Pathologic Substrates Of Quantitative Magnetic Resonance Imaging In Parkinsonisms PDF Download

Parkinsonisms -- a set of diseases characterized by motor presentations reminiscent of Parkinson's disease (PD) -- are progressive and debilitating neurodegenerative disorders. Motor signs and symptoms advance from tremors, weakness, and loss of balance, to significant challenges in eating, grooming, and other activities of daily living. Concurrent non-motor symptoms include mood disturbances, hallucinations, and cognitive decline. Presently, pharmaceutic and interventional therapies are available for symptomatic relief, but there are no curative measures. Within the wider class of movement disorders, parkinsonisms -- which include progressive supranuclear palsy, multiple system atrophy, and corticobasal degeneration -- are distinguished by the loss of dopaminergic neurons in the substantia nigra pars compacta (SNc), a midbrain structure that provides dopaminergic input to the striatum to regulate the motor pathways of the basal ganglia. Currently, it is unclear as to why these nigrostriatal neurons are particularly vulnerable. Outside of rare hereditary mutations predisposing individuals to PD, the majority of parkinsonism cases have no definitive etiology. Our best estimation is that they occur as a result of complex interactions between genetic and environmental risk factors. In the past few decades, there has been tremendous effort to develop magnetic resonance imaging (MRI) biomarkers that are sensitive to parkinsonism neuropathologic changes, both for the differential diagnosis of parkinsonisms and for the monitoring of their progression. MRI has the advantage of being a safe and high-resolution medical imaging capability. It currently is used only in ancillary studies investigating parkinsonisms. But researchers have continued to experiment with scanners, sequences, and advanced data processing techniques in the search of novel and robust quantitative MRI metrics. Presently, there are several MRI modalities being studied, but two frequent approaches are susceptibility MRI (sMRI) and diffusion tensor imaging (DTI), which respectively reflect iron-related changes and general alterations in tissue microstructural integrity. Both techniques have detected parkinsonism-related changes in cross-sectional and longitudinal studies of the SNc. But despite these promising findings, there is little known about the exact pathologies they represent. In this work, I discuss in greater depth the issues outlined above and present original research that advances our understanding of the pathologic substrates underling MRI in parkinsonisms. In first chapter, I begin by discussing parkinsonisms as a set of similarly presenting clinical syndromes with unique yet overlapping neuropathologies. In the second chapter, I provide an overview of sMRI and DTI as quantitative MRI biomarkers. I follow this in the third chapter with a demonstration of their ability to capture clinically relevant changes within limbic structures among parkinsonisms. In the fourth chapter I address the issue at hand and examine the pathologic substrates underlying sMRI and DTI signals in the parkinsonism SNc. Then in the fourth and fifth chapters, I respectively study a potential gene-environment interaction using sMRI and DTI of the SNc, and integrate the preceding findings to point to future directions. As a whole, this dissertation is by no means an exhaustive review or study of MRI in parkinsonisms. It addresses, however, key gaps in our current understanding and lays important groundwork for future investigations.