Graduation Year

2019

Document Type

Dissertation

Degree

Ph.D.

Degree Name

Doctor of Philosophy (Ph.D.)

Degree Granting Department

School of Aging Studies

Major Professor

Brent Small, Ph.D.

Committee Member

Ross Andel, Ph.D.

Committee Member

Paula Bickford, Ph.D.

Committee Member

Alyssa Gamaldo, Ph.D.

Committee Member

Cathy McEvoy, Ph.D.

Keywords

Aging, Cognition, Glucose

Abstract

Changes in cognitive status occur with aging and significant attention has been placed on developing interventions to possibly delay cognitive decline and identifying risk factors that exacerbate cognitive deficits. One issue that arises when studying interventions is that they do not always effectively translate from animal models to human subjects. When testing potentially modifiable risk factors related to cognitive impairment, more sensitive metrics could help in identifying targets for intervention at earlier time-points. Therefore, the aims of the current dissertation were twofold. The first study examined the ability to translate between species using a common behavioral paradigm, the Morris water maze (MWM). The second study evaluated human MWM performance and commonly used neuropsychological test performance in relation to a marker of glucose regulation, HbA1c.

The first study tested translation between rats and humans using the MWM paradigm. Using secondary data sources from a study of nutrition, inflammation, and aging among rats and the Czech Brain Aging Study among humans, differences in average performance and across trial learning were examined between young (3 months; n=10) and aged (20 months; n=13) rats as well age young-old (age 53-70; n=47) and old-old (age 71-85; n=30) human subjects. The cumulative distance was measured in rats and distance error to the hidden goal was measured in human subjects. Results indicated that age-related deficits in performance are greater in magnitude for rats than human subjects. Further, the across trial learning data is more sensitive to change in performance than average performance metrics. Across learning trials indicated poorer performance for aged rats than young rats. Significant effects of age were also observed for human subjects using with the allocentric and egocentric subtests.

The second study examined the influence of a measure of glucose regulation (HbA1c) on commonly used neuropsychological tests and a test of spatial navigation abilities among human subjects. Participants classified as cognitively normal, subjective cognitive decline, amnestic mild cognitive impairment (aMCI), and Alzheimer’s disease (AD) were evaluated on verbal memory, nonverbal memory, working memory, visuospatial skills, and executive function in addition to the virtual and real space versions of a human MWM paradigm. A total of 116 participants were included in the complete data sample and 133 participants were included in the multiple imputation sample. Results indicated that HbA1c influenced executive function but not any other measures of cognition. Higher HbA1c levels were associated with poorer performance. A significant interaction was observed between cognitive status and HbA1c. Those with cognitive impairment and higher HbA1c levels had poorer executive function performance. This effect, however, was not observed with the imputation sample.

Results of the first study indicated that the MWM paradigm serves as a good tool to assess translation between rats and human subjects. This would be helpful in examining interventions designed to improve normal age-related changes in cognition. It is important to note, however, that the differences observed among animals tend to be greater than human subjects. Therefore, the margin of improvement may be greater following treatment with studies utilizing animals rather than human subjects. The second study indicated that glucose levels may have an impact on cognitive abilities, particularly those related to executive function. Targeting blood glucose levels may be one effective way to keep executive function abilities more intact with age. Taken together, these studies will better inform future work related to delaying cognitive decline among older adults.

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