Translating research into practice: Investigating the impact of Alzheimer’s disease diagnostics in Canada (IMPACT-AD)

Early and accurate diagnosis of Alzheimer’s disease is critical as timely access to health care and community services has the potential to slow disease progression and improve quality of life. Current approaches for diagnosis rely on traditional imaging tests and observation of the signs and symptoms of the disease. Adding the measure of proteins found in cerebrospinal fluid (biomarkers) has been shown to help correctly identify the disease and predict those with mild symptoms that are likely to progress to dementia; however, such testing is not readily available in Canada.

The IMPACT-AD study specifically addresses barriers to uptake and use of Alzheimer’s disease biomarker testing in the Canadian health care system. This Canada-wide study will develop a comprehensive understanding of how biomarkers for Alzheimer’s disease impact clinical decision making and health care costs. Collaborating with patients, caregivers, and physicians, IMPACT-AD will also investigate the effect of testing on personal decision-making. The findings of this study will lay the necessary groundwork, modernize, and improve the care available to Canadians affected by Alzheimer’s disease and related forms of dementia.

IMPACT-AD is led by Dr. Mari DeMarco, a clinical chemist at St. Paul’s Hospital, and a clinical associate professor in Pathology and Laboratory Medicine at UBC. DeMarco is joined by a multidisciplinary team that includes both Canadian and international laboratory medicine specialists, geriatricians, neurologists, health economists, rural/remote clinicians, ethicists, and statisticians.

IMPACT-AD is funded by the generous support of Brain Canada, Michael Smith Foundation for Health Research, UBC Faculty of Medicine, Djavad Mowafaghian Centre for Brain Health, and Women's Brain Health Initiative; it is also being undertaken in collaboration with the Canadian Consortium on Neurodegeneration in Aging.

For more information about the study and how you can get involved, visit www.impactAD.org.

Delivery of self-management through a peer-support telehealth intervention in patients with cardiovascular disease: The Healing Circles Project

MSFHR is contributing matched funding for Dr. Scott Lear’s research, one of 22 projects as part of the Canadian Institutes for Health Research (CIHR) eHealth Innovation Partnership Program (eHIPP). eHIPP was designed to address gaps in health care—including supporting seniors with complex care needs in their home—by stimulating collaborations between health researchers and Canadian innovative technology companies. MSFHR is also contributing funds towards the eHIPP research projects of Drs. Ellen Balka and Kendall Ho.

Cardiovascular disease (CVD) is a leading cause of death and disability in Canada, resulting in an estimated $22.2 billion in health care costs and lost productivity annually. Older adults are afflicted more than any other population, with many dealing with complex chronic conditions in isolation.

Patient self-management has been found to play a key role in improving patient health and reducing hospital admissions. Correspondingly, social and peer support, and timely access to credible information on managing CVD, are essential for patient self-management and quality of life. Over a four-year period, Dr. Scott Lear, a professor in the Faculty of Health Sciences and the Department of Biomedical Physiology and Kinesiology at Simon Fraser University, and his team based at St. Paul’s Hospital, will study the use of a new application, Healing Circles, that offers support to seniors with CVD while staying in their homes and communities.

Healing Circles is a private and secure peer support and self-management platform created through a partnership between university-based researchers, industry, decision-makers, clinicians and patients. The Healing Circles application, accessible on smartphones, tablets, and desktop or laptop computers, was developed by Curatio, a digital mobile health company, headquartered in Vancouver. Expansion of the use of Healing Circles by seniors with CVD builds on Lear’s pilot study of the application involving women with heart disease from across Canada. After ten weeks, the women reported being better able to manage their health through the peer support and knowledge gained.

Healing Circles Project participants form virtual 'Circles' with 8 to 10 other patients to connect with and support one another as they learn to live day-to-day with their CVD. Additionally, the 250 study participants can interact with all members of the wider Healing Circles community to share experiences. Investigators anticipate that CVD patients using the Healing Circles platform in their homes will have improved self-management skills compared to patients receiving usual care, and improved quality of life, preventing secondary complications and reducing the need for health care and hospital use.

