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Matthew P. Frosch, MD, PhD
Lawrence J. Henderson Associate Professor of Pathology andHealth Sciences & Technology, Harvard Medical SchoolDirector, C.S. Kubik Laboratory for Neuropathology,Massachusetts General HospitalMassGeneral Institute for Neurodegenerative Diseases (MIND)
MassGeneral Institute for Neurodegenerative Diseases (MIND)Massachusetts General Hospital114 16th Street, Room 2700Charlestown, MA 02129Phone: 617-726-5156Fax: 617-724-1813Email: email@example.com
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 IINehal Patel, Tech IIHarvard NeuroDiscovery Center Staff
Charles Vanderburg, PhDOzge Casgal-Getkin, Tech II
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.
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Bibliography of Matthew P. Frosch via PubMed
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 neurofibril- lary tangle Braak staging. Acta Neuro- pathol. 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 microhe- morrhage 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 detec- tion in amyloid angiopathy: a high-reso- lution 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 postmor- tem brain tissue. Ann Neurol. 2015; 78(5):787-800.
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