Cerebral blood flow and white matter alterations in adults with phenylketonuria

Leonie Steiner; Raphaela Muri; Dilmini Wijesinghe; Kay Jann; Stephanie Maissen-Abgottspon; Piotr Radojewski; Katarzyna Pospieszny; Roland Kreis; Claus Kiefer; Michel Hochuli; Roman Trepp; Regula Everts

doi:10.1016/j.nicl.2023.103550

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.

Authors

Affiliations

¹ Department of Diabetes, Endocrinology, Nutritional Medicine and Metabolism, Inselspital, Bern University Hospital and University of Bern, Switzerland; Division of Neuropaediatrics, Development and Rehabilitation, Department of Paediatrics, Inselspital, Bern University Hospital and University of Bern, Switzerland.
² Department of Diabetes, Endocrinology, Nutritional Medicine and Metabolism, Inselspital, Bern University Hospital and University of Bern, Switzerland; Support Center for Advanced Neuroimaging (SCAN), University Institute of Diagnostic and Interventional Neuroradiology, Inselspital, Bern University Hospital and University of Bern, Switzerland; Translational Imaging Center (TIC), Swiss Institute for Translational and Entrepreneurial Medicine, Bern, Switzerland.
³ Laboratory of Functional MRI Technology (LOFT), Stevens Neuroimaging and Informatics Institute, Keck School of Medicine, University of Southern California, USA.
⁴ Department of Diabetes, Endocrinology, Nutritional Medicine and Metabolism, Inselspital, Bern University Hospital and University of Bern, Switzerland; Translational Imaging Center (TIC), Swiss Institute for Translational and Entrepreneurial Medicine, Bern, Switzerland.
⁵ Support Center for Advanced Neuroimaging (SCAN), University Institute of Diagnostic and Interventional Neuroradiology, Inselspital, Bern University Hospital and University of Bern, Switzerland.
⁶ Magnetic Resonance Methodology, Institute of Diagnostic and Interventional Neuroradiology, Inselspital, Bern University Hospital and University of Bern, Switzerland.
⁷ Support Center for Advanced Neuroimaging (SCAN), University Institute of Diagnostic and Interventional Neuroradiology, Inselspital, Bern University Hospital and University of Bern, Switzerland; Translational Imaging Center (TIC), Swiss Institute for Translational and Entrepreneurial Medicine, Bern, Switzerland.
⁸ Department of Diabetes, Endocrinology, Nutritional Medicine and Metabolism, Inselspital, Bern University Hospital and University of Bern, Switzerland.
⁹ Department of Diabetes, Endocrinology, Nutritional Medicine and Metabolism, Inselspital, Bern University Hospital and University of Bern, Switzerland; Division of Neuropaediatrics, Development and Rehabilitation, Department of Paediatrics, Inselspital, Bern University Hospital and University of Bern, Switzerland; Translational Imaging Center (TIC), Swiss Institute for Translational and Entrepreneurial Medicine, Bern, Switzerland. Electronic address: [email protected].

Abstract

Background: Phenylketonuria (PKU) represents a congenital metabolic defect that disrupts the process of converting phenylalanine (Phe) into tyrosine. Earlier investigations have revealed diminished cognitive performance and changes in brain structure and function (including the presence of white matter lesions) among individuals affected by PKU. However, there exists limited understanding regarding cerebral blood flow (CBF) and its potential associations with cognition, white matter lesions, and metabolic parameters in patients with PKU, which we therefore aimed to investigate in this study.

Method: Arterial spin labeling perfusion MRI was performed to measure CBF in 30 adults with early-treated classical PKU (median age 35.5 years) and 59 healthy controls (median age 30.0 years). For all participants, brain Phe levels were measured with ¹H spectroscopy, and white matter lesions were rated by two neuroradiologists on T2 weighted images. White matter integrity was examined with diffusion tensor imaging (DTI). For patients only, concurrent plasma Phe levels were assessed after an overnight fasting period. Furthermore, past Phe levels were collected to estimate historical metabolic control. On the day of the MRI, each participant underwent a cognitive assessment measuring IQ and performance in executive functions, attention, and processing speed.

Results: No significant group difference was observed in global CBF between patients and controls (F (1, 87) = 3.81, p = 0.054). Investigating CBF on the level of cerebral arterial territories, reduced CBF was observed in the left middle and posterior cerebral artery (MCA and PCA), with the most prominent reduction of CBF in the anterior subdivision of the MCA (F (1, 87) = 6.15, p = 0.015, surviving FDR correction). White matter lesions in patients were associated with cerebral blood flow reduction in the affected structure. Particularly, patients with lesions in the occipital lobe showed significant CBF reductions in the left PCA (U = 352, p = 0.013, surviving FDR correction). Additionally, axial diffusivity measured with DTI was positively associated with CBF in the ACA and PCA (surviving FDR correction). Cerebral blood flow did not correlate with cognitive performance or metabolic parameters.

Conclusion: The relationship between cerebral blood flow and white matter indicates a complex interplay between vascular health and white matter alterations in patients with PKU. It highlights the importance of considering a multifactorial model when investigating the impact of PKU on the brain.

Keywords: Arterial spin labeling; Cerebral blood flow; Cognition; Phenylketonuria; Spectroscopy; White matter.

MeSH terms

Adult
Brain / pathology
Cerebrovascular Circulation / physiology
Diffusion Tensor Imaging
Humans
Phenylketonurias* / diagnostic imaging
White Matter* / pathology