By 2031, there will be a projected 674,000 Canadians living with dementia. Early detection of dementia risk will thus be critical to reducing dementia prevalence. Circadian rhythms (i.e. the ~24-hour biological clock) are critical to the maintenance of the sleep-wake cycle, and sleep-wake disturbances are common in people at risk for and living with dementia. Several studies have identified circadian risk factors for cognitive decline and dementia using wrist-worn actigraphy (a common field measure for indexing the sleep-wake cycle of circadian rhythms). However, there are opportunities to use the power of artificial intelligence, specifically machine learning (ML), to enhance the sensitivity and specificity of wrist-worn actigraphy (WWA) for detecting sleep-wake cycle disturbances which are associated with increased dementia risk. Thus, I will use ML and WWA data from the UK Biobank (90,000+ participants with valid data) to identify risk factors for dementia from the 24-hour sleep-wake cycle. The results of my project may provide a non-invasive and sensitive method to identify patients at greater risk for cognitive decline and dementia.
Research Location: Djavad Mowafaghian Centre for Brain Health
Targeting amyloid propagation in Alzheimer disease: Structures, immunology and extracellular vesicle topology
Dr. Neil Cashman is one of five BC researchers supported through the British Columbia Alzheimer’s Research Award. Established in 2013 by the Michael Smith Foundation for Health Research (MSFHR), Genome British Columbia (Genome BC), The Pacific Alzheimer Research Foundation (PARF) and Brain Canada, the goal of the $7.5 million fund is to discover the causes of and seek innovative treatments for Alzheimer’s disease and related dementias.
As the incidence of Alzheimer’s disease (AD) continues to increase worldwide, a treatment or prevention for AD is a top priority for medical science. One of the main hallmarks of the disease are protein plaques that form inside the brain, and are believed to be the primary cause of brain cell (neuron) death. Research has shown that the protein, amyloid-β (A-beta) is the main component of these plaques.
While there are many forms of A-beta produced by brain cells, the specific one that causes AD is hotly debated by scientists. Dr. Neil Cashman, a neuroscientist and neurologist at the University of British Columbia (UBC) has discovered a novel way of identifying a unique form of A-beta that can become toxic and inflict the damage associated with AD.
Cashman, who holds the UBC Canada Research Chair in Neurodegeneration and Protein Misfolding, and his team have discovered immunological compounds that specifically recognize the potentially toxic form of the A-beta protein, and can exclusively detect this form in the brains and spinal fluids of AD patients. Furthermore, Cashman found that normal, healthy control patients did not have this dangerous form of A-beta. It was also found that some healthy people naturally develop immune responses against their A-beta oligomer-specific target.
Cashman’s team will exploit this knowledge and their unique tools to learn how toxic A-beta proteins can spread from cell-to-cell and region-to-region in the brain causing AD. The discoveries by Cashman’s lab may provide an effective early diagnostic tool for the disease, and ultimately could lead to the development of a preventative vaccine to neutralize the toxicity of abnormal A-beta, potentially slowing or stopping the spread of neurodegeneration in the brain.
Propagated protein misfolding of SOD1 in ALS: Exemplar for neurodegeneration
MSFHR supported Dr. Neil Cashman’s award as one of two interprovincial teams from across Canada funded through Brain Canada’s Multi-Investigator Research Initiative (MIRI) in 2013. The MIRI supports the research of multidisciplinary teams and aims to accelerate novel and transformative research that will fundamentally change the understanding of nervous system function and dysfunction and its impact on health. MSFHR committed funding over three years to support the work of Cashman’s BC-based research activities and research led by fellow MIRI recipient Dr. Terrance Snutch on the role of brain calcium channels in brain disorders. Additional support was provided by Genome BC, the University of British Columbia (UBC)/Vancouver Coastal Health and two Quebec-based research institutes.
