There is no known treatment for cerebral amyloid angiopathy (CAA), an important cause of hemorrhagic stroke and increasingly recognized contributor to vascular cognitive impairment and neurological dysfunction. We propose to use our prospective longitudinal study of patients with CAA-related intracerebral hemorrhage as the centerpiece of both a multidisciplinary investigation of the mechanisms by which CAA affects neurological function and a clinical research training program for early investigators in the fields of stroke and vascular cognitive impairment. Building on the Principle's Investigator's groundbreaking success in defining the diagnosis, clinical course, and pathophysiology of CAA, the proposed studies focus on 1) the interrelationship between CAA-related hemorrhages and white matter lesions, 2) the effects of these lesions on cognition, depressive symptoms, functional skills, and gait, and 3) their association with genetic and biochemical risk factors. Successful completion of these studies will represent a key step towards developing diagnostic markers, outcome markers, and candidate treatments for future trials aimed at prevention of CAA-related hemorrhage and cognitive dysfunction. The studies will be performed as part of long-standing collaborations with investigators (drawn from the rich Harvard Medical School research environment) at the Martinos Center for Biomedical Imaging (Dr. A. Gregory Sorensen, Co-Director), Program in Medical and Population Genetics (Dr. David Altschuler, Director), and Biostatistics Center (Dr. Rebecca Betensky). The multidisciplinary team of collaborators will also serve as the basis for an intensive patient-oriented research training program in key aspects of neurological research, including principles of patient-oriented research, neurological and cognitive assessment of intracerebral hemorrhage subjects, computer-assisted radiographic image analysis, human genetic analysis, and biostatistics. The Principle Investigator has an outstanding record of mentoring early clinical investigators, demonstrated by trainees'success in publication, research funding, and transition to independent careers. The Principle Investigator's consistent success in defining biologically based approaches to compelling research questions and obtaining NIH-funded R01 support make it extremely likely that the proposed studies will succeed both as cutting-edge clinical investigation and tools for training a new generation of stroke investigators.

National Institute of Health (NIH)
National Institute of Neurological Disorders and Stroke (NINDS)
Midcareer Investigator Award in Patient-Oriented Research (K24)
Project #
Application #
Study Section
NST-2 Subcommittee (NST)
Program Officer
Corriveau, Roderick A
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
Massachusetts General Hospital
United States
Zip Code
Gurol, M Edip; Greenberg, Steven M (2013) A physiologic biomarker for cerebral amyloid angiopathy. Neurology 81:1650-1
Anderson, Christopher D; Biffi, Alessandro; Rahman, Rosanna et al. (2011) Common mitochondrial sequence variants in ischemic stroke. Ann Neurol 69:471-80
Linn, J; Halpin, A; Demaerel, P et al. (2010) Prevalence of superficial siderosis in patients with cerebral amyloid angiopathy. Neurology 74:1346-50
Smith, Eric E; Nandigam, Kaveer R N; Chen, Yu-Wei et al. (2010) MRI markers of small vessel disease in lobar and deep hemispheric intracerebral hemorrhage. Stroke 41:1933-8
Nandigam, R N K; Viswanathan, A; Delgado, P et al. (2009) MR imaging detection of cerebral microbleeds: effect of susceptibility-weighted imaging, section thickness, and field strength. AJNR Am J Neuroradiol 30:338-43
Greenberg, Steven M; Nandigam, R N Kaveer; Delgado, Pilar et al. (2009) Microbleeds versus macrobleeds: evidence for distinct entities. Stroke 40:2382-6
Kimberly, W T; Gilson, A; Rost, N S et al. (2009) Silent ischemic infarcts are associated with hemorrhage burden in cerebral amyloid angiopathy. Neurology 72:1230-5
Smith, Eric E; Greenberg, Steven M (2009) Beta-amyloid, blood vessels, and brain function. Stroke 40:2601-6
Holland, Christopher M; Smith, Eric E; Csapo, Istvan et al. (2008) Spatial distribution of white-matter hyperintensities in Alzheimer disease, cerebral amyloid angiopathy, and healthy aging. Stroke 39:1127-33
Kinnecom, C; Lev, M H; Wendell, L et al. (2007) Course of cerebral amyloid angiopathy-related inflammation. Neurology 68:1411-6