Date of Award

2018

Document Type

Dissertation

Degree Name

Doctor of Philosophy (PhD)

Department

Neuroscience

College

College of Graduate Studies

First Advisor

Ann-Charlotte Granholm

Second Advisor

Steven L. Carroll

Third Advisor

DeAnna Adkins

Fourth Advisor

Andreana Benitez

Fifth Advisor

Aurélie Ledreux

Sixth Advisor

Catrina Robinson

Abstract

The number of people with dementia due to Alzheimer’s disease (AD) is increasing worldwide. Although AD pathology begins well before clinical symptoms are apparent, identifying individuals at risk of developing AD to provide early interventions is still a challenge. Brain-derived neurotrophic factor (BDNF) is produced by neurons and glial cells and has complex interactions with AD pathology. BDNF also crosses the blood-brain barrier and can be measured in serum or plasma. In this dissertation, I investigated the biomarker potential of serum BDNF for AD using post mortem human samples, an aged rat model of cognitive impairment, and blood samples from cognitively healthy older adults. In the first part of my dissertation, I investigated the relationship between CSF, serum, and brain tissue levels of BDNF and AD-related pathology using post mortem human brain tissue samples. In these studies, I demonstrated, for the first time, that serum proBDNF levels reflect brain BDNF levels and that low brain BDNF levels are associated with increased accumulation of pTau and amyloid in the hippocampus. In the next part of my dissertation, I investigated whether serum BDNF levels were altered in an aged rat model exposed to a combination of the locus coeruleus selective neurotoxin and inflammation caused by lipopolysaccharides (LPS). I found that serum BDNF levels have an inverse relationship with inflammatory markers, and BDNF levels increase at two weeks post LPS injection, suggesting a compensatory increase. Finally, in the last part of my dissertation, I investigated whether serum BDNF levels can predict early changes in neuropsychological performance and neuroimaging measures associated with AD in cognitively healthy older adults. In this cohort of older adults, we found significant differences between women and men. Women had higher serum BDNF levels than men, the changes of neuropsychological performance over time were different in women and men, and higher baseline BDNF levels were associated with greater declines in hippocampal volume and limbic FA in men but not in women. Overall, results from this dissertation indicate that serum BDNF levels correlate with brain BDNF levels, are reduced by neurodegeneration and inflammation, and may reflect clinically-relevant changes in older adults and, therefore, should be considered for inclusion in routine blood workup in a clinical setting.

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