ORCID
0000-0001-5110-0640
Date of Award
5-8-2024
Degree Name
Doctor of Philosophy (PhD)
Degree Type
Dissertation
Abstract
The overall goal of this dissertation is to gain a better understanding of how pathological tau burden and tau spread are related at early stages of Alzheimer Disease, and whether each tau component is uniquely informative to key elements of AD progression. A spatiotemporal pattern of tau pathological progression is observed in AD and is highly correlated to regional neurodegeneration and domain-specific cognitive impairment. This progression is reflective of two biological processes: the aggregation of tau neurofibrillary tangles in early brain regions (tau burden) as well as the transmission of pathological tau to additional brain regions (tau spread). Positron emission tomography has allowed for in vivo evaluation of tau pathology in AD, however the methods for quantifying tau largely assess tau burden as opposed to tau spread. In this dissertation, we propose a method for quantifying tau spread extent in order to assess similarities and differences between tau burden and tau spread as AD tau pathology first begins to develop. We hypothesize that metrics for tau burden and tau spread will be highly correlated, however each tau metric will be uniquely related to biological and cognitive markers for AD. In Chapter 2, we compare tau burden and tau spread across early disease-stage groups and levels of amyloid pathology. We found that the tau metrics are strongly correlated, but more variability is observed in tau spread during the preclinical AD stage, indicating that tau spread may capture additional early tau pathological progression of the disease for a subset of individuals that tau burden does not capture. In Chapter 3, we evaluate the tau metrics relative to cognitive domain composite scores assessing episodic memory, semantic memory, working memory, and attention. We found that tau burden is sensitive to baseline impairment in episodic and semantic memory while tau spread is sensitive to baseline impairment in attention. However, tau burden is better able to predict longitudinal impairment across all cognitive domains. In chapter 4, we compare tau burden and tau spread directly at regional levels as well as implement machine-learning algorithms to identify key regions from each tau metric for predicting domain-specific cognitive impairment. We found that regional tau burden continues to increase after tau has already spread throughout the entire region. Similar regions for tau burden and spread were predictive of cognitive impairment, but tau spread incorporated information from peripheral regions with ongoing pathological spread.
Language
English (en)
Chair and Committee
Tammie Benzinger
Recommended Citation
Doering, Stephanie Sierra, "Evaluating Pathological Tau Spread in Early Alzheimer Disease: Developing a Metric for Tau Positron Emission Tomography Quantifying Tau Spatial Spread" (2024). Arts & Sciences Electronic Theses and Dissertations. 3017.
https://openscholarship.wustl.edu/art_sci_etds/3017