The overall goal of this project is to develop a non-invasive, quantitative method to monitor progression of Neimann-Pick Type C (NPC) disease and its response to novel therapies. NPC disease is an inherited genetic defect that results in errant trafficking of intracellular cholesterol and gangliosides. Although it is rare, NPC is particularly devastating because most NPC sufferers present in early childhood with progressive ataxia and neurodegeneration that leads to death in the second decade of life. There is currently no effective therapy for NPC disease. However, development of new therapies is being aided by an increased understanding of the molecular ? mechanisms underlying NPC as well as the existence of an NPC mouse model. A major obstacle to research in NPC therapy is that current non-invasive therapeutic endpoints are limited to qualitative measures of neuromuscular response patterns or delayed onset of weight loss and death. These endpoints are far from ideal since they are neither sensitive nor quantitative. A reliable and quantitative method to monitor the progression of NPC disease and its response to successful therapy is greatly needed. Magnetic resonance imaging (MRI) has potential to be such a method. It is non-invasive and is equally applicable to investigations of animal models and human patients. In previous work within this project, we have demonstrated that the diffusion of water in white matter regions of the brain of end-stage NPC mice is significantly different than that of age-matched littermate control mice. Specifically, the fractional anisotropy (FA) of water, as measured by diffusion tensor imaging (DTI), was significantly reduced in the white matter of NPC mice. We also determined that T2-relaxation times in these regions were increased by the disease. These findings correlated with significant reductions of myelin, which is a hallmark of NPC in humans and animal models. The goal of the current project is to carefully characterize these MRI visible biomarkers, by investigating NPC mice through a continuum of the disease, and to correlate them to histological changes. The sensitivity of these markers to effective therapy will also be determined in longitudinal studies. These imaging techniques will also be used in evaluation of novel neurosteroidal therapies and in transgenic mice. Establishment of quantitative MRI methods that can be used to non-invasively follow the progression of NPC disease in animal models and in humans will expedite the development of effective therapies and add tremendous value to future clinical trials. The methodologies established in this project, while specific to NPC, will also have application to other neurological diseases. ? ? ?
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