Author ORCID Identifier

https://orcid.org/0000-0003-2057-3976

Year of Publication

2017

Degree Name

Doctor of Philosophy (PhD)

Document Type

Doctoral Dissertation

College

Medicine

Department

Anatomy and Neurobiology

First Advisor

Dr. Brian Gold

Abstract

The default mode network (DMN) consists of a set of interconnected brain regions supporting autobiographical memory, our concept of the self, and the internal monologue. These processes must be maintained at all times and consume the highest amount of the brain’s energy during its baseline state. However, when faced with an active, externally-directed cognitive task, the DMN shows a small, but significant, decrease in activity. The reduction in DMN activity during the performance of an active, externally-directed task compared to a baseline state is termed task-induced deactivation (TID), which is thought to ‘free-up’ resources required to respond to external demands. However, older adults show a reduced level of TID in the DMN. Recently, it has begun to be appreciated that this decrease in TID may be associated with poorer cognitive performance, especially during tasks placing high demands on executive function (EF). Diminished DMN TID has not only been associated with increasing age but also with multiple age-related neurobiological correlates such as accumulating Alzheimer’s disease (AD) pathology and reductions in white matter (WM) connectivity. However, these biological factors—age, WM connectivity reductions and increasing AD pathology—are themselves related. Based on the literature, we hypothesized that declining WM connectivity may represent a common pathway by which both age and AD pathology contribute to diminished DMN TID. Further, we hypothesized that declines in DMN function and WM connectivity would predict poorer in EF. Three experiments were carried out to test these hypotheses. Experiment 1 tested whether WM connectivity predicted the level of DMN TID during a task requiring a high level of EF. Results from 117 adults (ages 25-83) showed that WM connectivity declined with increasing age, and that this decline in WM connectivity was directly associated with reduced DMN TID during the task. Experiment 2 tested whether declines in WM connectivity explained both age-related and AD pathology-related declines in DMN TID. Results from 29 younger adults and 35 older adults showed that declining WM connectivity was associated with increasing age and AD pathology, and that this decline in WM connectivity was a common pathway for diminished DMN TID associated with either aging or AD pathology. Experiment 3 investigated whether measures of WM connectivity and DMN TID at baseline could predict EF measured using clinically-used tests. Results from 29 older adults from Experiment 2 showed that less DMN TID predicted poorer EF at baseline and diminished WM connectivity at baseline predicted a greater decline in EF after 3 years. Further, WM connectivity explained reductions in EF predicted by baseline AD pathology, as well as further reductions in EF not predicted by baseline AD pathology. Together the results of these studies suggest that WM connectivity is a key pathway for age-related and AD pathology-related patterns of diminished DMN TID associated with poorer EF. Further, WM connectivity may represent a potential therapeutic target for interventions attempting to prevent future declines in EF occurring in aging and AD.

Digital Object Identifier (DOI)

https://doi.org/10.13023/ETD.2017.367

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