Paramagnetic Metal Accumulation in the Deep Gray Matter Nuclei Is Associated With Neurodegeneration in Wilson’s Disease

Yuan, Xiang Zhen; Li, Gai Ying; Chen, Jia Lin; Li, Jian Qi; Wang, Xiaoping

doi:10.3389/fnins.2020.573633

Cited by 11 publications

(9 citation statements)

References 51 publications

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“…Consistent with previous studies ( Yuan et al, 2020 ; Dusek et al, 2021 ), we observed increased susceptibility in the bilateral PU, bilateral GP and right TH in WD patients. As for the nature of the susceptibility change of subcortical nuclei in WD patients, both iron and copper accumulation should be taken into consideration.…”

Section: Discussionsupporting

confidence: 93%

Microstructural and functional impairment of the basal ganglia in Wilson’s disease: a multimodal neuroimaging study

Zhang

et al. 2023

Front. Neurosci.

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ObjectivesMagnetic susceptibility changes in brain MRI of Wilson’s disease (WD) patients have been described in subcortical nuclei especially the basal ganglia. The objectives of this study were to investigate its relationship with other microstructural and functional alterations of the subcortical nuclei and the diagnostic utility of these MRI-related metrics.MethodsA total of 22 WD patients and 20 healthy controls (HCs) underwent 3.0T multimodal MRI scanning. Susceptibility, volume, diffusion microstructural indices and whole-brain functional connectivity of the putamen (PU), globus pallidus (GP), caudate nucleus (CN), and thalamus (TH) were analyzed. Receiver operating curve (ROC) was applied to evaluate the diagnostic value of the imaging data. Correlation analysis was performed to explore the connection between susceptibility change and microstructure and functional impairment of WD and screen for neuroimaging biomarkers of disease severity.ResultsWilson’s disease patients demonstrated increased susceptibility in the PU, GP, and TH, and widespread atrophy and microstructural impairments in the PU, GP, CN, and TH. Functional connectivity decreased within the basal ganglia and increased between the PU and cortex. The ROC model showed higher diagnostic value of isotropic volume fraction (ISOVF, in the neurite orientation dispersion and density imaging model) compared with susceptibility. Severity of neurological symptoms was correlated with volume and ISOVF. Susceptibility was positively correlated with ISOVF in GP.ConclusionMicrostructural impairment of the basal ganglia is related to excessive metal accumulation in WD. Brain atrophy and microstructural impairments are useful neuroimaging biomarkers for the neurological impairment of WD.

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Section: Discussionsupporting

confidence: 93%

Microstructural and functional impairment of the basal ganglia in Wilson’s disease: a multimodal neuroimaging study

Zhang

et al. 2023

Front. Neurosci.

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“… 21 , 46 , 66 , 67 Susceptibility values in these areas are higher in patients with neurological than hepatic presentations, 25 , 26 , 67 , 68 and correlate with UWDRS scores in some reports but not others. 46 , 69 , 70 In a post-mortem 7 T MRI study, Dusek et al . 16 demonstrated that increased susceptibility in the caudate, putamen and pallidum corresponds to increased iron but not copper content.…”

Section: Discussionmentioning

confidence: 99%

Neuroimaging correlates of brain injury in Wilson’s disease: a multimodal, whole-brain MRI study

