Evolution from Stroke Risk Factors to Brain Health Determinants

I wish to sincerely thank the organizing committee for inviting me over to this conference. I am incredibly humbled to be here to present the 11th Wepfer lecture. Several years ago, I sat at this same European Stroke Conference and listened to the many distinguished Wepfer lecturers, some of whom are in this audience today; so it is really a tremendous honor and privilege to be here to deliver this lecture.I would not be here today if not for the outstanding mentorship that I have been fortunate to have over the years. It is critical for all of us to reflect on the importance of the mentor-mentee relationship. Mentorship has meant so much to me in my career and I am sure it is the same for many of your own careers. Dr. Phil Wolf, a principal investigator from the Framingham Study, was my first mentor in medical school. I started working with him as a second year medical student and spent a summer in the basement of the Framingham Study offices sorting computer cards. He introduced me to neurology and epidemiology and mentored me through my first publication on the outcomes of stroke and supported me as a first author [1]. After graduating from medical school, I moved to New York City for neurology residency at the Neurological Institute at Columbia Presbyterian. There I met Dr. J.P. Mohr, who supported my career development early on as a resident, stroke fellow, assistant professor and up the ladder. I am incredibly grateful for all his support and for always encouraging me to ask important questions and challenge widely accepted concepts. I was also fortunate to be mentored by Dr. Allan Hauser who helped me with epidemiology even though his field was epidemiology of epilepsy. I am also indebted to my first chairman, Dr. Bud Rolland, who convinced me to stay in academics and Dr. Tim Pedley who encouraged me to get further formal training with a Master's of Science in Epidemiology at the Mailman School of Public Health at Columbia. Without mentorship many of us would not be here today. I hope all of you leave this conference and continue to mentor other young students, fellows and faculty to pursue careers in stroke research.I am also grateful to my collaborating team of investigators. I may be the one up here giving this lecture, but I share this award with all of the colleagues with whom I have had the pleasure of working. Not all of them are on this slide, but many of them are shown including Mitch Elkind, Professor of Neurology at Columbia and the co-principal investigator for the Northern Manhattan Study (NOMAS); Tatjana Rundek, who made the trek with me to the University of Miami as my Vice Chairman for Clinical Translational Research; Clinton Wright, Scientific Director of our McKnight Brain Institute who is really the mover behind some of the work that I am going to present today on brain health; and Marco Di Tullio, Professor of Medicine at Columbia and a cardiologist who has been a long-term collaborator. There are many other students, residents, fellows, faculty, and colleagues with whom I have had the privilege of working, including other European colleagues who aren't on this slide. I thank them for their support and helpful contributions along the way. Collaborations and teamwork are really the key ingredients to the success we have had in our programs.The title of my lecture is ‘Evolution from Stroke Risk Factors to Brain Health Determinants' (for summary points panel, see end of this article). Although this is the 24th European Stroke Conference, in the future this may evolve into the European Brain Health Conference. Some of the main concepts that I will amplify here are (1) traditional vascular risk factors are determinants of stroke, but brain health is also a determinant of stroke, and this will be an important concept to define more clearly as we think about the future; (2) factor combinations, as opposed to individual risk factors, are also incredibly important as we identify individuals who are at risk; (3) risk is usually continuous and cumulative and there are important precursor behavioral conditions that precede the actual risk factor; (4) sub-clinical vascular and brain measures are also determinants of brain health, and will enhance opportunities for us to detect and initiate treatment and prevention before one has a stroke or before one has a decrement in brain health; and (5) novel factors such as infectious burden and inflammatory markers are determinants of not only stroke, but also brain health.In the welcome address to ESC 2015, we heard from Dr. Michael Hennerici about the continued importance of stroke worldwide. Every country is affected by the increasing public health burden due to stroke. In 2010, 16.8 million new strokes occurred - 68% greater than in 1990 with greater incidence rates in low- to middle-income countries [2]. Moreover, 33 million people were living with stroke; more than double than what existed in 1990. Although incidence rates are lower in high-income countries, stroke prevalence is greater in high income than in low- to middle-income countries. Countries where people have a longer life span have a much higher prevalence of stroke; however, life expectancy is also increasing in low- to middle-income countries and consequently results in an increase in the number of stroke cases. Stroke, however, is probably only the tip of the iceberg.Globally, we are seeing the aging patterns of our population. The number of people aged over 65 will rise from 390 to 800 million by 2025 constituting nearly 10% of the population. The average life expectancy in 1995 was only 65 years but by 2025 it is expected to reach 73 years. By the year 2025, no country on the planet will have a life expectancy of <50. As we consider these demographic predictions, we need to consider the impact of stroke and brain health in humans.The aging patterns of our populations will require us to evolve from control of stroke risk factors to consideration of the determinants of a broader concept of brain health. Although many of us are neurologists, or even more specialized as vascular neurologists, perhaps in the future we will be considered by the public more as brain healthcare providers. The broader spectrum of brain health encompasses stroke, dementia, vascular cognitive impairment, cognitive aging, age-related memory loss, vascular functional impairment, and subclinical vascular diseases including white matter hyperintensities (WMHI), brain atrophy, silent brain infarctions, and cerebral microbleeds (table 1). The importance of cognitive aging was just addressed in an Institute of Medicine Report Entitled Cognitive Aging: Progress in Understanding and Opportunities for Action [3]. The broader definition of brain health allows us to consider how vascular risk factors have evolved to brain health determinants.The term ‘risk factor' was originally defined in 1961 by Dr. Bill Kannel, one of the leaders of the Framingham Heart Study, who I had the pleasure of knowing when I was a medical student [4]. In his prescient article, he wrote: ‘since it has been established that coronary atherosclerosis is present for many years prior to the development of symptomatic coronary heart disease, it seems evident that