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Cholesterol Metabolism in the Brain and Dementia

Hughes, Timothy Michael (2011) Cholesterol Metabolism in the Brain and Dementia. Doctoral Dissertation, University of Pittsburgh.

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    Abstract

    Introduction: Cholesterol metabolism in the brain is implicated in the development of Alzheimer's 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.


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    Item Type: University of Pittsburgh ETD
    Creators/Authors:
    CreatorsEmailORCID
    Hughes, Timothy Michaeltmh57@pitt.edu
    ETD Committee:
    ETD Committee TypeCommittee MemberEmailORCID
    Committee CoChairRosano, CaterinaRosanoC@edc.pitt.edu
    Committee CoChairKuller, LewisKullerL@edc.edu
    Committee MemberBecker, Jamesbeckerjt@pitt.edu
    Committee MemberWeissfeld, Lisalweis@pitt.edu
    Committee MemberLopez, Oscarollopez@pitt.edu
    Committee MemberEvans, RhobertEvansR@edc.pitt.edu
    Title: Cholesterol Metabolism in the Brain and Dementia
    Status: Unpublished
    Abstract: Introduction: Cholesterol metabolism in the brain is implicated in the development of Alzheimer's 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.
    Date: 29 June 2011
    Date Type: Completion
    Defense Date: 21 April 2011
    Approval Date: 29 June 2011
    Submission Date: 05 April 2011
    Access Restriction: 5 year -- Restrict access to University of Pittsburgh for a period of 5 years.
    Patent pending: No
    Institution: University of Pittsburgh
    Thesis Type: Doctoral Dissertation
    Refereed: Yes
    Degree: PhD - Doctor of Philosophy
    URN: etd-04052011-211650
    Uncontrolled Keywords: Alzheimer's disease; cerebrovascular disease; MRI; PiB-PET; mild cogntive impairment; oxysterols
    Schools and Programs: Graduate School of Public Health > Epidemiology
    Date Deposited: 10 Nov 2011 14:34
    Last Modified: 20 Apr 2012 09:58
    Other ID: http://etd.library.pitt.edu/ETD/available/etd-04052011-211650/, etd-04052011-211650

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