Understanding a potentially common upper airway disorder: Empty nose syndrome

Empty Nose Syndrome (ENS) is thought to be an unusual outcome of sinus surgery due to excessive loss of nasal tissues, particularly from a pair of structures called the inferior turbinates. Turbinates usually function to warm and humidify air flowing into the nose. Patients with ENS often have severe nasal symptoms and develop very poor quality of life as well as mental health problems. As a result of these mixed symptoms, ENS patients are often misdiagnosed, mismanaged, and left to their own devices.

Our research has shown that ENS patients can be identified based on specific clinical symptoms and imaging of the sinuses. We have also found that by rebuilding structures within the nasal cavity known as inferior turbinate augmentation (ITA) we can greatly improve nasal function. However, little is known about the specific changes in nasal function with ENS, how mental health problems develop, or how to best treat these patients.

Our objectives are three-fold: 1) to measure the patterns of nasal airflow and sense of smell present in ENS patients by using computer analysis and smell testing; 2) to understand how ITA might improve function in ENS patients by measuring nasal airflow and sense of smell before and after surgery; and 3) to study the impact of ENS on mental health using depression and anxiety survey scores, and then measure the change in these scores after ITA to study the relationship between the nasal and mental health problems in ENS. By studying the relationship between nasal and psychiatric symptoms in ENS we will both improve our understanding of how this syndrome develops and improve our understanding of how surgical interventions might help mend these symptoms.

Understanding the aging HIV lung from dysbiosis to cell injury

Patients with human immunodeficiency virus (HIV) are now living to older ages thanks to effective anti-HIV medicines. Despite these gains, many of them suffer from chronic lung disease that greatly impacts their ability to carry out their daily activities and impairs their quality of life. The type of lung disease they face is similar to what longtime smokers develop, a progressive narrowing of the airways and destruction of the lung. However, in HIV, the process appears to be accelerated and more severe. It's not unusual, for instance, to see patients in their 30s and 40s develop this lung disease (which is approximately 30-40 years earlier than expected). Also, it's not unusual for HIV patients who have never smoked before to develop this kind of disease. Unfortunately, the traditional medications we use to treat lung disease often interact with anti-HIV medicines, causing severe side effects. Management of breathing symptoms in HIV patients is therefore difficult and it is imperative that we find better agents to combat lung disease in this population. Only by understanding what causes and drives this lung injury process can this goal be achieved, though.

Multiple studies have now shown that smoking alone cannot explain the lung disease phenomenon in HIV. I believe that HIV injures the lung in a two phase process. First, the virus directly breaks down the protective layer of the airway known as the epithelium. Second, over time, as patients develop repeated lung infections due to their weakened immune systems, the bacterial community of the lung or microbiome shifts. I believe that this community disruption results in molecular changes that age the lung faster. My approach is to perform an in-depth investigation into the epithelium of the airway using two innovative methods. To explore the injury that HIV inflicts on the airway, I have created a novel model of the HIV airway using HIV-infected cells co-cultured on a cell culture model of the airway epithelium. We will use this model to see how HIV-infected cells break down the protective barrier of the lung. To explore the shifts in the microbiome, I have collected airway cells from HIV-infected and uninfected patients to not just describe what bacteria exist in the airway but also to determine what effect the community differences between the two groups have on the function of genes in the cells. We will measure how 'old' these cells are and compare these findings to uninfected patients.

Developing personalized anti-arrhythmic drug therapy for atrial fibrillation

Atrial fibrillation (AF) is the most common heart rhythm disorder. With an aging population, the number of people with AF is expected to rise dramatically. People with AF are twice as likely to die, are five times more likely to have a stroke, can develop worsening heart muscle function, and have a lower quality of life. We have learned that a person's genetic makeup, or DNA, has a major impact on their risk of developing AF; but we have a limited understanding of why, or how to use this information to treat people in a safer and more effective way. People with AF first receive drugs to control their irregular heart rhythm. Even people who have procedures to treat AF are also prescribed drugs. This is particularly important in the group of patients who have persistent AF, who require electrical or chemical therapy to change their heart rhythm, as the success of surgical procedures in this population is well below 50%. Unfortunately our current drugs are generally ineffective, and can be unsafe, with little progress in drug development over the last two decades.

