Date of Award

2020

Degree Type

Dissertation

Degree Name

Doctor of Philosophy (PhD)

Graduate Group

Neuroscience

First Advisor

David A. Wolk

Abstract

Amyotrophic lateral sclerosis (ALS) and frontotemporal degeneration (FTD) are earlier-onset, fatal neurodegenerative diseases that progressively rob affected individuals of their cognitive faculties and their ability to move freely, produce coherent speech, and be their former selves. Diagnosis precedes death by <10 >years, and current interventions are limited to palliative or disease-slowing therapies. Recent seminal research has revealed that ALS and FTD are phenotypic extremes on a continuous spectrum with shared symptoms, pathobiology, and genetics. Despite increased knowledge of ALS-FTD spectrum disease, prognostication and therapeutic development are limited by immense phenotypic heterogeneity. One source of this heterogeneity is cognition: individuals across the ALS-FTD disease spectrum suffer varying degrees of decline in cognition due to neurodegeneration in the frontal and temporal lobes. Cognition is inextricably linked to functional ability and survival, and is thus a promising candidate for a prognostic marker and therapeutic target. With this in mind, the goal of my thesis work is to elucidate factors that influence the heterogeneity of cognitive impairment and corresponding frontotemporal neurodegeneration in ALS-FTD spectrum disease. I pursue this goal by studying clinical, demographic, genetic, anatomic, and biologic data from deeply-phenotyped patient populations and applying robust statistical approaches including multimodal, nonparametric, and machine learning analyses. My work demonstrates strong environmental and genetic contribution to cognition and frontotemporal disease anatomy in ALS-FTD spectrum disease, and suggests their importance to advancements in clinical care and therapeutic development.

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