Peter Barker - US grants

"Unification" has been a paramount goal of science from its very beginnings. Thales proclaimed "All is water." Contemporary science continues this pursuit of unification. Maxwell, in the 19th century, unified the forces of electricity and magnetism and showed that light is but an electro-magnetic phenomenon. Einstein's final efforts were to find a grand unification theory of all forces. Indeed this effort continues in current physics as scientists try to complete the unification of the forces acting at the atomic level: the electro-magnetic, strong, weak and gravitational forces. While one can point to Thales and the other pre-Socratic philosophers as the first to attempt "unification" in science, the practical efforts at unification in science did not begin until the Scientific Revolution of the 16th and 17th Centuries. This effort culminated in Newton's theory of universal gravitation uniting the force that governed the motion of celestial bodies with the force that makes heavy bodies fall on Earth. That Newton was successful in this effort was due, in large respect, to the work of Johannes Kepler in determining the laws by which planets circle the sun. Under this grant, Professors Peter Barker and Bernard Goldstein are examining Kepler's unification of astronomy and physics, and his contribution to the norms of modern science, in the context of 16th century work on astronomy and astrology, rhetoric, and religious thought. They are studying the availability and use of these disciplines in books, letters, notes, and student theses by Kepler and his contemporaries. This setting illuminates Kepler's presentation of Ptolemy, Copernicus and Brahe, and his innovations in the content and methods of science. They present the development of Kepler's ideas from the Mysterium Cosmographicum of 1596 through the Apologia pro Tychone contra Ursum of 1600 and the De Fundamentis Astrologiae Certioribus of 1602 to the Astronomia Nova of 1609. Their examination of the context of Kepler's work draws on the expertise of an international group of consultants. This study will be the first presentation of Kepler's unification of physics and astronomy in its 16th century context, treating the portion of his work from 1596 to 1609 as a whole. In addition to yielding new knowledge about a major figure and a key episode, the project's contextual approach will establish links from the history of science to wider fields of Renaissance and Reformation studies, especially history, philosophy, rhetoric and religious thought. This study of Kepler's role in the development of the modern scientific methodology will also contribute to our understanding of the historical process by which science differentiated itself from the humanities and theology.

DESCRIPTION (provided by applicant): Breast cancer is the most common form of cancer in women. In the year 2000, it is predicted that approximately 180,000 new cases of breast cancer will be diagnosed in the United States, and 40,000 women will die from the disease. The key to successful treatment of breast cancer is early diagnosis, and the use of widespread mammography screening has resulted in significant improvements in breast cancer survival rates. However, a major problem with mammography is a lack of specificity; 70-80% of suspicious lesions on mammography referred for biopsy ultimately have a benign final diagnosis. These "unnecessary" biopsies represent a significant economic burden on health care systems, and are also invasive and unpleasant for the patient. Therefore, there is a need for the development of new non-invasive, cost-effective, and safe imaging procedures with enhanced specificity and sensitivity. Proton MR spectroscopic imaging (MRSI) is a non-invasive metabolic imaging technique, which has yet to be applied to human breast cancer. Preliminary data from our group and others, based on cell preparations, in vitro studies and single-voxel human spectroscopy, suggest that an elevated composite choline signal (detected in the proton MR spectrum) is a marker of malignant breast disease. Benign lesions and normal breast tissue have little or no detectable choline signal. However, technical developments are required before proton MRSI can become a clinical procedure for evaluating breast cancer. These include maximizing spatial resolution, optimizing water and lipid suppression techniques, development of quantitation methodology, and providing whole breast coverage within a clinically acceptable scan time. We will develop and test these techniques in years one and two of this proposal (phase I, R21), and in years 3 and 4 (phase II, R33) we will apply these techniques to a trial of proton MRSI in human breast cancer. Specifically, choline levels will be compared between histologically defined tissue types, in patients who are scheduled for breast biopsy. The sensitivity and specificity of proton MRSI in this patient group will be determined. The techniques developed in this proposal will also assist in the translation of proton MRSI to other organ systems and pathologies, and increase the acceptance of clinical proton MRSI as a diagnostic imaging modality.

