Antoine M. Hakim, O.C., MD, PhD, FRCPC

Telephone: 613-562-5462
Fax: 613-562-5403
Roger Guindon Hall (see Contact page for maps)

Director, Neuroscience, Ottawa Hospital Research Institute

Senior Scientist, Neuroscience, Ottawa Hospital Research Institute

Professor & University Chair, Neurology, University of Ottawa

CEO & Scientific Director, Canadian Stroke Network

Founding CEO and Scientific Director, Heart and Stroke Foundation Centre for Stroke Recovery

Dr. Antoine Hakim was first an engineer and at the age of 29 began his medical training at The Albany Medical College in New York. In 1979 he completed his residency in Neurology at the Montreal Neurological Institute at which time his research career in stroke began.
Dr. Hakim's research interests have included the study of the biochemical, ionic, molecular and receptor events that determine selective cerebral vulnerability in stroke and other conditions, the determination of conditions for neuroprotection against ischemic damage, and investigation of post-stroke plasticity and means of enhancing it.

He has experience in the private, academic and hospital sectors, and has chaired and served as a member of many committees and boards of granting agencies, foundations, hospitals and professional associations. In addition to teaching, research, and administrative duties, he maintains clinical duties as a neurologist at The Ottawa Hospital. He has received many honours during his career, including the Jonathan Ballon Award in 1985, Researcher of the Year in Ottawa Award in 1995, Award of Excellence by the Canadian Stroke Consortium in 2000, and the Ottawa Life Sciences Council Career Achievement Award in 2004. In 2005 the Canadian Stroke Network, a Network of Centres of Excellence originally awarded to Dr Hakim in 2000, was renewed for another 7-year cycle with a 30% increase in budget. In 2007, he was honoured to receive the Thomas Willis Award, a Lifetime Achievement Award from the American Stroke Association and delivered the Thomas Willis Lecture at the International Stroke Conference in San Francisco. He was appointed Officer of the Order of Canada in 2007. Also that year he received the MEDEC Award for Medical Achievement from Canada's Medical Device Technology Companies. In 2008, he was the 2nd Prize Winner of the STROKE Journal's Innovation Award for an article on brain small vessel disease entitled "Living Beyond Our Physiological Means". Also in 2008 he received the Dr. J. David Grimes Research Career Achievement Award from the Ottawa Hospital Research Institute. He was honoured in 2009 to participate in the review of the UK Stroke Initiative and Chair the European Stroke Network's external scientific committee. He is an advisor to the French strategy against Alzheimer's disease. He is Chair of the Best Practice Guidelines Subcommittee of the World Stroke Organization and a member of that organization's Board of Directors. In 2009, the Heart and Stroke Foundation of Ontario announced an annual research grant of $100,000 to be named the "Dr Tony Hakim Innovative Stroke Research Award" for an "out of the box" project proposal in the field of stroke recovery. Dr. Hakim was awarded the 2009 Thomas Willis Prize by the Spanish Society of Neurology in November 2009. In 2010, Dr. Hakim received the Partners In Research Biomedical Science Ambassador Award, Scientific Category. Finally, Dr. Hakim has been invited to give the "Hans-Chiari" lecture to the Austrian Society for Stroke Research in 2011.

Dr. Hakim wishes to recognize that his activities in support of scientific discovery and its application to improve stroke prevention, care and rehabilitation were only possible because of the commitment and dedication of many individuals and organizations at the University of Ottawa, at the Canadian Stroke Network, the Heart and Stroke Foundation Centre for Stroke Recovery, and the Canadian Stroke Strategy.

RESEARCH

1. Research Activities

A. Laboratory Studies
My laboratory-based research activities were frequently guided by my clinical exposure to patients with neurological problems. During my neurology residency I was intrigued with Wernicke-Korsakoff patients who exhibit severe memory deficits in association with alcoholism and thiamine deficiency but show only very limited brain lesions. I began to study how systemic conditions result in focal brain damage. This led to an interest in stroke because of the selective nature of the damage caused by ischemic deprivation. Specifically, my fundamental research activities have included:

Investigation 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, e.g. the appearance of alkalosis. The simultaneous measurement of pH and glucose utilization or blood flow was made possible by an innovation to autoradiography we developed involving sublimation of the pH marker after we had measured its radioactivity in brain.

