The goals of this request for a Clinical Investigator Development Award (CIDA) are to develop and validate accurate, high-resolution and high- sensitivity magnetic resonance (MR) methodologies for imaging cerebral perfusion and brain function. The methodologies are to be widely applicable to human populations to help detect and understand neurological disorders. Some neurological disorders have a causative, primary alteration in tissue blood flow (e.g., stroke, TIA, vasculitis), while others have a secondary, associated flow alteration (e.g., tumors, seizures). It is important not only to detect and understand these perfusion disorders, but also to search for perfusion changes in many other neurological disorders using sensitive imaging methodology. As there is a coupling between brain activity and tissue blood flow, it is possible that many neurological disorders might be associated with subtle perfusion abnormalities that are caused by alterations in brain function. Perfusion imaging might also provide a means of monitoring therapy and brain activity in neurological disorders. A further goal of this CIDA period is to train in the complex fields of cerebral perfusion biology and brain activation physiology through the sponsorship of Dr. Marcus Raichle and his positron emission tomography (PET) neuroscience group. The training will also involve instruction of medical and graduate students. The magnetic susceptibility effect of MR contrast media on signal intensity has been used recently to qualitatively assess cerebral perfusion. However, this signal loss (deltaR*) method has the potential disadvantage of a dependence on vessel geometry (e.g., capillary diameter, spacings, and orientations) and tissue water diffusion. As an alternative, the susceptibility effect on signal phase shift (deltaphi) has more recently been used to qualitatively assess cerebral perfusion. Preliminary theory predicts this deltaphi method to be insensitive to capillary geometry, compartmentation of contrast agent, and diffusion. The work proposed in this CIDA request is to better characterize this deltaphi effect. A complete theory of the physical processes causing this phenomenon will be undertaken, with experimentation designed to validate the theoretical assumptions. The physical, chemical and biological properties of several MR contrast agents will be tested to determine which agents behave as perfusion tracers. Both the deltaphi and the deltaR+ methods will be used with bolus contrast agents to produce images of cerebral blood volume, and results will be validated by many approaches, including positron emission tomography. The two methods will be investigated in animal models of stroke and blood brain barrier (BBB) breakdown to assess the effects of changes in diffusion and contrast agent compartmentation on accuracy. A red blood cell (RBC) contrast agent will be further developed and tested to enable high-sensitivity functional brain imaging using the deltaR+ and deltaphi perfusion imaging methodology.
