Imaging aquaporin activities and molecular changes in Parkinson’s disease using advanced MRI

This study will develop an advanced MRI(MISL and CEST) to image the aquaporin pathology, protein and specific molecular changes in Parkinson’s disease(PD). PD is a complex neurodegenerative disorder characterized by a progressive loss of dopaminergicneurons. Recent studies have implicated key roles of aquaporins in PD pathogenesis, especially its dysfunction could impair glymphatic clearance, aggravate α-synuclein accumulation and dopaminergic neuron loss. However, it is very challenging to imagethese changes in vivo during disease progression non-invasively and simultaneously, hindering our understanding of its role in early pathology. This proposal aims to address this challenge by imaging aquaporin and related PD pathologies using CEST and MISL.We hypothesize that multiple CEST and MISL contrasts can reveals key molecular events of PD and are sensitive to AQP4-dependent glymphatic function, α-synuclein accumulation and dopaminergic neurons loss and myelin abnormality. We demonstrated that CEST MRI could detect changes in protein, myelin and specific molecules in a sensitive manner, including protein aggregation and glymphatic dysfunction in Alzheimer’s disease, altered glucose uptake and utilization during glucose deprivation treatment in brain cancer, demyelination in multiple sclerosis and AQP4 function in rodent brain, using glucose, amine, amide proton transfer(APT) and nuclear Overhauser effect(NOE) CEST and MISL. Collectively, our pilot MRI studies strongly suggested that these advanced MRI contrasts enable the imaging of many key neuropathologies noninvasively and longitudinally, especially those related to PD.In this project, we will develop an advanced MRI imaging platform to assess the molecular changes during the PD development and upon treatment using MISL and multiple CEST contrasts. First, is to develop and optimize these advanced imaging parameters at 3T for imaging PD neuropathology. Second, is to study the multiple CEST contrasts when there are specific molecular changes during PD progression, and correlate with neuropathology in PD mice. Finally, we will assess the changes of AQP4 upon PD treatment and its interplay with other neuropathology via our multiple contrast analysis in specific brain regions, which could inform treatment efficacy. This advanced MRI platform enables the assess of PD neuropathology in a totally non-invasively imaging of PD neuropathology without contrast agents, especially imaging the role of aquaporin in protein accumulation and neuronal loss. This simultaneously imaging of multiple neuropathology could provide valuable information to monitor disease progression, evaluate treatment and to potentially enable early detection of PD.