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Abstract

Department of Biomedical EngineeringIn the brain, iron is an essential element in oxygen supply through blood vessels, energy metabolism, myelin formation, and neurotransmitter synthesis for brain development with maintaining homeostasis. However, even in healthy people, as they grow older, iron levels increase steadily in some regions of the brain. Among the inevitable iron deposits with aging, the unbound labile iron generates reactive oxygen and free radicals, which produce stress on the brain tissue and necrosis of cells, which are closely associated with neurodegenerative diseases. These finally promote neurodegenerative diseases, including Parkinson???s disease and Alzheimer???s disease, which accompany the damage in behavior and cognitive function. Therefore, developing magnetic resonance imaging-based biomarkers to detect various iron clusters deposited in the brain is crucial work for diagnosing and monitoring related diseases. However, it???s still impossible to classify the states of iron and separate the various forms of iron deposited in the brain. The aim of this study was to develop multi-color iron magnetic resonance imaging and the investigation of its in vivo feasibility through translation research from the preclinical trials including postmortem magnetic resonance imaging with histopathological validation to clinical application. In the first section, it was discovered that the neuromelanin pigment within the human substantia nigra is only sensitive to T2* than other magnetic resonance contrast due to its paramagnetic property. Subsequently, the technique for specific visualization of neuromelanin-iron clusters in postmortem substantia nigra tissue was developed using combined T2 and T2* (T2*/T2 or T2*/T22) with histopathological validation supported by the Monte Carlo simulation. Separate segmentations of the areas of iron detected in the T2 map and neuromelanin observed in the T2*/T2 map (or T2*/T22 map) were available within the substantia nigra. The dorsal linear mismatch of T2 and T2* was consistently detected in the brains of healthy controls. However, it was shortened in the diseased brains. In vivo feasibility and implication of developed technique as a clinical biomarker were quantitatively demonstrated in the patients of Parkinson???s disease compared to healthy subjects. In the second section, the iron deposition along the myelinated fiber of white matter was identified in the diseased brains. The iron-rich white matter at the frontal subcortical area contributes to the positive susceptibility in the patients of Adult-onset leukoencephalopathy with axonal spheroids and pigmented glia. Susceptibility-weighted imaging presented the noticeable phase signal showing the tree-like structure in the white matter of the frontal brain, with striking atrophy. This kind of rare tissue contrast in susceptibility-weighted imaging can aid to define Adult-onset leukoencephalopathy with axonal spheroids and pigmented glia. Besides, the deposited iron was verified on the myelinated fibers of the 3rd cranial nerve, which is the oculomotor nerve within the brain of progressive supranuclear palsy. Our results demonstrated the enhanced magnetic resonance susceptibility value between the area of substantia nigra and red nucleus shown in the brain of progressive supranuclear palsy derives from exaggerated iron concentration on the myelinated fibers of the nerves between two structures. In conclusion, the developed techniques of multi-color iron magnetic resonance imaging in this thesis can be useful imaging biomarkers to evaluate the progressive change of several iron-related neurodegenerative diseases, such as Perry syndrome, progressive supranuclear palsy, Parkinson???s disease, and Adult-onset leukoencephalopathy with axonal spheroids and pigmented glia. The advanced research will be implemented to validate the alteration of magnetic resonance signal with the presence of iron molecules chelated to beta-amyloid or tau with Alzheimer???s disease progression.ope