Subsequently, I focused on cerebral ischemia and correlated hyperglycemia with the severity of focal acidosis in that setting. The association of hyperglycemia with worsened outcome in stroke was subsequently shown in stroke patients. Concepts derived from our animal studies guided studies we performed 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 radiological/clinical outcomes. These studies allowed us to describe the ischemic penumbra in patients and show its progression in time and space. We went back to the animals and showed that cells in the penumbra region die by apoptosis while those in the ischemic core die by necrosis, and verified that as the ischemia becomes more prolonged necrosis sweeps over regions of apoptosis. This led us to investigate the molecular determinants of apoptotic cell death, and we showed that cyclin-dependent kinases trigger apoptosis and that inhibiting them leads to neuroprotection. We also reported that activating neuronal-apoptosis-inhibitory-protein (NAIP) provides neuroprotection in the setting of apoptotic cell death.

My laboratory also reported the dependence of calcium channel activity on focal blood flow changes, and in an ischemia-reperfusion model, showed the reversibility of calcium channel activation with associated tissue survival. In the stroke patients, we used PET to study the effect of administering nimodipine on metabolic function. Because clinical trials were contemplated with nimodipine, we studied and reported the kinetics of binding of nimodipine in vivo, which allowed us to suggest in various forums the enormous challenge this agent would face as a therapeutic modality.

Determination of conditions for neuroprotection against ischemic damage:
We first studied the relevance of interstitial glutamate levels on selective vulnerability in ischemia by correlating glutamate levels with activity of the calcium channels and histological outcome. This led us to investigate the concept of preconditioning, whereby short-duration ischemia, cortical depolarization, exposure to excitatory amino-acids or activation of calcium channels can improve the brain's resistance to subsequent ischemic damage. First, we described how short term global ischemia protects against subsequent focal ischemic damage, and then more thoroughly studied cortical spreading depression (CSD) as a laboratory tool to explain the preconditioning phenomenon and potentially use it therapeutically. We showed that CSD activated neurotrophic factors, decreased intra-ischemic glutamate levels, and down-regulated the transporters of the excitatory amino acids. More recently, we showed a number of molecular correlates of CSD, including a recent submission describing the changes in inflammatory cytokine protein levels in brain and plasma following CSD. My research colleagues and I are currently directing our attention to the modulation of a limited number of factors thought to play a role in the neuroprotective cascade.

Investigation of post-stroke plasticity and means of enhancing it:
My laboratory showed the regulation of nestin expression in focal brain injury. This is one of several developmental proteins activated in focal ischemia. Our special attention to this protein arose from our correlation of its activation with the mobilization of stem cells following focal ischemia, confirming that nestin is an essential protein in stem cell guidance. We have also published on the effect of low-dose amphetamine in patients recovering from stroke. This work has implications for our understanding of recovery and therapy after stroke.

B. Clinical Research Activity
My clinical studies focused on understanding the cerebral vulnerability to ischemia. I used PET in stroke patients to distinguish brain regions where cells are committed to die from those where they are still alive but not functioning, and 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. More recently we 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 this article, we outlined the shortcomings shared by previous stroke trials and described the experiments needed to increase the likelihood of success in translational stroke studies, a theme subsequently confirmed by the STAIR group. More recently, using data from the Registry of the Canadian Stroke Network, we reported the effect of calcium channel blockers on the outcome from stroke and showed that they could be beneficial. We are currently studying, using the data set in the Registry, the influence of statins on vulnerability to bleeding in response to t-PA in stroke patients. Earlier this year, we submitted a proposal to our Institutional Review Board to evaluate the response of stroke patients to Granulocyte Colony Stimulating Factor, an agent which releases bone marrow stem cells into the circulation and which may accelerate recovery from stroke.

2. Changing the Approach to Stroke Research and Care in Canada and Beyond
In 1999 a number of my colleagues, both scientists and clinicians, asked me to lead an application to establish the Canadian Stroke Network (CSN). Although this was a very competitive process, we were successful and were awarded a term of seven years, at $4.5M per year. I am the CEO and Scientific Director of the CSN. This organization brought together more than 100 scientists and clinicians to work collaboratively within a broad partnership that includes the academic research centres, the Heart and Stroke Foundation, industry and government. CSN's research falls 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". In addition to research and partnership development around stroke, the CSN accepted the mandate of preparing the future generation of stroke researchers and care givers. The CSN's ultimate goal is the alleviation of the burden of stroke to the individual, their family, and to the nation.

