Ann. N.Y. Acad. Sci. ISSN 0077-8923
A N N A L S O F T H E N E W Y O R K A C A D E M Y O F SC I E N C E S Issue: Human Disorders of Copper Metabolism II
Morphological and functional imaging in neurological and non-neurological Wilson’s patients Wieland Hermann Department of Neurology, Paracelsus Clinic Zwickau, Zwickau, Germany Address for correspondence: Wieland Hermann, Paracelsus Clinic Zwickau, Department of Neurology, Werdauer Str. 68, D-0860 Zwickau, Germany. [email protected]
Wilson’s disease causes disturbances of the central nervous system, affecting it both directly through copper toxicity and indirectly subject to a copper-induced hepatopathy, resulting in morphological and physiological changes in brain structures that can be captured by means of magnetic resonance imaging (MRI), 123 I--CIT (2-carbomethoxy-3 (4-iodophenyl)tropane)-SPECT (single photon emission computed tomography), 123 I-IBZM (benzamide)-SPECT and [18 F]FDG -PET (fluorodeoxyglucose–positron emission tomography). MRI can reveal even slight morphological changes in non-neurological Wilson’s patients. More marked findings in neurological Wilson’s patients become evident in T1- and T2-weighted MRI. T1-weighted MRI predominantly detects atrophic changes, whereas T2weighted MRI regularly records signal changes in the putamen. With the aid of these three nuclear-medicine examinations, nigrostriatal and metabolic disturbances are identified in neurological Wilson’s patients only. Sufficient decoppering therapy prevents progression and even tends to improve symptoms. A correlation between any of the imaging findings in patients with the genetic phenotype and the incidence of the most common mutation H1069Q (homozygote or compound heterozygote) or other mutations could not be substantiated. Keywords: Wilson’s disease; MRI; 123 I--CIT-SPECT; 123 I-IBZM-SPECT; [18 F]FDG-PET
Introduction As early as in 1898, Str¨umpell named Wilson’s disease, a genetically caused copper storage disease, hepatolenticular degeneration.1 Thus, he identified and correlated the basic pathoanatomical changes for which S.A.K. Wilson established a clinical– pathophysiological correlation.2 In clinical terms, hepatic symptoms appear alongside a variety of neurological findings,3,4 which initially resulted in a classification based on symptoms. It was Konovalov5 who devised the following distinctive clinical classification, modified by L¨ossner and Bachmann:6 a neurological disease course, including pseudoparkinsonism type (PP), pseudosclerosis type (PS), and arrhythmic hyperkinetic type (hybrid, H); and a nonneurological disease course, including asymptomatic type and hepatic type. Oder et al. also suggested a distinction of the neurological disease course into three subgroups comparable to the classification above, based on cardinal extrapyramidal motor symptoms such as bradykinesia, rigor, ataxia, tremor, dystonia, and
dysarthria, as well as cognitive and psychiatric disturbances. While in a clinical setting, the only distinction made is between neurological and nonneurological disease courses, some authors also distinguish a psychiatric form of Wilson’s disease.8,9 Following the discovery of the Wilson gene in 1993,10–12 the sheer variety of genetic mutations gave rise to the discussion of a genotype–phenotype correlation.13–15 However, some authors do not discern any verified correlation.16–20 Modern imaging methods have facilitated an increasingly accurate examination of the cerebral pathoanatomy and pathophysiology. To review clinical and genetic classification attempts, morphological and nuclear medicine parameters of the central nervous system (CNS) were analyzed. Cellular pathophysiology and pathoanatomy in the nervous system Direct effects of copper toxicity Examinations of liver cells for copper toxicity focused on the formation of free radicals and the doi: 10.1111/nyas.12343
