Ronald J. Killiany, Ph.D. - US grants

In this project, structural MRI data will be obtained at baseline from controls and non-demented subjects with cognitive impairments who will be recruited through the Clinical Core and followed over time. Subjects will be evaluated longitudinally with MRI when they cross specific transition boundaries, as defined by the Clinical Core. The overall goal of the MRI project is to determine whether structural MRI data can be used to predict which non-demented individuals with cognitive problems will develop progressive cognitive decline, which will progress to the point where they meet criteria for AD, and which will remain stable. In addition, we will seek to determine the evolution of brain changes that characterize prodromal AD, and how these measures relate to the clinical characteristics of the subjects. Underlying these goals is the assumption that structural MRI data can serve as an indirect measure of the neuronal loss that occurs when neuritic plaques and neurofibrillary tangles accumulate during the development of Alzheimer's disease (AD). In the proposed funding cycle we will use manually drawn regions of interest (R01), as we have done in the past, to evaluate atrophy in selected brain regions. We are also proposing to enhance and apply a new automated method for identifying ROIs automatically, and to compare this method to the manual measurements. Both types of MRI data will e used by other projects in the Program Project, and thus an additional responsibility of this Project is to distribute MRI images, and regions of interest derived from them, to investigators in Project by Johnson (SPECT) and Project by Sperling (fMRI). In addition, we will seek to determine the relationship between SPECT measures and other information obtained on the same individuals by the cores and the projects, including clinical data, genotype status, volumetric MRI, and fMRI signal change.

Within the next twenty years, 50% of all individuals in this country will be 50 years old or older, an aging time point that has been characterized in cross sectional data by the onset of cognitive decline. This shifting of the population to a proportionately greater number of older individuals has fueled concerns about the effects of aging and age-related diseases and their relationship to cognitive decline. One of the most common conditions affecting individuals as they age is hypertension, the incidence of which is 25% among all adults in the US., and greater than 50% among all adults over the age of 65. At present, this condition affects over 60 million people in the U S alone, of whom it is estimated 50% may be untreated. Moreover, evidence has accumulated to show convincingly that hypertension, in addition to aging, produces impairment in multiple domains of cognitive function, even at mildly elevated levels of blood pressure. In addition, hypertension is a major risk factor for cerebrovascular dementia which alone accounts for approximately 20% of all dementia and likely contributes to another 15% to 20% of the dementia cases. However, the mechanism by which hypertension induces neuropathological changes is poorly understood, in part because only limited animal models exist for studying these processes. The purpose of this project is to test a novel device for inducing hypertension in the non-human primate. The device is surgically implanted into the chest of the monkey surrounding the thoratic arota. The device can be adjusted externally to narrow the diameter of the arota (but not fully constricting it) resulting in increased blood flow and hypertension to the upper limbs and head. By adjusting the device gradually over a period of time, the blood pressure can be raised gradually until hypertension is induced. We will test this device in non-survival and short-term survival situations in five monkeys. They will be continuously monitored for blood pressure, body temperature, EKG and activity using radiotelemetry devices and values compare from pre-implant to post-implant levels. Finally, as part of a preliminary effort to understand the mechanism by which neuropatholoigical processes are induced in the brain, we will survey the brain and aorta for signs of pathology.

DESCRIPTION (provided by applicant): This proposal requests $1,944,611.50 in direct costs from the National Center for Research Resources (NCRR) High-End Instrumentation Grant Program (S10) to fund a crucial 3T quasar dual MRI scanner for multimodal and molecular imaging. This new instrumentation will replace the technically significantly inferior 3T Philips Intera MRI scanner currently operational at the Center for Biomedical Imaging of the Boston University Medical School. The Center for Biomedical Imaging (CBI) is a Core Research Center of the Boston University serving both the greater Boston University and Boston area biomedical research community. Currently, a total of more than 70 different biomedical imaging projects are being performed using the existing system, ranging from longitudinal assessment of Autism Spectrum Disease, changes in cortical metabolite concentration in Alcoholism, and Alzheimers Disease Neuroimaging Initiative. The explanatory power of our current 3T scanner for these important mental health questions, however, is greatly hampered due to the limited technical capabilities of the current scanner configuration, such as low gradient strength, lack of multinuclei MR spectroscopy capability, and limited number of receive channels. The new, quasar dual 3T MRI scanner will provide a quantum jump of improvements in our Center's capability to serve the critical imaging needs of our NIH funded investigators. The major improvements are: 1. Significant enhancement of the gradient strength: from current 2.5 Gauss to 8 Gauss/cm. 2. From current proton only to broadband multi-nuclei detection capabilities. 3. From current 6-receive channels to 16-receive channels. These increased capabilities will have an immensely positive impact on the many projects presently executed, and on those that are planned for future execution on the 3T scanner (see Project Narrative for further details). PUBLIC HEALTH RELEVANCE: The vastly improved technical capabilities resulting from the requested new instrumentation will be of highest relevance for the Boston University and Boston area biomedical research community. The improvements are more than incremental, resulting in qualitatively higher level of explanatory power for the 3T MRI data obtained in our Center. This in turn is expected to greatly facilitate the translation of basic biomedical imaging results into clinical reality.

The Whole Animal Imaging Core (WAIC) will establish and maintain a state of the art magnetic resonance imaging facility under BSL-4 containment in which whole animals (control and infected with category A, B and C agents) can be examined by NEIDL investigators. The facility is planned to take advantage of anticipated innovations in MRI and related imaging technologies such that state-of-the-art imaging capacity will be part of the research repertoire in the near and distant time frames. It is clear that longitudinal studies of organism pathogenesis, treatment response and immune protection studies of category A agents have been limited by the unavailability of modern imaging technologies in a BSL4 high containment environment. This is especially true for non-human primate studies where "point in time" necropsy studies have often had to substitute for longitudinal imaging studies. Because of the lack of such facilities little is known about the fine neuroanatomy of the BSL4 agents which cause central nervous system disease. Indeed there have been no studies using functional MRI on animals infected with BSL3 and BSL4 pathogens. Novel molecular imaging techniques are also rapidly developing which are capable of non invasively investigating such relevant topics as organ function during infection with category A, B and C agents, the trafficking of immune cells in control and infected animals, and the distribution and concentrations of pharmacologic agents in control and infected animals. For all these reasons it is essential that state of the art imaging facilities are necessary for the research agenda of NEIDL investigators over the next twenty years.