In its first term the CSN has established a new approach to stroke research. Multi-disciplinary, inter-institutional collaborations were formed to address major research challenges in the field of stroke and to ensure that the results of this research are translated into health and economic benefits. This approach produced a number of important research contributions. CSN scientists evaluated a potential role for stem cells in stroke, described the role of TRPM7 channels in imparting ischemic vulnerability and developed a blocker for them which are now being tested in phase I-II trials. CSN scientists also showed calcium movement in previously-unknown hemichannels which may activate inflammatory pathways. Based on a thorough review of the world literature, experts within CSN have also determined the best practices in stroke rehabilitation, and these are currently being tested in trial settings. The Registry of stroke patients has allowed a number of correlations between premorbid physiological and social characteristics of patients and stroke outcomes. Finally, in its first term the CSN put together a broad financial partnership which contributed to training 45 stroke scientists and clinicians.

The CSN has just been awarded a second seven year term, with an unprecedented 35% budget increase, to continue its research and 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, is a plan that starts with the premise that the best stroke research must be moved into practice. This strategy builds on the interactions developed by the CSN between basic researchers, clinicians and partner organizations and has been gaining momentum over the last four years. Working with health-care providers, patients, stroke champions, local partners and dedicated politicians, the CSN is committed to change the delivery of stroke care by ensuring the most recent stroke knowledge is transferred to health-care providers and implemented with patients. In prevention, the CSS proposed a broad coalition aimed at setting up stroke prevention clinics across the country. In acute therapy, the CSS instituted a program of national education not only of the public, but also of health care providers, 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. This is the only known treatment for stroke, but it is time sensitive requiring coordination of responses at various points in the care continuum. In rehabilitation, the CSS has identified what works, sponsored a double-blind trial to test it further, and proposes a substantial increase in the services available to improve functional recovery after stroke. Most recently, an economic analysis of the Canadian Stroke Strategy showed that applying these principles would not only result in fewer strokes and better outcomes, but also result in substantial savings to the treasury after all costs are covered. Across Canada eight provinces are in various stages of implementing stroke strategies using the models we have developed. As the Strategy becomes established the CSN looks forward to increasing further the coordination between stroke research and stroke prevention and care. This will accelerate the translation of stroke knowledge and facilitate the closing of care "gaps" identified by the Strategy.

Despite my growing commitment to improving stroke care in Canada and beyond, I have also been concerned that we need to recognize the changing realities of the stroke process itself. The literature suggests that there is a significant increase in the prevalence of covert strokes, small infarcts located 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 and may be a consequence of the increase in life-expectancy, obesity and diabetes in western society. I have described a hypothesis regarding covert strokes titled "Living Beyond Our Physiological Means: Small Vessel Disease Of The Brain Is An Expression Of A Systemic Failure In Arteriolar Function. A Unifying Hypothesis" which impressed the editorial board of the Journal STROKE sufficiently to bestow on it an "Innovation Award". The hypothesis suggests that small vessel disease is due to occlusion of arterioles, results from an inflammatory process, and in the same individuals will not only affect their brain with covert strokes leading to dementia, but also their retina leading to macular degeneration and their kidneys leading to renal failure. The article, which was published in May 2009, recommended various health care approaches to improve prevention and management of this systemic illness. I will follow it with an article on innovative approaches to managing hypertension world-wide, the major risk factor for small and large strokes.

It has also been a particular source of pride to the CSN to be advised that a coalition of European countries has proposed the establishment of a European Stroke Network patterned on the CSN, and asked me 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 days 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 was very successful in its mission, and identified a number of areas where international collaborations may be possible. I have also been advised by the Spanish Society of Neurology that they are inviting me to 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 am honoured that they will award me their Thomas Willis Prize at the meeting. Closer to home, NINDS and CSN are exploring a partnership in translational stroke research.

3. Other Responsibilities for Research Administration
In 2005, I accepted the Directorship of the Centre for Stroke Recovery, formed in 2002 as a partnership between the Heart and Stroke Foundation of Ontario, the Ottawa Health Research Institute, Baycrest Centre for Geriatric Care, and Sunnybrook Health Sciences Centre. The Centre for Stroke Recovery, with an annual budget of $1.2M supports an integrated approach to identifying, through multi-disciplinary research, the most effective means of promoting and sustaining stroke recovery. It links knowledge, skills, expertise and advanced technologies from the prominent research groups in the areas of brain recovery and stroke rehabilitation located at the three sites. The Heart and Stroke Foundation of Ontario has been so thrilled with the output from this Centre that it made a commitment to raise $25M for the Centre. The figure announced for the fund to date has already reached almost $30M !!