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inactivation of vital enzymes.21–23 Both lead especially to lysosomal and mitochondrial damage.24 In addition to lipid peroxidation, the mitochondrial respiratory chain is affected and protein biosynthesis is disturbed.25 The reduction in antioxidants diminishes the potential to repair cells. It can be assumed that following the redistribution of copper in the nerve cells, the same intercellular mechanisms lead to apoptosis or cell death, respectively. Thus, nerve cells are subject to direct copper toxicity. While under physiological conditions concentrations of copper can be found in the locus coeruleus and substantia nigra, in Wilson’s disease patients increased copper concentrations occur in all areas of the brain.26 Notwithstanding, vulnerability can be quite variable and predominantly affects the basal ganglia and cerebellar core areas.18,26 The area with the highest copper concentrations and the most pronounced lesions and astrocytic reactions is the putamen.26 In neuropathological terms, general brain atrophy is not obligatory; however, very often insular, cortical, cerebellar, and putamenal atrophy are present.27,28 Patients with the neurological type of Wilson’s disease are also afflicted with degeneration of the midbrain.29 Indirect effects of copper toxicity While the damage to neurons is presumed to be predominantly due to direct copper toxicity, there are glial abnormalities which point to hepatic insufficiency and therefore to the indirect effects of copper toxicity. Pathoanatomical examinations furnish ample proof of the incidence of typical astrocyte degeneration (Alzheimer type II glia) in Wilson’s disease in analogy to hepatopathies of different genesis.30,31 The degeneration manifests itself in cell enlargement, loss or plumpness of dendrites, and a hyperchromatic nucleus with central hypochromasia (vesicular nucleus).30 Furthermore, Alzheimer type I glia and Opalski cells with fine granular PAS+ cytoplasm occur as unspecific glia degeneration.32 The oligodendroglia appear to be decimated. Moreover, cytotoxic cell edemas are present.33 This leads to spongiform changes in the striatum, dentate nucleus, and cortical areas.33,34
Imaging in Wilson’s disease
Morphological MRI findings in the CNS Damage to the nervous system is thus caused both directly by copper toxicity and indirectly by hepatic encephalopathy.35 In T1-weighted MRI, symmetrical hypertension is described as a characteristic finding in hepatic encephalopathy. It is present in the globus pallidus and the putamen, with affection of the hypothalamus and midbrain as the disease progresses.36–38 Pathogenetically, this is attributed to a slight astrocytic edema and manganese deposits.36,39 However, in Wilson’s patients under stable therapy and compensated hepatic function, the morphological changes often go beyond this and persist. In T1-weighted images of patients in the neurological cohort, they frequently become manifest as slight signal changes in the basal ganglia and cerebellar regions (putamen, globus pallidus, substantia nigra, red nucleus, cerebellar nuclei) as well as in the pons.28 By contrast, there are regular occurrences of cerebral, cerebellar, putamenal, and mesencephalic atrophy in neurological patients compared to healthy subjects.20,28,29,40 In nonneurological Wilson’s patients, slight cerebral and cerebellar atrophic changes are also regularly present, and there are single cases with slight signal changes in the substantia nigra and the red nucleus.41,42 In the context of differential diagnostics, one must also always consider the presence of mild hepatic encephalopathy. In T2-weighted images, all neurological Wilson’s patients show signal changes in the putamen, while the other basal ganglia structures are only infrequently affected by lesions.28,40 Slight putamenal signal changes in T2-weighted MRI are also characteristic of nonneurological Wilson’s patients. The lesion pattern in the putamen corresponds to spongiform dystrophy.27 Within the neurological cohort, there were no discernible differences between the clinical disease courses (PP, PS, H) in either T1- or T2-weighted MRI data. We must emphasise the fact that even the nonneurological patients can exhibit slight lesion patterns despite the absence of neurological symptoms. Nevertheless, under morphological imaging aspects, significant differences between the neurological and nonneurological disease courses are apparent in both the severity of signal changes and the frequency of their incidence.41,42 This may
