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.
- Klíčová slova
- MRI, Wilson disease, brain atrophy, brainstem, hepatic, morphometry, white matter,
- MeSH
- bílá hmota patologie diagnostické zobrazování MeSH
- dospělí MeSH
- hepatolentikulární degenerace * patologie diagnostické zobrazování MeSH
- játra patologie diagnostické zobrazování MeSH
- lidé středního věku MeSH
- lidé MeSH
- magnetická rezonanční tomografie * MeSH
- mladý dospělý MeSH
- mozek * patologie diagnostické zobrazování MeSH
- šedá hmota patologie diagnostické zobrazování MeSH
- studie případů a kontrol MeSH
- Check Tag
- dospělí MeSH
- lidé středního věku MeSH
- lidé MeSH
- mladý dospělý MeSH
- mužské pohlaví MeSH
- ženské pohlaví MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
BACKGROUND AND OBJECTIVES: Noninvasive and accurate biomarkers of neurologic Wilson disease (NWD), a rare inherited disorder, could reduce diagnostic error or delay. Excessive subcortical metal deposition seen on susceptibility imaging has suggested a characteristic pattern in NWD. With submillimeter spatial resolution and increased contrast, 7T susceptibility-weighted imaging (SWI) may enable better visualization of metal deposition in NWD. In this study, we sought to identify a distinctive metal deposition pattern in NWD using 7T SWI and investigate its diagnostic value and underlying pathophysiologic mechanism. METHODS: Patients with WD, healthy participants with monoallelic ATP7B variant(s) on a single chromosome, and health controls (HCs) were recruited. NWD and non-NWD (nNWD) were defined according to the presence or absence of neurologic symptoms during investigation. Patients with other diseases with comparable clinical or imaging manifestations, including early-onset Parkinson disease (EOPD), multiple system atrophy (MSA), progressive supranuclear palsy (PSP), and neurodegeneration with brain iron accumulation (NBIA), were additionally recruited and assessed for exploratory comparative analysis. All participants underwent 7T T1, T2, and high-resolution SWI scanning. Quantitative susceptibility mapping and principal component analysis were performed to illustrate metal distribution. RESULTS: We identified a linear signal intensity change consisting of a hyperintense strip at the lateral border of the globus pallidus in patients with NWD. We termed this feature "hyperintense globus pallidus rim sign." This feature was detected in 38 of 41 patients with NWD and was negative in all 31 nNWD patients, 15 patients with EOPD, 30 patients with MSA, 15 patients with PSP, and 12 patients with NBIA; 22 monoallelic ATP7B variant carriers; and 41 HC. Its sensitivity to differentiate between NWD and HC was 92.7%, and specificity was 100%. Severity of the hyperintense globus pallidus rim sign measured by a semiquantitative scale was positively correlated with neurologic severity (ρ = 0.682, 95% CI 0.467-0.821, p < 0.001). Patients with NWD showed increased susceptibility in the lenticular nucleus with high regional weights in the lateral globus pallidus and medial putamen. DISCUSSION: The hyperintense globus pallidus rim sign showed high sensitivity and excellent specificity for diagnosis and differential diagnosis of NWD. It is related to a special metal deposition pattern in the lenticular nucleus in NWD and can be considered as a novel neuroimaging biomarker of NWD. CLASSIFICATION OF EVIDENCE: The study provides Class II evidence that the hyperintense globus pallidus rim sign on 7T SWI MRI can accurately diagnose neurologic WD.
