PURE-MRI - a Proposal to Determine the Prevalence and Consequences of Covert Ischemia in Canada


Principal Investigators:

Smith, Eric (University of Calgary) and O'Donnell, Martin (McMaster University)


Dagenais, Gilles (Hôpital Laval); Lear, Scott (Simon Fraser University); Poirier, Paul (Hôpital Laval); Rangarajan, Sumathy (McMaster University); Teo, Koon (McMaster University); Wielgosz, Andy (University of Ottawa); Yusuf, Salim (McMaster University).

1. What is the health issue?

Clinically overt stroke is the leading cause of acquired adult disability in Canada. It is now recognized that clinically overt stroke represents only a fraction of all stroke affecting the brain. Covert ischemia, meaning brain damage due to reduced blood flow without obvious clinical signs of stroke, is now known to be more common than clinically overt stroke. As the name suggests, the impact of covert ischemia is subtle and insidious, but likely to have a major health impact on Canadians because we suspect it is very common. Covert ischemia may be subdivided into covert infarction, typically caused by small subcortical infarcts in the internal brain structures, and white matter lesions (WML), caused by ischemic demyelination.
Covert ischemia has been associated with cognitive decline, dementia, depression, vascular Parkinsonism, gait impairment and falls. Over time, accumulation of these covert strokes results in a slow deterioration in physical and cognitive functioning, often ending with premature nursing home placement or death. Reducing the prevalence of covert ischemia would likely result in substantial improvements in the health of older Canadians, and possibly major health savings in health costs for the care of the elderly. A U.S.-based study estimates that a 20% reduction in covert brain infarction would decrease the lifetime incidence of dementia by 4.5%, with a cost savings of $17.2 billion dollars to the U.S. health system. A number of population-based studies have examined the prevalence of covert infarcts and WML, based on MRI, in the United States, Europe and Japan. Relatively large sample sizes are required to provide stable age-stratified estimates of the prevalence of covert ischemia.
The prevalence, risk factors and consequences of covert ischemia in Canada is currently not known. This information will be critically necessary for public policy decision-making and for planning clinical trials for prevention of covert ischemia in Canada. We propose to address this limitation by carrying out an MRI study of covert ischemia in Canada, embedded within the ongoing Prospective Urban Rural Epidemiological Study (PURE) study, a prospective longitudinal cohort study currently being carried out in four communities across Canada.  

2. Objectives of the study

1) To determine the prevalence and of covert cerebral ischemia (on MRI) in community-dwelling people in Canada.
2) To determine the cross-sectional and longitudinal relationship between covert cerebral ischemia and cognitive function, mood and activities of daily living.
3) To determine the role of individual (including genetics), household, societal and environmental factors for development and progression of covert cerebral ischemia.

3. Relevance

Previous studies have demonstrated that covert ischemia is common in non-Canadian populations. These same studies have determined that the presence of one or more covert infarcts is associated with a 2-4 fold increased risk of subsequent dementia or clinically overt stroke. Similarly, persons with covert infarcts or large amounts of WML at baseline are at substantially higher risk of developing new covert infarcts or WML progression, which has been linked with declining cognitive performance. Overall, these data suggest that clinical interventions or public health interventions to prevent new covert ischemia would reduce disability. There is a need for more information on the impact of covert ischemia on activities of daily living and mood, however.
Previous studies suggest that age, hypertension and smoking are the strongest risk factors for covert infarction and WML. The risk factors for covert ischemia may not be the same as for clinically overt stroke, however. Most of the variation in WML severity appears to be caused by genetic factors that remain to be discovered. Prior large population-based studies were predominantly conducted 10-15 years ago, and there is a need for additional studies to determine the prevalence of covert ischemia in the context of increasing rates of obesity and diabetes mellitus. 
Little to no research has been done on dietary risk factors, or community and society determinants of covert ischemia, even though such research could point to effective prevention strategies. For example, it is known that access to tobacco plays a role in community rates of smoking. Linking access to tobacco to the prevalence of covert ischemia in different communities could suggest public policy initiatives that might decrease the incidence of covert ischemia. 
The proposed PURE-MRI study will address current limitations by determining the prevalence, risk factors and consequences of covert ischemia in Canada. A feature of the ongoing PURE study is collection of genetic data and detailed risk factor data at multiple levels, including the individual, household, community, society and environment.

4. Impact

Funding support will facilitate a cross-sectional study to determine Canadian prevalence rates of covert ischemia. Critically, this study will provide valid estimates of the prevalence, risk factors and consequences of covert ischemia in Canadians drawn from several communities spanning the country. Embedding this study within the established PURE cohort will reduce costs and enhance efficiency.  
Using these data we plan to secure additional funding to extend longitudinal study follow-up, including repeat MRI to determine incidence rates of new covert ischemia in Canada. Successful establishment of a Canadian cohort should enable us to subsequently broaden the study to PURE sites in other countries, allowing comparisons between Canada and other countries. Estimates of the prevalence of covert ischemia in a Canadian population will allow the planning and conduct of future Canadian trials for the prevention of cognitive and functional decline caused by covert ischemia. The identification of novel risk factors for covert ischemia should lead to new ideas for clinical interventions, and public policy initiatives, to prevent covert ischemia in Canada.