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Discoveries and Innovations

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BRAIN IMAGING TO BETTER UNDERSTAND FOOD INTAKE REGULATION AND OBESITY IN HUMANS

Obesity now recognized as a neurobehavioral disease resulting from a neurological vulnerability combined with an environment referred to as obesogenic. The obesity characterized by an excessive fat accumulation in the abdominal cavity reflects an increased risk of developing metabolic disorders, including type 2 diabetes, cardiovascular diseases and hypertension. Recent studies show that obesity is linked to an impaired cognitive function and an increased risk of neurodegenerative diseases. It was even suggested that metabolic disorders linked to obesity may result in alterations in the function and structure of the brain, explaining the link between obesity and a cognitive dysfunction.

Over the last few years, the development of brain imaging techniques, such as magnetic resonance imaging (MRI), allowed us to revolutionize our understanding of the human brain. Thanks to these more and more advanced techniques, it is now possible to study exactly the structural and functional complexity of the brain. By way of example, structural MRI generates high-quality anatomical images allowing us to examine the relationship between characteristics of the brain structure (for example, the cortical or subcortical volume and the cortical thickness) as well as the behaviours or the development of some pathologies. Functional MRI (fMRI), for its part, is an imaging technique which allows visualizing the activity of the human brain in response to a cognitive task. This method, now used in several areas of research, allowed us to better understand how the human brain performs complex executive functions. Research works of Dr. Andréanne Michaud use these imaging techniques in order to better understand the neurobehavioural determinants regulating food intake and obesity in humans.

In an interesting way, several recent MRI studies show that obese individuals are characterized by gray matter atrophy in brain regions involved in decision-making and emotional control. White matter atrophy as well as increased sensitivity to food stimuli are also observed in these individuals. The mechanisms explaining observed changes in the brain in a context of obesity are not yet understood. As we know, bariatric surgery is an effective treatment which may result in a significant weight loss and a resolution for comorbitities, in individuals with severe obesity. So, it represents an ideal model to assess whether such changes enable to reverse the neurobehavioural alterations observed with obesity.

Our ongoing work, in close collaboration with the bariatric surgical team, aims, among others, to examine the brain function and the neuroanatomical and neurobehavioural changes occurring in response to a weight loss induced by this surgery. Execution of this work is possible thanks to the existence of the advanced imaging platform, at the Institute’s Research Centre, providing researchers state-of-the-art equipment including one 3 Tesla MRI. The first results from this longitudinal study are pretty striking since we observe a rapid recovery of the white matter and the grey matter volume following surgery, suggesting the plasticity of the brain structures after weight loss and improved metabolic alterations. The use of brain imaging techniques, in combination with numerous behavioural and metabolic measurements, will allow us to better understand the weight-loss effect and the concomitant improved metabolic complications on the structure and function of the human brain, in addition to allowing the identification of mechanisms that underlie these changes.

There is no question that the potential applications of brain imaging in obesity are promising and will contribute in an interesting way to improve our understanding of food intake regulation in humans. Other research projects at the Institute will also use these innovative techniques to assess the effects of new pharmacological and nutritional interventions on food intake regulation and weight loss in humans. To term, all of this work will allow us to better understand the neurological causes and consequences of obesity and to improve the management of individuals who suffer from it.

Andréanne Michaud, Ph. D.

Prevent

PROJECT ÇA MARCHE DOC!: TO RAISE PUBLIC AWARENESS ABOUT THE RELATIONSHIP BETWEEN URBAN PLANNING AND HEALTH, ONE WALKER AT A TIME!

Surveys conducted in Quebec and in Canada indicate that health is the most important concern among the population. Health professionals have, in the eyes of the last, very great credibility. The synergy created between urbanism and medicine is new information that fosters the interest of citizens. It is a great incentive to change by allowing us to reach and to convince an audience not converted to the now been proven benefits of the presence of urban trees, green spaces, pedestrian networks, bicycle paths and collective transportation on a decreased prevalence of cardiovascular and respiratory diseases, mental illnesses, cancer and other chronic conditions.

The project Ça marche Doc! is a unique achievement that brings as well people together, emerged out of the desire to put on the map this relationship between health and urban planning to the population and to decision makers, in order to direct cities toward the development of supportive environment to health.

Proposed by Drs. Paul Poirier, cardiologist and researcher at the Institute, and Johanne Elsener, DMV, the project Ça marche Doc! is multifaceted. It started in 2016 by a series of 39 radio commentaries on ICI Radio-Canada Première and continued in the fall of 2017 with 41 television programs on MAtv. The objective of the project is to highlight, in a way that is fun and educational, the scientific knowledge in terms of planning and health.

