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Thus, we quantitatively assessed white matter characteristics in adults with phenylketonuria and assessed their relationship to concurrent brain and blood phenylalanine levels, historical metabolic control and cognitive performance. Diffusion tensor imaging and 1H spectroscopy were performed in 30 adults with early-treated classical phenylketonuria (median age 35.5 years) and 54 healthy controls (median age 29.3 years). Fractional anisotropy and mean, axial and radial diffusivity were investigated using tract-based spatial statistics, and white matter lesion load was evaluated. Brain phenylalanine levels were measured with 1H spectroscopy whereas concurrent plasma phenylalanine levels were assessed after an overnight fast. Retrospective phenylalanine levels were collected to estimate historical metabolic control, and a neuropsychological evaluation assessed the performance in executive functions, attention and processing speed. Widespread reductions in mean diffusivity, axial diffusivity and fractional anisotropy occurred in patients compared to controls. Mean diffusivity and axial diffusivity were decreased in several white matter tracts and were most restricted in the optic radiation (effect size rrb = 0.66 to 0.78, P &amp;lt; 0.001) and posterior corona radiata (rrb = 0.83 to 0.90, P &amp;lt; 0.001). Lower fractional anisotropy was found in the optic radiation and posterior corona radiata (rrb = 0.43 to 0.49, P &amp;lt; 0.001). White matter microstructure in patients was significantly associated with cognition. Specifically, inhibition was related to axial diffusivity in the external capsule (rs = \u22120.69, P &amp;lt; 0.001) and the superior (rs = \u22120.58, P &amp;lt; 0.001) and inferior longitudinal fasciculi (rs = \u22120.60, P &amp;lt; 0.001). Cognitive flexibility was associated with mean diffusivity of the posterior limb of the internal capsule (rs = \u22120.62, P &amp;lt; 0.001), and divided attention correlated with fractional anisotropy of the external capsule (rs = \u22120.61, P &amp;lt; 0.001). Neither concurrent nor historical metabolic control was significantly associated with white matter microstructure. White matter lesions were present in 29 out of 30 patients (96.7%), most often in the parietal and occipital lobes. However, total white matter lesion load scores were unrelated to patients\u2019 cognitive performance and metabolic control. In conclusion, our findings demonstrate that white matter alterations in early-treated phenylketonuria persist into adulthood, are most prominent in the posterior white matter and are likely to be driven by axonal damage. Furthermore, diffusion tensor imaging metrics in adults with phenylketonuria were related to performance in attention and executive functions.<\/jats:p>","DOI":"10.1093\/braincomms\/fcad155","type":"journal-article","created":{"date-parts":[[2023,5,15]],"date-time":"2023-05-15T07:00:50Z","timestamp":1684134050000},"source":"Crossref","is-referenced-by-count":16,"title":["Compromised white matter is related to lower cognitive performance in adults with phenylketonuria"],"prefix":"10.1093","volume":"5","author":[{"given":"Raphaela","family":"Muri","sequence":"first","affiliation":[{"name":"Department of Diabetes, Endocrinology, Nutritional Medicine and Metabolism, Inselspital, Bern University Hospital and University of Bern , 3010 Bern , Switzerland"},{"name":"Support Center for Advanced Neuroimaging (SCAN), University Institute of Diagnostic and Interventional Neuroradiology, Inselspital, Bern University Hospital and University of Bern , 3010 Bern , Switzerland"},{"name":"Graduate 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Austria"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8618-6875","authenticated-orcid":false,"given":"Roland","family":"Kreis","sequence":"additional","affiliation":[{"name":"Translational Imaging Center (TIC), Swiss Institute for Translational and Entrepreneurial Medicine , 3010 Bern , Switzerland"},{"name":"Magnetic Resonance Methodology, Institute of Diagnostic and Interventional Neuroradiology, Inselspital, Bern University Hospital and University of Bern , 3010 Bern , Switzerland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Maike","family":"Hoefemann","sequence":"additional","affiliation":[{"name":"Translational Imaging Center (TIC), Swiss Institute for Translational and Entrepreneurial Medicine , 3010 Bern , Switzerland"},{"name":"Magnetic Resonance Methodology, Institute of Diagnostic and Interventional Neuroradiology, Inselspital, Bern University Hospital and University of Bern , 3010 Bern , Switzerland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Piotr","family":"Radojewski","sequence":"additional","affiliation":[{"name":"Support Center for Advanced Neuroimaging (SCAN), University Institute of Diagnostic and Interventional Neuroradiology, Inselspital, Bern University Hospital and University of Bern , 3010 Bern , Switzerland"},{"name":"Translational Imaging Center (TIC), Swiss Institute for Translational and Entrepreneurial Medicine , 3010 Bern , Switzerland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Katarzyna","family":"Pospieszny","sequence":"additional","affiliation":[{"name":"Support Center for Advanced Neuroimaging (SCAN), University Institute of Diagnostic and Interventional Neuroradiology, Inselspital, Bern University Hospital and University of Bern , 3010 Bern , Switzerland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Michel","family":"Hochuli","sequence":"additional","affiliation":[{"name":"Department of Diabetes, Endocrinology, Nutritional Medicine and Metabolism, Inselspital, Bern University Hospital and University of Bern , 3010 Bern , Switzerland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Roland","family":"Wiest","sequence":"additional","affiliation":[{"name":"Support Center for Advanced Neuroimaging (SCAN), University Institute of Diagnostic and Interventional Neuroradiology, Inselspital, Bern University Hospital and University of Bern , 3010 Bern , Switzerland"},{"name":"Translational Imaging Center (TIC), Swiss Institute for Translational and Entrepreneurial Medicine , 3010 Bern , Switzerland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4641-9539","authenticated-orcid":false,"given":"Rupert","family":"Lanzenberger","sequence":"additional","affiliation":[{"name":"Department of Psychiatry and Psychotherapy, Medical University of Vienna , 1090 Vienna , Austria"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Roman","family":"Trepp","sequence":"additional","affiliation":[{"name":"Department of Diabetes, Endocrinology, Nutritional Medicine and Metabolism, Inselspital, Bern University Hospital and University of Bern , 3010 Bern , Switzerland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6556-3419","authenticated-orcid":false,"given":"Regula","family":"Everts","sequence":"additional","affiliation":[{"name":"Department of Diabetes, Endocrinology, Nutritional Medicine and Metabolism, Inselspital, Bern University Hospital and University of Bern , 3010 Bern , Switzerland"},{"name":"Translational Imaging Center (TIC), Swiss Institute for Translational and Entrepreneurial Medicine , 3010 Bern , Switzerland"},{"name":"Division of Neuropaediatrics, Development and Rehabilitation, Department of Paediatrics, Inselspital, Bern University Hospital and University of Bern , 3010 Bern , 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