Abhijit J. Chaudhari, Ph.D. - US grants

DESCRIPTION (provided by applicant): Dynamic-contrast enhanced magnetic resonance imaging (DCE-MRI) biomarkers are displaying significant promise as early indicators of therapeutic response in the modern clinic. As a consequence, they possess an evolving role in the current realm of individualized medicine. Challenges remain however regarding their application in cross-sectional contemporaneous or longitudinal studies - it is critical in these studies to decouple errors due to intra-scan patient motion or repositioning on the scanner from anatomical or functional changes occurring due to treatment that these biomarkers reflect. Tools that are capable of rapid, but reliable derivation of DCE-MRI biomarkers are therefore urgently needed. The GOAL of this proposed work is to develop, implement and validate three-dimensional image registration technology for enabling the rapid derivation of disease-associated biomarkers from clinical DCE-MRI. The focus is on the alignment of intra-subject anatomical images of body regions that involve both rigid (bone) and non-rigid (soft tissue) components. In our innovative registration scheme, pre-determined components such as bones deform in a rigid manner while soft tissue warps non-rigidly. We HYPOTHESIZE therefore that our method will provide better modeling of patient repositioning compared to currently clinically used technologies as well as state-of-the-art registration methods. In our SPECIFIC AIMS, we will: (1) develop the quasi-rigid, intra-subject registration method for MR image alignment, and (2) validate the registration method using MR images of adult patients with soft tissue sarcoma in a retrospective setting. Both computer-based and human observers will be used to compare the performance of the proposed method against conventional rigid and non-rigid registration methods. A novel system for radiologic scoring of the merits of image registration is devised and will be tested. The registration method will be developed as an open-source technique allowing easy distribution. DCE-MRI biomarkers are currently being evaluated as surrogate end-points in clinical trials of several novel drug treatments. The proposed registration method will enable rapid quantitative change analyses of DCE-MRI biomarkers over the treatment period. Physicians will be able to use this information to tailor therapeutic strategies according to the individual requirements of their patients. In this context, techniques developed in this proposal are applicable to a broad class of human diseases, e.g., oncologic (e.g., sarcomas, head and neck cancer, etc) or musculoskeletal disease (e.g., arthritis, etc). This work is a close collaboration with Robert Canter, a surgical oncologist who specializes in the clinical management of soft tissue sarcoma, Michael Buonocore, an MRI physicist whose expertise lies in clinical MRI protocol design and image analysis, Robert Boutin, a clinical radiologist with expertise in soft tissue sarcoma and consultant Wayne Monsky, an expert in cancer imaging biomarker development.

PROJECT SUMMARY/ABSTRACT The Animal Imaging Shared Resource (AISR) is comprised of: The Center for Molecular and Genomic Imaging (CMGI), which provides services for small animals, mainly rodents, and The Center for Imaging Sciences (CIS), which provides services for large animals, companion animals as well as domestic livestock. The AISR provides cancer researchers at UC Davis with services that include initial consultation, study design, scanning, radiopharmaceutical synthesis, animal handling, data processing, and image analysis. CMGI is a state-of-the- art imaging center has resources for a broad range of imaging modalities, microPET, microSPECT, microCT, microMR, and optical imaging. The facility also houses a biomedical cyclotron and chemistry facilities (hot and cold) for contrast agent development. The center is staffed with experts in animal handling, physiology and imaging overseen by faculty in the Department of Biomedical Engineering. CIS addresses the need to maintain a central facility containing state-of-the-art imaging equipment and core faculty with expertise in medical imaging investigations. The services that the CIS currently provide include diagnostic radiology, x-ray helical and cone beam computed tomography, magnetic resonance imaging, diagnostic ultrasound, radiation therapy, interventional radiology and image analysis for in vitro and animal research.

Abstract Alzheimer?s disease (AD) affects an estimated 5.7 million Americans, a number expected to reach 14 million by 2050. Despite several decades of research, the initiation and progression of AD continues to be poorly understood, and we currently lack reliable biomarkers to longitudinally monitor disease progression. Synaptic dysfunction is being evaluated as a potential early biomarker for evaluating AD risk; however, most studies to date have relied on cross-sectional or endpoint, ex vivo analyses. We hypothesize that in vivo imaging measures of synapse density, which will be carefully validated against histologic measures, will be predictive biomarkers of AD pathology that precede detection of amyloid deposition and neurofibrillary tangles by in vivo imaging. A positive outcome from testing this hypothesis would enable the identification of at-risk individuals and the application of therapeutic strategies to arrest disease progression before substantial neuronal loss occurs. Our studies will utilize PET and MR imaging in a novel transgenic rat model that presents key pathologic features of significance in human AD. Our first specific aim will establish the spatial correlation between in vivo imaging measures (synapse density, amyloid deposition and tauopathy via PET and structural measures via MRI) and concurrent histopathology in the Tg344-AD transgenic rat model versus congenic age- matched wildtype animals. Our second specific aim will map the spatiotemporal patterns of synapse density, amyloid deposition, tauopathy and neurodegeneration via in vivo PET and MRI in TgF344-AD rats and age- matched control animals. PET using the radiotracers 18F-UCB-H, 18F-florbetapir and 18F-T807, as proxy measures of synapse density, amyloid-beta deposition and tau accumulation, respectively, and structural MRI, based on T2-weighted scanning, will be performed over the time course of presentation of synaptic and AD- related pathology. Brains from a subset of animals at each time will be analyzed for histopathologic markers of neuronal loss and degeneration to provide ground-truth measures for correlating with the in vivo imaging measures. This study will unleash the potential to: (i) robustly validate in vivo imaging measures of synapse dysfunction as early biomarkers of AD against other imaging measures and histopathology, which is a necessary step towards their evidence-based clinical translation; (ii) provide preliminary data to support future mechanistic hypotheses about the regional and temporal relationships between synapse dysfunction and other AD-associated pathologies, with the ultimate goal of improving our understanding of AD risk; and (iii) understand concordance and discordance between the different in vivo imaging and histopathology measures, which will have implications for therapy design and testing. In summary, this project will provide key translational elements that will inform future human studies assessing the role of synapse loss in AD and for monitoring treatments to preserve synapse density and function.

