The Impact of Phenylalanine Elevations on Metabolic, Cognitive, and Neural Functioning in Adults Heterozygous for Phenylketonuria (PKU)
Trial Snapshot
- Phase
- Not Applicable
- Status
- Recruiting
- Enrollment
- 36
- Locations
- 1
- Primary Endpoint
- Blood Phenylalanine Levels
Study Overview
Brief Summary
The goal of this clinical trial is to advance our understanding of the cognitive and neurophysiologic sequelae associated with suboptimal phenylalanine (Phe) metabolism in heterozygous carriers of phenylketonuria (PKU). The main questions it aims to answer are:
- Do PKU carriers experience prolonged elevations in brain Phe levels following oral ingestion of dietary Phe?
- Do PKU carriers experience disruptions in cognitive functioning following oral ingestion of dietary Phe?
- Do PKU carriers experience atypical brain activity following oral ingestion of dietary Phe? Researchers will compare PKU carriers and non-carriers following oral ingestion of dietary Phe and a placebo.
Participants will:
- Consume Phe or a placebo at two separate visits to our facility
- At each visit, they will complete a series of MRIs and cognitive tests throughout the day
Detailed Description
Limitations inherent in past studies of phenylketonuria (PKU) carriers (e.g., poor genetic characterization of sample resulting in inclusion of homozygous non-PKU relatives, reliance on rudimentary or overly broad behavioral assessment tools) make it difficult to conclude the extent to which neurophysiologic and cognitive processes are affected in these individuals. To address this gap in the literature, we propose to conduct a double-blind crossover study in a sample of genetically-confirmed sample of 18 heterozygous PKU carriers and 18 non-carriers. A principled investigation of the effects of elevated phenylalanine (Phe) on neurocognition will involve participants performing an fMRI n-back WM task, resting state scan, and a battery of select cognitive tests at 3 timepoints: baseline (pre-load), 2 hours and 4 hours after starting oral administration of Phe or placebo. Blood and brain levels of Phe and Tyr will also be assessed at each timepoint.
Study Design
- Study Type
- Interventional
- Allocation
- Randomized
- Intervention Model
- Crossover
- Primary Purpose
- Basic Science
- Masking
- Double (Participant, Investigator)
Eligibility Criteria
- Ages
- 18 Years to 60 Years (Adult)
- Sex
- All
- Accepts Healthy Volunteers
- Yes
Inclusion Criteria
- •Age 18-60 years
- •For the PKU carrier group: Individuals who are the parent of an individual with PKU or who are otherwise have confirmed PKU carrier status (e.g., a sibling of someone with PKU who has had genetic testing done)
- •For the non-carrier group: Individuals who do not have PKU or a family history of PKU
Exclusion Criteria
- •Obesity as defined by a body mass index (BMI) over 30*
- •Taking oral contraceptives on the day of testing session*
- •Positive cotinine urine test showing nicotine use
- •History of major neurologic condition (e.g., multiple sclerosis, severe closed head injury, Parkinson's disease)) unrelated to PKU and known to adversely impact brain health and function
- •Contraindications for safe MRI participation such as (a) pregnancy or plans to become pregnant during period of study enrollment; or (b) metallic objects inside the body (e.g., surgical staples left in the body following surgery, middle ear prosthesis, metal foreign objects lodged inside the eye, heart pacemakers).
Arms & Interventions
Non-Carriers
Individuals who do not carry a pathogenic variant of the PAH gene
Intervention: Phenylalanine (Phe) (Dietary Supplement)
Non-Carriers
Individuals who do not carry a pathogenic variant of the PAH gene
Intervention: Placebo (Dietary Supplement)
PKU Carriers
Heterozygous carriers of a pathogenic variant of the PAH gene associated with phenylketonuria (PKU)
Intervention: Phenylalanine (Phe) (Dietary Supplement)
PKU Carriers
Heterozygous carriers of a pathogenic variant of the PAH gene associated with phenylketonuria (PKU)
Intervention: Placebo (Dietary Supplement)
Outcomes
Primary Outcomes
Blood Phenylalanine Levels
Time Frame: 3 timepoints: baseline (pre-load), 2 hours and 4 hours after starting oral administration of Phe or placebo
Brain Phenylalanine Levels
Time Frame: 3 timepoints: baseline (pre-load), 2 hours and 4 hours after starting oral administration of Phe or placebo
Brain Phenylalanine Levels estimated using magnetic resonance spectroscopy (MRS)
Brain Phenylalanine-to-Tyrosine Ratio
Time Frame: 3 timepoints: baseline (pre-load), 2 hours and 4 hours after starting oral administration of Phe or placebo
Ratio of Phenylalanine-to-Tyrosine concentrations in the brain as estimated using magnetic resonance spectroscopy (MRS)
Neural Activity during Go/No-Go Task
Time Frame: 3 timepoints: baseline (pre-load), 2 hours and 4 hours after starting oral administration of Phe or placebo
Pattern of brain activation as captured using functional MRI while performing a go/no-go inhibitory task
Operational Span Task
Time Frame: 3 timepoints: baseline (pre-load), 2 hours and 4 hours after starting oral administration of Phe or placebo
Performance-based measure of working memory ability. In this task, participants first solve a math problem and then see a letter, and then solve another math problem, and see another letter. This math-letter sequence is repeated from three to seven times for each trial with an unpredictable length each time. After each math-letter sequence, participants are asked to recall, in order, the preceding letters. Scores are calculated by summing the number of letters correctly recalled in the correct order.
Multi-Source Interference Task
Time Frame: 3 timepoints: baseline (pre-load), 2 hours and 4 hours after starting oral administration of Phe or placebo
Performance-based measure of focused attention. ). In this task, participants are shown a display containing three horizontally-aligned numbers (i.e., 1, 2, or 3) and asked to respond as quickly as possible to the location (position #1, 2, or 3) of the number stimulus that is different from the others. The location may be congruent (e.g., "323") or incongruent (e.g., "112") with identity of the target number. Mean response time and error rate will served as the outcome variables.
Grooved Pegboard Test
Time Frame: 3 timepoints: baseline (pre-load), 2 hours and 4 hours after starting oral administration of Phe or placebo
Performance-based measure of processing speed \& fine motor control
Resting-State Functional Connectivity
Time Frame: 3 timepoints: baseline (pre-load), 2 hours and 4 hours after starting oral administration of Phe or placebo
Synchronization of neural activity within brain networks as measured by functional MRI while participants are at rest
Secondary Outcomes
- PROMIS Anxiety - Short Form 8a(Baseline only)
- • Executive Function, Attention, and Speed Symptom Inventory (EASSI)(Baseline only)
- Brain concentrations of glutamate, glutathione, creatine, and other metabolites(3 timepoints: baseline (pre-load), 2 hours and 4 hours after starting oral administration of Phe or placebo)
- PROMIS Fatigue - Short Form 8a(Baseline only)
- PROMIS Depression - Short Form 8a(Baseline only)
- PROMIS Sleep - Short Form 8a(Baseline only)
- PROMIS Cognitive Function - Short Form 8a(Baseline only)
- Adult ADHD Self-Report Scale (ASRS)(Baseline only)
- Matrix Reasoning subtest from the WASI-2(Baseline only)
Investigators
Shawn Christ
Professor, Psychological Sciences
University of Missouri-Columbia