In addition to the national leadership responsibility implied by the Canadian Stroke Network, Canadian Stroke Strategy and the Heart and Stroke Foundation Centre for Stroke Recovery, I have been the Chair of Neurology and the Director of Neuroscience Research at the University of Ottawa since 1992, and the Director of the Neuroscience Research Program of the Ottawa Health 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. This level of excellence was achieved through a three-fold approach: 1) a demanding selection and evaluation process that precedes recruitment; 2) the ability to put together recruitment packages that are competitive with other institutions; and 3) selection of excellent individuals who value collaboration as well as personal success. This was made possible by nurturing a strong relationship with private donors and foundations, and developing well-conceived partnerships that lead to synergies with the private sector.

HONOURS RECEIVED

1. Hans-Chiari Award – Present the “Hans-Chiari Lecture at the Joint Meeting of the Austrian and the Hungarian Stroke Societies, Friday, January 21, 2011, Vienna, Austria.
2. PIR Biomedical Science Ambassador Award (Scientific Category) at The Partnership In Research, The Ottawa Evening 2010" Gala in celebration of Canada’s World-Class Achievements – May 12, 2010.
3. Heart & Stroke Foundation of Canada – Merit Award – February 6, 2010
4. Awarded the 2009 Thomas Willis Prize by the Spanish Society of Neurology November 2009.
5. September 2009, the Heart and Stroke Foundation of Ontario announced an annual research grant of $100,000 to be named the “Dr Tony Hakim Innovative Stroke Research Award” for an “out of the box” project proposal in the field of stroke recovery.
6. Invited, supported by the French Government, to advise them on their national strategy against Alzheimer’s disease – April-May 2009.
7. 2nd Prize Winner of the Journal STROKE’s Innovation Award for article submitted entitled: “Living Beyond Our Physiological Means: Small Vessel Disease Of The Brain Is An Expression Of A Systemic Failure In Arteriolar Function.  A Unifying Hypothesis.” Stroke. Accepted Dec 2008 and published May 2009.
8. Dr. J. David Grimes Research Career Achievement Award, The Ottawa Health Research Institute, November 2008.
9. Consultant to select Director of the Florey Neuroscience Institute, Australia.  Florey is an amalgamation of three existing institutes (National Stroke Research Institute, Brain Research Institute, Howard Florey Institute) - January 2008.
10. Personality of the Year - presented by LeDroit  and CBC Radio -2008
11. Participated (by invitation only) in the Princeton Stroke Conference, Houston, Texas – March 28, 2008
12. Chair, Scientific Advisory Committee, the European Stroke Network, 2007 - present.
13. Advisor to the French Strategy against Alzheimer Disease. 2007-2009.
14. Member of the Board of Directors, Fonds de la Rechèrche en Santé du Quebec, 2007 - present.
15. Received the MEDEC Award for Medical Achievement from Canada's Medical Device Technology Companies, 2007.
16. Received the Thomas Willis Award, a Lifetime Achievement Award from the American Stroke Association and delivered the Thomas Willis Lecture at the International Stroke Conference in San Francisco on February 7, 2007.
17. Appointed Officer of Order of Canada, announced in February 2007.

