MOST SIGNIFICANT CONTRIBUTIONS
1. Changing the Approach to Stroke Research and Care in Canada
In 1999 a number of colleagues, both scientists and clinicians, asked me to lead an application to establish the Canadian Stroke Network (CSN). We were successful and were awarded a term of seven years, renewable once, with myself as the CEO and Scientific Director of the CSN.
The CSN’s ultimate goal was the alleviation of the burden of stroke to the individual, their family, and to the nation. By all accounts, the CSN succeeded brilliantly
In its first term, the CSN established a broad partnership that included hospitals and the academic research centres, the Heart and Stroke Foundation, industry and government. It brought together more than 100 scientists and clinicians to work collaboratively within four themes: Better Stroke Prevention, Optimizing Acute Stroke Care, Reducing Cell Death and Minimizing Stroke Damage, and Enhancing Brain Repair and Functional Recovery Post-Stroke. The CSN also accepted the mandate of preparing the future generation of stroke researchers and care providers.
Notably, CSN scientists: described the role of TRPM7 channels in imparting ischemic vulnerability and developed a blocker for them, which is now being tested in a stroke clinical trial, confirmed the need for longer cardiac monitoring to reduce stroke recurrence, determined the Best Practices in stroke prevention, treatment, and rehabilitation, based on a thorough review of the world literature. The Registry of stroke patients not only allowed a number of correlations between premorbid physiological and social characteristics of patients and stroke outcomes, but also identified where energy should be expended to improve services to stroke patients.
The CSN was awarded a second seven year term in 2006, with an unprecedented 35% budget increase, to establish and promote a Canadian Stroke Strategy (CSS). The Strategy, devised by the CSN in partnership with the Heart and Stroke Foundation of Canada, aimed at moving the best stroke research into practice. In prevention, the CSN contributed to setting up stroke prevention clinics across the country. In acute therapy, the CSN instituted a program of national education not only of the public, but also of health care providers – from paramedics to emergency room physicians - thus bringing about a change in the delivery of acute stroke care through coordination of services and implementation of best practice. This has resulted in very substantial improvement (sometimes ten-fold increases) in the rate of t-PA administration in several Canadian sites. Stroke Centres in Ontario hold the international record of administering tPA to 42% of stroke patients arriving within 2.5 hours from stroke, likely the theoretical maximum since not all stroke patients can receive this drug. This is the only known treatment for stroke, but it is time sensitive, which required the CSN to promote the coordination of responses at various points in the care continuum. Economic analysis of this progress in treating stroke patients in the acute phase estimated that billions of dollars are being saved by the Canadian health care system annually.
In rehabilitation, the CSN identified what works, sponsored several double-blind trials to test the new ideas, and proposed a substantial increase in the services available to improve functional recovery after stroke.
Across Canada eight provinces have implemented stroke strategies using the models we have developed.
Despite my growing commitment to improving stroke care in Canada and beyond, I have also advocated that we need to recognize the changing realities of the stroke process itself. In 2007, I described a hypothesis regarding covert strokes which suggested that small vessel disease in the brain, resulting from occlusion of arterioles, is associated with an inflammatory process, and in the same individuals will not only affect their brain with covert strokes impairing cognition, but also their retina leading to macular degeneration and their kidneys leading to renal failure. The article recommended various health care approaches to improve prevention and management of this systemic illness. The scientific and clinical literature in the past five years have confirmed both the enormous impact of small vessel disease and its multi-organ distribution. The literature suggests that there is a significant increase in the prevalence of covert strokes, small infarcts located predominantly in the white matter, which do not result in sudden major neurological deficits but cumulatively can cause dementia. It is estimated that these occur at 8-10 times the frequency of major catastrophic strokes, may be associated with the increase in life-expectancy, obesity and diabetes in western society, and are major drivers of the dementia epidemic worldwide. An article I wrote on the topic appeared in Nature in 2014.
2. International Contributions to Improving Stroke Research and Care
It has also been a particular source of pride to me and to the CSN to be advised that a coalition of European countries proposed in 2006 the establishment of a European Stroke Network patterned on the CSN. I was asked to chair its Scientific Advisory Board. In addition, I was honoured to be invited by Dr. Joel Ménard in France, who was assigned by President Sarkozy the responsibility of establishing a national strategy against Alzheimer’s disease, to spend a few weeks advising him and his colleagues on the most effective methods to alleviate the burden of vascular disease in France. This visit, which occurred in April/May 2009, was supported by the French Government and identified a number of areas where international collaborations may be possible. Also in 2009, I was invited as an advisor to the United Kingdom’s stroke strategy. The Spanish Society of Neurology invited me for their 2009 meeting to address them on the organization of stroke care, as the Spanish Ministry of Health had approved the establishment of a National Stroke Strategy for Spain. I was honoured that they awarded me their Thomas Willis Prize at the meeting. Similarly, the Austrian and Hungarian Stroke Societies asked me to share the CSN’s experiences with them and they presented me with an Honorary Membership in the Austrian Stroke Society. Finally, a symposium organized by the NY Academy of Sciences on thrombolysis in late 2011 allowed me to share with U.S. colleagues the methodology we pursued in Canada to advance stroke care in the acute phase.
