David A. Gutman - US grants

DESCRIPTION (provided by applicant): The increasing availability of high-quality digital scanners has enabled the generation of large collections of histology images, confocal/multichannel images, and accompanying metadata. However there is a dearth of robust open- source solutions to efficiently visualize, process and manage these ever growing imaging collections. Our goal is to open-source, document and further develop integrative technologies leveraging our experience with the Cancer Digital Slide Archive (CDSA), a tool we have developed to facilitate analysis of data provided by the NCI's the Cancer Genome Atlas (TCGA). This tool is NOT and will not be limited to the analysis of TCGA data, however by working backwards from public data already available we can ensure the informatics technologies developed are scaleable and usable by the cancer community. In our proposal, we will first go through a process of software engineering review to improve the ease of installation to facilitate distribution to other research groups. We have partnered with Kitware for this proposal allowing us to use their 15+ years of experience in building and maintain quality open source software. The rest of the proposal will focus on the testing and integration of new features such as the ability to perform image quantification (e.g. cell counting, cell profiling), image markup and labeling, as well as perform basic group level analysis allowing the correlation of imaging features with user defined variables of interest. As an example, a user may classify an individual slide based on the mean density of nuclei and correlate this imaging parameter with patient survival, or with tumor grade.

This project will investigate features of neural system organization that can be linked to altered social behavior, including reduced or increased aggression. Two species of canids, experimentally domesticated silver foxes (Vulpes vulpes) and domestic dogs (Canis familiaris), have been selectively bred by humans for altered social behavior. These behavioral changes occurred alongside a restricted set of genetic changes, creating an unparalleled opportunity to link the evolution of behavioral characteristics (phenotypes) to neural phenotypes. Recent technological advancements enable detailed, non-invasive studies of brain anatomy at relatively low cost. This project will take advantage of these innovations to create high-resolution three-dimensional (3D) brain maps using structural magnetic resonance imaging, diffusion tensor imaging, and digitized histology. Expected products of this research include: (1) identification of features of neural organization that are linked to reduced or increased sociality or aggression, expected to be generalizable to other species, (2) the production of online fox and dog brain atlases that will be publicly available as a research tool for the general scientific community, (3) training opportunities for young scientists, and (4) outreach efforts using blog and social media posts for the general public. Because dogs are a "common denominator" across various cultures, this research has a unique opportunity to be personally relevant and compelling to people from all walks of society, and to enhance public appreciation for science.

Both experimentally-domesticated foxes and domestic dogs are distinguished from their wild forebears by altered social approach-avoidance behavior. Previous research in rodents and primates, and the researchers' own preliminary data, allow for the formation of well-grounded hypotheses about neural adaptations that result from selection pressure on social approach-avoidance behavior. Specifically, this project will investigate limbic and fronto-limbic systems governing social behavior and response selection. In order to identify features of neural system organization associated with altered social behavior, whole-brain white and gray matter organization will be compared (a) between various breeds of domestic dogs, each tested for social approach-avoidance/aggression behavior, and (b) between strains of foxes bred for social avoidance behavior, which react aggressively to social contact, versus foxes bred for social approach behavior, which are tame and friendly like dogs, versus wild type foxes. Whole-brain MRI and DTI images will be collected using 3.0 and 9.4 Tesla MRI scanners. Histology images will be digitally scanned and aligned to MRI images. Analyses will include voxel-based morphometry, tract-based spatial statistics, probabilistic tractography, and k-means connectivity-based parcellation. The research will advance knowledge about how evolution modified brain organization in response to selection for social approach and avoidance.

The goal of the parent AMP-AD project is to identify proteomic networks from cortical tissue and identify protein co-expression modules that are strongly associated with diagnosis, cognition and neuropathology. These studies hinge on accurate neuropathologic diagnosis and staging of the brain tissue. These assessments typically involve semi-quantitative evaluation of tissues and there is a need for robust, reliable, and scalable deeper phenotyping to provide a firmer foundation for precision medicine approaches. We have developed the Digital Slide Archive (DSA) platform at Emory, which has been funded through a U24 and U01 grants from the NCI/NIH and has primarily been optimized for Cancer related image analysis workflows. In this project, we propose to deploy and customize a web-based instance of our open source management and visualization platform, the Digital Slide Archive (DSA). Ultimately, we will enable collaborative team science and adapt the existing DSA platform for a neuropathologist?s workflow. This will directly enhance the value of our proteomic work by allowing us to better annotate our brain/proteomic samples. In this proposal, we propose enhancing the user interface of the DSA to better accommodate a neuropathologist?s workflow for reviewing brain tissue, and develop an easily installable Neuropath plugin for the DSA. We will also benchmark and optimize our analysis suite (HistomicsTK) on NP slide sides on local and cloud-based computational resources, and prepare tutorials demonstrating how our tools can be used for ADRD related image analysis tasks. These aims paired with the complementary and synergistic expertise of our informatics, pathology, and engineering will aid in development of robust, scalable, reliable, and sharable platforms to provide a foundation for innovative transformative science addressing a critical unmet need in neurodegenerative disease research.