Wilson disease (WD) primarily presents with hepatic and neurological symptoms. While hepatic symptoms typically precede the neurological manifestations, copper accumulates in the brain already in this patient group and leads to subclinical brain MRI abnormalities including T2 hyperintensities and atrophy. This study aimed to assess brain morphological changes in mild hepatic WD. WD patients without a history of neurologic symptoms and decompensated cirrhosis and control participants underwent brain MRI at 3T scanner including high-resolution T1-weighted images. A volumetric evaluation was conducted on the following brain regions: nucleus accumbens, caudate, pallidum, putamen, thalamus, amygdala, hippocampus, midbrain, pons, cerebellar gray matter, white matter (WM), and superior peduncle, using Freesurfer v7 software. Whole-brain analyses using voxel- and surface-based morphometry were performed using SPM12. Statistical comparisons utilized a general linear model adjusted for total intracranial volume, age, and sex. Twenty-six WD patients with mild hepatic form (30 ± 9 years [mean age ± SD]); 11 women; mean treatment duration 13 ± 12 (range 0-42) years and 28 healthy controls (33 ± 9 years; 15 women) were evaluated. Volumetric analysis revealed a significantly smaller pons volume and a trend for smaller midbrain and cerebellar WM in WD patients compared to controls. Whole-brain analysis revealed regions of reduced volume in the pons, cerebellar, and lobar WM in the WD group. No significant differences in gray matter density or cortical thickness were found. Myelin or WM in general seems vulnerable to low-level copper toxicity, with WM volume loss showing promise as a marker for assessing brain involvement in early WD stages.

2nd Department of Neurology Institute of Psychiatry and Neurology Warsaw Poland

4th Department of Internal Medicine 1st Faculty of Medicine Charles University and General University Hospital Prague Prague Czechia

Department of Medicine 1st Faculty of Medicine Charles University and Military University Hospital Prague Czechia

Department of Neurology and Center of Clinical Neuroscience 1st Faculty of Medicine Charles University and General University Hospital Prague Prague Czechia

MR Unit Department of Diagnostic and Interventional Radiology Institute for Clinical and Experimental Medicine Prague Czechia

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Yu XE, Gao S, Yang RM, Han YZ. MR imaging of the brain in neurologic Wilson disease. AJNR Am J Neuroradiol. 2019;40(1):178‐183. doi:10.3174/ajnr.A5936 PubMed DOI PMC

Li M, Ma J, Wang W, Yang X, Luo K. Mutation analysis of the ATP7B gene and genotype‐phenotype correlation in Chinese patients with Wilson disease. BMC Gastroenterol. 2021;21(1):339. doi:10.1186/s12876-021-01911-5 PubMed DOI PMC

Członkowska A, Litwin T, Dusek P, et al. Wilson disease. Nat Rev Dis Primers. 2018;4(1):21. doi:10.1038/s41572-018-0018-3 PubMed DOI PMC

Kasztelan‐Szczerbinska B, Cichoz‐Lach H. Wilson's disease: an update on the diagnostic workup and management. J Clin Med. 2021;10(21):5097. doi:10.3390/jcm10215097 PubMed DOI PMC

Dusek P, Bahn E, Litwin T, et al. Brain iron accumulation in Wilson disease: a post mortem 7 tesla MRI ‐ histopathological study. Neuropathol Appl Neurobiol. 2017;43(6):514‐532. doi:10.1111/nan.12341 PubMed DOI

Litwin T, Gromadzka G, Członkowska A, Gołębiowski M, Poniatowska R. The effect of gender on brain MRI pathology in Wilson's disease. Metab Brain Dis. 2013;28(1):69‐75. doi:10.1007/s11011-013-9378-2 PubMed DOI PMC

Dusek P, Smolinski L, Redzia‐Ogrodnik B, et al. Semiquantitative scale for assessing brain MRI abnormalities in Wilson disease: a validation study. Mov Disord. 2020;35(6):994‐1001. doi:10.1002/mds.28018 PubMed DOI

