Michael D. Boska - US grants

magnetic resonance imaging; nuclear magnetic resonance spectroscopy; biomedical equipment purchase;

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. Lithium (Li) is efficacious in the treatment of bipolar illness and recurrent episodes of mania. Since Li is a CMS drug, its concentration in the brain might be expected to relate more closely to clinical response. The distribution of lithium in the brain is of importance in Li therapy and in localizing its action in the brain. Thus, an in vivo measure of brain Li concentration is necessary. Magnetic resonance (MR), a method that does not involve any ionizing radiation or radioactive isotopes, can be used to observe Li non-destructively in an in vivo setup. As a part of the overall goal to quantify and map brain lithium, we will develop Spectroscopic Imaging (SI) with nuclear Overhauser enhancement of Li nucleus under the limits of Specific Absorbed Radiation (SAR). Further developments will be undertaken using shorter brain only coil operating in the quadrature mode. Optimization of the method will include: a) volume localization and b) outer volume saturation prior to SI data collection. Li intensities in the rat brain will be measured using the most optimal method. The SI data are then corrected for Point Spread Function (PSF) induced intensity changes. Concentrations are obtained upon comparing the intensities with those from equivalent voxels from a phantom of known concentration. Finally, the MR method will be validated against the "gold standard" such as atomic absorption (AA) method and the agreement between the two methods established. The newly validated methodology will be used to map out Li distribution in the rat brain at different stages of Li passage through the brain. Regional pharmacokinetics will be studied from broad anatomical areas of relevance to bipolar illness.

This core will provide state-of-the-art bioimaging support for projects 1, 2, and 3, J. Zheng, H. Gendelman, and Y. Persidsky. The work will include quantitative magnetic resonance imaging (MRI), MR spectroscopic imaging (MRSI), and single photon emission computed tomography (SPECT). Two 7-Tesla small animal MRI/S systems, now operative at the University of Nebraska Medical Center, will provide quantitative neuroimaging and superparamagnetic iron oxide (SPIO) labeled cell tracking for rodent neuroAIDS animal models of HIV-1 associated dementia (HAD). One GammaMedica Ideas animal SPECT will be used in determining biodistribution of gamma emitter labeled cells or molecular probes and provides an excellent complement to MRI cell tracking methods. The image-processing laboratory has developed custom MRI/SPECT animal holders incorporating visible fiducial markers to allow coregistration of these two modalities. This allows anatomical details for SPECT images and validation of cell quantification by MRI. The bioimaging core methods also include quantitative mapping of blood-brain barrier permeability (project 3, Y. Persidsky), quantitative arterial spin labeled perfusion mapping, and quantitative proton MRSI (1H MRSI) (projects 2 and 3, H. Gendelman and Y. Persidsky). In addition, advanced imaging and spectroscopic analysis methods have been developed within the MRI/S core facility to allow automated mouse brain subimaging and coregistration/warping of imaging results with histology (all projects). This core will also support developmental therapeutics relevant to microglial activation in HAD. The long-term aims of these works are to assess the physiological MRI and biochemical 1H MRSI predictors of neuropathology and cell migration dynamics (MRI and SPECT) in mouse models of neuroAIDS. This will provide sensitive and specific screens of the onset and/or progression of disease as well as providing response kinetics to a variety of therapeutic interventions. The results obtained from this core will have direct applicability for monitoring the course of human neurodegenerative disorders. Significant modifications of the core were made in both focus and design so that it can unambiguously provide novel data that cannot readily be btained by histopathological examinations alone.