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correspond to a gradual conversion of a hepatic to a neurological disease course following the release of free copper from apoptotic liver cells. Manifestation takes place only once the neuronal and glia compensation ability has been exhausted. Potentially, there is a parallel to other neurodegenerative disorders, such as Parkinson’s disease, where extrapyramidal motor symptoms only become manifest following a dopaminergic cell loss of 50–70% in the substantia nigra pars compacta.43 Pathophysiological findings in the nigrostriatal system 123
I-β-CIT-SPECT The radiopharmacon 123 I--CIT, a cocaine analogue, binds to the dopamine transporter of the presynaptic nerve endings of nigrostriatal neurons in the striatum.44 The 123 I--CIT binding in the cerebellum at a normal ratio of 11.7 ± 2.8 (striatal/ cerebellar pulse rate ratio) serves as reference value.45 The pulse rate coefficient for the nonneurological cohort is normal, with values remaining stable under drug therapy throughout the course of the disease.41,42,46 Therefore, nigrostriatal dopaminergic projection can be considered intact in these Wilson’s patients. However, neurological Wilson’s patients show a symmetrically reduced pulse rate in the striatum, with putamenal accentuation corresponding to a disturbed nigrostriatal function.42,45–48 No significant differences among the three neurological disease types (PP, PS, H) could be detected.45 There is evidence that the pulse rate tends to improve under sufficient decoppering drug therapy administered over a course of 4 years.41,42 123
I-IBZM-SPECT The radioactively marked benzamide 123 I-IBZM is a selective dopamine D2 receptor antagonist.49,50 Its binding to striatal dopamine receptors can be captured by means of SPECT and represents a measure for their density and the integrity of postsynaptic neurons.49,51 The pulse rate is measured and related to values for the frontal cortex. In healthy subjects, this ratio is 2.0 ± 0.19 (striatal/frontal pulse rate ratio).48 All neurological Wilson’s patients have a reduced pulse rate in the striatum.42,48,52 Under therapy, this value remains stable. The 123 I-IBZM findings do not allow for distinction between the aforementioned clinical 26
disease courses of neurological Wilson’s patients. The nonneurological patients exhibit normal pulserate values.42,48,49 In summary, SPECT findings prove that presynaptic and postsynaptic functions in the striatum are normal in the nonneurological cohort. Under decoppering drug therapy, nigrostriatal function remains unaffected in the further course of the disease. A symmetrically disturbed presynaptic and postsynaptic function in the nigrostriatal system is characteristic of neurological Wilson’s patients. Therapy can prevent progression with a tendency to even slightly improve function. Metabolic findings in [18 F]FDG-PET The radiopharmacon [18 F]FDG allows for a PET examination of the glucose metabolic rate both globally and regionally, using three-dimensional region-of-interest (ROI) technology.53,54 Values are compared with those for a healthy subject cohort.42,53,54 Initially, the glucose metabolic rate was calculated pixel by pixel using the modified Sokoloff model, for a representative entire horizontal cross section at the basal ganglia level (striatum).55 Subsequently, the glucose metabolic rate was ascertained in the following four regions: the caudate nucleus, putamen, thalamus, and cerebellum (dentate nucleus). In neurological Wilson’s patients, the glucose metabolic rate is significantly reduced throughout the entire horizontal cross section at the striatal level (cortical and basal ganglia). The glucose metabolic rate is also reduced in the four scrutinized regions. In the process, four different constellations of regionally disturbed glucose metabolic rates were identified within the neurological cohort.54 The area most severely and regularly affected is the caudate nucleus.40,53,54,56 Compared with the normal population, the reduction of the glucose metabolic rate is significant;57 however, no correlation to the clinical course types (PP, PS, H) is discernible.53 Nonetheless, a number of patterns of regional metabolic disturbances may hint to the variability of extrapyramidal motor symptoms.54 It was not possible to establish a genotype–phenotype relation based on the evidence of regional glucose metabolic-rate disturbances.42 In none of the regions do the nonneurological Wilson’s patients have a reduced glucose metabolic rate, which stands in stark contrast to the results for the neurological cohort.42,53