Viveiros A, Beliveau V, Panzer M, et al. Neurodegeneration in hepatic and neurologic Wilson's disease. Hepatology. 2021;74(2):1117‐1120. doi:10.1002/hep.31681 PubMed DOI PMC

Schilsky ML, Roberts EA, Bronstein JM, et al. A multidisciplinary approach to the diagnosis and management of Wilson disease: 2022 practice guidance on Wilson disease from the American Association for the Study of Liver Diseases. Hepatology. 2022. doi:10.1002/hep.32801 PubMed DOI

Członkowska A, Tarnacka B, Möller JC, et al. Unified Wilson's disease rating scale ‐ a proposal for the neurological scoring of Wilson's disease patients. Neurol Neurochir Pol. 2007;41(1):1‐12. PubMed

Sterling RK, Lissen E, Clumeck N, et al. Development of a simple noninvasive index to predict significant fibrosis in patients with HIV/HCV coinfection. Hepatology. 2006;43(6):1317‐1325. doi:10.1002/hep.21178 PubMed DOI

Pugh RN, Murray‐Lyon IM, Dawson JL, Pietroni MC, Williams R. Transection of the oesophagus for bleeding oesophageal varices. Br J Surg. 1973;60(8):646‐649. doi:10.1002/bjs.1800600817 PubMed DOI

Fischl B. FreeSurfer. Neuroimage. 2012;62(2):774‐781. doi:10.1016/j.neuroimage.2012.01.021 PubMed DOI PMC

Sanfilipo MP, Benedict RH, Zivadinov R, Bakshi R. Correction for intracranial volume in analysis of whole brain atrophy in multiple sclerosis: the proportion vs. residual method. Neuroimage. 2004;22(4):1732‐1743. doi:10.1016/j.neuroimage.2004.03.037 PubMed DOI

Dahnke R, Yotter RA, Gaser C. Cortical thickness and central surface estimation. Neuroimage. 2013;65:336‐348. doi:10.1016/j.neuroimage.2012.09.050 PubMed DOI

Pomponio R, Erus G, Habes M, et al. Harmonization of large MRI datasets for the analysis of brain imaging patterns throughout the lifespan. Neuroimage. 2020;208:116450. doi:10.1016/j.neuroimage.2019.116450 PubMed DOI PMC

Salimi‐Khorshidi G, Smith SM, Nichols TE. Adjusting the effect of nonstationarity in cluster‐based and TFCE inference. Neuroimage. 2011;54(3):2006‐2019. doi:10.1016/j.neuroimage.2010.09.088 PubMed DOI

Catani M, Thiebaut de Schotten M. A diffusion tensor imaging tractography atlas for virtual in vivo dissections. Cortex. 2008;44(8):1105‐1132. doi:10.1016/j.cortex.2008.05.004 PubMed DOI

Shribman S, Bocchetta M, Sudre CH, et al. Neuroimaging correlates of brain injury in Wilson's disease: a multimodal, whole‐brain MRI study. Brain. 2022;145(1):263‐275. doi:10.1093/brain/awab274 PubMed DOI PMC

Kozić D, Svetel M, Petrović B, Dragasević N, Semnic R, Kostić VS. MR imaging of the brain in patients with hepatic form of Wilson's disease. Eur J Neurol. 2003;10(5):587‐592. doi:10.1046/j.1468-1331.2003.00661.x PubMed DOI

Diao SP, Zhuang YS, Huang YQ, Zhou ZH, Liu AQ, Hong MF. Analysis of risk factors for neurological symptoms in patients with purely hepatic Wilson's disease at diagnosis. BMC Neurol. 2023;23(1):89. doi:10.1186/s12883-023-03105-w PubMed DOI PMC

Dusek P, Litwin T, Członkowska A. Neurologic impairment in Wilson disease. Ann Transl Med. 2019;7(Suppl 2):S64. doi:10.21037/atm.2019.02.43 PubMed DOI PMC

