Cognitive Fluctuations in a Rare Disease Population: Leveraging Cognitive and Speech Ecological Momentary Assessment in Individuals with Phenylketonuria.

Background: Phenylketonuria (PKU) is a rare, hereditary disease that causes disruption in phenylalanine (Phe) metabolism. Despite early intervention, individuals with PKU may have difficulty in several different cognitive domains, including verbal fluency, processing speed, and executive functioning.

Objective: The overarching goal of the Evaluating Fluctuations in Cognitive and Speech Characteristics in Phenylketonuria study (CSP Study) is to characterize the relationships among cognition, speech, mood, and blood-based biomarkers (Phe, Tyr) in individuals with early treated PKU. We describe our initial optimization pilot results that are guiding the ongoing CSP Study, while establishing feasibility and reliability of using ecological momentary assessment (EMA) in this clinical population.

Methods: Twenty adults with PKU were enrolled in this study between December 2022 and March 2023 through the National PKU Alliance. Eighteen participants completed an extended baseline assessment followed by six EMAs over one month. The EMAs included digital cognitive tests measuring processing speed, sustained attention, executive functioning, as well as speech (semantic fluency) and mood measures. Participants had 60 minutes to complete the assessment; completion rates were around 70% (on average 4.78 out of 6 EMAs).

Results: Completion rates of EMAs were above 70%, with stable performances across baseline measures and EMAs. Between person reliability (BPR) of the EMAs, representing the variance due to differences between individuals versus within individuals, is satisfactory with values close to (semantic fluency BPR: 0.7, sustained attention BPR: 0.72) or exceeding (processing speed: 0.93, executive functioning: 0.88) those data collected from a large normative database (N= 5039-10703), as well as slightly below or matching a prior study using a clinical group (N=18). As applicable, within person reliability was also computed; we demonstrated strong reliability for processing speed (0.87). A control analyses ensured that time of day (i.e., morning, afternoon, evening) did not impact performance; performance on tasks did not decrease if tested earlier versus later in the day (all ps>0.09). Similarly, to assess variability in task performance over the course of all EMAs, the coefficient of variability was computed: 28% for the task measuring sustained attention, 37% percent for semantic fluency, 15.8 % for the task measuring executive functioning, and 17.6% for processing speed. Performance appears more stable in tasks measuring processing speed and executive functioning than on tasks of sustained attention and semantic fluency.

Conclusions: Preliminary results of this study demonstrate strong reliability of cognitive EMA, indicating that EMA is a promising tool for evaluating fluctuations in cognitive status in this population. Future work should refine and expand the utility of these digital tools, determine how variable EMA frequencies might better characterize changes in functioning as they relate to blood-based biomarkers, and validate a singular battery that could be rapidly administered at scale and in clinical trials to determine progression of disease.