Pathology - Pathology Service Staff

My laboratory is interested in the development and characterization of animal models of human neurodegenerative diseases, particularly Alzheimer and Parkinson diseases.

The current major research emphasis in my lab focuses on the development of cerebral amyloid angiopathy (CAA) in mouse models. In this disease, the peptide A-beta deposits in the walls of blood vessels and is associated with risk of hemorrhage (‘lobar hemorrhages’). This peptide is the same material that forms the plaques of Alzheimer disease, and nearly all patients with Alzheimer disease have pathologic evidence of CAA as well. CAA also occurs in the absence of histologic evidence of Alzheimer disease, and can present with hemorrhages or with cognitive changes. In a recent clinicopathologic study, we have found that this latter presentation is associated with the presence of an inflammatory response, often containing giant cells. This subset of patients can have dramatic recoveries of cognitive function after immunosuppressive therapy. For these reasons, we are interested in learning what the sequence of events is by which the A-beta is deposited in blood vessels, what factors determine the distribution of involvement, what the consequences are for the cells of the vessel and how this material can respond to therapeutic interventions that have been shown to alter A-beta deposits in the brain. We are pursuing these studies using multiphoton imaging as applied both ex vivo to fixed brains and in vivo through a glass window placed in the skull. These investigations are to be complemented by a series of immunohistochemical studies and image reconstruction to match the vessel structure and integrity with the 3-dimensional image generated using the multiphoton approach. We also aim to use laser capture microdissection to define alterations in gene expression that occur in smooth muscle cells in the proximity of amyloid deposits of CAA.

In addition to the activities of my laboratory, I am strongly connected to the activities of the Center for Molecular Pathology of the Harvard Center for Neurodegeneration and Repair (HCNR). As the faculty coordinator for the activities of the Center, I am involved in the design and implementation of programs that can support tissue-based research into a wide range of neurodegenerative disorders, as pursued across the Harvard neuroscience community (including basic and clinical investigations). Among the resources we have developed is the Advanced Tissue Resource Center, based in Building 114, which includes a staffed Laser Capture Microdissection facility that is available to users. There is a virtual brain bank which allows investigators to locate tissue resources. Additionally, genetic outreach program has been created which can provide assistance to: patients and families through the services of a genetic counselor; to investigators designing clinical studies looking for guidance in the collection of banked biological samples; and to investigators trying to identify resources that have already been collected within the neurodegenerative disease community. We are working to create banked collections of biological samples (serum, CSF, DNA) from individuals who have been well characterized clinically. With the informatics program of HCNR, we hope to combine this physical resource with clinical information in ways that protect patient identity and confidentiality but allow for investigators to make the best use of these resources.