- MeSH
- ATPasy transportující měď metabolismus genetika MeSH
- dospělí MeSH
- globus pallidus diagnostické zobrazování metabolismus MeSH
- hepatolentikulární degenerace * diagnostické zobrazování metabolismus MeSH
- lidé středního věku MeSH
- lidé MeSH
- magnetická rezonanční tomografie * metody MeSH
- měď metabolismus MeSH
- mladiství MeSH
- mladý dospělý MeSH
- mozek diagnostické zobrazování metabolismus MeSH
- Check Tag
- dospělí MeSH
- lidé středního věku MeSH
- lidé MeSH
- mladiství MeSH
- mladý dospělý MeSH
- mužské pohlaví MeSH
- ženské pohlaví MeSH
- Publikační typ
- časopisecké články MeSH
- Názvy látek
- ATP7B protein, human MeSH Prohlížeč
- ATPasy transportující měď MeSH
- měď MeSH
Background Abnormal findings at brain MRI in patients with neurologic Wilson disease (WD) are characterized by signal intensity changes and cerebral atrophy. T2 signal hypointensities and atrophy are largely irreversible with treatment; their relationship with permanent disability has not been systematically investigated. Purpose To investigate associations of regional brain atrophy and iron accumulation at MRI with clinical severity in participants with neurologic WD who are undergoing long-term anti-copper treatment. Materials and Methods Participants with WD and controls were compared in a prospective study performed from 2015 to 2019. MRI at 3.0 T included three-dimensional T1-weighted and six-echo multigradient-echo pulse sequences for morphometry and quantitative susceptibility mapping, respectively. Neurologic severity was assessed with the Unified WD Rating Scale (UWDRS). Automated multi-atlas segmentation pipeline with dual contrast (susceptibility and T1) was used for the calculation of volumes and mean susceptibilities in deep gray matter nuclei. Additionally, whole-brain analysis using deformation and surface-based morphometry was performed. Least absolute shrinkage and selection operator regression was used to assess the association of regional volumes and susceptibilities with the UWDRS score. Results Twenty-nine participants with WD (mean age, 47 years ± 9 [standard deviation]; 15 women) and 26 controls (mean age, 45 years ± 12; 14 women) were evaluated. Whole-brain analysis demonstrated atrophy of the deep gray matter nuclei, brainstem, internal capsule, motor cortex and corticospinal pathway, and visual cortex and optic radiation in participants with WD (P < .05 at voxel level, corrected for family-wise error). The UWDRS score was negatively correlated with volumes of putamen (r = -0.63, P < .001), red nucleus (r = -0.58, P = .001), globus pallidus (r = -0.53, P = .003), and substantia nigra (r = -0.50, P = .006) but not with susceptibilities. Only the putaminal volume was identified as a stable factor associated with the UWDRS score (R2 = 0.38, P < .001) using least absolute shrinkage and selection operator regression. Conclusion Individuals with Wilson disease (WD) had widespread brain atrophy most pronounced in the central structures. The putaminal volume was associated with the Unified WD Rating Scale score and can be used as a surrogate imaging marker of clinical severity. © RSNA, 2021 Supplemental material is available for this article. See also the editorial by Du and Bydder in this issue.
- MeSH
- atrofie MeSH
- hepatolentikulární degenerace diagnostické zobrazování farmakoterapie metabolismus patologie MeSH
- lidé středního věku MeSH
- lidé MeSH
- magnetická rezonanční tomografie metody MeSH
- mozek diagnostické zobrazování metabolismus patologie MeSH
- prospektivní studie MeSH
- studie případů a kontrol MeSH
- stupeň závažnosti nemoci MeSH
- železo metabolismus MeSH
- Check Tag
- lidé středního věku MeSH
- lidé MeSH
- mužské pohlaví MeSH
- ženské pohlaví MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
- Názvy látek
- železo MeSH
BACKGROUND: MRI is a sensitive method for the assessment of brain abnormalities in Wilson disease, that is, T2 hyperintensities, T2 hypointensities, and atrophy, but a validated scoring system for the classification of radiological severity is lacking. The objective of this study was to develop and validate a brain MRI visual rating scale for Wilson disease. METHODS: The proposed Wilson disease brain MRI severity scale consists of acute toxicity and chronic damage subscores from predefined structures. The former, calculated by summing scores of T2 hyperintensities (excluding cavitation), is likely to be partially reversible with treatment. The latter, representing the sum of scores of T2 hypointensities and brain atrophy, reflects pathology that is not readily reversible. Validation was performed on MRI scans acquired using 1.5T system from 39 Wilson disease patients examined at baseline and after 24 months on anticopper treatment. Intraclass correlation coefficients of 5 ratings from 3 raters were calculated. Temporal evolution of the MRI severity score and its association with clinical severity, assessed using the Unified Wilson Disease Rating Scale part III, was calculated. RESULTS: Intrarater and interrater agreement were good (r > 0.93; P < 0.001; and r > 0.74; P < 0.001, respectively). In neurologic Wilson disease patients, the total MRI severity score improved over 2 years (P = 0.032), mainly because of reduced acute toxicity (P = 0.0015), whereas the chronic damage score deteriorated (P = 0.035). Unified Wilson Disease Rating Scale part III score was positively associated with chronic damage and total score at baseline (P = 0.005 and P = 0.003, respectively) and in month 24 (P < 0.001 and P = 0.001, respectively). CONCLUSIONS: The Wilson disease brain MRI severity scale is a simple, reliable, and valid instrument that allows semiquantitative assessment of radiological Wilson disease severity. © 2020 International Parkinson and Movement Disorder Society.
