NYU Researchers Expand MRI to Molecular Imaging
ALZHEIMER’S DISEASE: EARLY DIAGNOSIS IN MICE AND MEN
A good example of the new directions in molecular imaging is in the area of targeted MRI methods for the early diagnosis of Alzheimer’s Disease (AD), an increasingly prevalent problem in an aging population in the United States and around the world. A hallmark feature of AD is the early formation of plaques in the brain, which are extracellular aggregates of the protein amyloid-beta. Several transgenic mouse models have been constructed that mimic the amyloid deposition seen in AD, providing an important new system to study plaque formation. Some researchers have suggested that, in addition to being an early disease marker in AD patients and mouse models, the amyloid plaques are themselves part of the pathogenic process, and have proposed experimental therapeutic strategies for clearing the plaques, first in the mouse models and then in human AD subjects. Although this “amyloid hypothesis” is currently controversial, with different experts arguing both for and against the pathogenic role of amyloid in AD, imaging amyloid plaques with MR is an important and active area of research, and one in which molecular imaging approaches can be applied.
At NYU, a collaboration between researchers in the Department of Radiology — Youssef Zaim Wadghiri, Ph.D., and Dr. Turnbull — and the Department of Neurology — Einar Sigurdsson, Ph.D., and Thomas Wisniewski, M.D. — resulted in the first demonstration that amyloid plaques could be detected in vivo in transgenic mice with MRI, using magnetically labeled peptides that bind selectively to amyloid-beta. Ongoing investigations are aimed at overcoming some of the limitations of those initial studies, including the development of targeted agents with reduced potential toxicity, and agents that have increased permeability to the blood-brain barrier, the normal defense mechanism of the brain against blood-borne pathogens, which also impedes delivery of many therapeutic and diagnostic imaging agents. New directions in this research have been provided by the work of several investigators in the Department of Chemistry, including Kent Kirshenbaum, Ph.D., whose laboratory is engineering novel peptide-like agents known as peptoids, which are designed with dual functions as amyloid-binding and blood-brain barrier-permeable delivery agents. Alternative approaches are being investigated by Young-Tae Chang, Ph.D., using combinatorial organic chemistry methods to screen for small molecules that target amyloid plaques in the brains of transgenic mice, and Marc Walters, Ph.D., working on micelle-based agents, a type of chemical shell designed to carry large numbers of targeted paramagnetic contrast agents across the blood-brain barrier. In all of these projects, Dr. Wadghiri provides the final proof of concept, testing each novel strategy for in vivo plaque detection using MRI in transgenic mouse models of AD.
The emphasis at NYU on MR is logical, reflecting the research and clinical strength of the institution. In addition to the multitude of clinical MRI systems at NYU Medical Center, NYU has a suite of high field research magnets at the CBI under the direction of Joseph Helpern, Ph.D. The CBI has two 3 Tesla (T) scanners and a wholebody 7T human scanner, one of only a handful of such systems in the country. Plans are in place to build a molecular imaging program, which will include installation of a 7T small-animal scanner, enabling translational research from the animal to the human. Ongoing studies range from the testing of contrast agents and preclinical imaging in rodents, to clinical trials in human subjects, on systems operating at the same magnetic field strength. Other research magnets at NYU include a 3T system for human and primate brain imaging under the direction of Souheil Inati, Ph.D., at the Center for Neural Science; a 7T system for imaging mice, directed by Daniel Turnbull, Ph.D., at the Skirball Institute of Biomolecular Medicine; and three additional research magnets for human and animal imaging at the Center for Advanced Brain Imaging at the NYU-affiliated Nathan Kline Institute in Orangeburg, NY. Most significant in this endeavor is the recruitment of faculty and establishment of research groups energizing these investigations. The Department of Radiology, under the leadership of Louis Marx Professor and Chairman Robert I. Grossman, M.D., has rapidly expanded the number of research MRI faculty and has integrated these new faculty members into collaborative relationships with the basic science programs through initiatives such as the MICA group. NYU Radiology appreciates the potential importance of molecular imaging and is committing the requisite resources to become a leader in the emerging field of molecular MRI.
Dr. Turnbull prepares to load the mouse coil into the 7T animal magnet.
In parallel to work on paramagnetic contrast agents targeted to amyloid, Dr. Helpern and Fatima Falangola, M.D., Ph.D., in the Department of Radiology have shown that some amyloid plaques can be detected in the brains of transgenic mouse models of AD based on the accumulation of iron, an endogenous paramagnetic agent in all living organisms. This discovery led to a collaboration with Dr. Jensen, an expert on the MRI effects of iron, to design more sensitive quantitative MRI methods to detect iron and other biophysical changes associated with amyloid deposition both in mouse models and AD. Key to the success of these approaches, as well as the work on targeted amyloid probes, is the ready availability of high-field MRI systems at NYU, which provide increased sensitivity to both endogenous iron and to the experimental paramagnetic contrast agents described above.
MOLECULAR MRI FOR BASIC BIOLOGICAL STUDIES
Working among mouse developmental biologists and neurobiologists in the Skirball Institute of Biomolecular Medicine, the Turnbull laboratory has also devised molecular imaging methods for analyzing brain and vascular evolution in normal and genetically modified mice. As one example of this research, Ph.D. student Xin Yu has invented a method using paramagnetic manganese ions, which selectively accumulate in active neurons, enabling contrast-enhanced MRI studies of sound-evoked brain activity. In another project, M.D./Ph.D. student Abby Deans is investigating iron-based contrast agents for cell labeling in the young mouse brain, including genetic approaches for modifying MRI contrast. Motivated by the fact that iron acts as an endogenous contrast agent, the Turnbull laboratory engineered cells that would express proteins involved in cellular iron internalization and storage. The resulting increase in cellular iron produces significant changes in MRI contrast, a feature which will be utilized in future studies to follow the fates of specific cells in vivo. Interestingly, the iron-induced cellular contrast was much more pronounced at 7T compared to the conventional field strength of 1.5T, arguing for the importance of high-field MR in molecular imaging. We fully expect that these basic biological studies will ultimately impact patient care. Efficient cell-labeling methods will be required in the future to assess fundamental processes such as immune cell trafficking and tumor metastasis, as well as monitoring the behavior of experimental stem cell therapies. Research in mouse biology will translate into future human advances.
In summary, NYU has entered the world of molecular imaging through the MR door, developing and testing contrast agents targeted to specific cells and disease markers such as amyloid-beta in AD. The challenges ahead require multidisciplinary approaches and strong collaborations. The bridges being built today between the School of Medicine and the basic science departments at Washington Square will provide the infrastructure for future success. All indications suggest that high-field MR will prove critical for these achievements, and the talented researchers at NYU, empowered by our tremendous resource of high-field MR technology, will be in the vanguard of this emerging field!
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