Project Summary/Abstract Alzheimer?s disease (AD) is an extremely prevalent and severely disabling disease. Despite several decades of research, AD pathogenesis continues to be poorly understood, and we currently lack reliable biomarkers to spatiotemporally track and predict disease progression. Our overall goal is to address these challenges and develop enhanced biomarkers for diagnosing AD-pathology early and objectively tracking treatments. To that end, this proposal will utilize our highly translational monkey model of the early ?synaptic phase? of AD to assess the merits of in vivo imaging measures (from PET for synaptic density (using 11C-UCB-J) and glucose metabolism (using 18F-FDG), with structural MRI) against postmortem, state-of-the-art microscopic and histologic analysis of brain tissue, in a longitudinal study design. Our hypothesis is that PET measures, as surrogates for quantifying synaptic loss and metabolic dysfunction, will serve as early, independent predictive biomarkers for elevated AD risk and cognitive dysfunction. Our first specific aim will establish the correlation of our in vivo imaging measures with postmortem tissue markers of AD-associated pathologies in our monkey model versus age- and sex-matched control animals. Our second specific aim will map the spatiotemporal patterns of PET synaptic loss versus cerebral glucose metabolism in our monkey model versus control animals over a 12-week period. Completion of both aims will provide novel data to improve our understanding of synaptic neuropathology in AD development. Therefore, this proposal is highly responsive to the PAR-18-760. Positive findings would corroborate recent human studies investigating the role of synaptic dysfunction as a major factor for increased AD risk. Validation of in vivo imaging strategies in a relevant model system will contribute towards (i) optimizing the therapeutic window for future early AD treatments so that their efficacy can be maximized; (ii) testing mechanistic hypotheses associated with the role/blockage of synapse loss; (iii) rapidly evaluating new treatment strategies and their dose-response relationships. In summary, this project has the potential to provide key translational elements that will inform human studies evaluating in vivo markers of synaptic dysfunction.

Project Summary The EXPLORER system, built via funding from an NIH transformative R01 award, is a unique PET/CT scanner that offers: (1) an axial field of view that covers the whole adult human body in one shot; (ii) significant radiation dose reduction compared to current PET/CT protocols; (3) scans of the entire body in under 1 min; and (4) ability to visualize small structure and joints that is significantly better than current PET/CT systems. We hypothesize that EXPLORER will offer an exceptional insight into systemic Rheumatoid Arthritis (RA) pathology and provide quantitative, in vivo measures (biomarkers) for enabling a comprehensive assessment of RA disease activity and treatment response. In our first specific aim, we will establish the association between EXPLORER measures with standardized RA outcome measures. In our second specific aim, we will evaluate the capabilities of EXPLORER measures to track changes in these outcome measures in response to RA treatment. Our study will involve two groups of participants with RA. Participants in the first group will have had an inadequate response to RA non- biologic therapy and will be candidates for starting standard-of-care RA biologic therapy in addition to non- biologic therapy. These participants will be scanned on the EXPLORER system at two time points; before starting biologic therapy and 3 months after starting biologic therapy. Participants in the second group will have stable disease and will have chosen to continue to manage their RA based on the same standard-of-care non-biologic therapy. These participants will be scanned at two time points, 3 months apart. A total of 60 participants (30 per group) will be enrolled in the study. This work is innovative because the characteristics of the newly-developed EXPLORER system in terms of its field-of-view, sensitivity and spatial resolution would enable new findings relevant to both clinical and basic science research in RA. This work is significant because systemic assessment and quantification of RA disease activity based on total-body and low-dose PET/CT imaging capabilities of EXPLORER could enable improved risk stratification and precise monitoring of the effects of RA treatments on joints, and other crucial organs across the body, with scan times of just a few minutes. The ultimate beneficiaries will be RA patients as their therapeutic options will widen and treatments will be more personalized. This observational study is well-suited for the PAR- 18-597 because it focuses on associating objective imaging biomarkers with established outcome measures of RA and addresses significant obstacles in the rheumatology field regarding the applicability of an advanced imaging technique (PET/CT) in future clinical studies and clinical practice.