- Klíčová slova
- MRI, Wilson disease, clinical scales, neuroradiology,
- MeSH
- hepatolentikulární degenerace * diagnostické zobrazování MeSH
- lidé MeSH
- magnetická rezonanční tomografie MeSH
- mozek diagnostické zobrazování MeSH
- nemoci mozku * MeSH
- reprodukovatelnost výsledků MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
BACKGROUND: In Wilson's disease (WD), demyelination, rarefaction, gliosis, and iron accumulation in the deep gray matter cause opposing effects on T2 -weighted MR signal. However, the degree and interplay of these changes in chronically treated WD patients has not been quantitatively studied. PURPOSE: To compare differences in brain multiparametric mapping between controls and chronically treated WD patients with neurological (neuro-WD) and hepatic (hep-WD) forms to infer the nature of residual WD neuropathology. STUDY TYPE: Cross-sectional. POPULATION/SUBJECTS: Thirty-eight WD patients (28 neuro-WD, 10 hep-WD); 26 healthy controls. FIELD STRENGTH/SEQUENCE: 3.0T: susceptibility, T2 *, T2 , T1 relaxometry; 1.5T: T2 , T1 relaxometry. ASSESSMENT: The following 3D regions of interest (ROIs) were manually segmented: globus pallidus, putamen, caudate nucleus, and thalamus. Mean bulk magnetic susceptibility, T2 *, T2 , and T1 relaxation times were calculated for each ROI. STATISTICAL TESTS: The effect of group (neuro-WD, hep-WD, controls) and age was assessed using a generalized least squares model with different variance for each ROI and quantitative parameter. A general linear hypothesis test with Tukey adjustment was used for post-hoc between-group analysis; P < 0.05 was considered significant. RESULTS: Susceptibility values were higher in all ROIs in neuro-WD compared to controls and hep-WD (P < 0.001). In basal ganglia, lower T2 and T2 * were found in neuro-WD compared to controls (P < 0.01) and hep-WD (P < 0.05) at 3.0T. Much smaller intergroup differences for T2 in basal ganglia were observed at 1.5T compared to 3.0T. In the thalamus, increased susceptibility in neuro-WD was accompanied by increased T1 at both field strengths (P < 0.001 to both groups), and an increased T2 at 1.5T only (P < 0.001 to both groups). DATA CONCLUSION: We observed significant residual brain MRI abnormalities in neuro-WD but not in hep-WD patients on chronic anticopper treatment. Patterns of changes were suggestive of iron accumulation in the basal ganglia and demyelination in the thalamus; 3.0T was more sensitive for detection of the former and 1.5T of the latter abnormality. LEVEL OF EVIDENCE: 2 Technical Efficacy Stage: 3 J. Magn. Reson. Imaging 2020;51:1829-1835.