DESCRIPTION (provided by applicant): This application proposes to upgrade the gradients and electronics of a 7 Tesla small animal magnetic resonance imaging (MRI) and spectroscopy (MRS) system located in the bioimaging core facility at the University of Nebraska Medical Center (UNMC). The present system is used for 16 NIH-funded projects including two program projects and a nanomedicine COBRE, and is supported by a Core Support P30 grant. Currently funded projects use an average of 20 hours per week of MRI system time per scanner which represents 80% of the current system use. The proposed upgrade will enhance the quality and throughput of imaging studies for a wide range of projects, including neuroimaging, spectroscopy, and cell- and nanoparticle-tracking studies in the neurosciences and in nanotechnology development. Nanotechnology projects include development of drug delivery platforms for antiretroviral, anti-inflammatory, neuroprotective, and anti-cancer medications. The system to be upgraded is a Bruker Biospec 7T/21cm system installed in 2001. Because of the age of the system's hardware, current and future operating system software releases are no longer compatible. Thus, the upgrades proposed here will serve three important functions. First, the proposed hardware upgrade will improve signal to noise, gradient performance, and system stability, improvements that will be particularly useful for spectroscopic studies used for MRI assessment of neurological dysfunction and disease. Second, enhanced digitizer speed and the associated software update will allow short and zero echo time imaging, a technique that provides robust positive contrast for super paramagnetic iron oxide (SPIO) tracer studies. Zero echo time imaging combined with T2* weighted imaging will make possible the development of automated detection algorithms for cell and nanoparticle biodistribution studies via the correlated positive and negative signal intensity changes that occur in the presence of SPIO. Third, the upgrades will include a multichannel receiver and coil to take advantage of "parallel imaging" methods available in the newer software releases. This feature will significantly improve the quality and spatial fidelity of single shot imaging techniques, improving diffusion tensor imaging and allowing the migration of relaxivity and perfusion mapping techniques to echo planar or spiral imaging based single shot methods. Public Health Relevance: Imaging-based disease detection methods and new therapies for brain diseases, rheumatoid arthritis, and cancer using nanoparticle drug delivery are being developed at the University of Nebraska Medical Center. A critical link in the development of these new drug delivery methods is the ability to track their distribution and therapeutic effectiveness non-invasively using imaging methods first in animal models of disease and then in humans. This application proposes to upgrade an MRI scanner to current standards, allowing efficient and clinically relevant imaging methods to be employed while studying small animal models of disease for development of drug delivery nanoparticles.

PROJECT SUMMARY (See instructions): This core is designed to provide quantitative magnetic resonance imaging (MRI), image localized spectroscopy (MRS), spectroscopic imaging (MRSI) and single photon emission computed tomography/Xray computed tomography (SPECT/CT) for in-vivo assays of cell and drug biodistribution and efficacy. Project support includes pharmacokinetic measures of nanomaterial biodistribution (Projects 6, 7, 9, 10), measures of disease progression/drug efficacy (Project 7), and tissue perfusion measurements (Project 7). In addition. Core faculty will be involved in the training of new investigators on available methods to accelerate in-vivo studies of nanomedication effects. Methods including cardiac and vascular function, tumor morphology and perfusion, diffusion tensor imaging, and magnetic resonance spectroscopy (MRS), both 31P MRS and IH MRS, are available. Some of these methods have been extensively used by other nanomedicine researchers in investigations of the effects of disease and the ability for nanoformulations to ameliorate these changes. These abilities will be critical to the advancement of the nanomedicine program in general and the ability to meet the needs of current and future NCN faculty.

Abstract: Imaging Core The Imaging Core of the Chronic HIV Infection, Aging and NeuroAIDS (CHAIN) Center consists of two laboratories, the Preclinical Imaging Laboratory (M. Boska, Co-PI) and the Human Structural and Functional Neuroimaging Laboratory (T. Wilson, Co-PI). The primary goals of the Core are to support CHAIN PIs and other neuroAIDS investigators in the identification and quantification of HIV-related alterations in brain function, structure, and metabolism, and to aid in understanding how emerging therapeutics modulate brain function to ameliorate and/or reverse these HIV-related alterations. Discovery of neural biomarkers of HIV-associated neurocognitive disorders (HAND) and the basic mechanisms of HIV-related brain injury remains a high priority, with 35-70% of all HIV-infected patients developing HAND in the post cART era. Surprisingly, despite this persistently high prevalence, there are currently no diagnostic tests or any specific biomarkers that can precisely pinpoint HAND, be used to monitor disease progression, or as an assay of an emerging treatment?s beneficial effects. The CHAIN Imaging Core has been designed for biomarker discovery and optimization, as the same imaging assessments can be performed in parallel in animal models and human trials. Such a parallel approach allows bidirectional feedback between animal and human studies, and will enhance abilities to diagnosis, monitor, and predict HAND in humans, while providing targets for detailed histological and biochemical studies of the underlying mechanisms. Alterations will be assessed with regard to age, viral status, sex, drug treatment, and effects of drugs of abuse. In short, this Core will use animal models of HIV-infection to provide noninvasive imaging indicators of altered neuronal function and neurotoxicity, and investigate the biochemical mechanisms of these functional abnormalities in collaboration with the Omics Core. Potential biomarkers of altered function can then be tested in humans in the Imaging Core using advanced structural and functional imaging in collaboration with the Developmental Core. Conversely, as functional deficits are detected in human studies, regions identified as demonstrating abnormal neuronal function can be targeted for more thorough investigation in animal studies to (1) replicate the findings using similar imaging methodologies in a better controlled model (e.g., without lifestyle issues) and (2) investigate the cellular and biochemical source(s) of these functional abnormalities in collaboration with the Omics Core and the Cell, Tissue, and Animal Core. These studies will provide new diagnostic capabilities, uncover the biochemical and functional deficits associated with HAND, and allow monitoring of the effects of new therapies on brain biochemistry and function in animals and humans.