Amyotrophic lateral sclerosis (ALS), better known as Lou Gehrig’s disease, is a progressive fatal disease that affects the nerve cells responsible for muscle movement (motor neurons). ALS is characterized by the systematic paralysis of muscles due to the progressive death of motor neurons. An estimated 2,500 to 3,000 Canadians suffer from the disease, for which there is no cure or effective treatment. Each day, two to three people are lost to ALS, with 80 percent of affected individuals dying within two to five years of diagnosis.
A study led by clinical neurologist and neuroscientist Dr. Neil Cashman at UBC has revealed how factors that cause ALS can be transmitted from cell to cell throughout the nervous system and suggests the spread of the disease could be blocked, pointing to new therapeutic approaches.
Neurodegenerative diseases like ALS belong to a larger group of illnesses known as protein misfolding diseases. Cashman, who holds the UBC Canada Research Chair in Neurodegeneration and Protein Misfolding, built on his hypothesis that certain proteins implicated in ALS, when abnormally shaped or misfolded, are prone to accumulate and cause motor neuron death. This disease mechanism has also been found in other neurological diseases, such as Alzheimer’s and Parkinson diseases.
Cashman’s team used therapeutic antibodies that target and block these misfolded proteins to better understand the protein misfolding process and how the disease is transmitted throughout the nervous system. Cashman’s work can lead to identifying the best ways to stop the progressive neurological damage seen in ALS through the development of targeted treatments.
Brain channelopathies – Target validation and novel therapeutic strategies
MSFHR supported Dr. Terry Snutch’s award as one of five interprovincial teams from across Canada funded through Brain Canada’s Multi-Investigator Research Initiative (MIRI). The MIRI supports the research of multidisciplinary teams and aims to accelerate novel and transformative research that will fundamentally change the understanding of nervous system function and dysfunction and its impact on health. MSFHR committed funding over three years to support the work of Snutch’s BC-based research activities and research led by fellow MIRI recipient Dr. Neil Cashman on the role of protein misfolding in Amyotrophic Lateral Sclerosis (ALS).
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CCNA Team 13: Frontotemporal dementia
Dr. Robin Hsiung’s research is part of the Canadian Consortium for Neurodegeneration in Aging (CCNA) initiative funded by a national partnership between the Canadian Institutes of Health Research (CIHR) and 14 organizations from the public and private sectors across Canada, including MSFHR. The CCNA was created in 2014, bringing together more than 350 clinicians and researchers from across Canada. Organized into 20 teams based on their area of specialized expertise, researchers will focus on preventing and delaying the onset of dementia, as well as improving the quality of life for the estimated 560,000 Canadians affected. MSFHR is also supporting the research of two other BC-based researchers leading CCNA teams: Dr. Neil. Cashman (protein misfolding) and Dr. Cheryl Wellington (lipid and lipoprotein metabolism).
Frontotemporal dementia (FTD) is a progressive neurodegenerative syndrome, and the second most common cause of young-onset dementia after Alzheimer’s disease. FTD is an umbrella term for a diverse group of disorders characterized by the gradual wasting away of the brain’s frontal and anterior temporal lobes, progressively affecting mental function, personality and behaviour, while leaving memory largely intact.
Dr. Ging-Yuek Robin Hsiung, an associate professor in the Department of Medicine (Division of Neurology) at the University of British Columbia (UBC), and staff neurologist at the UBC Hospital Clinic for Alzheimer and Related Disorders, is leading the CCNA Frontotemporal Dementia (FTD) Team.
The team of more than 15 researchers from 8 institutions across Canada will examine the factors that cause FTD and explore new laboratory and imaging techniques to help identify and distinguish the various types of dementia. The goal of the FTD team includes establishing a registry of FTD subjects from across Canada that will contribute genetic and epidemiological information and organized into a national repository of samples. The data will provide important insights into related neurodegenerative disorders such as Alzheimer’s disease and amyotrophic lateral sclerosis (ALS), as well as other more uncommon brain disorders including ancorticobasal degeneration (CBD) and progressive supranuclear palsy (PSP).