PUBLICATIONS

1. Endres M, Heuschmann PU, Laufs U, Hakim A. Frontiers in cardiovascular medicine “Primary prevention of stroke: Blood pressure, lipids and heart failure”. Invited Comprehensive Clinical Review Article for the European Heart Journal (EHJ).  Accepted October 2010.*
2. Sharma M, Hakim A. The Management of Hypertension for Primary Stroke Prevention: A proposed Approach. International Journal of Stroke. Accepted August 2010.*
3. Hachinski V, Donnan GA, Gorelick PB, Hacke W, Cramer SC, Kaste M, Fisher M, Brainin M, Buchan AM, Lo EH, Skolnick BE, Furie KL, Hankey GJ, Kivipelto M, Morris J, Rothwell PM, Sacco RL, Smith SC Jr, Wang Y, Bryer A, Ford GA, Iadecola C, Martins SC, Saver J, Skvortsova V, Bayley M, Bednar MM, Duncan P, Enney L, Finklestein S, Jones TA, Kalra L, Kleim J, Nitkin R, Teasell R, Weiller C, Desai B, Goldberg MP, Heiss WD, Saarelma O, Schwamm LH, Shinohara Y, Trivedi B, Wahlgren N, Wong LK, Hakim A, Norrving B, Prudhomme S, Bornstein NM, Davis SM, Goldstein LB, Leys D, Tuomilehto J., Department of Clinical Neurological Sciences, London Health Sciences Center, University of Western Ontario, and St. Joseph's Healthcare London, London, Ont., USA.. Stroke: Working toward a Prioritized World Agenda. Cerebrovasc Dis. 2010 May 24;30(2):127-147.**
4. Hachinski V, Donnan GA, Gorelick PB, Hacke W, Cramer SC, Kaste M, Fisher M, Brainin M, Buchan AM, Lo EH, Skolnick BE, Furie KL, Hankey GJ, Kivipelto M, Morris J, Rothwell PM, Sacco RL, Smith SC Jr, Wang Y, Bryer A, Ford GA, Iadecola C, Martins SC, Saver J, Skvortsova V, Bayley M, Bednar MM, Duncan P, Enney L, Finklestein S, Jones TA, Kalra L, Kleim J, Nitkin R, Teasell R, Weiller C, Desai B, Goldberg MP, Heiss WD, Saarelma O, Schwamm LH, Shinohara Y, Trivedi B, Wahlgren N, Wong LK, Hakim AM, Norrving B, Prudhomme S, Bornstein NM, Davis SM, Goldstein LB, Leys D, Tuomilehto J. troke: Working toward a Prioritized World Agenda. Stroke. 2010 Jun;41(6):1084-99. Review**
5. Saposnik G, Black S, Hakim A, Fang J, Tu J and Kapral M. Age disparities in Stroke Quality of Care and Delivery of Health Services.  Stroke. 2009 Oct;40(10):3328-35.**
6. Dowlatshahi D, Hakim A, Fang J, Sharma M. Pre-admission antithrombotics are associated with improved outcomes following ischemic stroke: a cohort from the Registry of the Canadian Stroke Network.  International Journal of Stroke, October 2009,4: 328–334.**
7. Charron C, Schock S, Proulx G, Thompson C, Hakim A, Plamondon H.  Protection conferred by Corticotropin-releasing hormone in rat primary cortical neurons against chemical ischemia involves opioid receptor activation.  Brain Research.2009 Feb 27 1257: 117-127.**
8. Thompson C and Hakim A.  Living Beyond Our Physiological Means: Small Vessel Disease Of The Brain Is An Expression Of A Systemic Failure In Arteriolar Function.  A Unifying Hypothesis. Stroke 2009 May; 40 (5): E 322-30.*
9. Hakim A and Thompson C. Gene Induction, Protein Synthesis and Related Issues. Handbook of Clinical Neurology. 2008; 92:137-47.*
10. Schock, SC, LeBlanc D, Hakim AM, Thompson CS.  ATP release by way of connexin 36 hemichannels mediates ischemic tolerance in vitro. Biochem Biophys Res Comm. 2008 Mar. 368 (1): 138-144.**
11. Hakim AM, Vascular Disease: The Tsunami of Health Care - The 2007 Willis Lecture. Stroke. 2007 Dec. 38 (12) 0039-2499. *
12. Schock SC, Munyao N, Yakubchyk Y, Sabourin L, Hakim AM, Ventureyra ECG, Thompson CS.   Cortical spreading depression releases ATP into the extracellular space and purinergic receptor activation contributes to the induction of ischemic tolerance.  Brain Res. 2007 Sep 7, 1168C: 129-138. *
13. Hester I, McKee S, Pelletier P, Thompson C, Storbeck C, Mears A, Schulz JB, Hakim AM, Sabourin L.Transient expression of Nxf, a bHLH-PAS transactivator Induced by neuronal preconditioning, confers neuroprotection in cultured cells.Brain Res. 2007 Mar 2;1135(1):1–11.*

 

RESEARCH AWARDS

Research Grants

1. INSTITUTIONAL
   
   Heart and Stroke Foundation of Ontario and Matching Funds                         
   Centre of Excellence – Heart and Stroke Foundation Centre for Stroke Recovery
   Scientific Director
   2001 – 2011                                                                                                    $12,000,000
   Additional fundraising goal set in 2005                                                         $25,000,000
   Achieved to Date                                                                                          $25,000,000   
   Goal raised to $40,000,000
   
   Networks of Centres of Excellence Program - 
   Network of Centres of Excellence for the Canadian Stroke Network (CSN)
   CEO and Scientific Director, Dr. Antoine M. Hakim
   Network grant with 145 investigators from across Canada
   2000 - 2006                                                                                         $32,900,000
   2006 – 2013                                                                                        $44,800,000

Please note that Dr. Hakim is not accepting new students or post-docs at this time.  Many of his colleagues in the OHRI Neuroscience Program and the uOttawa Neuroscience Program are however and you may wish to communicate with them.