Brain Aging in Patients With Phenylketonuria
试验速览
- 阶段
- 不适用
- 状态
- 招募中
- 入组人数
- 90
- 试验地点
- 1
- 主要终点
- Brain Age Gap
研究概览
简要总结
Background: Historically, the primary goal in managing phenylketonuria (PKU) has been to prevent severe and irreversible intellectual disability, as well as to address nutritional deficiencies that could lead to growth impairments or intellectual decline. Since the introduction of neonatal PKU screening in the mid-1960s, early treatment during childhood with a low phenylalanine diet or pharmacological interventions have been effective and prevent severe long-term sequelae. However, concerns persist that insufficient treatment during adulthood may cause subtle and, over time, possibly increasing cognitive and brain alterations. Recently, the first generation of early-treated patients has reached mid-adulthood. Hence, there is an urgent need to understand how PKU and metabolic control impact cognitive and brain aging and vice versa. The investigators preliminary cross-sectional findings suggest that brain aging trajectories may diverge significantly between patients with PKU and healthy controls in mid-adulthood. Until now, no comprehensive research has longitudinally tracked brain aging in patients with PKU through MRI markers and their correlation with cognition, metabolic control, and cardiometabolic risk factors. The "brain age" approach enables the identification of individual health characteristics and risk patterns for age-related changes. The evaluation of brain age in addition to the chronological age allows for the development and monitoring of personalized neuroprotective treatments and interventions. Advancing the investigators understanding of disease progression during aging in patients with PKU and identifying strategies for preventing potential harm later in life is of utmost importance for patients' well-being and clinical practice and, through this, follows the WHO's brain health plan.
Study aims: This longitudinal study will, for the first time, investigate the trajectory of brain aging relative to chronological aging across early and middle adulthood in individuals with PKU compared to healthy controls. Data collected in the investigators previous SNSF study (Nr 192706; 184453) will serve as baseline data and allow the examination of brain health by means of brain age modeling. The association between brain age trajectories and cognitive performance, metabolic control, and cardiometabolic risk factors will be studied to disentangle risk patterns of accelerated brain aging in patients with a rare disease.
Relevance of the study: This study will show whether and how the brain aging trajectory is accelerated in patients with PKU and will determine the functional relevance of brain aging with respect to cognitive performance and metabolic control (i.e., phenylalanine levels). This is one of the first studies to closely examine long-term brain and cognitive changes in PKU during early and mid-adulthood. Its findings could provide valuable insights into the long-term effects of PKU on brain structure and aging processes. Furthermore, the results may support the development of future treatment strategies and improve the quality of life for adults with PKU.
详细描述
Detailed Research Plan:
The investigators' preliminary findings suggest that patients with PKU might show altered aging trajectories compared to controls. The present study will investigate the aging trajectory in patients with PKU and its association with cognitive and metabolic aging over a 5-year time period. The investigators will use the well-established "Brain Age Gap" metric, which defines the biological brain age relative to the chronological age across different brain regions. Based on the investigators' preliminary and published results the following hypotheses are postulated:
A) There is accelerated brain aging in certain brain regions (as measured with an increasing Brain Age Gap) over a 5-year follow-up period in patients with PKU.
B) The Brain Age Gap relates to cognitive performance, blood-Phe levels, and other metabolic parameters in patients with PKU.
C) In patients, age-related changes in gray matter metrics (prefrontal cortical thickness), white matter microstructure, and cerebral blood flow will be more pronounced over the 5-year follow-up period than in controls.
研究设计
- 研究类型
- Observational
- 观察模型
- Case Control
- 时间视角
- Other
入排标准
- 年龄范围
- 18 Years 至 —（Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 是
入选标准
- •Participation in PICO-Study and/or:
- •PKU diagnosed after a positive newborn screening
- •Treatment with Phe-restricted diet starting within the first 30 days of life
- •Age ≥18 years
- •Written informed consent
排除标准
- •Patients with PKU not following a Phe-restricted diet within 6 months before the study
- •Phe concentration above 1600 µmol/L within 6 months before the study
- •Concomitant disease states suspected to significantly affect primary or secondary outcomes
- •Women who are pregnant or who are breast feeding
- •Conditions interfering with MRI such as magnetic (metallic) particles in the skull or brain, cardiac pacemaker, deep brain stimulators, cochlear implant, braces or permanent retainers
- •Healthy controls
- •Inclusion Criteria:
- •Age ≥18 years
- •Written informed consent
- •Exclusion Criteria:
- •Concomitant disease states suspected to significantly affect primary or secondary outcomes
- •Women who are pregnant or who are breast feeding
- •Inability to follow the procedures of the study, e. g. due to language problems (lack of fluency in German or French), psychological disorders, dementia, etc. of the participant
- •Conditions interfering with MRI such as magnetic (metallic) particles in the skull or brain, cardiac pacemaker, deep brain stimulators, cochlear implant, braces or permanent retainers
结局指标
主要结局
Brain Age Gap
时间窗: Time Point 2 (5-year follow-up)
Defines the biological brain age relative to the chronological age across different brain regions. Machine learning models will be used to estimate brain age based on MRI-derived measures. For each participant, an estimate of the Brain Age Gap (predicted brain age minus chronological age, indicating the degree of brain maintenance) will be calculated using XGBoost. XGBoost uses gradient tree boosting based on 1118 features to predict the Brain Age Gap. These features are extracted using Freesurfer. The features consist of thickness, area, and volume measurements from a multimodal parcellation of the cerebral cortex, cerebellum, and subcortex. Possible changes in the Brain age gap will be evaluated by comparing the baseline measurement with the 5 year follow up.
