Introduction: Cholesterol metabolism in the brain is implicated in the development of Alzheimers disease (AD). Understanding the relationship between markers of brain cholesterol metabolism and the structural changes occurring in the aging brain has particular public health relevance to the treatment and prevention of AD.
Methods: This dissertation consists of a systematic review of the literature and two papers of original research. Our systematic review: critically evaluates the literature regarding brain cholesterol metabolism and AD, identifies gaps in our current understanding, and proposes directions for future research. The two papers of original research were designed to address these gaps in knowledge. We examined the relationship between plasma oxysterol metabolites and cerebrovascular disease, amyloid deposition in the brain, and incident cognitive impairment using two longitudinal cohorts of older adults with extensive characterization of cognition and brain structure. Quantitative marker of brain structure were prior to clinical disease using magnetic resonance imaging (MRI) and positron emission tomography (PET).
Results: Our review found inconsistent associations between brain-derived plasma oxysterols and AD. Epidemiological design issues and methodological limitations may explain these conflicting results; these include: residual confounding, lack of temporal of associations, and inconsistent direction of associations resulting from stage of the disease at which oxysterols were measured. A major methodological limitation is the scarcity of objective measures to quantify underlying structural changes occurring the brain. Our original research examined the longitudinal association between oxysterols, cognition and brain imaging markers in non-demented older adults. We found higher levels of brain-derived oxysterols were associated with MRI markers of cerebrovascular disease and a greater risk of cognitive impairment over 8 years of follow-up. Furthermore, we found that lipid-lowering drugs modify the association between plasma oxysterols levels and amyloid deposition in the brain, visualized using PET.
Conclusions: There are important relationships between brain degeneration, cholesterol metabolism and dementia that need to be better understood. Brain-derived metabolites of cholesterol appear to be elevated in the early stages of disease prior to the onset of cognitive impairment. Brain-derived plasma oxysterols may be an important marker of underlying cerebrovascular disease preceding cognitive impairment and risk for developing cognitive impairment.
| Identifer | oai:union.ndltd.org:PITT/oai:PITTETD:etd-04052011-211650 |
| Date | 29 June 2011 |
| Creators | Hughes, Timothy Michael |
| Contributors | Rhobert Evans, Caterina Rosano, Lewis Kuller, Oscar Lopez, James Becker, Lisa Weissfeld |
| Publisher | University of Pittsburgh |
| Source Sets | University of Pittsburgh |
| Language | English |
| Detected Language | English |
| Type | text |
| Format | application/pdf |
| Source | http://etd.library.pitt.edu/ETD/available/etd-04052011-211650/ |
| Rights | restricted, I hereby certify that, if appropriate, I have obtained and attached hereto a written permission statement from the owner(s) of each third party copyrighted matter to be included in my thesis, dissertation, or project report, allowing distribution as specified below. I certify that the version I submitted is the same as that approved by my advisory committee. I hereby grant to University of Pittsburgh or its agents the non-exclusive license to archive and make accessible, under the conditions specified below, my thesis, dissertation, or project report in whole or in part in all forms of media, now or hereafter known. I retain all other ownership rights to the copyright of the thesis, dissertation or project report. I also retain the right to use in future works (such as articles or books) all or part of this thesis, dissertation, or project report. |
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