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Summary The four present imaging methods substantiate that all neurological Wilson’s patients are afflicted with morphological, physiological, and metabolic disturbances. MRI proves the most sensitive device, as it is the only imaging method that detects morphological changes even before the incidence of extrapyramidal motor symptoms, also in the nonneurological cohort. Overall, the imaging methods do not represent suitable diagnostic methods for the confirmation of Wilson’s disease, as they lack specificity. However, they do play a role in follow-up examination, the verification of therapy efficiency, and an early recognition of a continuous toxic impact of copper. The nuclear-medicine methods 123 I-IBZM-SPECT, and (123 I--CIT-SPECT, 18 [ F]FDG-PET) allow for a clear and unmistakable verification of functional deficits in the presence of neurological symptoms. The glucose metabolic rate data furnish evidence for cortical and subcortical disturbances with the focus being on the caudate nucleus. All Wilson’s patients were grouped into the following three categories according to the mutations identified in them: homozygote for H1069Q, compound heterozygote for H1069Q, and sundry mutations of both alleles.42 With an incidence of 65% in the examined cohort, H1069Q is the most common point mutation.42,58,59 The allocation of imaging data to these three genotypes fails to identify a genotype–phenotype correlation.20,42 Nor does any cerebral MRI or nuclear medicine data support the clinical classification according to Konovalov. All morphological and pathophysiological disturbances in the CNS appear to be predominantly due to the toxic impact of copper on the nerve cells. Conflicts of interest The author declares no conflicts of interest.
References ¨ 1. Str¨umpell, A. 1898. Uber die Westphal`sche Pseudosclerosis und u¨ ber diffuse Hirnsclerosis, insbesondere bei Kindern. Dtsch Z Nervenheilk. 12: 115–149. 2. Wilson, S.A.K. 1912. Progressive lenticular degeneration: a familiar nervous disease associated with cirrhosis of the liver. Brain 34: 259–509. 3. Roberts, E.A. & D.W. Cox. 1998. Wilson disease. Bailli`ere`s Clin. Gastroenterol. 12: 237–256.
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4. Hermann, W. 2012. Morbus Wilson. In Leitlinie f¨ur Diagnostik und Therapie in der Neurologie. 5th ed H.C. Diener et al., Eds.: 200–209. Stuttgart, Germany: Thieme. 5. Konovalov, N.V. 1960. Gepato-tserebralnaya distrofia. Moskva Medgiz. 6. L¨oßner, J., H. Bachmann, D. Biesold, et al. 1980. Untersuchungen zur Wilsonschen Erkrankung in der DDR. Teil II: pathogenese und Klinik. Z. gesamte Inn. Med. 35: 136–141. 7. Oder, W., L. Payer, G. Grimm, et al. 1993. Wilson´s disease: evidence of subgroups derived from clinical findings and brain lesions. Neurology 43: 120–124. 8. Dening, T.R. & G.E. Berrios. 1989. Wilson`s disease. Psychiatric symptoms in 195 cases. Arch. Gen. Psych. 46: 1126–1134. 9. Rathbun, J.K. 1996. Neuropsychological aspects of Wilson`s disease. Int. J. Neurosci. 85: 221–229. 10. Bull, P.C., G.R. Thomas, J.M. Rommens, et al. 1993. The Wilson disease gene is a putative copper transporting P-Type ATPase similar to the Menkes gene. Nat. Genet. 5: 327–337. 11. Petrushkin, K., S.G. Fischer, M. Piratsu, et al. 1993. Mapping, cloning and genetic characterization of the region containing the Wilson’s disease gene. Nat. Genet. 5: 338–343. 12. Yamaguchi, Y., M.E. Heiny & J.D. Gitlin 1993. Isolation and characterization of a human liver cDNA as a candidate gene for Wilson disease. Biocem. Biophyse. Res. Commun. 197: 271–277. 13. Maier-Dobersberger, T., P. Ferenci, C. Polli, et al. 1997. Detection of the His1069Gln mutation in Wilson disease by rapid polymerase chain reaction. Ann. Intern. Med. 127: 21–26. 14. Thomas, G.R., J.R. Forbes, E.A. Roberts, et al. 1995. The Wilson disease gene: spectrum of mutations and their consequences. Nat. Genet. 9: 210–217. 