[unreadable] DESCRIPTION (provided by applicant): Breast cancer is the most common form of cancer in women. In the year 2004, it was estimated that approximately 217,000 new cases of breast cancer were diagnosed in the United States, and that 40,000 deaths were attributed to the disease. The key to successful treatment of breast cancer is early diagnosis, and the use of widespread mammography screening has resulted in significant improvements in breast cancer survival rates. However, a major problem with mammography is a lack of specificity; in some studies, as many of 70-80% of suspicious lesions on mammography referred for biopsy ultimately have a benign final diagnosis. These 'unnecessary" biopsies represent a significant economic burden on health care systems, and are also invasive and unpleasant for the patient. Therefore, there is a need for the development of new non-invasive, cost-effective, and safe diagnostic imaging procedures with enhanced specificity and sensitivity. Proton MR spectroscopic imaging (MRSI) is a non-invasive metabolic imaging technique that shows promise for the non-invasive diagnosis of human breast cancer. Preliminary data from our group and others suggests that an elevated choline signal (detected in the proton MR spectrum) is a marker of malignant breast disease. However, the low signal-to-noise ratio of proton MRSI currently limits this methodology to quite large lesions (e.g. 1 cm or greater), and makes detection of small Cho signals difficult. Also, few previous studies have investigated the spatial distribution of Cho in breast cancer lesions. In this proposal, we therefore propose to develop methods for MRSI on high field MR systems (3 and 7 Tesla) that are expected to exhibit higher sensitivity and resolution than lower field scanners. Methods will be developed for full breast coverage at high magnetic fields in short scan times, using phased-array receiver coils, and optimal water and lipid suppression. Methods will also be developed for the quantitative determination of lesion choline concentrations. These methods will be developed in years 1 and 2, and, in years 3 through 5, the clinical value of MRSI will be investigated. Specifically, choline levels will be compared between histologically defined tissue types (malignant and benign), in patients who are scheduled for breast biopsy. The sensitivity and specificity of proton MRSI in this patient group will be determined, and compared between field strengths. In addition, the diagnostic value of MRSI will be compared to that of conventional MRI in the same population. [unreadable] [unreadable] [unreadable] [unreadable] [unreadable]

DESCRIPTION (provided by applicant): N-acetylaspartylglutamate (NAAG) is the most abundant peptide in the human brain. Levels of NAAG have been suggested to be abnormal in patients with disorders such as schizophrenia and amyotrophic lateral sclerosis, amongst others. Until recently, there were no means available for the non-invasive determination of brain NAAG levels. Conventional in vivo proton magnetic resonance spectroscopy has been frequently used to measure the combined resonance of NAAG and N-acetylaspartate (NAA), but it has only limited ability to separately detect the individual components, NAAG and NAA, because of their structural and spectral similarity. We have recently demonstrated that;(a) at field strengths of 3 Tesla, it is possible to use spectral editing techniques to selectively detect NAAG (and NAA) with high specificity, and (b) at very high magnetic field strength (e.g. 7 Tesla for human brain) and with sufficient homogeneity, it is possible to resolve NAA and NAAG directly using proton MR spectroscopic imaging (MRSI). In this pilot R21 application, we propose to further develop and validate methods for NAAG detection and quantitation at both 3 and 7T, and to apply these techniques to a pilot study of patients with schizophrenia at 3T. Regional NAAG levels in 20 patients will be measured and compared to age- and sex-matched normal control subjects. It is expected that this R21 project will provide preliminary data for subsequent, larger studies that will fully elucidate the role of NAAG in schizophrenia. PUBLIC HEALTH RELEVANCE: N-acetylaspartylglutamate (NAAG) is the most abundant peptide in the brain, and is believed to play a central role in the pathogenesis of many cerebral disorders, including schizophrenia, amyotrophic lateral sclerosis, and others. Until recently, there was no direct way of measuring NAAG in the intact human brain. We have developed a new method for measuring NAAG using magnetic resonance spectroscopy (MRS). The purpose of this R21 grant is to extend this technique and map the spatial distribution of NAAG in the brain using MR spectroscopic imaging on high field scanners. The techniques developed will be applied to a pilot study of NAAG levels in patients with schizophrenia. In the long term, this research may lead to a better understanding of schizophrenia and treatment approaches.

The vision of our JHU ICMIC Career Developmental Component (CDC) is to generate a small select group of scientists to provide academic scientific leadership in molecular imaging of cancer in the 21st century. The career trajectories of our awardees from the previous funding period are proof that this vision was, and will continue to be, successfully realized. We have established a training environment enriched with a multidisciplinary group of mentors with outstanding skills ranging from imaging, imaging probe design, visualization, oncology, to molecular biology and pathology. These human resources and the instrumentation and facilities continue to offer unprecedented word-class opportunities for the application of novel imaging approaches to understanding cancer. The specific aim of the CDC is to provide formal training as well as inculcate independent research activities in a flourishing research environment. Targeted recruitment of women and minorities will be carried out including summer training for minority students. We will advertise one award every year at the postdoctoral or junior faculty level. Our purpose is to create a transition environment within the backdrop of the JHU ICMIC for the trainee to acquire the necessary skills and expertise to become an investigator capable of establishing an independent multidisciplinary imaging research program. To do this it is important to provide the necessary mentoring, and create independent thinkers capable of making decisions regarding the direction of their project, and the utilization of their resources. Providing trainees with their own independent budget that pays for percent effort, research supplies, and other expenses is highly motivational, and inculcates confidence and independence. Each trainee will be assigned a CDC sponsor from the CDC Faculty who will monitor and facilitate their training progress, and assist in the selection of a research mentor from the JHU ICMIC Faculty to perform ICMIC related research. Trainees will also be required to attend formal courses and training to complement their existing background and expertise. This will result in the generation of outstanding scientists with a well-rounded training in imaging, oncology and molecular biology.

