gene therapy to treat Alzheimer’s and help improve memory and boost brain health.

One of those methods uses focused ultrasound technology, where ultrasound waves are precisely directed to a targeted area of the brain to help open the blood-brain barrier (BBB), which can allow potentially helpful medications to reach brain regions involved in Alzheimer’s and dementia, without having to use scalpels. Research teams have shown evidence that the BBB can be temporarily opened safely using focused ultrasound, an exciting first step in exploring a new way for therapeutics to be delivered to the brain.

Who will get Alzheimer’s disease?

Sunnybrook scientists are also using artificial intelligence and machine learning to try and detect early signs and symptoms of dementia to improve treatment and prevention of the disease.

Research is also underway to learn more about risk factors for dementia among diverse ethnic groups including individuals of South Asian and Chinese descent, as these groups are often under-represented in dementia studies.

The latest Sunnybrook research has also demonstrated that having poor vascular health may accelerate cognitive decline in patients with dementia and small vessel disease.

Preventing Alzheimer’s

Researchers are finding out how lifestyle can protect individuals from dementia.

While it is critical for cutting edge studies to continue in the search for new treatment and care for patients with Alzheimer’s and dementia, it can also be helpful for individuals to take action themselves to learn more about dementia and how activity can help boost brain health in more ways than one.

From prevention to diagnostics and potential treatment innovations, “We’re at the forefront of discovery for dementia and Alzheimer’s at Sunnybrook,” says Dr. Black. “There’s a lot to be optimistic about.”

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“The main theme of both studies is that people who have both Alzheimer’s disease and poor vascular health decline much more quickly than people who have only one of these conditions,” says Dr. Rabin, a scientist at SRI in the Hurvitz Brain Sciences Program.

There is growing evidence that vascular health and Alzheimer’s disease are closely intertwined, and that poor vascular health may promote the build-up of amyloid and tau in the brain, the two abnormal proteins associated with Alzheimer’s disease. “Preventing vascular disease may also help to prevent Alzheimer’s disease,” says Dr. Rabin.

The findings of the first study were published in Brain and the results of the second study were published in Neurology. Both are highly prestigious journals. Dr. Rabin, who was the only Canadian researcher involved in the studies, collaborated with U.S. colleagues to conduct the research.

Scientist Dr. Jennifer Rabin

What did you learn about the connection between CAA and Alzheimer’s disease?

The Brain study looked at a cerebrovascular condition known as cerebral amyloid angiopathy (CAA), which results from the build-up of amyloid in the blood vessel walls of the brain. When there is accumulating amyloid in the vessel walls it can cause vascular brain changes, such as small hemorrhages and blood flow problems. Although amyloid plays a central role in both CAA and Alzheimer’s disease, the two conditions are considered distinct.

The study is titled, “Cerebral amyloid angiopathy interacts with neuritic amyloid plaques to promote tau and cognitive decline.”

Dr. Rabin and colleagues from multiple U.S. centres asked the question: What influence does CAA have on the build-up of tau (the more detrimental hallmark pathology of Alzheimer’s disease) and cognitive decline, either alone or in combination with amyloid burden?

They analysed data from 1,722 autopsied subjects recruited from one of three long-running medical studies. Data included annual clinical and cognitive evaluations, along with neuropathology. The researchers tested associations between CAA, tau burden and cognitive decline, both independently and together with amyloid burden.

They found that the combination of CAA and higher amyloid levels were associated with the greatest tau burden and the fastest rates of cognitive decline.

“Not everyone with CAA has Alzheimer’s disease and not everyone with Alzheimer’s disease has CAA. But they do co-occur at a high rate,” says Dr. Rabin. “We found that if you have both of these conditions, you were much more likely to have tau burden and faster cognitive decline.”

How do classic vascular risk factors affect the brain?

The study in Neurology looked at whether classic vascular risk factors, such as obesity, high blood pressure, smoking and diabetes, leads to faster brain tissue loss and faster cognitive decline when they co-occur with amyloid.

The study is titled “Association of β-Amyloid and Vascular Risk on Longitudinal Patterns of Brain Atrophy.”

Dr. Rabin and colleagues from Massachusetts General Hospital analysed clinical and neuroimaging data from 196 subjects in the Harvard Aging Brain Study, a long-standing, community-based study.