15. Houwen, R.H., J. Juyn, T.U. Hoogenraad, et al. 1995. H714Q mutation in Wilson disease is associated with late neurological presentation. J. Med. Genet. 32: 480–482. 16. Gollan, J.L. & T.J. Gollan. 1998. Wilson disease in 1998: genetic, diagnostic and therapeutic aspects. J. Hepatol. 28: 28–36. 17. Harada, M., S. Sakisaka, K. Terada, et al. 2001. A mutation of the Wilson disease protein, ATP7B, is degraded in the proteasomes and forms protein aggregates. Gastroenterology. 120: 967–974. 18. Hermann, W., P. G¨unther, J.P. Schneider, et al. 2006. Klinische und Genotyp-Ph¨anotyp-Korrelation epidemiologischer, bildgebender und neurologischer Befunde bei Patienten mit Morbus Wilson. Fortschr. Neurol. Psychiat. 74: 558–566. 19. Leggio, K., G. Addolorato, G. Loudianes, et al. 2006. Genotype-phenotype correlation of the Wilson disease ATP7B gene. Am. J. Med. Genet. A. 140: 933. 20. Hermann, W., P. G¨unther, H.J. K¨uhn, et al. 2007. FAEP und Morphometrie des Mesenzephalons bei Morbus Wilson. Aktuelle Neurologie. 34: 547–553. 21. Harris, Z.L. & J.D. Gitlin. 1996. Genetic and molecular basis for copper toxicity. Am. J. Clin. Nutr. 63: 836–841. 22. Rubin, R. & E. Rubin. 2008. The liver and biliary system. In Rubin’s Pathology. 5th ed. R. Rubin, D. Strayer, E. Rubin, J.M. McDonald, G.K. Michalopoulos, J.Q. Trojanowski, P.A.
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the conscious and anesthetized albino rat. J. Neurochem. 28: 897–916. 56. Hawkins, R.A., J.C. Mazziotta & M.E. Phelps. 1987. Wilson´s disease studied with FDG and positron emission tomography. Neurology 37: 1707–1711. 57. Kuwert, T., H. Hefter, D. Scholz, et al. 1992. Regional cerebral glucose consumption measured by positron emission tomography in patients with Wilson´s disease. Eur. J. Nucl. Med. 19: 96–101.
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58. Czlonkowska, A., M. Rodo, J. Gajda, et al. 1997. Verv high frequnecy of the His1069Gln mutation in Polish Wilson disease patients. J. Neurol. 244: 591– 592. 59. Maier-Dobersberger, T., P. Ferenci, C. Polli, et al. 1997. Detection of the His1069Gln mutation in Wilson disease by rapid polymerase chain raction. Ann. Intern. Med. 127: 21–26.
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A N N A L S O F T H E N E W Y O R K A C A D E M Y O F SC I E N C E S Issue: Human Disorders of Copper Metabolism II
Morphological and functional imaging in neurological and non-neurological Wilson’s patients Wieland Hermann Department of Neurology, Paracelsus Clinic Zwickau, Zwickau, Germany Address for correspondence: Wieland Hermann, Paracelsus Clinic Zwickau, Department of Neurology, Werdauer Str. 68, D-0860 Zwickau, Germany. [email protected]
Wilson’s disease causes disturbances of the central nervous system, affecting it both directly through copper toxicity and indirectly subject to a copper-induced hepatopathy, resulting in morphological and physiological changes in brain structures that can be captured by means of magnetic resonance imaging (MRI), 123 I--CIT (2-carbomethoxy-3 (4-iodophenyl)tropane)-SPECT (single photon emission computed tomography), 123 I-IBZM (benzamide)-SPECT and [18 F]FDG -PET (fluorodeoxyglucose–positron emission tomography). MRI can reveal even slight morphological changes in non-neurological Wilson’s patients. More marked findings in neurological Wilson’s patients become evident in T1- and T2-weighted MRI. T1-weighted MRI predominantly detects atrophic changes, whereas T2weighted MRI regularly records signal changes in the putamen. With the aid of these three nuclear-medicine examinations, nigrostriatal and metabolic disturbances are identified in neurological Wilson’s patients only. Sufficient decoppering therapy prevents progression and even tends to improve symptoms. A correlation between any of the imaging findings in patients with the genetic phenotype and the incidence of the most common mutation H1069Q (homozygote or compound heterozygote) or other mutations could not be substantiated. Keywords: Wilson’s disease; MRI; 123 I--CIT-SPECT; 123 I-IBZM-SPECT; [18 F]FDG-PET
