Brain Aging in Phenylketonuria

NCT06969209 | Recruiting

• 1 other identifier: PICO-5
• Study Type: observational
• Target: 90
• Locations: 1 country
• Sites: 1

Brief Summary

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.

Conditions

Phenylketonuria (PKU)

Keywords

Phenylketonuria (PKU); Brain aging; Brain age gap; Cognition; Magnetic resonance imaging; Metabolic control; Rare disease; Longitudinal study

Outcome Measures

Primary Outcomes (6)

• Brain Age Gap

  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.

  Time Point 2 (5-year follow-up)

• Sustained Attention

  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.

  Time Point 2 (5-year follow-up)

• Cognitive flexibility

  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.

  Time Point 2 (5-year follow-up)

• Plasma concentration of Phe

  Plasma Phenylalanine (Phe) concentrations are measured in patients with PKU

  Time Point 2 (5-year follow-up)

• Diffusion tensor imaging (DTI)

  DTI is used to assess white matter integrity in patients with PKU and healthy controls.

  Time Point 2 (5-year follow-up)

• Arterial Spin Labeling (ASL)

  ASL is used to assess cerebral blood flow in patients with PKU and healthy controls.

  Time Point 2 (5-year follow-up)

Secondary Outcomes (35)

• 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)

Other Outcomes (6)

• Mood

  Time Point 1 (Baseline) and Time Point 2 (5-year follow-up)

• Depression

  Time Point 1 (Baseline) and Time Point 2 (5-year follow-up)

• PKU Quality of Life

  Time Point 1 (Baseline) and Time Point 2 (5-year follow-up)

Study Arms (2)

Patients

Adult patients with Phenylketonuria

Controls

Healthy controls

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: Yes
• Age Groups: Adult (18-64), Older Adult (65+)
• Sampling Method: Probability Sample

Study Population

Patients with PKU were recruited in the framework of the PICO study (2019-2022) and will be recontacted in respect to study participation to the PICO-5-study.

You may qualify if:

• 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

You may not qualify if:

• 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
• Age ≥18 years
• Written informed consent
• 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

Sponsors & Collaborators

• Insel Gruppe AG, University Hospital Bern: lead

Study Sites (1)

University Hospital Inselspital, Department of Diabetes, Endocrinology, Nutritional Medicine and Metabolism (UDEM)

Bern, 3010, Switzerland

RECRUITING

Related Publications (6)

• Trepp R, Muri R, Maissen-Abgottspon S, Haynes AG, Hochuli M, Everts R. Cognition after a 4-week high phenylalanine intake in adults with phenylketonuria - a randomized controlled trial. Am J Clin Nutr. 2024 Apr;119(4):908-916. doi: 10.1016/j.ajcnut.2023.11.007. Epub 2024 Feb 9.

  PMID: 38569786 BACKGROUND

• Steiner L, Muri R, Wijesinghe D, Jann K, Maissen-Abgottspon S, Radojewski P, Pospieszny K, Kreis R, Kiefer C, Hochuli M, Trepp R, Everts R. Cerebral blood flow and white matter alterations in adults with phenylketonuria. Neuroimage Clin. 2024;41:103550. doi: 10.1016/j.nicl.2023.103550. Epub 2023 Dec 9.

  PMID: 38091797 BACKGROUND

• Trepp R, Muri R, Abgottspon S, Bosanska L, Hochuli M, Slotboom J, Rummel C, Kreis R, Everts R. Impact of phenylalanine on cognitive, cerebral, and neurometabolic parameters in adult patients with phenylketonuria (the PICO study): a randomized, placebo-controlled, crossover, noninferiority trial. Trials. 2020 Feb 13;21(1):178. doi: 10.1186/s13063-019-4022-z.

  PMID: 32054509 BACKGROUND

• Muri R, Rummel C, McKinley R, Rebsamen M, Maissen-Abgottspon S, Kreis R, Radojewski P, Pospieszny K, Hochuli M, Wiest R, Trepp R, Everts R. Transient brain structure changes after high phenylalanine exposure in adults with phenylketonuria. Brain. 2024 Nov 4;147(11):3863-3873. doi: 10.1093/brain/awae139.

  PMID: 38723047 BACKGROUND

• Muri R, Maissen-Abgottspon S, Reed MB, Kreis R, Hoefemann M, Radojewski P, Pospieszny K, Hochuli M, Wiest R, Lanzenberger R, Trepp R, Everts R. Compromised white matter is related to lower cognitive performance in adults with phenylketonuria. Brain Commun. 2023 May 15;5(3):fcad155. doi: 10.1093/braincomms/fcad155. eCollection 2023.

  PMID: 37265600 BACKGROUND

• Muri R, Maissen-Abgottspon S, Rummel C, Rebsamen M, Wiest R, Hochuli M, Jansma BM, Trepp R, Everts R. Cortical thickness and its relationship to cognitive performance and metabolic control in adults with phenylketonuria. J Inherit Metab Dis. 2022 Nov;45(6):1082-1093. doi: 10.1002/jimd.12561. Epub 2022 Sep 27.

  PMID: 36117142 BACKGROUND

Related Links

• The official website provides a brief overview of the PICO-5 study and its main focus on cognitive and cerebral aging in patients with phenylketonuria. Additionally, it includes information on financial support, collaborators, and principal investigators
• The SNSF data portal provides an overview of the funding and includes a brief summary and scientific abstract of the PICO-5 study.

Biospecimen

Retention: SAMPLES WITHOUT DNA

Blood samples of patients will be collected following an 8-12 hour overnight fast to assess plasma concentrations of phenylalanine (Phe), tyrosine (Tyr), and tryptophan (Trp) for all participants. Dry blood samples will be collected twice weekly during the month before and at the 5-year follow-up (TP2) to determine the amino acid profile in patients only.

MeSH Terms

Conditions

Phenylketonurias; Rare Diseases

Condition Hierarchy (Ancestors)

Brain Diseases, Metabolic, Inborn; Brain Diseases, Metabolic; Brain Diseases; Central Nervous System Diseases; Nervous System Diseases; Amino Acid Metabolism, Inborn Errors; Metabolism, Inborn Errors; Genetic Diseases, Inborn; Congenital, Hereditary, and Neonatal Diseases and Abnormalities; Metabolic Diseases; Nutritional and Metabolic Diseases; Disease Attributes; Pathologic Processes; Pathological Conditions, Signs and Symptoms

Study Officials

• Regula Everts, Prof. Dr. phil.

  Department of Diabetes, Endocrinology, Nutritional Medicine and Metabolism, Inselspital, Bern University Hospital and University of Bern, Switzerland

  PRINCIPAL INVESTIGATOR

Central Study Contacts

Regula Everts, Prof. Dr. phil.

CONTACT

+41 31 63 2 84 97; regula.everts@insel.ch

Study Design

• Study Type: observational
• Observational Model: CASE CONTROL
• Time Perspective: OTHER
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: March 10, 2025
• First Posted: May 13, 2025
• Study Start: January 13, 2025
• Primary Completion (Estimated): May 30, 2030
• Study Completion (Estimated): August 30, 2030
• Last Updated: May 13, 2025

Record last verified: 2025-05

Data Sharing

• IPD Sharing: Will share

Locations

CH (1)