Cerebral microhemorrhages (CMB) detected using brain MRI are increasingly recognized as important markers of subclinical cerebrovascular disease. CMB are more frequent in advanced age, and are attributed to hypertensive vasculopathy or cerebral amyloid angiopathy. They have been related to an increased risk of stroke (especially brain hemorrhage) cognitive impairment and dementia. Their presence complicates prevention and treatment efforts for ischemic stroke and Alzheimer's disease. However the underlying pathophysiology, incidence and genetic determinants of CMB are not well understood. In the Framingham Heart Study, we have collected longitudinal data on cardiovascular risk factors, and also have genetic, biomarker and subclinical cardiovascular disease measures. Participants have had brain MRI, and simultaneous measures of cognitive performance. In the proposed grant we hypothesize that the prevalence and incidence of CMB increase with age, and relate to cardiovascular risk factors. We will investigate the relation of CMB to subclinical measures of atherosclerosis and hypertensive organ damage, and to novel circulating biomarkers of inflammation and vascular dysfunction. We will also relate CMB to other MRI measures of brain ischemic damage and aging, and cognitive performance. Finally we will study genetic determinants of CMB using already available genome-wide association data. The present project will be part of a career advancement program for Dr. Romero. He has training as a Vascular Neurologist and is an Assistant professor of Neurology at the Boston University Medical Campus. He has a long-standing interest in subclinical cerebrovascular disease, and in cerebrovascular disease prevention. Dr. Romero has already been actively involved in clinical research at the Framingham Heart Study and now proposes to obtain the training required to become an independent investigator in this team. He has short term plans to develop expertise in Neuroepidemiology through a structured program at the Boston University School of Public Health and is committed to a long term career as a clinical investigator in Vascular Neurology, studying CMB. The present project is to be conducted in the context of the Framingham Heart Study, using the resources of the study and involving the mentorship of a group of internationally recognized experts in Neuroepidemiology, Biostatistics, Neuroradiology, and Genetic Epidemiology. The proposed research project will not only advance our understanding of the pathophysiology of CMB, but also serve as the basis for further comprehensive studies of CMB as subclinical markers of cerebrovascular disease.

Public Health Relevance

Small hemorrhages that are seen on a brain MRI but typically cause no obvious symptoms when they happen are called cerebral microbleeds (CMB);they are more frequent in older persons and have been associated with an increased risk of ischemic stroke and of brain hemorrhage, especially in persons being treated for ischemic stroke. They have also been associated with poor cognitive performance and Alzheimer's dementia. We propose to study the prevalence, incidence and characteristics of CMB in the middle-aged, community-based Framingham Heart Study. We will relate these data to cardiovascular and genetic risk factors, markers of carotid and heart disease and to novel serum biomarkers. We will also study how CMB are related to other MRI measures of aging and brain ischemia, and to cognitive function. Understanding the pathophysiology of CMB could help prevent stroke and dementia.

National Institute of Health (NIH)
National Institute on Aging (NIA)
Mentored Patient-Oriented Research Career Development Award (K23)
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National Institute on Aging Initial Review Group (NIA)
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Anderson, Dallas
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Boston University
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United States
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Shoamanesh, Ashkan; Preis, Sarah R; Beiser, Alexa S et al. (2016) Circulating biomarkers and incident ischemic stroke in the Framingham Offspring Study. Neurology 87:1206-11
Romero, José R; Preis, Sarah R; Beiser, Alexa et al. (2016) Carotid Atherosclerosis and Cerebral Microbleeds: The Framingham Heart Study. J Am Heart Assoc 5:e002377
Saber, Hamidreza; Himali, Jayandra J; Shoamanesh, Ashkan et al. (2015) Serum Leptin Levels and the Risk of Stroke: The Framingham Study. Stroke 46:2881-5
Shoamanesh, Ashkan; Preis, Sarah R; Beiser, Alexa S et al. (2015) Inflammatory biomarkers, cerebral microbleeds, and small vessel disease: Framingham Heart Study. Neurology 84:825-32
Martinez-Ramirez, Sergi; Romero, Jose-Rafael; Shoamanesh, Ashkan et al. (2015) Diagnostic value of lobar microbleeds in individuals without intracerebral hemorrhage. Alzheimers Dement 11:1480-8
Romero, José Rafael; Preis, Sarah R; Beiser, Alexa et al. (2014) Risk factors, stroke prevention treatments, and prevalence of cerebral microbleeds in the Framingham Heart Study. Stroke 45:1492-4
Schilling, Sabrina; DeStefano, Anita L; Sachdev, Perminder S et al. (2013) APOE genotype and MRI markers of cerebrovascular disease: systematic review and meta-analysis. Neurology 81:292-300
Romero, Jose R; Wolf, Philip A (2013) Epidemiology of Stroke: Legacy of the Framingham Heart Study. Glob Heart 8:67-75
Romero, José Rafael; Preis, Sarah R; Beiser, Alexa S et al. (2012) Lipoprotein phospholipase A2 and cerebral microbleeds in the Framingham Heart Study. Stroke 43:3091-4
Fornage, Myriam; Debette, Stephanie; Bis, Joshua C et al. (2011) Genome-wide association studies of cerebral white matter lesion burden: the CHARGE consortium. Ann Neurol 69:928-39

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