- Klíčová slova
- Wilson's disease, brain, magnetic resonance imaging, quantitative susceptibility mapping, relaxation time,
- MeSH
- hepatolentikulární degenerace * diagnostické zobrazování MeSH
- lidé MeSH
- magnetická rezonanční tomografie MeSH
- mapování mozku MeSH
- mozek diagnostické zobrazování MeSH
- průřezové studie MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
Transcranial sonography (TCS) can reveal pathology in brain structures including insula. This study compared insula echogenicity among 22 patients with Wilson's disease (WD), 21 patients with early-onset Parkinson's disease (EO-PD) and 24 healthy patients. Echogenicity of predefined brain structures (insula, lentiform nucleus, caudate nucleus, substantia nigra and raphe nuclei) was evaluated using digitized analysis of TCS fusion imaging with magnetic resonance. Cortical, subcortical and cerebellar atrophy and ventricle diameters were determined from magnetic resonance images. The mean echogenicity index of insula did not differ between males and females (p = 0.92), but the echogenicity of insula was higher in patients with WD than in patients with EO-PD and healthy patients (p < 0.05). The substantia nigra echogenicity was higher in patients with EO-PD, and lentiform nucleus echogenicity was higher in patients with WD (p < 0.05). The echogenicity of insula correlated with lentiform nucleus echogenicity (r = 0.75) but not with age (r = -0.14), disease duration (r = -0.36), symptom severity (r = 0.28), cortical (r = 0.11) nor subcortical (r = 0.05) atrophy.
- Klíčová slova
- Echogenicity, Magnetic resonance, Parkinson's disease, Transcranial sonography, Wilson's disease,
- MeSH
- dospělí MeSH
- hepatolentikulární degenerace diagnostické zobrazování MeSH
- lidé středního věku MeSH
- lidé MeSH
- magnetická rezonanční tomografie * MeSH
- mozek diagnostické zobrazování MeSH
- mozková kůra diagnostické zobrazování MeSH
- multimodální zobrazování MeSH
- Parkinsonova nemoc diagnostické zobrazování MeSH
- ultrasonografie dopplerovská transkraniální * MeSH
- Check Tag
- dospělí MeSH
- lidé středního věku MeSH
- lidé MeSH
- mužské pohlaví MeSH
- ženské pohlaví MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
- srovnávací studie MeSH
5 Technical Efficacy: Stage 3 J. Magn. Reson. Imaging 2018;47:282-285.
- Klíčová slova
- Wilson's disease, iron accumulation, relaxometry, transcranial sonography, ultra-high field MRI,
- MeSH
- časové faktory MeSH
- chelátory škodlivé účinky terapeutické užití MeSH
- dospělí MeSH
- hepatolentikulární degenerace diagnostické zobrazování farmakoterapie metabolismus MeSH
- lidé MeSH
- longitudinální studie MeSH
- magnetická rezonanční tomografie MeSH
- měď analýza MeSH
- mladiství MeSH
- mladý dospělý MeSH
- penicilamin škodlivé účinky terapeutické užití MeSH
- počítačové zpracování obrazu MeSH
- šedá hmota diagnostické zobrazování účinky léků MeSH
- studie případů a kontrol MeSH
- tkáňová distribuce MeSH
- ultrasonografie dopplerovská transkraniální MeSH
- železo analýza terapeutické užití MeSH
- Check Tag
- dospělí MeSH
- lidé MeSH
- mladiství MeSH
- mladý dospělý MeSH
- mužské pohlaví MeSH
- ženské pohlaví MeSH
- Publikační typ
- časopisecké články MeSH
- kazuistiky MeSH
- práce podpořená grantem MeSH
- Názvy látek
- chelátory MeSH
- měď MeSH
- penicilamin MeSH
- železo MeSH
AIMS: In Wilson disease (WD), T2/T2*-weighted (T2*w) MRI frequently shows hypointensity in the basal ganglia that is suggestive of paramagnetic deposits. It is currently unknown whether this hypointensity is related to copper or iron deposition. We examined the neuropathological correlates of this MRI pattern, particularly in relation to iron and copper concentrations. METHODS: Brain slices from nine WD and six control cases were investigated using a 7T-MRI system. High-resolution T2*w images were acquired and R2* parametric maps were reconstructed using a multigradient recalled echo sequence. R2* was measured in the globus pallidus (GP) and the putamen. Corresponding histopathological sections containing the lentiform nucleus were examined using Turnbull iron staining, and double staining combining Turnbull with immunohistochemistry for macrophages or astrocytes. Quantitative densitometry of the iron staining as well as copper and iron concentrations were measured in the GP and putamen and correlated with R2* values. RESULTS: T2*w hypointensity in the GP and/or putamen was apparent in WD cases and R2* values correlated with quantitative densitometry of iron staining. In WD, iron and copper concentrations were increased in the putamen compared to controls. R2* was correlated with the iron concentration in the GP and putamen, whereas no correlation was observed for the copper concentration. Patients with more pronounced pathological severity in the putamen displayed increased iron concentration, which correlated with an elevated number of iron-containing macrophages. CONCLUSIONS: T2/T2*w hypointensity observed in vivo in the basal ganglia of WD patients is related to iron rather than copper deposits.