They found that people who had multiple vascular risk factors and high levels of amyloid had greater rates of brain tissue loss and cognitive decline over time. “The take away,” says Dr. Rabin, “is that managing vascular risk factors may slow the progression of Alzheimer’s disease dementia.” This includes controlling blood pressure, lowering cholesterol, maintaining a healthy weight, and refraining from smoking. A good rule of thumb is that what’s good for the heart is good for the brain.

What do these results mean for patients and care providers?

These two studies provide greater support for the idea that vascular health and Alzheimer’s disease interact in ways that increase the likelihood of a dementia diagnosis. “These findings have implications for developing treatments for Alzheimer’s disease,” says Dr. Rabin, “because they suggest that vascular health should be taken into account. Treatments that target poor vascular health and Alzheimer’s pathology are likely to be the most effective.”

How you can get involved

If you are interested in getting involved in Dr. Rabin’s research studies, please send an email to cbhlab@sunnybrook.ca.

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By developing advanced machine learning and artificial intelligence (AI) models and applying them to some of the largest data sets in the world, Dr. Goubran’s team is learning to detect, with greater precision than ever before, cognitive decline years before symptoms arise. Also at the heart of this work is discovering what minute structural and functional changes and network breakdown within the brain can be used as biomarkers, or early/accurate indicators, of neurodegenerative disorders.

“A key missing piece in neurodegeneration research are the algorithms that learn from large amounts of individual data from magnetic resonance imaging (MRI), PET scanning, genomic analysis, and demographics, combined with results from cognitive testing, that can be applied in the clinic,” says Dr. Goubran, a scientist in the physical sciences platform at SRI. “This work is of critical importance because it can provide urgently needed guidance on prevention and personalized treatment decisions.”

[mks_pullquote align=”left” width=”300″ size=”20″ bg_color=”#ffffff” txt_color=”#000000″]“This work is of critical importance because it can provide urgently needed guidance on prevention and personalized treatment decisions.”

Dr. Maged Goubran
Scientist
Sunnybrook Research Institute

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Alzheimer’s disease is one of Canada’s greatest healthcare challenges, currently having a devastating emotional and physical burden (directly or indirectly) on more than 1.1 million people. This number is expected to rise dramatically in the next 20 years. The disease has an estimated health care cost of $10.4 billion annually.

A big focus of Alzheimer’s research and care has been on preventing symptoms earlier in the progression of disease. This tactic relies on identifying healthy adults at high risk of future cognitive decline; these people may have small changes in their brains starting a few decades before the first symptoms appear. While much research has been done in this area, Dr. Goubran and his team are improving on previous approaches in several ways: by building more powerful computational models than in the past, by using larger, more robust population data sets, by focusing on individual rather than group-level predictions (to address the large patient variability) and by pinpointing Alzheimer’s progression in asymptomatic rather than only symptomatic individuals.

Tracking progression of disease

Dr. Goubran is building on earlier research that establishes shrinkage of the hippocampus as a possible early sign of dementia. The hippocampus is the brain’s centre for memory and navigation; it is often one of the first areas to be impacted by Alzheimer’s disease.

The team is developing AI algorithms to map changes in not just the volume but also the shape of the hippocampi (and its subdivisions), as well as other important structures and vascular lesions of the brain during aging. The models are informed by hundreds of brain MRIs from multiple studies including the Sunnybrook Dementia Study led by Dr. Sandra Black, senior scientist and director of the Sandra Black Centre for Brain Resilience and Recovery at SRI. The researchers will use these imaging biomarkers and a normative population of thousands of Canadians to track and predict patient progression.

Others around the world will benefit from these AI techniques, as the team will validate and share them as open-source tools. “We plan to make our algorithms publicly available and easy to use for the research community,” says Dr. Goubran. For patients and clinicians, this could mean improved diagnosis, customized treatments, and better ways to monitor disease-modifying therapies currently being studied.

Mapping network changes

Another area of his research involves studying how well different brain regions are connecting with one another. Altered connectivity could signal problems down the road. “In neurodegenerative diseases like Alzheimer’s, a network disorder, there are a lot of changes in function and structure of brain networks, so we’re doing also a lot of work on that front, trying to develop novel signatures of network dysfunction,” says Dr. Goubran.

