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Lenticular nucleus hyperechogenicity in Wilson’s disease reflects local copper, but not iron accumulation

  • Neurology and Preclinical Neurological Studies - Original Article
  • Published:
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Abstract

In patients with Wilson’s disease (WD) transcranial brain sonography typically reveals areas of increased echogenicity (hyperechogenicity) of the lenticular nucleus (LN). Correlation with T2-hypointensity on magnetic resonance images suggested that LN hyperechogenicity in WD is caused by trace metal accumulation. Accumulation of both, copper and iron, in the brain of WD patients has been reported. The present study was designed to elucidate whether LN hyperechogenicity in WD reflects accumulation of copper or iron. Post-mortem brains of 15 WD patients and one non-WD subject were studied with ultrasonography in an investigator-blinded fashion. LN hyperechogenicity was measured planimetrically by manual tracing as well as using digitized image analysis. The putaminal copper content was determined in samples of 11 WD brains and the non-WD brains using inductively coupled plasma mass spectrometry, and iron content was assessed using flame atomic absorption spectroscopy. LN was normal on ultrasonography only in the non-WD brain, but abnormal (hyperechogenic) in all WD brains. Digitized image analysis measures of LN hyperechogenicity and, by trend, manual measures correlated with putaminal copper content (Pearson test; digitized: r = 0.77, p = 0.04; manual: r = 0.57, p = 0.051) but not with iron content (each, p > 0.18). LN hyperechogenicity measures were unrelated to age at death of patients, age at onset of WD, WD duration, age of brain specimen, serum copper or serum ceruloplasmin (each, p > 0.1). We conclude that LN hyperechogenicity in WD reflects copper, but not iron accumulation. Further studies are warranted to elucidate the use of transcranial brain sonography for monitoring therapeutic effects of chelating agents in WD patients.

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References

  • Becker G, Berg D, Rausch WD, Lange HK, Riederer P, Reiners K (1999) Increased tissue copper and manganese content in the lentiform nucleus in primary adult-onset dystonia. Ann Neurol 46:260–263

    Article  PubMed  CAS  Google Scholar 

  • Becker G, Berg D, Francis M, Naumann M (2001) Evidence for disturbances of copper metabolism in dystonia: from the image towards a new concept. Neurology 57:2290–2294

    Article  PubMed  CAS  Google Scholar 

  • Berg D, Hoggenmüller U, Hofmann E et al (2000) The basal ganglia in haemochromatosis. Neuroradiology 42:9–13

    Article  PubMed  CAS  Google Scholar 

  • Blahuta J, Soukup T, Jelinkova M et al (2013) A new program for highly reproducible automatic evaluation of the substantia nigra from transcranial sonographic images. Biomed Pap Med Fac Univ Palacky Olomouc Czech Repub. doi:10.5507/bp.2013.029

    PubMed  Google Scholar 

  • Bruehlmeier M, Leenders KL, Vontobel P, Calonder C, Antonini A, Weindl A (2000) Increased cerebral iron uptake in Wilson’s disease: a 52Fe-citrate PET study. J Nucl Med 41:781–787

    PubMed  CAS  Google Scholar 

  • Brüggemann N, Schneider SA, Sander T, Klein C, Hagenah J (2010) Distinct basal ganglia hyperechogenicity in idiopathic basal ganglia calcification. Mov Disord 25:2661–2664

    Article  PubMed  Google Scholar 

  • Brüggemann N, Wuerfel J, Petersen D, Klein C, Hagenah J, Schneider SA (2011) Idiopathic NBIA—clinical spectrum and transcranial sonography findings. Eur J Neurol 18:e58–e59

    Article  PubMed  Google Scholar 

  • Eicke M, Briner J, Willi U, Uehlinger J, Boltshauser E (1992) Symmetrical thalamic lesions in infants. Arch Dis Child 67:15–19

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  • Hare DJ, Gerlach M, Riederer P (2012) Considerations for measuring iron in post-mortem tissue of Parkinson’s disease patients. J Neural Transm 119:1515–1521

    Article  PubMed  CAS  Google Scholar 

  • Hayashi H, Hattori A, Tatsumi Y et al (2013) Various copper and iron overload patterns in the livers of patients with Wilson disease and idiopathic copper toxicosis. Med Mol Morphol 46:133–140

    Article  PubMed  Google Scholar 

  • Heckmann JM, Eastman RW, De Villiers JC, Hewlett R (1994) Wilson’s disease: neurological and magnetic resonance imaging improvement on zinc treatment. J Neurol Neurosurg Psychiatry 57:1273–1274

