Neuroinflammation plays a major role in many neurological diseases, including both acute (e.g. stroke and traumatic injury) and chronic disorders (e.g. inherited leukodystrophies, Alzheimer's and Parkinson's disease, multiple sclerosis and malignant CNS neoplasms). Non-invasive in vivo imaging techniques for specific imaging of inflammatory markers hold great promise for the early identification of inflammation, understanding disease mechanisms and effective therapeutic interventions. As one of the treatment strategies, nonsteroidal anti-inflammatory drugs (NSAIDs) have shown beneficial effects for Alzheimer's and Parkinson's disease, especially when taken in the early stage of disease. This proposal aims to develop a novel MR approach for targeted neuroinflammation imaging, using NSAIDs as Chemical Exchange Saturation Transfer agents, eliminating the need for additional metal-based imaging agents. NSAIDs mainly function through inhibition of cyclooxygenase (COX) enzymes involved prostaglandins synthesis, which are the crucial molecular biomarkers in the cascade of neuroinflammation and neurodegeneration. The technique will lead to visualizing expression of the inflammatory biomarkers (e.g. COX-1 and COX-2), such as in targeted PET imaging by radiolabeling the NSAIDs with 18F or 11C. Together with the exquisite anatomical and functional information of MRI, the success of the project will lead to a sensitive and specific tool for imaging neuroinflammation and visualizing the related biomarkers that will be readily translatable to the clinic. It also enables comprehensive diagnosis and prognosis of neurological diseases especially suitable for routine screening and longitudinal monitoring in chronic diseases compared to PET, and also promoting the neuroscience research. Based on literature research and our previous research results, the approach is feasible with specificity and sensitivity both because of the specific and enhanced accumulation of the NSAIDs and their unique chemical structure for specific and sensitive in vivo detection. To more systematically establish the feasibility of the approach, we have set three specific aims: 1) Assess accumulation of NSAIDs in inflamed brain tissue ex vivo by CEST MRI, validated by LC/MS/MS; 2) Optimize image acquisition and post-processing methods, to enable specific and sensitive quantification of the NSAID agents. The sensitive in vivo detection of NSAIDs is the key of this study. 3) Monitor NSAID accumulation and COX expression in vivo in a rodent neuroinflammation model. The innovation of the studies lies in three aspects: a) The concept of employing small-molecular anti-inflammatory drugs for MR molecular imaging is unique, allowing for the efficient delivery and enhanced-accumulation on the inflammatory sites. b) Superior to conventional methods, the proposed agent features IM-SHY with improved exchange properties and the image acquisition and processing employs a multi-parametric saturation scheme, allowing for specific and sensitive in vivo detection. c) The experimental design and validation methods are unique, based on ex vivo organotypic rodent slice culture and the LC/MS/MS measurement.
The project is relevant to public health because it is expected to result in the early identification of neuroinflammation in a variety of neurological diseases, such as the inherited leukodystrophies, and other diseases e.g. Alzheimer, Parkinson, multiple sclerosis and also malignant CNS neoplasms, providing better understanding of mechanisms, and possible leading to effective therapeutic interventions. This proposed technology enables targeted MR imaging of neuroinflammation by directly monitoring the accumulation of nonsteroidal anti- inflammatory drugs (NSAIDs) using Chemical Exchange Saturation Transfer technique, eliminating the need for additional metal-based imaging agents. Successful accomplishment of the proposed research will form the basis of a clinically translatable MR imaging platform to improve existing therapies, which is highly relevant to mission of NIH.
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