The Impact of Phenylalanine Elevations on Metabolic, Cognitive, and Neural Functioning in Adults Heterozygous for Phenylketonuria (PKU)
试验速览
- 阶段
- 不适用
- 状态
- 招募中
- 入组人数
- 36
- 试验地点
- 1
- 主要终点
- Blood Phenylalanine Levels
研究概览
简要总结
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
详细描述
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.
研究设计
- 研究类型
- Interventional
- 分配方式
- Randomized
- 干预模型
- Crossover
- 主要目的
- Basic Science
- 盲法
- Double (Participant, Investigator)
入排标准
- 年龄范围
- 18 Years 至 60 Years（Adult）
- 性别
- All
- 接受健康志愿者
- 是
入选标准
- •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
排除标准
- •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).
研究组 & 干预措施
PKU Carriers
Heterozygous carriers of a pathogenic variant of the PAH gene associated with phenylketonuria (PKU)
干预措施: Phenylalanine (Phe) (Dietary Supplement)
PKU Carriers
Heterozygous carriers of a pathogenic variant of the PAH gene associated with phenylketonuria (PKU)
干预措施: Placebo (Dietary Supplement)
Non-Carriers
Individuals who do not carry a pathogenic variant of the PAH gene
干预措施: Phenylalanine (Phe) (Dietary Supplement)
Non-Carriers
Individuals who do not carry a pathogenic variant of the PAH gene
干预措施: Placebo (Dietary Supplement)
结局指标
主要结局
Blood Phenylalanine Levels
时间窗: 3 timepoints: baseline (pre-load), 2 hours and 4 hours after starting oral administration of Phe or placebo
Brain Phenylalanine Levels
时间窗: 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
时间窗: 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
时间窗: 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
时间窗: 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
时间窗: 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
时间窗: 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
时间窗: 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
次要结局
- 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)
研究者
Shawn Christ
Professor, Psychological Sciences
University of Missouri-Columbia