Ça marche Doc! is also the result of a fruitful partnership between the Centre intégré universitaire de santé et de services sociaux (CIUSSS) de la Capitale-Nationale, the Centre intégré de santé et de services sociaux (CISSS) de Chaudière-Appalaches, the CHU de Québec – Université Laval, the Institut universitaire de cardiologie et de pneumologie de Québec – Université Laval, the Institut national de santé publique du Québec, the Green Fund through the Government of Quebec’s 2013–20 Action Plan on Climate Change and several external partners, such as the Université Laval, the Conseil régional de l’environnement de la Capitale-Nationale, Radio-Canada and MAtv. The contribution of multiple partners is central to the success of this project combining everyone’s expertise, which includes different types of stakeholders and that addresses themes aiming at moving to action for the creation of health-promoting planning. In fact, the project recently received the 2019 Prix d’excellence de la santé et des services sociaux in the category Partenariat.

The essence of the project Ça marche Doc! remains its exploratory walks accompanied by a physician in a different urban environment in the Capitale-Nationale or Chaudière-Appalaches. They are free, open to all without registration and take place on Saturday mornings from September to June. They aim to raise awareness and to explain to people, in a strategy of preventive medicine, the importance of moving and increasing the urban tree canopy and the modal shift toward collective and active transportation. Several medical studies have proven that not appropriate urban planning cause significative negative health impacts on exposed populations. Conversely, numerous studies demonstrate that urban trees, green spaces and shift toward collective and active transportation have a protective effect on health.

According to some studies, the urban greening could decrease by about 39% the prevalence of stress, 7% the prevalence of depression, 11 to 19% the prevalence of autism, 14% the risk of diabetes, 13% the risk of arterial hypertension, and 40% of the risk for overweight or becoming obese. In countries of high-income economies like Canada, the air pollution has been linked to 33% of the cardiovascular diseases, 16% of the COPD, 12% of the lower respiratory tract infections, and 8% of the trachea, bronchus or lung cancers. Particularly, in the Quebec City region, the atmospheric pollution has been linked to about 300 premature deaths on an annual basis. In addition, recent studies link air pollution to dementia. However, the urban trees could capture about 24% of the fine particles from polluted air. Considering the annual cost estimates of these diseases in Quebec, their decreased prevalence by greening would allow to term to save significant sums of money in health care. This does not include the beneficial impact of urban greening on climate change mitigation, and on other diseases that were not accounted for (ADHD, allergic rhinitis, skin cancer, etc.). These data are still largely unknown to the general public.

Over the next few years, two factors will have a major impact on costs related to health care. The aging of the population is one of them. In a recent study from the Centre for Interuniversity Research and Analysis on Organizations, the public health spending report on the Government of Quebec’s revenues will move from 42.9% to 68.9% of the total incomes between 2013 and 2030. The other factor is related to climate change. This time, an Ouranos study, published in 2015, has proven that public health spending associated with the context of climate change will increase on an annual basis of about $800 M (in millions of $ in 2012) by 2065. An urban greening becoming optimal coupled with a shift toward sustainable mobility could alleviate these impacts. Ça marche Doc! helps to raise awareness among the general public and the decision makers to these issues while proposing inspiring solutions related to urbanism in order to allow people to do exercise in safe and pleasant environments. Finally, a project like Ça marche Doc! is exportable in all regions of Quebec. If each region rally a group of motivated people like the Ça marche Doc! team, it would have a positive impact on chronic diseases far beyond the medication intake that is very costly in Quebec. We must think about taking seriously this shift (supportive urban planning, exercise and good nutrition), because in health, we have to ask ourselves if we still have the means to realize our ambitions…

Paul Poirier, M.D., Ph. D., FRCPC, FCCS, FACC, FAHA

Cure

HISTORY OF A DISCOVERY AT THE INSTITUTE, HALF A CENTURY OF CLINICAL AND GENETIC EXPLORATION: THE INHERITED CAUSE OF A NEW FAMILIAL FORM OF EMPHYSEMA FINALLY REVEALED

By the wealth of its clinical activities, the Institute is a conducive environment that values discovery. Working in a referral hospital in cardiology, respirology and obesity, which serves eastern Quebec, the physicians from the Institute are regularly exposed to unusual clinical situations, sometimes intriguing and are requiring innovative approaches in order to resolve them.

We are in 1992 and Dr. François Maltais, who start his clinical practice in respirology at Hôpital Laval, assesses four people with an unusually early and severe form of emphysema. The clinical assessment quickly highlighted that these individuals belonged to the same family, in which emphysema seemed to be transmitted from one generation to the next in the form autosomal dominant. Interestingly, this family does not suffer from the Alpha-1 antitrypsin deficiency, the only inherited form of emphysema recognized and that was described in the early 1960s. Dr. Maltais is also informed that three other members of this same family who were affected by emphysema were assessed and being cared for at Hôpital Laval in the 1970s and 1980s by Drs. Lionel Montmigny, Pierre Corriveau and Marc Desmeules, respirologists. In fact, Dr. Maltais has only rediscovered what his predecessors had already suspected, namely the inherited character and the unusual nature of the emphysema transmitted within this family. Given that the clinical observation is not sufficient to confirm the genetic character of a disease, it was not possible to do more at that time, due to a lack of modern tools in genetics.