Introduction As early as in 1898, Str¨umpell named Wilson’s disease, a genetically caused copper storage disease, hepatolenticular degeneration.1 Thus, he identified and correlated the basic pathoanatomical changes for which S.A.K. Wilson established a clinical– pathophysiological correlation.2 In clinical terms, hepatic symptoms appear alongside a variety of neurological findings,3,4 which initially resulted in a classification based on symptoms. It was Konovalov5 who devised the following distinctive clinical classification, modified by L¨ossner and Bachmann:6 a neurological disease course, including pseudoparkinsonism type (PP), pseudosclerosis type (PS), and arrhythmic hyperkinetic type (hybrid, H); and a nonneurological disease course, including asymptomatic type and hepatic type. Oder et al. also suggested a distinction of the neurological disease course into three subgroups comparable to the classification above, based on cardinal extrapyramidal motor symptoms such as bradykinesia, rigor, ataxia, tremor, dystonia, and
dysarthria, as well as cognitive and psychiatric disturbances. While in a clinical setting, the only distinction made is between neurological and nonneurological disease courses, some authors also distinguish a psychiatric form of Wilson’s disease.8,9 Following the discovery of the Wilson gene in 1993,10–12 the sheer variety of genetic mutations gave rise to the discussion of a genotype–phenotype correlation.13–15 However, some authors do not discern any verified correlation.16–20 Modern imaging methods have facilitated an increasingly accurate examination of the cerebral pathoanatomy and pathophysiology. To review clinical and genetic classification attempts, morphological and nuclear medicine parameters of the central nervous system (CNS) were analyzed. Cellular pathophysiology and pathoanatomy in the nervous system Direct effects of copper toxicity Examinations of liver cells for copper toxicity focused on the formation of free radicals and the doi: 10.1111/nyas.12343
24
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inactivation of vital enzymes.21–23 Both lead especially to lysosomal and mitochondrial damage.24 In addition to lipid peroxidation, the mitochondrial respiratory chain is affected and protein biosynthesis is disturbed.25 The reduction in antioxidants diminishes the potential to repair cells. It can be assumed that following the redistribution of copper in the nerve cells, the same intercellular mechanisms lead to apoptosis or cell death, respectively. Thus, nerve cells are subject to direct copper toxicity. While under physiological conditions concentrations of copper can be found in the locus coeruleus and substantia nigra, in Wilson’s disease patients increased copper concentrations occur in all areas of the brain.26 Notwithstanding, vulnerability can be quite variable and predominantly affects the basal ganglia and cerebellar core areas.18,26 The area with the highest copper concentrations and the most pronounced lesions and astrocytic reactions is the putamen.26 In neuropathological terms, general brain atrophy is not obligatory; however, very often insular, cortical, cerebellar, and putamenal atrophy are present.27,28 Patients with the neurological type of Wilson’s disease are also afflicted with degeneration of the midbrain.29 Indirect effects of copper toxicity While the damage to neurons is presumed to be predominantly due to direct copper toxicity, there are glial abnormalities which point to hepatic insufficiency and therefore to the indirect effects of copper toxicity. Pathoanatomical examinations furnish ample proof of the incidence of typical astrocyte degeneration (Alzheimer type II glia) in Wilson’s disease in analogy to hepatopathies of different genesis.30,31 The degeneration manifests itself in cell enlargement, loss or plumpness of dendrites, and a hyperchromatic nucleus with central hypochromasia (vesicular nucleus).30 Furthermore, Alzheimer type I glia and Opalski cells with fine granular PAS+ cytoplasm occur as unspecific glia degeneration.32 The oligodendroglia appear to be decimated. Moreover, cytotoxic cell edemas are present.33 This leads to spongiform changes in the striatum, dentate nucleus, and cortical areas.33,34
Imaging in Wilson’s disease