Shribman

Bocchetta

Sudre

et al. 2021

Brain

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Wilson’s disease is an autosomal-recessive disorder of copper metabolism with neurological and hepatic presentations. Chelation therapy is used to ‘de-copper’ patients but neurological outcomes remain unpredictable. A range of neuroimaging abnormalities have been described and may provide insights into disease mechanisms, in addition to prognostic and monitoring biomarkers. Previous quantitative MRI analyses have focussed on specific sequences or regions of interest, often stratifying chronically-treated patients according to persisting symptoms as opposed to initial presentation. In this cross-sectional study, we performed a combination of unbiased, whole-brain analyses on T1-weighted, fluid-attenuated inversion recovery, diffusion-weighted and susceptibility-weighted imaging data from 40 prospectively-recruited patients with Wilson’s disease (age range 16–68). We compared patients with neurological (n = 23) and hepatic (n = 17) presentations to determine the neuroradiological sequelae of the initial brain injury. We also subcategorized patients according to recent neurological status, classifying those with neurological presentations or deterioration in the preceding six months as having ‘active’ disease. This allowed us to compare patients with active (n = 5) and stable (n = 35) disease and identify imaging correlates for persistent neurological deficits and copper indices in chronically-treated, stable patients. Using a combination of voxel-based morphometry and region-of-interest volumetric analyses, we demonstrate that grey matter volumes are lower in the basal ganglia, thalamus, brainstem, cerebellum, anterior insula and orbitofrontal cortex when comparing patients with neurological and hepatic presentations. In chronically-treated, stable patients, the severity of neurological deficits correlated with grey matter volumes in similar, predominantly subcortical regions. In contrast, the severity of neurological deficits did not correlate with the volume of white matter hyperintensities, calculated using an automated lesion segmentation algorithm. Using tract-based spatial statistics, increasing neurological severity in chronically-treated patients was associated with decreasing axial diffusivity in white matter tracts whereas increasing serum non-caeruloplasmin-bound (‘free’) copper and active disease were associated with distinct patterns of increasing mean, axial and radial diffusivity. Whole-brain quantitative susceptibility mapping identified increased iron deposition in the putamen, cingulate and medial frontal cortices of patients with neurological presentations relative to those with hepatic presentations and neurological severity was associated with iron deposition in widespread cortical regions in chronically-treated patients. Our data indicate that composite measures of subcortical atrophy provide useful prognostic biomarkers, whereas abnormal mean, axial and radial diffusivity are promising monitoring biomarkers. Finally, deposition of brain iron in response to copper accumulation may directly contribute to neurodegeneration in Wilson’s disease.

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“…Patients with neurological WD signs and symptoms almost always present with magnetic resonance imaging (MRI) brain alterations. T1-weighted MRI predominantly detects atrophic changes while T2-weighted MRI records signal changes in the putamen [ 59 ]. The “face of the giant panda” sign present in the midbrain is considered a characteristic WD feature [ 60 ].…”

Section: Diagnostic Approach To Patients With Wilson’s Disease Suspicionmentioning

confidence: 99%

Wilson’s Disease: An Update on the Diagnostic Workup and Management

Kasztelan-Szczerbińska

Cichoż‐Lach

2021

JCM

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Wilson’s disease (WD) is a rare autosomal recessive disorder of hepatocellular copper deposition. The diagnostic approach to patients with WD may be challenging and is based on a complex set of clinical findings that derive from patient history, physical examination, as well as laboratory and imaging testing. No single examination can unequivocally confirm or exclude the disease. Timely identification of signs and symptoms using novel biomarkers and modern diagnostic tools may help to reduce treatment delays and improve patient prognosis. The proper way of approaching WD management includes, firstly, early diagnosis and prompt treatment introduction; secondly, careful and lifelong monitoring of patient compliance and strict adherence to the treatment; and, last but not least, screening for adverse effects and evaluation of treatment efficacy. Liver transplantation is performed in about 5% of WD patients who present with acute liver failure at first disease presentation or with signs of decompensation in the course of liver cirrhosis. Increasing awareness of this rare inherited disease among health professionals, emphasizing their training to consider early signs and symptoms of the illness, and strict monitoring are vital strategies for the patient safety and efficacy of WD therapy.

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Paramagnetic Metal Accumulation in the Deep Gray Matter Nuclei Is Associated With Neurodegeneration in Wilson’s Disease

Cited by 11 publications

References 51 publications

Microstructural and functional impairment of the basal ganglia in Wilson’s disease: a multimodal neuroimaging study

Microstructural and functional impairment of the basal ganglia in Wilson’s disease: a multimodal neuroimaging study

Neuroimaging correlates of brain injury in Wilson’s disease: a multimodal, whole-brain MRI study

Wilson’s Disease: An Update on the Diagnostic Workup and Management

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