Matthew P. Frosch, MD, PhD
Lawrence J. Henderson Associate Professor of Pathology and Health Sciences & Technology, Harvard Medical School
Director, C.S. Kubik Laboratory for Neuropathology, Massachusetts General Hospital
MassGeneral Institute for Neurodegenerative Diseases (MIND)
114 16th Street, Room 2700
Charlestown, MA 02129
Explore This Lab
My 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, 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.
We 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, we use 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. We 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. We 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.
I also work 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.
- Isabel Costantino, Tech II
- Nehal Patel, Tech II
Harvard NeuroDiscovery Center Staff
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Marquié M, Siao Tick Chong M, Antón- Fernández A, Verwer EE, Sáez-Calveras N, Meltzer AC, Ramanan P, Amaral AC, Gonzalez J, Normandin MD, Frosch MP, Gómez-Isla T. [F-18]-AV-1451 binding correlates with postmortem neurofibrillary tangle Braak staging. Acta Neuropathol. 2017; 134(4):619-628.
van Veluw SJ, Kuijf HJ, Charidimou A, Viswanathan A, Biessels GJ, Rozemuller AJ, Frosch MP, Greenberg SM. Reduced vascular amyloid burden at microhemorrhage sites in cerebral amyloid angiopathy. Acta Neuropathol. 2017; 133(3):409-415.
van Veluw SJ, Charidimou A, van der Kouwe AJ, Lauer A, Reijmer YD, Costantino I, Gurol ME, Biessels GJ, Frosch MP, Viswanathan A, Greenberg SM. Microbleed and microinfarct detection in amyloid angiopathy: a high-resolution MRI-histopathology study. Brain. 2016; 139(Pt 12):3151-3162.
Matrix metalloproteinase 9-mediated intracerebral hemorrhage induced by cerebral amyloid angiopathy. Zhao L, Arbel-Ornath M, Wang X, Betensky RA, Greenberg SM, Frosch MP, Bacskai BJ. Neurobiol Aging. 2015 Nov;36(11):2963-71.
Marquié M, Normandin MD, Van- derburg CR, Costantino IM, Bien EA, Rycyna LG, Klunk WE, Mathis CA, Iko- nomovic MD, Debnath ML, Vasdev N, Dickerson BC, Gomperts SN, Growdon JH, Johnson KA, Frosch MP, Hyman BT, Gómez-Isla T. Validating novel tau positron emission tomography tracer [F-18]-AV-1451 (T807) on postmortem brain tissue. Ann Neurol. 2015; 78(5):787-800.
- Associate Pathologist, Massachusetts General Hospital
- Subspecialty Head, Neuropathology
- Lawrence J. Henderson Associate Professor of Pathology and Health Sciences and Technology, Harvard Medical School