AD is a complex, progressive neurodegenerative disease and is the most common cause ofdementia among the elderly. It has a clear spatial and temporal progression; multiple lines ofevidence show that the degeneration patterns seen in AD are not random but show acharacteristic anatomical sequence as the pathology advances over decades. The mechanismsthat cause these spatial patterns are poorly understood and basic questions about the relativecontributions of microscopic molecular mechanisms versus macroscopic anatomical changes indriving AD progression remain unclear.Unfortunately, whole brain techniques like MRI lacks the necessary molecular contrast andresolution to answer these questions. Histology can reveal the microscopic, molecularsignatures, but is constrained to small 2D sections due to technical limitations with large scalehistology, particularly 3D histology. These limitations make it difficult to map AD progressionand limit the usefulness of post-mortem tissue that might reveal crucial clues about AD.In this proposal we will address this barrier by providing a fee-for-service sectioning, slicemounting, staining, and imaging platform that will offer non-specialized labs the ability toobtain high quality 3D serial section reconstructions of post-mortem human brains up to entirehemispheres. Specimens can be sent to TissueVision where they will be sectioned at thicknessesranging from 50 microns to 2 mm, with alternating block face imaging between sections to helpfacilitate 3D reconstruction. Each mounted section is available for further staining anddigitization at high resolution with Whole Slide imaging (WSI) and served over the cloud to theclient with optional 3D modeling. The physical sections can be returned to the client or storedfor further follow-up analyses.This proposal combines expertise in microscopy and 3D histology at TissueVision with world-class clinical researchers at Indiana University and builds on existing work at TissueVision. Thesection capture and slide mounting is based on existing technology contained within ourTissueCyte 1600FC STPT platform for mouse and rat brains. We also build on a strongcollaboration with Jackson Labs and the MODEL-AD center with an existing TissueVision PhaseII NIA SBIR to map AD spatial progression in mouse model brains. We will extend thecollaboration to clinical collaborators at the Model-AD at Indiana University who will besupplying post-mortem human tissue and providing guidance and feedback on the histologicalquality. While our focus is on AD in this project, the proposed technology will have broad impactacross a wide range of disciplines, from cardiac biology, infectious diseases, cancer, and basicresearch. PROJECT NARRATIVE
This proposal describes a novel 3D histological reconstruction platform for multi-scale post-
mortem analysis of human Alzheimer's Disease brains. It is based on an existing microtomy and
automated tissue sectioning and slide mounting platform developed for mouse brains at
TissueVision. We will extend the technology to allow researchers to automatically section brain
tissues up to entire human hemispheres and automatically mount the sections onto indexed
slides for further targeted downstream molecular analysis that can be mapped back onto the
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