With these challenges in mind, the first goal of my research program is to identify and understand the genes that play a role in the development and progression of AF, and determine which are most common and most important in the Canadian population. To do this, I am gathering a biobank of AF patients and performing the largest scale detailed genetic testing in this population to date. I am also focused on understanding the effect that genes can have on the safety and efficacy of rhythm controlling drugs, and have already started a trial, funded by the Canadian Cardiovascular Society, that will link a person's genetic makeup to these important outcomes. I will then be able to take this large clinical and genetic data set to the laboratory where we have developed the unique ability to generate patient-specific stem cell disease models of AF. The ultimate goal of my research program is to directly tailor therapy for AF patients based on their genetic makeup, using information from clinical research and personalized disease modeling.

 

Addressing morbidity, mortality and health care costs among patients evaluated for addiction care in acute care settings

Substance use disorders account for a significant burden of disease among Canadians and place an enormous burden on the acute care system. The annual cost of harms associated with substance use in Canada is estimated to be approximately $40 billion, with health care being the single largest contributor. In British Columbia (BC) there is clear urgency to address this challenge, given the recent steady increase in hospitalization rates due to substance use and the unprecedented number of drug overdose deaths prompting the recent declaration of a public health emergency.

While in hospital, individuals with a substance use disorder often have access to evidence-based addiction care, though successfully transitioning these individuals from acute to community settings remains a key clinical and research challenge. Specifically, this patient population often leaves hospital against medical advice, may be non-adherent to addiction care recommendations and often requires costly repeat hospital readmissions. Addressing these circumstances is critical, given the enormous cost implications and opportunity for more effective addiction services to dramatically reduce morbidity and mortality.

Specifically, investigating acute substance use needs and long-term solutions in acute care through after-care environments presents an urgent clinical health research priority given the frequent intersection between individuals with a substance use disorder and hospital environments. To address this, the proposed research project will establish a prospective cohort study of hospitalized individuals with a substance use disorder who are assessed for treatment of their addiction. Individuals will complete a one-time questionnaire and provide consent to the use of their personal identifiers for linkage to a variety of health care databases to allow for ongoing community follow-up over a five-year period. Creation of this study will offer the unique opportunity to identify patient characteristics of individuals accessing addiction care in the hospital setting, evaluate patient flow and predictors of outcome between hospital and community settings and determine subsequent health outcomes and health care utilization. In doing so, this research platform will generate evidence that will contribute to future interventions and knowledge advancement, and help inform best practices for the optimal delivery of addiction treatment to this population with high morbidity and mortality.

Understanding the spatial and contextual inequities of health access and use by people living with or vulnerable to HIV in British Columbia

Access to health care services is critical to improving the health and well-being of people living with or vulnerable to HIV. Factors such as density of services or neighbourhood violence play a substantial role as barriers or facilitators to health care access in broader populations, but limited research is available to show that this is also true for people living with or vulnerable to HIV. This study will investigate, within BC:

  1. The distribution of access and use of health services, especially health services in HIV testing and treatment.
  2. The barriers and facilitators related to access.
  3. How to develop a rigorous methodology to capture, quantify and analyze data on access and use of health services.

The proposal will draw data from several large, multi-year studies conducted by the BC Centre for Excellence in HIV/AIDS and will link to external datasets for the development of key measures. This project will focus on analyzing data regarding health care services utilization across different regions in BC over time. The proposal aims to improve access to services for earlier diagnosis and improved treatment for people living with HIV.

Investigation of aging-related pathways associated with an increased risk of emphysema in HIV-infected patients

Because antiretroviral therapy has enabled people to live longer, those with HIV now face a growing epidemic of age-related chronic diseases such as chronic obstructive pulmonary disease (COPD). The reason for this increased risk, however, remains unknown. Compelling evidence suggests that HIV infection triggers an inflammatory process which causes the premature aging of inflammatory and structural cells due to cell exhaustion from repeated divisions and oxidative stress. This concept of “inflamm-aging” (coined by Claudio Franceschi) applies fittingly to the development of COPD as well, where the primary trigger is cigarette smoke.