Other international responsibilities have included Board membership in the World Stroke Organization from 2006 to 2012, and the chairmanship of their Best Practice Guidelines subcommittee. In this setting, we have conducted the first International Survey of Stroke Care and made an effort to harmonize national Best Practice Guidelines in stroke to produce an international standard of stroke care practices.
3. Laboratory Research
My laboratory-based research activities were frequently guided by my clinical exposure to patients with neurological problems. Specifically, my fundamental research activities have included the study of the biochemical, ionic, molecular and receptor events that determine cerebral vulnerability in metabolic deficiencies and in stroke.
My laboratory described the focal cerebral events that precede the appearance of pathological damage during prolonged deficiency of thiamine and B12. In these settings, and subsequently in focal ischemia, we correlated in time and space the glucose utilization and acidosis that precede the focal appearance of histologically evident damage, and showed how reversing the metabolic or vascular deficiency resulted in a specific sequence of reversal of these metabolic abnormalities.
Subsequently, I focused on cerebral ischemia. I correlated hyperglycemia with the severity of focal acidosis in the first laboratory models of focal ischemia. The association of hyperglycemia with worsened outcome in stroke was subsequently shown in stroke patients. We also showed in the animals that as the ischemia became more prolonged necrosis swept over the penumbra regions where cells die by apoptosis.
My laboratory also reported the dependence of calcium channel activity on focal blood flow changes. In an ischemia-reperfusion model, we showed the reversibility of calcium channel activation with associated tissue survival. This was one of the early proofs that if the ischemic brain is reperfused rapidly, some vulnerable brain regions could be returned to normal function. Concepts derived from these animal studies guided studies I led in stroke patients in the acute phase, using Positron Emission Tomography (PET). We correlated in these patients the anatomic-metabolic-functional parameters with focal cerebral blood flow changes and both radiological and clinical outcomes. These studies allowed us to describe the ischemic penumbra in patients and show its progression in time and space. This and other publications provided intellectual support for the trial of tissue Plasminogen Activator (tPA) a “clot buster”- in the acute setting of stroke in patients. A publication by the Canadian Institutes of Health Research (CIHR) titled “Project Retrosight: A Retrospective Look at Cardiovascular and Cerebrovascular Research” identified this work as having “High Impact” and quoted several reports showing that it converted stroke from a desperate illness with chronic life-long consequences into a treatable condition.
Other laboratory studies I conducted led to the determination of conditions for neuroprotection against ischemic damage, the identification of means of enhancing post-stroke plasticity, and the potential role microparticles play in vascular disease.
4. Contribution to Clinical Research
My clinical studies focused on understanding the cerebral vulnerability to ischemia. My team was among the first to use Position Emission Tomography (PET) in stroke patients to distinguish brain regions where cells are committed to die from those where they are still alive but not functioning. We tested the effect of various therapies administered in the acute phase on brain metabolic and perfusion parameters and correlated these with clinical and radiologic outcomes. I also contributed to studies which confirmed that, in stroke associated with atrial fibrillation, Coumadin was the appropriate therapy to prevent stroke recurrence. I reviewed the lessons learned from negative stroke trials in an article titled: “Toward Wisdom from Failure: Lessons Learned from Negative Stroke Treatment Trials and New Therapeutic Frontiers”.
In my lecture accepting the Willis Award in 2007, I referred to the systemic nature of small vessel disease and advocated for the coordination of clinical and research activities in vascular diseases of these multiple organs, at an international level, rather than the current silo approach. I have also written on measures to improve prevention of vascular diseases, with special emphasis on hypertension management. More recently, I have described in separate articles the negative impact of heart disease, depression and maternal pre-eclampsia on cognitive functions. I have also given multiple public lectures on the role of vascular disease in the impending epidemic of dementia in the world.
5. Other Responsibilities for Research Administration
In 2005, I accepted the position of CEO & Scientific Director of the Centre for Stroke Recovery (the Centre), which I formed in 2002 in partnership with Heart and Stroke Foundation of Ontario, Baycrest Centre for Geriatric Care, and Sunnybrook Health Sciences Centre. The Centre supported an integrated approach to identifying, through multi-disciplinary research, the most effective means of promoting and sustaining stroke recovery. Since the Centre’s inception in 2002, over $33M were raised by the HSFO for the Centre, which announced in 2011 an additional $10M in continued funding for research.
In addition to the national leadership responsibility implied by the Canadian Stroke Network, the Canadian Stroke Strategy and the Centre for Stroke Recovery, I was the Chair of Neurology in Ottawa from 1992 to 2011 and the Director of the Neuroscience Research Program of the Ottawa Hospital Research Institute since 2001. A 2005 Survey by “Science Watch”, an organization that evaluates research effectiveness, identified the Neuroscience Research Program at the University of Ottawa as the group publishing neuroscience manuscripts with the highest per capita impact in Canada. In 2011, I was honoured that my University would select me to be the Founding Director of the University of Ottawa Brain and Mind Institute. The goal of this institute is to develop and support a research strategy in the field of cognition in order to prevent cognitive impairment from occurring and develop strategies to treat it when it does. I was delighted to pass on the leadership of this Institute to my colleague Dr David Park in 2014.
