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Title

POSTMORTEM MRI OF THE ELDERLY HUMAN BRAIN: METHODS AND APPLICATIONS TO HISTOPATHOLOGICALLY VERIFIED ALZHEIMER’S DISEASE AND OTHER NEUROPATHOLOGIES OF AGING

Creator

Dawe, Robert J.

Date

2011-04-08, 2011-05

Description

Currently, a definitive diagnosis of Alzheimer’s disease is only possible postmortem, when the distribution and type of pathology in the brain...
Show moreCurrently, a definitive diagnosis of Alzheimer’s disease is only possible postmortem, when the distribution and type of pathology in the brain can be directly verified via histology. Clinical diagnostic techniques in use today rely on behavioral and neuropsychological criteria and only provide diagnoses of possible or probable Alzheimer’s disease, both of which indicate that significant irreversible neuronal damage has already occurred. Therefore, a neuroimaging technique for detection of Alzheimer’s pathology during life is highly sought after. Such a technique would be noninvasive, could provide a quantitative evaluation of potential therapies in patients, and could eventually be used for early detection of Alzheimer’s disease. The purpose of this work was to investigate the use of magnetic resonance imaging (MRI) as diagnostic tool for Alzheimer’s and other types of pathology that are common in the elderly human brain. In order to correlate imaging data with a diagnosis of neuropathology that was guaranteed to be accurate, we focused on imaging cerebral hemispheres postmortem (ex vivo), when a complete pathology report was available from a board-certified neuropathologist. The main difference between this work and any other study is the abundance of postmortem imaging data paired with neuropathology data in a relatively large pool of subjects. First, we examined the relation between postmortem hippocampal volume, measured from MR images, and pathological diagnosis of Alzheimer’s and other common types of pathology. It was shown that Alzheimer’s, along with hippocampal sclerosis, are associated with a dramatic reduction in hippocampal volume. Furthermore, the pattern of hippocampal atrophy differs between these two types of neuropathology, which may provide a means of distinguishing one from the other in vivo using MR images. Next, the transverse relation time constant, T2, was examined over time in five postmortem hemispheres that were undergoing chemical fixation via immersion in formaldehyde solution. This investigation yielded two important pieces of information: (a) for the purposes of obtaining stable measurements of T2, the ideal time to conduct postmortem MRI of the human brain is at least one month postmortem, and (b) correction of T2 measurements for the postmortem interval to imaging is both possible and necessary for analysis of T2 alterations associated with pathology. Using the information gleaned from the study of changes in transverse relaxation over time, we next examined the dependence of T2 on the presence of Alzheimer’s pathology. Significant prolongation of T2 was demonstrated in various white matter regions in cases of Alzheimer’s, suggesting degeneration of that tissue. Significant shortening of T2 was detected in the basal ganglia, suggesting that accumulation of iron in that region is associated with the progression of Alzheimer’s disease. Finally, a method of conducting high quality diffusion tensor MRI of postmortem cerebral hemispheres was developed. Compared to in vivo diffusion tensor MRI, the postmortem variant of the technique is much more challenging, since the signal to noise ratio is affected very negatively by a combination of faster transverse relaxation, reduced water diffusivity, and the resulting need for longer diffusion-sensitizing gradients. To a large extent, these problems have been solved, and we have now implemented a protocol for routine diffusion tensor MRI of recently deceased human brains which takes less than one hour of scan time. This work examined three MRI techniques that hold great promise in their ability to detect Alzheimer’s and other types of neuropathology: hippocampal volumetry, mapping of the transverse relaxation time constant T2, and diffusion tensor imaging. The fact that all three techniques were carried out postmortem is an important contribution, since it allows for imaging results to be correlated with a complete and accurate pathological diagnosis of disease. Findings from postmortem studies could one day be translated to the in vivo case, where they can potentially be used for antemortem diagnosis of Alzheimer’s disease.
Ph.D. in Biomedical Engineering, May 2011
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