Given the dual pro-inflammatory states of HIV and COPD, Dr. Leung hypothesizes that the accelerated development of emphysema in HIV is driven in part by inflammation-induced cell aging related to the HIV infection and potentiated in the lungs by cigarette smoke. Dr. Leung's laboratory has found peripheral leukocyte telomere lengths, a marker of cell senescence, are shorter in HIV-infected patients who also have COPD compared to HIV-infected patients without COPD. Those with the most severe airflow obstruction on spirometry and those with the greatest extent of emphysema as visualized on CT scanning also appear to have the shortest telomere lengths. The laboratory group is now exploring whether similar relationships hold in lung cells obtained from HIV-infected patients.

The role of the airway epithelium NLRP3 inflammasome in asthma pathogenesis

Asthma is a respiratory disease that afflicts more than two million Canadians. Asthmatics experience both airway inflammation and changes in the airway structure, called airway remodeling, when they inhale allergens, pollutants and other insults, and this leads to an exacerbation. The airway epithelium is the first site of contact for inhaled substances and has been shown to be different in asthmatics than in non-asthmatics. In specific cells of the body, including the airway epithelium, a danger sensor called the “inflammasome” can signal as part of the immune system to produce inflammation in response to an insult. Currently, we do not know if this airway epithelium danger sensor functions differently in asthmatics than in members of the general population and if this contributes to the development and progression of asthma.

Dr. Jeremy Hirota's hypothesis is that if the airway epithelium danger sensor is present, it increases airway inflammation and contributes to development and progression of asthma. His research goal is to determine the specific mechanisms responsible for airway epithelium danger sensor activation and to find out if it is more active in asthmatics. He is using three distinct approaches for his proposed research: 1) Using lungs that have been donated for medical research, he will compare the danger sensor between non-asthmatics and asthmatics. 2) Using the same donated lungs, he will grow human airway epithelial cells and expose them to an allergen or mechanical wound and then measure the resulting inflammation. 3) He will explore the role of the airway epithelium danger sensor during periods of allergen exposure by comparing normal mice to mice with a dysfunctional danger sensor.

The increasing prevalence of asthma in Canada demonstrates a requirement for a greater understanding of mechanisms leading to disease development and for new approaches to prevent or treat this disease. This research has the potential to highlight new therapeutic targets to control both excessive airway inflammation and the development of asthma.

Innate immunity and its influence on cardiovascular function

In Canada, severe infection, or sepsis, is the most common acute illness causing death. Patients with severe infections can go into shock as a result of progressive cardiac collapse and can die within 24 to 48 hours. The mortality rate of sepsis is 40%. The fact that this rate has not changed in the last 30 years illustrates that very little is known about how infection causes cardiovascular dysfunction and that very little is known about the best ways to prevent this from occurring.

Dr. John Boyd's research program is using a two-pronged approach to understand how sepsis causes progressive cardiac collapse. The objective of his clinical research program is to identify prognostic factors and to characterize the cardiac response to infection in patients with sepsis. Specifically, he is focusing on very early enrollment of acutely ill patients with infection presenting to the St. Paul's Hospital emergency department in order to identify prognostic factors such as new biomarkers and the presence of emerging infections. He will characterize their cardiovascular response to infection using a bedside cardiac ultrasound. Although previous work in this area has been done, patients were recruited from critical care units 24 to 36 hours following admission, too late to identify prognostic markers and intervene to improve outcome.

As a complementary approach, Dr. Boyd's pre-clinical (basic) research program is taking a molecular approach and using the immune system as a tool in the fight against cardiovascular collapse. He has identified a "counter-regulatory" receptor which appears able to reverse the heart damage induced by other receptors in the same family. The identification of this receptor will hopefully lead to the development of a targeted intervention for sepsis-related cardiovascular dysfunction. Dr. Boyd's clinical research program aims to answer simple but as-yet unstudied questions such as the optimal volume of IV fluid and how one can reliably diagnose infection. Although the results of his laboratory work are not yet close to reaching the bedside, they may potentially lead to therapies in the future.