Representative Publications
Staff
Our research focuses on the pathogenesis, diagnosis, and treatment of cerebral amyloid angiopathy (CAA). CAA is an important cause of cerebral hemorrhage in the elderly. It is currently one of the few kinds of stroke without effective prevention or treatment strategies.
Our research focuses on the pathogenesis, diagnosis, and treatment of cerebral amyloid angiopathy (CAA). CAA is an important cause of cerebral hemorrhage in the elderly. It is currently one of the few kinds of stroke without effective prevention or treatment strategies. CAA is closely related to Alzheimer's disease (AD) at a molecular level, each involving deposition of the amyloid ß-peptide. CAA may thereby prove to be an important vantage for understanding AD. Despite the molecular similarities of the diseases, they are clinically, genetically, and pathologically distinct.
Our research is divided into a clinical program that focuses on the molecular epidemiology of CAA and a laboratory program studying its pathogenesis. Our clinical research program has assembled a cohort of patients with probable CAA-related cerebral hemorrhage. By comparing this cohort to patients with other types of hemorrhages (e.g. those related to hypertension) and to control patients without hemorrhage, we have determined that apolipoprotein E (APOE) genotype is a risk factor for CAA. We have also followed CAA patients over time for evidence of disease progression. These studies have allowed us to identify several factors that predict risk of future hemorrhagic stroke, including APOE genotype and the number of old hemorrhages detected by gradient-echo MRI. Our ability to track the progression of CAA have allowed us to enter into the first clinical drug trial of a candidate treatment of CAA. In a study funded by the National Institutes of Health (NIH) and the biopharmaceutical company Neurochem, Inc., we have begun to explore the safety, tolerability, and efficacy of the glycosaminoglycan-mimetic Cerebrill TM. Our major long-term goal is to identify safe and effective treatments for lowering the risk of recurrent hemorrhage and other forms of clinical deterioration in patients with CAA.
Other major interests in our clinical research group include the genetics of CAA and other forms of intracerebral hemorrhage and the effects of CAA on blood vessel function and risk of vascular cognitive impairment. In conjunction with theProgram for Medical and Population Genetics of the Broad Institute of MIT and Harvard, we are conducting an NIH-funded search for genes that increase risk for spontaneous and anticoagulant-associated hemorrhagic stroke. The ultimate goal of these studies is to predict a patient’s risk for hemorrhage and thereby allow treatments that affect blood clotting to be used more safely and effectively. We are also studying the possible effects of CAA on blood vessel function. We have found a high prevalence of white matter changes in patients with CAA and a close relationship between advanced white matter disease and cognitive impairment. In a subset of patients with advanced CAA, the vascular amyloid appears to cause an inflammatory reaction, causing rapidly progressive cognitive changes that in some cases are reversible. These findings suggest that effective treatment of CAA might help prevent the increasingly recognized problem of vascular cognitive impairment as well as lower the risk of hemorrhagic stroke.
Our laboratory research program focuses on transgenic mouse models of CAA. In collaboration with Drs. Brian Bacskai and Matthew Frosch of the MassGeneral Institute for Neurodegenerative Disease, we have used multiphoton imaging techniques to demonstrate progressive growth of ß-amyloid deposition in superficial cerebral blood vessels of living mice. These studies offer a promising approach for devising and testing new candidate treatments for preventing progression of CAA.
Greenberg SM, Rebeck GW, Vonsattel JPG, Gomez-Isla T, Hyman BT. Apolipoprotein E e4 and cerebral hemorrhage associated with amyloid angiopathy. Ann Neurol 1995;38:254-259.
Greenberg SM, Vonsattel JPG. Diagnosis of cerebral amyloid angiopathy: Sensitivity and specificity of cortical biopsy. Stroke 1997; 28:1418-1422.
O'Donnell HC, Rosand J, Knudsen KA, Furie KL, Segal AZ, Chiu RI, Ikeda D, Greenberg SM. Apolipoprotein E genotype and risk of recurrent lobar intracerebal hemorrhage. New Engl J Med 2000;342:240-245.
Rosand J, Hylek EM, O'Donnell HC, Greenberg SM. Warfarin-related hemorrhage and cerebral amyloid angiopathy. A genetic and pathological study. Neurology 2000;55:947-955.
Knudsen KA, Rosand J, Karluk D, Greenberg SM. Clinical diagnosis of cerebral amyloid angiopathy. Validation of the Boston criteria. Neurology 2001;56:537-539.
Grabowski TJ, Cho HS, Vonsattel JPG, Rebeck GW, Greenberg SM. A novel APP mutation in an Iowa family with dementia and severe cerebral amyloid angiopathy. Ann Neurol 2001; 49:697-705.
Smith EE, Rosand J, Knudsen KA, Hylek EM, Greenberg SM. Leukoaraiosis is associated with warfarin-related hemorrhage following ischemic stroke. Neurology 2002;59:193-197.
Greenberg SM, Shin Y, Grabowski TJ, Cooper GE, Rebeck GW, Iglesias S, Chapon F, Tournier-Lasserve E, Baron J-C. Hemorrhagic stroke associated with the Iowa amyloid precursor protein mutation. Neurology 2003;60:1020-1022.
Eckman MH, Rosand J, Knudsen KA, Singer DE, Greenberg SM. Can patients be anticoagulated following intracerebral hemorrhage? A decision analysis. Stroke 2003;34:1710-1716.
Rosand J, Eckman MH, Knudsen KA, Singer DE, Greenberg SM. The effect of warfarin and intensity of anticoagulation on outcome of intracerebral hemorrhage. Arch Int Med 2004; 164:880-884.
Eng JA, Frosch MP, Choi K, Rebeck GW, Greenberg SM. Clinical manifestations of cerebral amyloid angiopathy-related inflammation. Ann Neurol 2004;55:246-252.
Greenberg SM, Eng JA, Ning MM, Smith EE, Rosand J. Hemorrhage burden predicts recurrent intracerebral hemorrhage following lobar hemorrhage. Stroke 2004;35:1415-1420.
Flibotte JJ, Hagan N, O’Donnell J, Greenberg SM, Rosand J. Warfarin, hematoma expansion, and outcome of intracerebral hemorrhage. Neurology 2004; in press.
Smith EE, Gurol ME, Eng JA, Engel CR, Nguyen TN, Rosand J, Greenberg SM. White matter lesions, cognition, and recurrent hemorrhage in lobar intracerebral hemorrhage. Neurology 2004; in press.
Greenberg SM, Scheider AT, Pettigrew LC, Gandy SE, Fitzsimmons B-F, Schwab K, Laurin J, Garceau D. Phase II Study of Cerebril, a candidate treatment for intracerebral hemorrhage related to cerebral amyloid angiopathy. Neurology (abs) 2004 .
Robbins EM, Domnitz SB, Hyman BT, Greenberg SM, Frosch MP, Bacskai BJ. Serial imaging of cerebral amyloid angiopathy progression in transgenic mice with multiphoton microscopy. Soc Neurosci Abs 2004.
Steven M. Greenberg, M.D., Ph.D.
Jonathan Rosand, M.D.
Eric Smith, M.D.
Kristin M. Schwab
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