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No description available.

No description available.

No description available.

Rats were injected daily with two doses of HCY (20-mg/kg and 200-mg/kg) for variable duration and spatial memory was assessed in the water maze.  Animals were tested 30min after injection using two paradigms: 1) the reference memory (RM) paradigm in which the position of the platform in the water maze was kept constant over days in order to test long-term memory, 2) the delayed matching to position (DMTP) paradigm in which the platform position changed every day in order to test working/short-term memory.  We found that HCY induced a differential effect on memory depending on animal’s age and the task employed. In the first group of animals, HCY administration for 13 weeks, in contrast to all expectations, enhanced reversal learning in reference memory paradigm in 8-10 weeks old animals, with no effect on the acquisition or memory retention in the probe trials. In the second group of animals, in contrast to young animals, HCY administration enhanced memory of young-adult rats (5-month old) when a DMTP task was employed.  At the level of receptors, HCY enhancement is unlikely to be mediated via NMDA receptors alone, because HCY failed to revert MK801-induced (NMDA receptors antagonist) memory impairment observed with a DMTP task.  Surprisingly, we found that HCY partially reversed scopolamine-induced memory impairment, which may indicate that HCY has some activity on cholinergic system. In the third group of animals (1-year-old), HCY administration for 2 weeks, in contrast to the 5-month old rats, impaired memory in the DMTP task.  Also, we found that HCY plasma level in the 200-mg/kg group was about 600% more than controls.  This may reflect a reduced ability to clear HCY which may explain the absence of any impairment in young animals where HCY level increased by 50% only after 13 weeks of treatment. In conclusion, given that memory impairment was observed in old animals may indicate that hyperhomocysteinemia probably plays a role in AD.  However, HCY effects are overt only in already predisposed old patients.

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Despite the association between hippocampal atrophy and a vast array of highly debilitating neurological diseases, such as Alzheimer’s disease and frontotemporal lobar degeneration, tools to accurately and robustly quantify the degeneration of this structure still largely elude us. In this thesis, we firstly evaluate previously-developed hippocampal segmentation methods (FMRIB’s Integrated Registration and Segmentation Tool (FIRST), Freesurfer (FS), and three versions of a Classifier Fusion (CF) technique) on two clinical MR datasets, to gain a better understanding of the modes of success and failure of these techniques, and to use this acquired knowledge for subsequent method improvement (e.g., FIRSTv3). Secondly, a fully automated, novel hippocampal segmentation method is developed, termed Fast Marching for Automated Segmentation of the Hippocampus (FMASH). This combined region-growing and atlas-based approach uses a 3D Sethian Fast Marching (FM) technique to propagate a hippocampal region from an automatically-defined seed point in the MR image. Region growth is dictated by both subject-specific intensity features and a probabilistic shape prior (or atlas). Following method development, FMASH is thoroughly validated on an independent clinical dataset from the Alzheimer’s Disease Neuroimaging Initiative (ADNI), with an investigation of the dependency of such atlas-based approaches on their prior information. In response to our findings, we subsequently present a novel label-warping approach to effectively account for the detrimental effects of using cross-dataset priors in atlas-based segmentation. Finally, a clinical application of MR hippocampal segmentation is presented, with a combined MR-PET analysis of wholefield and subfield hippocampal changes in Alzheimer’s disease and frontotemporal lobar degeneration. This thesis therefore contributes both novel computational tools and valuable knowledge for further neurological investigations in both the academic and the clinical field.