- Klíčová slova
- Wilson disease, brain, iron accumulation, pathology, post mortem 7T MRI,
- MeSH
- astrocyty MeSH
- bazální ganglia diagnostické zobrazování metabolismus patologie MeSH
- corpus striatum metabolismus patologie MeSH
- dospělí MeSH
- hepatolentikulární degenerace diagnostické zobrazování metabolismus patologie MeSH
- lidé středního věku MeSH
- lidé MeSH
- magnetická rezonanční tomografie MeSH
- makrofágy MeSH
- měď metabolismus MeSH
- mladý dospělý MeSH
- železo metabolismus MeSH
- Check Tag
- dospělí MeSH
- lidé středního věku MeSH
- lidé MeSH
- mladý dospělý MeSH
- mužské pohlaví MeSH
- ženské pohlaví MeSH
- Publikační typ
- časopisecké články MeSH
- Názvy látek
- měď MeSH
- železo MeSH
INTRODUCTION: Wilson's disease (WD) is a hereditary disorder caused by ATP7B mutations resulting in systemic copper accumulation. WD may manifest as early-adulthood parkinsonism; and atypical cases may be difficult to distinguish from early-onset Parkinson's disease (EO-PD), a neurodegenerative disorder with onset ≤40 years of age. The aim of our study was to compare transcranial sonography (TCS)-magnetic resonance fusion imaging in WD and EO-PD and examine whether TCS can provide clinically useful information. METHODS: We examined 22 WD, 16 EO-PD, and 24 healthy control subjects. We measured echogenicity and determined presence of MRI signal changes in T2-weighted images in the substantia nigra (SN) and lentiform nucleus (NL). TCS with the capability of magnetic resonance fusion and Virtual Navigator was used. The echogenicity indices of SN and NL were processed using digital image analysis to eliminate subjective evaluation errors. RESULTS: Mean SN echogenicity index in EO-PD (39.8 ± 5.9 [SD]) was higher compared to WD (28.0 ± 4.6, p < 0.0001) and control subjects (28.8 ± 4.9, p < 0.0001). Mean NL echogenicity index was higher in WD (117.5 ± 37.0) compared to EO-PD (61.6 ± 5.4, p < 0.0001) and control subjects (54.9 ± 11.2, p < 0.0001). The SN hyperechogenicity had sensitivity 93.8%, and specificity 90.9%, while the NL hyperechogenicity had sensitivity 95.5% and specificity 93.8% for differentiation of WD and EO-PD. NL hyperechogenicity was more pronounced in WD subjects with putaminal MRI T2 hyperintensity (p < 0.05) but was also present in subjects without MRI abnormality. CONCLUSIONS: There are distinct TCS findings in WD and EO-PD complementary to MRI that can be utilized as highly sensitive and specific biomarkers of these disorders.
- Klíčová slova
- Copper, Early-onset Parkinson's disease, MRI, Transcranial sonography, Wilson's disease,
- MeSH
- biologické markery MeSH
- corpus striatum diagnostické zobrazování MeSH
- dospělí MeSH
- hepatolentikulární degenerace diagnostické zobrazování MeSH
- lidé středního věku MeSH
- lidé MeSH
- magnetická rezonanční tomografie normy MeSH
- multimodální zobrazování MeSH
- Parkinsonova nemoc diagnostické zobrazování MeSH
- senzitivita a specificita MeSH
- ultrasonografie dopplerovská transkraniální normy MeSH
- Check Tag
- dospělí MeSH
- lidé středního věku MeSH
- lidé MeSH
- mužské pohlaví MeSH
- ženské pohlaví MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
- srovnávací studie MeSH
- Názvy látek
- biologické markery MeSH