DESCRIPTION (provided by applicant): Schizophrenia a disabling psychiatric disorder that affects approximately 1% of the population. The cost to society resulting from this illness is high Despite extensive research, the underlying biochemical causes of schizophrenia remain elusive, with evidence to suggest that the dopaminergic, glutamatergic and GABAergic neurotransmitter systems all play a role in the development of symptoms. An improved understanding of regional neurotransmitter levels is a first step towards the design of new treatments. Over the last few years, there has been particular interest in the roles of glutamate (Glu), N-acetyl aspartyl glutamate (NAAG) and ?-aminobutyric acid (GABA) in schizophrenia. Glu and GABA the primary excitatory and inhibitory neurotransmitters in the human brain, respectively. NAAG is a precursor of Glu and also binds to receptors involved in the glutamatergic system. High field (7 Telsa) magnetic resonance spectroscopy (MRS), in conjunction with spectral editing techniques, has the potential to measure various neurotransmitters in vivo in the human brain, including Glu and GABA, with higher sensitivity and specificity than at lower field strengths. We have also recently demonstrated that it is possible to reliably determine NAAG in the brain using MRS. The aims of this proposal are therefore to (1) to establish that 7T MRS can reliably measure a 'neurotransmitter profile' of Glu, NAAG and GABA in multiple brain regions in patients with schizophrenia, (2) investigate the differences in neurotransmitter levels between healthy volunteers, early-stage, and later stage patients with schizophrenia, and to also measure the same compounds in first degree relatives of subjects with schizophrenia who demonstrate some of the same traits as patients with schizophrenia. Patients will also be thoroughly evaluated with neuropsychological testing, and neurotransmitter levels will be examined for correlations with both positive and negative symptoms of schizophrenia. An important reason for studying first degree relatives is that they will be unmedicated, allowing observation of disease related neurochemical changes free from the possible confounding effects of medication. The long term goal of this study is to firmly establish the role of Glu, NAAG and GABA (as well as other metabolites) in the pathophysiology of schizophrenia, and investigate their relationship to symptom severity. This knowledge will aid in the design of future treatment trials. We also expect that the establishment of these noninvasive biomarkers by high-field MRS will be useful in the future for evaluating disease severity, progression and treatment response in patients with schizophrenia. PUBLIC HEALTH RELEVANCE: Schizophrenia is a disabling psychiatric disorder that affects approximately 1% of the US population. This research proposal will use high field magnetic resonance spectroscopy methods to measure neurotransmitter levels in patients with schizophrenia, to investigate their relationship to symptom severity, and also study 1st degree relatives of patients with schizophrenia. The long term goal is to develop biomarkers and better understand brain biochemistry in patients with schizophrenia, which in the future may lead to new and improved treatments.