This research direction has two foci. One is preclinical work in the laboratory to develop newer signatures (read-outs) of network dysfunction in Alzheimer’s models. The other is developing new computational techniques to analyse functional and diffusion MRI scans in order to better understand and map network changes in-vivo and develop biomarkers. Dr. Goubran was recently awarded a New Investigator Grant from the Alzheimer Society of Canada to help support this work. He collaborates closely on these projects with Dr. Bojana Stefanovic, Dr. JoAnne McLaurin, Dr. Jennifer Rabin, and Dr. Black, as well as groups at McGill and Harvard universities.

The hope is that when altered connectivity between brain regions is detected, a combination drug treatment that targets abnormal buildup of two proteins involved in Alzheimer’s disease – amyloid and Tau – will slow deterioration of key cognitive networks or, if caught early enough in the pre-symptomatic stage, may be able to restore normal connectivity and cognition.

“We’re hoping our work will lead to larger scale efforts to develop combined therapies that will eventually get to the clinic and really push the development of personalized medicine for neurodegenerative diseases,” says Dr. Goubran.

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Dementia is an umbrella term used to describe a decline in thinking abilities that is severe enough to interfere with one’s day-to-day activities. While some degree of forgetfulness is completely normal as we age, the memory loss experienced in the context of dementia is much more severe.

AD is the most common cause of dementia, and is defined by the abnormal build-up of two proteins in the brain: amyloid plaques and tau tangles. The build of these proteins leads to the death of brain cells, which causes the brain to shrink and impacts memory and thinking abilities.

There are many risk factors for dementia. Some, like older age and genetics, can’t be changed. But recent research has shown that up to 40 per cent of dementia cases are linked to risk factors that people can control.

Vascular Risk Factors

Vascular Risk Factors (VRF) are conditions that affect the health of blood vessels that supply oxygen and nutrients to the brain. These include high blood pressure, high cholesterol, obesity, diabetes and smoking. Each of these conditions on their own can increase the risk of dementia, and when they present together, the risk is even higher.

The good news is that we know how to treat VRF. If you have been prescribed medication for high blood pressure, high cholesterol or diabetes, take it as directed and keep up with routine doctor visits. Eat a healthy diet and exercise regularly, as these lifestyle changes can reduce the risk of these conditions. There are also effective strategies to manage obesity and smoking, so don’t hesitate to reach out to your health care team. A good rule of thumb is that what’s good for the heart is good for the brain!

Cognitive Reserve

Cognitive reserve refers to your brain’s ability to cope and keep working, even in the face of damage from diseases like AD. Research has suggested that engaging in mentally stimulating activities throughout own’s life can help build up a high cognitive reserve, offering some protection from AD and other dementias.

Because of these findings, researchers now recommend keeping your mind active throughout your whole life, especially after you retire.

It’s not clear which activities may be most beneficial for the brain, so choose any challenging activity you enjoy. Some examples include playing chess, learning a new instrument or language, doing a puzzle or even socializing with family and friends.

Physical Activity

Several studies have shown that regular exercise can significantly reduce the risk of developing dementia. In our own research, we found that people who engaged in regular physical activity – even in older adults with Alzheimer’s changes in their brain – had less decline in their memory over time compared to those who were sedentary.

It doesn’t really matter what type of physical activity you engage in, as long as it elevates your heart rate. We know that people are more likely to exercise if they participate in activities they enjoy. Choosing social activities, like walking and dancing, can have the added benefit of exercising the body and the mind. Current guidelines suggest doing at least 150 minutes of moderate intensity activity per week, but remember that some movement is always going to be more beneficial than nothing.

Sleep

All of us know that a bad night’s sleep can impair our ability to think the following day. Research has also shown that getting too few hours of sleep may also increase the risk of  developing AD and dementia. It appears that sleep acts like a dishwasher, helping clear out harmful toxins – including amyloid –  from the brain.

To optimize quality sleep, try to go to bed at the same time each night and get up at the same time each morning. Make sure your bedroom is quiet, dark and at a comfortable temperature. Avoid using electronic devices two to three hours before going to sleep. Also, engaging in physically activity during the day can reduce the time it takes to fall asleep at night.

For people who gravitate towards naps, keep in mind that in some cases they can be a sign of a larger health issue or insufficient stimulation during waking hours. Generally, naps can be restorative, as long as they are limited and don’t interrupt your normal and healthy wake/sleep cycle.

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