Neuropathology

Dr. Hyman serves as Co-Lead for the ACTC Neuropathology Unit, and serves on the Project Evaluation Committee (PEC).  He is the John B. Penney, Jr. Professor of Neurology at Harvard University.  His laboratory studies the anatomical and molecular basis of dementia in Alzheimer’s disease and dementia with Lewy bodies. Approaches focus on transgenic mouse models and human neuropathological samples, using advanced microscopy techniques for in vivo longitudinal imaging, direct imaging on neuropathological processes including cell death, and functional imaging including in vivo assessment of calcium reporters. Quantitative approaches have been developed to apply to clinical pathological and genotype/phenotype analyses. Recent studies have developed the use of multiphoton microscopy for in vivo anatomical and functional imaging in transgenic mouse models of Alzheimer’s disease and the utilization of gene transfer techniques to introduce potentially disease-modifying genes into specific cortical regions. We have also developed fluorescence resonance energy transfer (FRET) approaches to allow observation of protein-protein interactions with subcellular resolution, both in vitro and in vivo. These techniques are utilized to examine the alterations that occur in Alzheimer’s disease brain, and in mouse models expressing genetic mutants that are linked to Alzheimer’s disease.

Dr. Frosch serves as Co-Lead for the ACTC Neuropathology Unit.  He is the Lawrence J. Henderson Associate Professor of Pathology and Health Sciences & Technology at Harvard Medical School, and Director of the C.S. Kubik Laboratory for Neuropathology at Massachusetts General Hospital, for the MassGeneral Institute for Neurodegenerative Diseases (MIND) Dr. Frosch’s lab aims to understand cerebral amyloid angiopathy (CAA), using mouse models and human tissue. In this disease, the peptide Ab 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 clinicopathologic studies, his lab has 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. Dr. Frosch and his team are interested in the sequence of events by which Ab 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 focused on Ab currently in clinical trials. For in vivo studies, Frosch’s team uses serial multiphoton imaging with specific probes for these various processes and link the spatial and temporal distribution of the pathologic changes with the development of CAA. They complement these studies with work on human autopsy tissue, collected through the Massachusetts Alzheimer Disease Research Center Neuropathology Core. Those samples are examined through combinations of high field ex vivo MRI, optical clearing and volumetric imaging. They are particularly interested in the changes which result in bleeding in the setting of CAA (hemorrhagic strokes) as well as microinfarcts which can markedly impair cognition. Dr. Frosch also works with a range of collaborators to understand the relationship between neuropathologic findings in the setting of disease — including Alzheimer disease, Parkinson disease, Amyotrophic Lateral Sclerosis and others — and other biochemical or functional markers of disease. These studies include advancing imaging methods (DTI, OCT and others) as well as various genetic studies (deep sequencing as well as GWAS), cell biology and structural biology.