Date of Award

Fall 10-2-2023

Embargo Period

12-31-2023

Document Type

Dissertation

Degree Name

Doctor of Philosophy (PhD)

Department

Neuroscience

College

College of Graduate Studies

First Advisor

Jane Joseph

Second Advisor

Jens Jensen

Third Advisor

Andrew Lawson

Fourth Advisor

Brian Dean

Fifth Advisor

Stephano Berto

Abstract

Subjective Cognitive Decline (SCD) has garnered much interest as a potential identifiable preclinical stage and indicator of risk for cognitive decline in Alzheimer’s Disease and related dementias (ADRD). Identification of individuals in this stage though is difficult, as they present with objectively normal cognitive evaluation scores, relying instead upon self-report of concern about decline in cognitive abilities. The use of non-invasive in-vivo imaging methods like BOLD functional imaging and diffusion tensor have allowed for complex mapping of both the functional and structural network features unique to this condition. This study furthers this network biomarker map of SCD by investigating the link between Mean Kurtosis integrity metric of white matter fibers and functional network changes, specifically focusing on the vulnerable inter-community hubs of the functional connectome. In the first chapter we investigate baseline differences between SCD and healthy subjects by first identifying five major functional hubs, then analyzing white matter tractography associated with these hubs. We find that there is a disparity in the group differences of the two modalities, with hubness of all five hubs being lower in SCD as measured by diversity coefficient (DC), while in several of the hubs, associated white matter had significantly higher integrity metrics as measured by mean kurtosis (MK). In SCD, these metrics were related such that a higher MK was necessary to achieve healthy control-like levels of hub DC. In chapter 2, we analyze longitudinal follow-up scans of the same subjects, finding that fewer of the hubs in SCD have significantly lower DC hubness, and fewer fibers are identified in which MK integrity is significantly higher in SCD. In the left insular cortex, baseline MK in SCD was predictive of the degree of hubness decline, with higher baseline MK resulting in a healthy control-like longitudinal change pattern. These observations provide evidence supporting a mix of existing SCD-ADRD models, with functional results matching existing progressive decline, while white matter results match paradoxical increase hypotheses of hub vulnerability. In conclusion, we have identified a unique multi-modal model of SCD, emphasizing

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