Impact of Phenylalanine Elevations on Brain and Cognition in Adult PKU Carriers

Official title

The Impact of Phenylalanine Elevations on Metabolic, Cognitive, and Neural Functioning in Adults Heterozygous for Phenylketonuria (PKU)

Overview

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.

Interventions

• Dietary supplement Phenylalanine (Phe)
  Oral ingestion of phenylalanine (Phe)
• Dietary supplement Placebo
  Oral ingestion of Placebo (Vitamin C)

Primary outcome measures

• 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-to-Tyrosine Ratio [Time frame: 3 timepoints: baseline (pre-load), 2 hours and 4 hours after starting oral administration of Phe or placebo]
• 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]
• Operational Span Task [Time frame: 3 timepoints: baseline (pre-load), 2 hours and 4 hours after starting oral administration of Phe or placebo]
• Multi-Source Interference Task [Time frame: 3 timepoints: baseline (pre-load), 2 hours and 4 hours after starting oral administration of Phe or placebo]
• Grooved Pegboard Test [Time frame: 3 timepoints: baseline (pre-load), 2 hours and 4 hours after starting oral administration of Phe or placebo]
• Resting-State Functional Connectivity [Time frame: 3 timepoints: baseline (pre-load), 2 hours and 4 hours after starting oral administration of Phe or placebo]

Secondary outcome measures (9)

• Brain concentrations of glutamate, glutathione, creatine, and other metabolites [Time frame: 3 timepoints: baseline (pre-load), 2 hours and 4 hours after starting oral administration of Phe or placebo]
• PROMIS Anxiety - Short Form 8a [Time frame: Baseline only]
• PROMIS Depression - Short Form 8a [Time frame: Baseline only]
• PROMIS Sleep - Short Form 8a [Time frame: Baseline only]
• PROMIS Fatigue - Short Form 8a [Time frame: Baseline only]
• PROMIS Cognitive Function - Short Form 8a [Time frame: Baseline only]
• • Executive Function, Attention, and Speed Symptom Inventory (EASSI) [Time frame: Baseline only]
• Adult ADHD Self-Report Scale (ASRS) [Time frame: Baseline only]
• Matrix Reasoning subtest from the WASI-2 [Time frame: Baseline only]

Eligibility criteria

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).

Criteria are shown verbatim from the registry (in English). Final eligibility is always assessed by the study center.

Healthy volunteers: Yes

Study design

Allocation

Randomized

Model

Crossover

Masking

Double blind

Primary purpose

Basic science

Study locations

United States · 1 center

• University of Missouri-Columbia — Columbia

Identifiers

NCT: NCT07220265 · 2092228 · R21HD115129-01A1

Primary sources (government registries)

• ClinicalTrials.gov (US NIH)

View this study on ClinicalTrials.gov ↗