DESCRIPTION (provided by applicant): Glioblastoma multiforme (GBM) is the most common primary brain tumor and is uniformly fatal. During carcinogenesis, tumor suppressor genes are silenced by aberrant histone deacetylase (HDAC) activity. Reversing this modification has become a goal for tumor therapy. Suberoylanilide hydroxamic acid (SAHA) is an orally-active potent inhibitor of HDAC. This agent may not only help control tumors but also alter cerebral biochemistry to improve depressive symptoms afflicting many GBM patients. An NCI-funded multi-institutional trial for GBM combining SAHA with standard chemoradiation is scheduled to open soon. However, the lack of reliable biomarkers to predict early response severely hampers the treatment of GBM patients with HDAC inhibitors. Magnetic resonance imaging (MRI) is the standard tool for monitoring therapeutic response in GBMs. Although useful, conventional MRI has shortcomings including difficulty at distinguishing true tumor progression from pseudo-progression that is often seen soon after completion of chemoradiation. MRI may also not be ideal for evaluating new therapies, many of which help only a subset of patients. For GBMs, therapeutic response is mainly evaluated by assessing for tumor changes on conventional MRIs, since repeat surgical biopsy is too invasive and may be prone to sampling error. However, this is not ideal for evaluating response to SAHA since our preliminary data indicate that drug response is associated with redifferentiation rather than killing/shrinking tumors, which may normalize cancer cell metabolism. While conventional MRI detects tumor size and location, it cannot detect this type of normalization. We propose to fill this void by using MR spectroscopic imaging (MRSI), which uses special techniques in an MRI scanner to measure the metabolism of cancer cells as well as normal brain. While MRSI is not new, it has not gained widespread clinical use due to poor resolution, long scan times, and difficulty integrating with other types of brain scans. We propose to implement state-of-art MRSI technology that can rapidly generate metabolite maps of the entire brain coupled with introduction of an imaging registration/analysis program that combines MRSI data with other imaging studies in a clinically useful fashion. Our long-term goal is to develop MRSI into a practical clinical tool that can be readily implemented at most institutions. The establishment of reliable MRSI metabolic biomarkers to assess early response would be of great value in developing new treatments, especially those such as SAHA which do not work by simply killing cells. By allowing clinicians to detect normalization of cancer metabolism in as little as one week of therapy, patients destined to benefit from treatment may be reassured, while those not showing a metabolic response can be switched from an ineffective treatment without further wasting of time. This would clearly be a highly innovative use of MRSI. Importantly, in addition to monitoring tumor response to SAHA therapy, our MRSI-based tool will allow assessment of the biochemical content of normal brain, and may thus indirectly monitor the subject's quality-of-life.

PROJECT SUMMARY Edited magnetic resonance spectroscopy allows the non-invasive detection of low-concentration metabolites within the brain, free from overlap from other, more abundant compounds. Until recently, spectral- editing techniques have generally focused on measuring individual metabolites in one brain region at a time (for instance, the well-known ?MEGA-PRESS? method). However, this is a time-consuming approach which severely limits clinical applicability when multiple metabolites and/or brain regions are involved. The main goal of this proposal is therefore to develop and establish the reproducibility edited experiments that can detect multiple edited molecules in multiple brain regions, all within a single acquisition. We will develop multi-voxel localization techniques to combine with our recently developed multi-metabolite editing methods, including the Hadamard-encoded ?HERMES? approach as well as the new ?HERCULES? method which allows for up to 13 metabolites to be simultaneously determined. For applications that may require a limited number of voxels to be acquired, we will developed multi-band excitation and parallel acquisition ?PRIAM? methods in combination with HERMES and HERCULES. For applications that require greater spatial coverage and/or the ability to map out the spatial distribution of metabolite levels, edited MR spectroscopic imaging (MRSI) techniques will be developed for use in combination with HERMES and HERCULES editing. Since edited-MRSI is very sensitive to head motion and other instabilities, acquisition and processing methods will be implemented for robust, motion-insensitive edited-MRSI. Rigor and reproducibility will be carefully assessed; newly developed methodologies will be validated by comparison to conventional measurements in the same subjects. Expected improvements in temporal signal- to-noise ratios and reproducibility will also be measured. The resulting data acquisition and analysis tools will be made available for dissemination to the clinical neuroscience and neuroimaging communities.

Project Summary/Abstract Schizophrenia is a disabling psychiatric disorder that affects approximately 1% of the population, and which places an enormous burden on society. While antipsychotic medications are usually effective at controlling the positive symptoms of schizophrenia, persistent negative symptoms and deficits in cognition contribute to significant morbidity and functional impairment. There is increasing evidence that multiple factors may be associated with cognitive deficits in patients with schizophrenia, including both those intrinsic to the brain, behavioral comorbidities, long-term antipsychotic use, as well as systemic factors. Prior studies using magnetic resonance spectroscopy (MRS) have indicated that brain glutamine (Gln) levels are elevated in patients with chronic schizophrenia, and which are negatively correlated with cognitive performance. The underlying mechanism of Gln elevation is unknown, however; it may be related to altered Gln metabolism and/or subclinical increases in blood ammonia levels. The goal of this pilot study is to probe the relationship between brain Gln and blood ammonia levels, both in patients with schizophrenia and control subjects. The relationship between these factors and cognitive function will be evaluated using detailed neuropsychological testing. High-field (7T) MRS will be used, since it provides more accurate estimation of brain Gln compared to MRS performed at lower field strengths. Improved understanding of the relationship between altered Gln and cognitive deficits in schizophrenia may inform future mechanistic studies using back-translational approaches in animal models, and ultimately guide novel therapeutic interventions in schizophrenia.