Dezortova M, Lescinskij A, Dusek P, et al. Multiparametric quantitative brain MRI in neurological and hepatic forms of Wilson's disease. J Magn Reson Imaging. 2020;51(6):1829‐1835. doi:10.1002/jmri.26984 PubMed DOI

Ferenci P, Litwin T, Seniow J, Czlonkowska A. Encephalopathy in Wilson disease: copper toxicity or liver failure? J Clin Exp Hepatol. 2015;5(Suppl 1):S88‐S95. doi:10.1016/j.jceh.2014.09.002 PubMed DOI PMC

Smolinski L, Ziemssen T, Akgun K, et al. Brain atrophy is substantially accelerated in neurological Wilson's disease: a longitudinal study. Mov Disord. 2022;37(12):2446‐2451. doi:10.1002/mds.29229 PubMed DOI

Tinaz S, Arora J, Nalamada K, et al. Structural and functional brain changes in hepatic and neurological Wilson disease. Brain Imaging Behav. 2021;15(5):2269‐2282. doi:10.1007/s11682-020-00420-5 PubMed DOI

Lui CC, Chen CL, Chang YF, Lee TY, Chuang YC, Hsu SP. Subclinical central pontine myelinolysis after liver transplantation. Transplant Proc. 2000;32(7):2215‐2216. doi:10.1016/s0041-1345(00)01640-7 PubMed DOI

Herynek V, Babis M, Trunecka P, et al. Chronic liver disease: relaxometry in the brain after liver transplantation. Magma. 2001;12(1):10‐15. doi:10.1007/BF02678268 PubMed DOI

Lee J, Lacomis D, Comu S, Jacobsohn J, Kanal E. Acquired hepatocerebral degeneration: MR and pathologic findings. AJNR Am J Neuroradiol. 1998;19(3):485‐487. https://www.ajnr.org/content/ajnr/19/3/485.full.pdf PubMed PMC

Park SA, Heo K. Prominent cerebellar symptoms with unusual magnetic resonance imaging findings in acquired hepatocerebral degeneration. Arch Neurol. 2004;61(9):1458‐1460. doi:10.1001/archneur.61.9.1458 PubMed DOI

Melzer N, Grimm A, Meuth SG, Solymosi L, Stoll G. A pure cerebellar syndrome with corresponding ponto‐cerebellar atrophy in acquired hepatocerebral degeneration. J Neurol Sci. 2010;292(1–2):96‐98. doi:10.1016/j.jns.2010.02.022 PubMed DOI

Guevara M, Baccaro ME, Gómez‐Ansón B, et al. Cerebral magnetic resonance imaging reveals marked abnormalities of brain tissue density in patients with cirrhosis without overt hepatic encephalopathy. J Hepatol. 2011;55(3):564‐573. doi:10.1016/j.jhep.2010.12.008 PubMed DOI

Kuang Y, Wu X, Lai H, et al. Abnormal corpus callosum induced by overt hepatic encephalopathy impairs interhemispheric functional coordination in cirrhosis patients. Ann Transl Med. 2021;9(20):1579. doi:10.21037/atm-21-5109 PubMed DOI PMC

Zhang LJ, Qi R, Zhong J, Xu Q, Zheng G, Lu GM. The effect of hepatic encephalopathy, hepatic failure, and portosystemic shunt on brain volume of cirrhotic patients: a voxel‐based morphometry study. PLoS One. 2012;7(8):e42824. doi:10.1371/journal.pone.0042824 PubMed DOI PMC

Zou L, Song Y, Zhou X, Chu J, Tang X. Regional morphometric abnormalities and clinical relevance in Wilson's disease. Mov Disord. 2019;34(4):545‐554. doi:10.1002/mds.27641 PubMed DOI

Vogel F, Evans J. Morphologic alterations produced by copper in neural tissues with consideration of the role of the metal in the pathogenesis of Wilson's disease. J Exp Med. 1961;113(6):997‐1004. doi:10.1084/jem.113.6.997 PubMed DOI PMC