Morphological MRI findings in the CNS Damage to the nervous system is thus caused both directly by copper toxicity and indirectly by hepatic encephalopathy.35 In T1-weighted MRI, symmetrical hypertension is described as a characteristic finding in hepatic encephalopathy. It is present in the globus pallidus and the putamen, with affection of the hypothalamus and midbrain as the disease progresses.36–38 Pathogenetically, this is attributed to a slight astrocytic edema and manganese deposits.36,39 However, in Wilson’s patients under stable therapy and compensated hepatic function, the morphological changes often go beyond this and persist. In T1-weighted images of patients in the neurological cohort, they frequently become manifest as slight signal changes in the basal ganglia and cerebellar regions (putamen, globus pallidus, substantia nigra, red nucleus, cerebellar nuclei) as well as in the pons.28 By contrast, there are regular occurrences of cerebral, cerebellar, putamenal, and mesencephalic atrophy in neurological patients compared to healthy subjects.20,28,29,40 In nonneurological Wilson’s patients, slight cerebral and cerebellar atrophic changes are also regularly present, and there are single cases with slight signal changes in the substantia nigra and the red nucleus.41,42 In the context of differential diagnostics, one must also always consider the presence of mild hepatic encephalopathy. In T2-weighted images, all neurological Wilson’s patients show signal changes in the putamen, while the other basal ganglia structures are only infrequently affected by lesions.28,40 Slight putamenal signal changes in T2-weighted MRI are also characteristic of nonneurological Wilson’s patients. The lesion pattern in the putamen corresponds to spongiform dystrophy.27 Within the neurological cohort, there were no discernible differences between the clinical disease courses (PP, PS, H) in either T1- or T2-weighted MRI data. We must emphasise the fact that even the nonneurological patients can exhibit slight lesion patterns despite the absence of neurological symptoms. Nevertheless, under morphological imaging aspects, significant differences between the neurological and nonneurological disease courses are apparent in both the severity of signal changes and the frequency of their incidence.41,42 This may
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correspond to a gradual conversion of a hepatic to a neurological disease course following the release of free copper from apoptotic liver cells. Manifestation takes place only once the neuronal and glia compensation ability has been exhausted. Potentially, there is a parallel to other neurodegenerative disorders, such as Parkinson’s disease, where extrapyramidal motor symptoms only become manifest following a dopaminergic cell loss of 50–70% in the substantia nigra pars compacta.43 Pathophysiological findings in the nigrostriatal system 123
I-β-CIT-SPECT The radiopharmacon 123 I--CIT, a cocaine analogue, binds to the dopamine transporter of the presynaptic nerve endings of nigrostriatal neurons in the striatum.44 The 123 I--CIT binding in the cerebellum at a normal ratio of 11.7 ± 2.8 (striatal/ cerebellar pulse rate ratio) serves as reference value.45 The pulse rate coefficient for the nonneurological cohort is normal, with values remaining stable under drug therapy throughout the course of the disease.41,42,46 Therefore, nigrostriatal dopaminergic projection can be considered intact in these Wilson’s patients. However, neurological Wilson’s patients show a symmetrically reduced pulse rate in the striatum, with putamenal accentuation corresponding to a disturbed nigrostriatal function.42,45–48 No significant differences among the three neurological disease types (PP, PS, H) could be detected.45 There is evidence that the pulse rate tends to improve under sufficient decoppering drug therapy administered over a course of 4 years.41,42 123
I-IBZM-SPECT The radioactively marked benzamide 123 I-IBZM is a selective dopamine D2 receptor antagonist.49,50 Its binding to striatal dopamine receptors can be captured by means of SPECT and represents a measure for their density and the integrity of postsynaptic neurons.49,51 The pulse rate is measured and related to values for the frontal cortex. In healthy subjects, this ratio is 2.0 ± 0.19 (striatal/frontal pulse rate ratio).48 All neurological Wilson’s patients have a reduced pulse rate in the striatum.42,48,52 Under therapy, this value remains stable. The 123 I-IBZM findings do not allow for distinction between the aforementioned clinical 26
