Date of Award

5-23-2025

Author's School

Graduate School of Arts and Sciences

Author's Department

Psychology

Degree Name

Doctor of Philosophy (PhD)

Degree Type

Dissertation

Abstract

Background: Many individuals with phenylketonuria (PKU), a rare genetic disorder, find current treatments inadequate and believe new treatments must be developed (Brown, 2018). Although approvals of existing treatments have largely been based on decreases in phenylalanine (Phe) levels, the Food and Drug Administration (FDA) has indicated that instruments to assess functional outcomes are needed in future PKU clinical trials. The National Institutes of Health (NIH) Toolbox Cognition Battery (Toolbox) meets criteria that are crucial for such trials. Methods: Data from 58 individuals with early-treated PKU (aged 8–55 years) enrolled in an ongoing NIH-funded longitudinal study of hyperphenylalaninemia were used to provide an early step in validating use of the Toolbox in PKU clinical trials. Associations between Toolbox performance and performance on validation instruments were examined through linear regression modeling to demonstrate convergent validity. The Toolbox performance of our PKU sample relative to the normative sample was also examined to demonstrate Toolbox sensitivity to compromise in key domains of cognition in PKU. Finally, the association between Toolbox performance and most recent Phe level was examined through linear regression modeling to demonstrate Toolbox sensitivity to metabolic control. Results: Toolbox Total Cognition, Fluid Cognition, and Crystallized Cognition Composite scores were significantly predictive of scores on comparable Wechsler Abbreviated Scale of Intelligence Indices. The Toolbox Executive Function Composite was significantly predictive of scores on the Cambridge Neuropsychological Test Automated Battery and on the Conners Continuous Performance Test. Our PKU sample exhibited significantly lower scores than normative samples, as well as a higher proportion of scores in the clinically elevated range (i.e., one standard deviation or more below the mean of the normative sample), on the Toolbox Total Cognition, Fluid Cognition, and Executive Function Composites. Conclusion: Consistent with our hypotheses, the Toolbox demonstrated good convergent validity with established cognitive assessments and demonstrated sensitivity to compromise in key domains of cognition in PKU. Contrary to our hypothesis, there was no demonstrable relationship between Toolbox performance and most recent Phe level. Overall, our results support consideration of the Toolbox for use in PKU clinical trials.

Language

English (en)

Chair and Committee

Desiree White

Committee Members

Denise Head; Lori Markson; Michael Strube; Shawn Christ

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