Dusek P, Lescinskij A, Ruzicka F, et al. Associations of brain atrophy and cerebral iron accumulation at MRI with clinical severity in Wilson disease. Radiology. 2021;299(3):662‐672. doi:10.1148/radiol.2021202846 PubMed DOI

Sinha S, Taly AB, Ravishankar S, Prashanth LK, Vasudev MK. Central pontine signal changes in Wilson's disease: distinct MRI morphology and sequential changes with de‐coppering therapy. J Neuroimaging. 2007;17(4):286‐291. doi:10.1111/j.1552-6569.2007.00120.x PubMed DOI

Hedera P, Brewer GJ, Fink JK. White matter changes in Wilson disease. Arch Neurol. 2002;59(5):866‐867. doi:10.1001/archneur.59.5.866 PubMed DOI

Wang A, Wei T, Wu H, et al. Lesions in white matter in Wilson's disease and correlation with clinical characteristics. Can J Neurol Sci. 2023;50(5):710‐718. doi:10.1017/cjn.2022.286 PubMed DOI

Aikath D, Gupta A, Chattopadhyay I, et al. Subcortical white matter abnormalities related to drug resistance in Wilson disease. Neurology. 2006;67(5):878‐880. doi:10.1212/01.wnl.0000234130.27871.03 PubMed DOI

Lawrence A, Saini J, Sinha S, et al. Improvement of diffusion tensor imaging (DTI) parameters with decoppering treatment in Wilson's disease. JIMD Rep. 2016;25:31‐37. doi:10.1007/8904_2015_466 PubMed DOI PMC

Davies KM, Hare DJ, Cottam V, et al. Localization of copper and copper transporters in the human brain. Metallomics. 2013;5(1):43‐51. doi:10.1039/c2mt20151h PubMed DOI

Hu S, Xu C, Dong T, et al. Structural and functional changes are related to cognitive status in Wilson's disease. Front Hum Neurosci. 2021;15:610947. doi:10.3389/fnhum.2021.610947 PubMed DOI PMC

Iwański S, Seniów J, Leśniak M, Litwin T, Członkowska A. Diverse attention deficits in patients with neurologically symptomatic and asymptomatic Wilson's disease. Neuropsychology. 2015;29(1):25‐30. doi:10.1037/neu0000103 PubMed DOI

Hanuška J, Dušek P, Rusz J, Ulmanová O, Burgetová A, Růžička E. Eye movement abnormalities are associated with brainstem atrophy in Wilson disease. Neurol Sci. 2020;41(5):1097‐1103. doi:10.1007/s10072-019-04225-3 PubMed DOI

Vicario‐Feliciano R, Hernández‐Hernández CI, Camacho‐Pastor IC, Martínez‐Cruzado JC. A custom‐made newborn screening test for Wilson's disease in Puerto Rico. Cureus. 2022;14(4):e24446. doi:10.7759/cureus.24446 PubMed DOI PMC

Huang X, Wu D, Zhu L, et al. Application of a next‐generation sequencing (NGS) panel in newborn screening efficiently identifies inborn disorders of neonates. Orphanet J Rare Dis. 2022;17(1):66. doi:10.1186/s13023-022-02231-x PubMed DOI PMC

Collins CJ, Yi F, Dayuha R, et al. Direct measurement of ATP7B peptides is highly effective in the diagnosis of Wilson disease. Gastroenterology. 2021;160(7):2367‐2382.e1. doi:10.1053/j.gastro.2021.02.052 PubMed DOI PMC

Stenton SL, Campagna M, Philippakis A, O'Donnell‐Luria A, Gelb MH. First‐tier next generation sequencing for newborn screening: an important role for biochemical second‐tier testing. Genet Med Open. 2023;1(1):100821. doi:10.1016/j.gimo.2023.100821 PubMed DOI PMC