disease courses of neurological Wilson’s patients. The nonneurological patients exhibit normal pulserate values.42,48,49 In summary, SPECT findings prove that presynaptic and postsynaptic functions in the striatum are normal in the nonneurological cohort. Under decoppering drug therapy, nigrostriatal function remains unaffected in the further course of the disease. A symmetrically disturbed presynaptic and postsynaptic function in the nigrostriatal system is characteristic of neurological Wilson’s patients. Therapy can prevent progression with a tendency to even slightly improve function. Metabolic findings in [18 F]FDG-PET The radiopharmacon [18 F]FDG allows for a PET examination of the glucose metabolic rate both globally and regionally, using three-dimensional region-of-interest (ROI) technology.53,54 Values are compared with those for a healthy subject cohort.42,53,54 Initially, the glucose metabolic rate was calculated pixel by pixel using the modified Sokoloff model, for a representative entire horizontal cross section at the basal ganglia level (striatum).55 Subsequently, the glucose metabolic rate was ascertained in the following four regions: the caudate nucleus, putamen, thalamus, and cerebellum (dentate nucleus). In neurological Wilson’s patients, the glucose metabolic rate is significantly reduced throughout the entire horizontal cross section at the striatal level (cortical and basal ganglia). The glucose metabolic rate is also reduced in the four scrutinized regions. In the process, four different constellations of regionally disturbed glucose metabolic rates were identified within the neurological cohort.54 The area most severely and regularly affected is the caudate nucleus.40,53,54,56 Compared with the normal population, the reduction of the glucose metabolic rate is significant;57 however, no correlation to the clinical course types (PP, PS, H) is discernible.53 Nonetheless, a number of patterns of regional metabolic disturbances may hint to the variability of extrapyramidal motor symptoms.54 It was not possible to establish a genotype–phenotype relation based on the evidence of regional glucose metabolic-rate disturbances.42 In none of the regions do the nonneurological Wilson’s patients have a reduced glucose metabolic rate, which stands in stark contrast to the results for the neurological cohort.42,53
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Summary The four present imaging methods substantiate that all neurological Wilson’s patients are afflicted with morphological, physiological, and metabolic disturbances. MRI proves the most sensitive device, as it is the only imaging method that detects morphological changes even before the incidence of extrapyramidal motor symptoms, also in the nonneurological cohort. Overall, the imaging methods do not represent suitable diagnostic methods for the confirmation of Wilson’s disease, as they lack specificity. However, they do play a role in follow-up examination, the verification of therapy efficiency, and an early recognition of a continuous toxic impact of copper. The nuclear-medicine methods 123 I-IBZM-SPECT, and (123 I--CIT-SPECT, 18 [ F]FDG-PET) allow for a clear and unmistakable verification of functional deficits in the presence of neurological symptoms. The glucose metabolic rate data furnish evidence for cortical and subcortical disturbances with the focus being on the caudate nucleus. All Wilson’s patients were grouped into the following three categories according to the mutations identified in them: homozygote for H1069Q, compound heterozygote for H1069Q, and sundry mutations of both alleles.42 With an incidence of 65% in the examined cohort, H1069Q is the most common point mutation.42,58,59 The allocation of imaging data to these three genotypes fails to identify a genotype–phenotype correlation.20,42 Nor does any cerebral MRI or nuclear medicine data support the clinical classification according to Konovalov. All morphological and pathophysiological disturbances in the CNS appear to be predominantly due to the toxic impact of copper on the nerve cells. Conflicts of interest The author declares no conflicts of interest.
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