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  • Horoupian DS, Sternlieb I, Scheinberg ICH (1988) Neuropathological findings in penicillamine-treated patients with Wilson’s disease. Clin Neuropathol 7:62–67

    PubMed  CAS  Google Scholar 

  • Kim JM, Ko SB, Kwon SJ et al (2005) Ferrous and ferric iron accumulates in the brain of aged Long-Evans Cinnamon rats, an animal model of Wilson’s disease. Neurosci Lett 382:143–147

    Article  PubMed  CAS  Google Scholar 

  • King AD, Walshe JM, Kendall BE et al (1996) Cranial MR imaging in Wilson’s disease. AJR Am J Roentgenol 167:1579–1584

    Article  PubMed  CAS  Google Scholar 

  • Kostić VS, Svetel M, Mijajlović M, Pavlović A, Ječmenica-Lukić M, Kozić D (2012) Transcranial sonography in pantothenate kinase-associated neurodegeneration. J Neurol 259:959–964

    Article  PubMed  Google Scholar 

  • Krogias C, Meves S, Schoellhammer M, Gold R, Andrich J (2009) Sonographic detection of bilateral striopallidodentate calcinosis. J Neurol 256:266–267

    Article  PubMed  Google Scholar 

  • Litwin T, Gromadzka G, Członkowska A (2012) Gender differences in Wilson’s disease. J Neurol Sci 312:31–35

    Article  PubMed  CAS  Google Scholar 

  • Litwin T, Gromadzka G, Szpak GM, Jabłonka-Salach K, Bulska E, Członkowska A (2013) Brain metal accumulation in Wilson’s disease. J Neurol Sci 329:55–58

    Article  PubMed  CAS  Google Scholar 

  • Martínez-Fernández R, Caballol N, Gómez-Choco M (2013) MRI and transcranial sonography findings in Wilson’s disease. Mov Disord 28:740

    Article  PubMed  Google Scholar 

  • Meenakshi-Sundaram S, Mahadevan A, Taly AB, Arunodaya GR, Swamy HS, Shankar SK (2008) Wilson’s disease: a clinico-neuropathological autopsy study. J Clin Neurosci 15:409–417

    Article  PubMed  CAS  Google Scholar 

  • Pfeiffenberger J, Gotthardt DN, Herrmann T et al (2012) Iron metabolism and the role of HFE gene polymorphisms in Wilson disease. Liver Int 32:165–170

    Article  PubMed  CAS  Google Scholar 

  • Pfeiffer RF (2011) Wilson’s disease. Handb Clin Neurol 100:681–709

    Article  PubMed  Google Scholar 

  • Ricciardi MC, Sirimarco G, Vicenzini E et al (2010) Transcranial sonographic findings in Wilson disease. J Ultrasound Med 29:1143–1145

    PubMed  Google Scholar 

  • Roberts EA, Schilsky ML; American Association for Study of Liver Diseases (AASLD) (2008) Diagnosis and treatment of Wilson disease: an update. Hepatology 47:2089–2111

    Article  Google Scholar 

  • Schrag M, Dickson A, Jiffry A, Kirsch D, Vinters HV, Kirsch W (2010) The effect of formalin fixation on the levels of brain transition metals in archived samples. Biometals 23:1123–1127

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  • Sharonova IN, Vorobjev VS, Haas HL (1998) High-affinity copper block of GABAA receptor-meditated currents in acutely isolated cerebellar Purkinje cells of the rat. Eur J Neurosci 10:522–528

    Article  PubMed  CAS  Google Scholar 

  • Sinha S, Taly AB, Ravishankar S et al (2006) Wilson’s disease: cranial MRI observations and clinical correlation. Neuroradiology 48:613–621

    Article  PubMed  CAS  Google Scholar 

  • Skjørringe T, Møller LB, Moos T (2012) Impairment of interrelated iron- and copper homeostatic mechanisms in brain contributes to the pathogenesis of neurodegenerative disorders. Front Pharmacol 3:169

    Article  PubMed  PubMed Central  Google Scholar 

  • Skowronska M, Walter U, Kmiec T, Członkowska A (2013a) Transcranial sonography in mitochondrial membrane protein-associated neurodegeneration. Parkinsonism Relat Disord 19:1061–1063

    Article  PubMed  Google Scholar 

  • Skowronska M, Dziezyc K, Członkowska A (2013b) Transcranial sonography in manganese-induced parkinsonism caused by drug abuse. Clin Neuroradiol. doi:10.1007/s00062-013-0256-4