Sustained Attention
时间窗: Time Point 2 (5-year follow-up)
Changes in sustained attention over 5-years are assessed with the respective subtest "sustained attention" of the Test of Attentional Performance (TAP) in patients with PKU and healthy controls. In this subtest, stimuli with varying features (color, shape, size, filling) appear on a monitor. A target stimulus matches the previous one in one of two predefined dimensions (same shape or same color). Sustained attention is measured in milliseconds, with higher values showing slower reaction time to target stimulus.
Cognitive flexibility
时间窗: Time Point 2 (5-year follow-up)
Changes in cognitive flexibility over 5-years are assessed using the fourth condition "inhibition/switching" of the color-word interference test of the Delis-Kaplan Executive Function System (D-KEFS) in patients with PKU and healthy controls. Time is measured in seconds with higher completion time indication worse performance in cognitive flexibility.
Plasma concentration of Phe
时间窗: Time Point 2 (5-year follow-up)
Plasma Phenylalanine (Phe) concentrations are measured in patients with PKU
Diffusion tensor imaging (DTI)
时间窗: Time Point 2 (5-year follow-up)
DTI is used to assess white matter integrity in patients with PKU and healthy controls.
Arterial Spin Labeling (ASL)
时间窗: Time Point 2 (5-year follow-up)
ASL is used to assess cerebral blood flow in patients with PKU and healthy controls.
次要结局
- Bone density(Time Point 2 (5-year follow-up))
- Body Mass Index(Time Point 2 (5-year follow-up))
- Resting-state fMRI(Time Point 1 (Baseline) and Time Point 2 (5-year follow-up))
- FLAIR-sequence(Time Point 1 (Baseline) and Time Point 2 (5-year follow-up))
- MPRAGE(Time Point 1 (Baseline) and Time Point 2 (5-year follow-up))
- General intelligence(Time Point 1 (Baseline) and Time Point 2 (5-year follow-up))
- Processing speed(Time Point 1 (Baseline) and Time Point 2 (5-year follow-up))
- Working memory(Time Point 1 (Baseline) and Time Point 2 (5-year follow-up))
- Inhibition(Time Point 1 (Baseline) and Time Point 2 (5-year follow-up))
- Design fluency(Time Point 1 (Baseline) and Time Point 2 (5-year follow-up))
- Motor control and speed(Time Point 1 (Baseline) and Time Point 2 (5-year follow-up))
- Verbal fluency(Time Point 1 (Baseline) and Time Point 2 (5-year follow-up))
- Body fat(Time Point 2 (5-year follow-up))
- Tyrosine(Time Point 1 (Baseline) and Time Point 2 (5-year follow-up))
- Tryptophan(Time Point 1 (Baseline) and Time Point 2 (5-year follow-up))
- Dry blood samples(Time Point 1 (Baseline) and Time Point 2 (5-year follow-up))
- Total cholesterol(Time Point 1 (Baseline) and Time Point 2 (5-year follow-up))
- LDL cholesterol(Time Point 1 (Baseline) and Time Point 2 (5-year follow-up))
- HDL cholesterol(Time Point 2 (5-year follow-up))
- Triglycerides(Time Point 2 (5-year follow-up))
- Apolipoprotein B (ApoB)(Time Point 2 (5-year follow-up))
- Lipoprotein (a)(Time Point 2 (5-year follow-up))
- Fasting Glucose(Time Point 2 (5-year follow-up))
- HbA1c(Time Point 2 (5-year follow-up))
- High-sensitivity C-reactive protein(Time Point 2 (5-year follow-up))
- Blood pressure(Time Point 2 (5-year follow-up))
- Heart rate(Time Point 2 (5-year follow-up))
- Total tau(Time Point 2 (5-year follow-up))
- Total tau and phosphorylated tau(Time Point 2 (5-year follow-up))
- Neurofilament light chain(Time Point 2 (5-year follow-up))
- Myeloid Cells 2(Time Point 2 (5-year follow-up))
- Glial fibrillary acidic(Time Point 2 (5-year follow-up))
- CC-chemokine ligand 11 and C-C Motif Chemokine Ligand 2(Time Point 2 (5-year follow-up))
- Albumin(Time Point 2 (5-year follow-up))