Oberlin, Lauren
(2019)
Inflammation and Preclinical AD: Associations between Peripheral Inflammatory Biomarkers, Cognition, and Amyloid-B deposition in Non-demented Older Adults.
Doctoral Dissertation, University of Pittsburgh.
(Unpublished)
Abstract
The central role of inflammatory processes in the development of beta-amyloid (Aβ) pathology has been widely shown in rodent models, but has yet to be elucidated in humans, particularly prior to the onset of clinical symptoms. We examined associations between peripheral inflammatory mediators, cognition, and two neuroimaging Alzheimer’s disease (AD) biomarkers, Aβ plaques and hippocampal atrophy, in non-demented older adults. Cross-sectional and longitudinal data were used to assess associations between peripheral inflammatory biomarkers (soluble CD14, TNF-α receptor concentrations, and IL-6) and memory performance on the California Verbal Learning Test (CVLT) and Rey-Osterrieth Complex Figure Test in 173 non-demented older adults. Of these 173 participants, 134 were cognitively normal (CN) and 34 had MCI. Ninety of these participants underwent repeated assessments at 24 months. Structural MRI and Pittsburgh compound B-PET imaging were used to quantify hippocampal volume and Aβ plaque deposition. After adjusting for demographics, linear regression analysis revealed that higher levels of TNF-α and IL-6 predicted poorer global and verbal memory performance in the full sample, and the CN subsample. Elevated concentrations of pro-inflammatory markers were also associated with higher global Aβ deposition, specifically among those that also exhibited greater hippocampal atrophy. Secondary analysis using template-derived regions of interest showed that these moderation effects were specific to PiB uptake in the anterior cingulate gyrus, frontal cortex, and precuneus. These associations remained after adjusting for hypertension, diabetes, heart disease and white matter lesions (all p<0.05). Furthermore, higher levels of circulating IL-6 predicted subsequent conversion to MCI and increased longitudinal accumulation of Aβ pathology in regions susceptible to early amyloid deposition. Hippocampal volume moderated the association between inflammatory markers and Aβ deposition, suggesting potential disease-state-dependent differences in peripheral inflammatory profiles during the preclinical phase of AD. These findings highlight potential protein signatures that may vary depending on the prodromal phase of disease progression, and could help identify those in specific preclinical stages. from CN to MCI. Moreover, chronic, low-level systemic inflammation may accelerate the deposition of Aβ pathology and, consequently, place individuals at a higher risk of developing clinically significant cognitive impairment.
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Details
| Item Type: |
University of Pittsburgh ETD
|
| Status: |
Unpublished |
| Creators/Authors: |
|
| ETD Committee: |
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| Date: |
25 September 2019 |
| Date Type: |
Publication |
| Defense Date: |
26 November 2018 |
| Approval Date: |
25 September 2019 |
| Submission Date: |
6 August 2019 |
| Access Restriction: |
No restriction; Release the ETD for access worldwide immediately. |
| Number of Pages: |
143 |
| Institution: |
University of Pittsburgh |
| Schools and Programs: |
Dietrich School of Arts and Sciences > Psychology |
| Degree: |
PhD - Doctor of Philosophy |
| Thesis Type: |
Doctoral Dissertation |
| Refereed: |
Yes |
| Uncontrolled Keywords: |
Aging, Alzheimer's Disease, Amyloid, Cognition,Inflammation, PET Imaging |
| Date Deposited: |
25 Sep 2019 19:51 |
| Last Modified: |
25 Sep 2019 19:51 |
| URI: |
http://d-scholarship.pitt.edu/id/eprint/37301 |
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