    PubMed  Google Scholar 

  • Stys PK, You H, Zamponi GW (2012) Copper-dependent regulation of NMDA receptors by cellular prion protein: implications for neurodegenerative disorders. J Physiol 590:1357–1368

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  • Svetel M, Mijajlović M, Tomić A, Kresojević N, Pekmezović T, Kostić VS (2012) Transcranial sonography in Wilson’s disease. Parkinsonism Relat Disord 18:234–238

    Article  PubMed  Google Scholar 

  • Toscano M, Canevelli M, Giacomelli E et al (2011) Transcranial sonography of basal ganglia calcifications in Fahr disease. J Ultrasound Med 30:1032–1033

    PubMed  Google Scholar 

  • Van de Loo S, Walter U, Behnke S et al (2010) Reproducibility and diagnostic accuracy of substantia nigra sonography for the diagnosis of Parkinson’s disease. J Neurol Neurosurg Psychiatry 81:1087–1092

    Article  PubMed  Google Scholar 

  • Waggoner DJ, Bartnikas TB, Gitlin JD (1999) The role of copper in neurodegenerative disease. Neurobiol Dis 6:221–230

    Article  PubMed  CAS  Google Scholar 

  • Walter U (2010) Transcranial sonography in brain disorders with trace metal accumulation. Int Rev Neurobiol 90:166–178

    Article  PubMed  Google Scholar 

  • Walter U, Krolikowski K, Tarnacka B, Benecke R, Członkowska A, Dressler D (2005) Sonographic detection of basal ganglia lesions in asymptomatic and symptomatic Wilson disease. Neurology 64:1726–1732

    Article  PubMed  CAS  Google Scholar 

  • Walter U, Dressler D, Lindemann C, Slachevsky A, Miranda M (2008) Transcranial sonography findings in welding-related Parkinsonism in comparison to Parkinson’s disease. Mov Disord 23:141–145

    Article  PubMed  Google Scholar 

  • Walter U, Witt R, Wolters A, Wittstock M, Benecke R (2012) Substantia nigra echogenicity in Parkinson’s disease: relation to serum iron and C-reactive protein. J Neural Transm 119:53–57

    Article  PubMed  CAS  Google Scholar 

  • Walter U, Blitzer A, Benecke R, Grossmann A, Dressler D (2014) Sonographic detection of basal ganglia abnormalities in spasmodic dysphonia. Eur J Neurol 21:349–352

    Article  PubMed  CAS  Google Scholar 

  • Weiser T, Wienrich M (1996) The effects of copper ions on glutamate receptors in cultured rat cortical neurons. Brain Res 742:211–218

    Article  PubMed  CAS  Google Scholar 

Download references

Acknowledgments

This study was supported by the Polish National Science Centre (grant No. NN 402472340).

Conflict of interest

The authors have no financial interests that relate to research covered in this article.

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Authors and Affiliations

  1. Department of Neurology, University of Rostock, Rostock, Germany

    Uwe Walter

  2. Department of Neurology II, Institute of Psychiatry and Neurology, Warsaw, Poland

    Marta Skowrońska, Tomasz Litwin & Anna Członkowska

  3. Department of Neuropathology, Institute of Psychiatry and Neurology, Warsaw, Poland

    Grażyna Maria Szpak

  4. Faculty of Chemistry, University of Warsaw, Warsaw, Poland

    Katarzyna Jabłonka-Salach & Ewa Bulska

  5. Department of Neurology, Faculty of Medicine and Dentistry, Palacky University Olomouc, Olomouc, Czech Republic

    David Skoloudík

  6. Department of Experimental and Clinical Pharmacology, Medical University, Warsaw, Poland

    Anna Członkowska

  7. Neurologische Universitätsklinik, Gehlsheimer Str. 20, 18147, Rostock, Germany

    Uwe Walter

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  1. Uwe Walter
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  2. Marta Skowrońska
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  3. Tomasz Litwin
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  4. Grażyna Maria Szpak
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Correspondence to Uwe Walter.

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Walter, U., Skowrońska, M., Litwin, T. et al. Lenticular nucleus hyperechogenicity in Wilson’s disease reflects local copper, but not iron accumulation. J Neural Transm 121, 1273–1279 (2014). https://doi.org/10.1007/s00702-014-1184-4

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  • DOI: https://doi.org/10.1007/s00702-014-1184-4

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