efforts at prevention must begin many years before the appearance of clinical CHD'. That was in 1961 where he coined the term ‘factors of risk'. We all now appreciate that these factors of risk or risk factors take years to develop. They do not happen overnight. In fact, Phil Wolf has stated: ‘there was nothing accidental about stroke'. The term ‘cerebrovascular accident' is a misnomer, since there is nothing accidental about its occurrence; rather it takes many years of risk to eventually develop into a stroke.Individuals advance over time from disease-free to the occurrence of sub-clinical disease to crossing that clinical threshold of developing symptoms. All too often, it is during that symptomatic stage that we get involved as physicians, sometimes too late to effectively prevent the occurrence of disease. Most individuals are born healthy, with or without a genetic predisposition for vascular disease, and subsequently develop induction behaviors that interact with sociocultural factors and lead to the development of risk factors. In the primordial development of risk factors, the individual is still in the disease-free stage. Sub-clinical disease begins to develop when risk factors are inadequately controlled, whether it is small amounts of plaque in the carotid or other arterial vessels, subclinical changes in myocardial function, or early changes in brain structure. The progression of subclinical disease can lead to an individual eventually crossing that clinical threshold. Therefore, most physicians, clinicians and healthcare providers are getting involved too late in the process. A patient may have already had a stroke, a TIA, or an MI, but then we are working at the end of the curve to reverse or alter progression of symptomatic disease. We should be thinking more broadly about focusing on the earlier stages of risk for stroke and brain health decline. We have made amazing strides in treating and preventing stroke and need to do the same for preventing other vascular morbidities including improving brain health.As J.P. Mohr mentioned in his introduction, we started the NOMAS about 23 years ago. Many students, residents, fellows, faculty and colleagues have worked on this study that continues even today. Originally we sought to define the incidence of stroke across various ethnic groups in the race and ethnically diverse population of Northern Manhattan [5]. The study originated when I was at the Columbia University with NINDS grant support. When I packed my bags to move further south to warmer weather as the Chairman of Neurology at the University of Miami in 2007, the study was competitively renewed and continued. This success has been based on maintaining great teams in place across 2 universities and continuing to collaboratively work together as colleagues. NOMAS was originally designed as a stroke incidence study and population-based case-control study. After the first 5-year grant cycle, the study was expanded and it evolved into a Framingham-like study design by enrolling a cohort of 3,298 people who were prospectively followed annually originally for stroke, MI and vascular death. With each 5-year NINDS renewal, NOMAS evolved with new aims addressing traditional and novel vascular risk factors and measuring subclinical disease of the heart, carotids, and brain. Magnetic resonance imaging (MRI) of the brain and neuropsychological testing was completed on nearly 1,300 members of the cohort. Consequently, as the cohort aged, the primary focus has shifted from stroke to cognition, cognitive decline, and dementia. Therefore, NOMAS has evolved from a stroke risk factor study to a brain health study.The conceptual of the study was to detect individual risk factors as it to clinical vascular including stroke, MI and vascular 1). earlier were on sub-clinical vascular of the Dr. has worked on the of carotid plaque and and other measures on a of outcomes with we many determinants of stroke including and we have been the brain and and cognitive decline. 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Therefore, of have shown us that more health is with risk of vascular disease is also when you at health is not just the of control of and that are with but also the impact of increasing number of behavioral factors. increase in the number of health we a in the risk of stroke, MI and vascular even with of the health factors of and Health such as and are not in our patient is one of the most important the population is so the health lower of stroke, MI and vascular it is to that health is a determinant of brain health. We have new from NOMAS on the of neuropsychological of function, memory and and how to health. the cognitive with the number of factors. The more health, the the for with cognitive function, cognitive for function, and were with the of factors. Therefore, health is a of stroke, MI, and vascular as as measures of and cognitive decline. 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This of some subclinical that may be a novel risk factor for has also us to sub-clinical vascular brain such as and and them as stroke risk factors and brain health They are on in Dr. Clinton has our efforts to these 1,300 NOMAS own and that of have that and are stroke risk factors. 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I to future European Brain Health where the to determinants of stroke, cognition, and functional can be health, and subclinical vascular measures of the carotid and of the and are all to various brain health brain measures such as and silent and even may be important determinants of brain health. of infectious burden also with brain health that we are still to these the of a genetic are still genetic has some in and with many of these determinants to alter our individual risk of stroke and other brain health of stroke risk or we will be a future brain health I think this us with an to think more broadly about the burden of diseases is a new The and have made a of for a in from disease, including stroke, and by Most of the for 2025 are still on the traditional health factors - many factors that have been defined by health, including and We still have great in effectively behaviors and these health factors, of the novel risk factors that we are still to define in Northern The future is going to further stroke and and require thinking more broadly about brain health, and functional the future burden of stroke and brain health is and is to increase when you think about the aging of our populations across health can stroke, MI and vascular but also Risk factors, continuous and sub-clinical determinants risk and earlier risk factors and determinants can future to brain health. and treating determinants of risk as early as before clinical We are to the of to vascular as as vascular The is that we need to as teams our individual across countries, and across to these health and population health if we are going to the 2025 for am to the NINDS for the support I have had over the years. I am grateful to all the colleagues and teams I have worked with at Columbia and at the University of I am for my and my for I would not be here today this Wepfer lecture without all their is supported by from the Heart Stroke of and the McKnight Brain Dr. has as a for for the