Some 20 years later, in 2012, always in the context of his clinical practice, Dr. Maltais assesses two other people with early and severe emphysema. To his great astonishment, it was actually members of the same family already identified in the 1990s.

Here, being able to work in an academic environment, where the clinician scientists are regularly collaborating with PhD researchers, becomes so important. Under the leadership of Dr. Denis Richard, Ph.D., the Institute’s Research Centre was booming and recruited in 2008, Dr. Yohan Bossé, a researcher in genetics who have an interest in chronic respiratory diseases such as asthma and emphysema. This one was quickly made aware of this family incredible story and the two researchers were sharing their expertise and initiated a research project, which will involve a clinical, physiological, tomodensitometric, and genetic assessment of a large number of members from it. Between 2014 and 2017, it is therefore 55 members of this family, representing five generations who will be hence assessed by the research teams. To this you can add the assessment of medical records from eight people who died when this research project was launched.

Using genomic and bioinformatics approaches, researchers listed all the genetic variations found in DNA of these family members and then reveal the one that was transmitted with the disease. That is the way the genetic cause of emphysema in this family could be identified. It is a deleterious mutation in the gene encoding the protein tyrosine phosphatase non-receptor type 6 (PTPN6 or SHP-1), which is located on chromosome 12. The carriers (heterozygotes) of this mutation are particularly susceptible to the development of early, severe and often lethal pulmonary emphysema. Compared to the only other cause of hereditary emphysema reported, the Alpha-1 antitrypsin deficiency, the penetrance of the mutation in the gene PTPN6 for the development of emphysema is much higher. The genetic predisposition for the development of emphysema is much higher for this new mutation compared to the Alpha-1 antitrypsin deficiency. Indeed, 21 of the 27 heterozygous individuals that were studied have emphysema while only a fraction of people with Alpha-1 antitrypsin deficiency are affected by this. The mutation identified in this family results in a loss of function for the SHP-1 protein, a negative modulator of several immune cells, and an important regulator of many pro-inflammatory pathways. The prestigious journal “The Lancet Respiratory Medicine”, in fact, recognized the great interest of this discovery by publishing the scientific article that summarizes this work in its May 2019 issue. This also inspired a New York artist in creating the achievement which appears on this issue cover.

This second form of hereditary emphysema discovered is important, not only for members of this Quebec family, for whom knowing the cause of the disease that afflicts them provides some comfort. These hope, of course, that this discovery could lead to an effective and a specific treatment. Research is not there yet, but is allowed to hope. Indeed, researchers think it will be possible for them to upregulated the mutant protein activity and in so doing correct the consequences of the genetic deficit. Research works under the direction of Dr. Mathieu Morissette are, in fact, already well underway thanks to the availability of a murine model carrying the same mutation as the family. The Canadian Institutes of Health Research just in fact awarded Dr. Morissette, jointly with Drs. Yohan Bossé, Ynuk Bossé and François Maltais, an important grant which will allow moving the research forward to discover new treatments for emphysema. This important discovery could also benefit the far too numerous individuals with emphysema, for whom it could lead to developments in therapeutics for a disease still today incurable and too often deadly.

Central to this discovery, the unique and fertile environment what constitutes the Institute. The proximity of clinical and basic research teams within this Institute offers countless opportunities. The sample collection from the Institute’s biobank, the clinical and genetic expertise, the availability of modern tools in genetics and most of all, the presence of competent research professionals as well as graduate students able to take advantage of these tools and to interpret the results were crucial elements that led to this discovery. In addition to Drs. Bossé and Maltais, the research team included Maxime Lamontagne, Nathalie Gaudreault, Christine Racine, Marie-Hélène Lévesque, Benjamin M. Smith, Dominique Auger, Alisson Clemenceau, Marie-Ève Paré, Louis Laviolette, Victor Tremblay, Bruno Maranda and Mathieu C. Morissette.

Researchers also relied on an exemplary collaboration from numerous members of this family, who were studied over five generations, an exceptional situation for the research in genetics. Research works were supported by the IUCPQ Foundation and the Fonds sur les maladies respiratoires J.-D. Bégin – P.-H. Lavoie, as well as the Canadian Institutes of Health Research.

François Maltais, M.D.
Yohan Bossé, Ph. D.