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

ABSTRACT: Background:Neuropathological studies have revealed copper and iron accumulation in the deep gray matter (DGM) nuclei of patients with Wilson's disease (WD). However, the association between metal accumulation and neurodegeneration in WD has not been well studied in vivo. The study was aimed to investigate whether metal accumulation in the DGM was associated with the structural and functional changes of DGM in neurological WD patients. Methods:Seventeen neurological WD patients and 20 healthy controls were recruited for the study. Mean bulk susceptibility values and volumes of DGM were obtained from quantitative susceptibility mapping (QSM). Regions of interest including the head of the caudate nucleus, globus pallidus, putamen, thalamus, substantia nigra, red nucleus, and dentate nucleus were manually segmented. The susceptibility values and volumes of DGM in different groups were compared using a linear regression model. Correlations between susceptibility values and volumes of DGM and Unified Wilson's Disease Rating Scale (UWDRS) neurological subscores were investigated. Results:The susceptibility values of all examined DGM in WD patients were higher than those in healthy controls (P < 0.05). Volume reductions were observed in the head of the caudate nucleus, globus pallidus, putamen, thalamus, and substantia nigra of WD patients (P < 0.001). Susceptibility values were negatively correlated with the volumes of the head of the caudate nucleus (r p = -0.657, P = 0.037), putamen (r p = -0.667, P = 0.037), and thalamus (r p = -0.613, P = 0.046) in WD patients. UWDRS neurological subscores were positively correlated with the susceptibility values of all examined DGM. The susceptibility values of putamen, head of the caudate nucleus, and dentate nucleus could well predict UWDRS neurological subscores. Conclusion:Our study provided in vivo evidence that paramagnetic metal accumulation in the DGM was associated with DGM atrophy and neurological impairment. The susceptibility of DGM could be used as a biomarker to assess the severity of neurodegeneration in WD.

SUBMITTER: Yuan XZ

PROVIDER: S-EPMC7525019 | biostudies-literature | 2020

REPOSITORIES: biostudies-literature

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

Yuan Xiang-Zhen XZ Li Gai-Ying GY Chen Jia-Lin JL Li Jian-Qi JQ Wang Xiao-Ping XP

Frontiers in neuroscience 20200916

<h4>Background</h4>Neuropathological studies have revealed copper and iron accumulation in the deep gray matter (DGM) nuclei of patients with Wilson's disease (WD). However, the association between metal accumulation and neurodegeneration in WD has not been well studied <i>in vivo</i>. The study was aimed to investigate whether metal accumulation in the DGM was associated with the structural and functional changes of DGM in neurological WD patients.<h4>Methods</h4>Seventeen neurological WD patie ...[more]

PMID: 33041766

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Project description:BackgroundHistopathological studies in Wilson's disease (WD) have revealed increased copper and iron concentrations in the deep gray matter nuclei. However, the commonly used mean bulk susceptibility only reflects the regional metal concentration rather than the total metal content, and regional atrophy may affect the assessment of mean bulk susceptibility. Our study aimed to quantitatively assess the changes of metal concentration and total metal content in deep gray matter nuclei by quantitative susceptibility mapping to distinguish patients with neurological and hepatic WD from healthy controls.MethodsQuantitative susceptibility maps were obtained from 20 patients with neurological WD, 10 patients with hepatic WD, and 25 healthy controls on a 3T magnetic resonance imaging system. Mean bulk susceptibility, volumes, and total susceptibility of deep gray matter nuclei in different groups were compared using a linear regression model. The area under the curve (AUC) was calculated by receiver characteristic curve to analyze the diagnostic capability of mean bulk susceptibility and total susceptibility.ResultsMean bulk susceptibility and total susceptibility of multiple deep gray matter nuclei in patients with WD were higher than those in healthy controls. Compared with patients with hepatic WD, patients with neurological WD had higher mean bulk susceptibility but similar total susceptibility in the head of the caudate nuclei, globus pallidus, and putamen. Mean bulk susceptibility of putamen demonstrated the best diagnostic capability for patients with neurological WD, the AUC was 1, and the sensitivity and specificity were all equal to 1. Total susceptibility of pontine tegmentum was most significant for the diagnosis of patients with hepatic WD, the AUC was 0.848, and the sensitivity and specificity were 0.7 and 0.96, respectively.ConclusionBrain atrophy may affect the assessment of mean bulk susceptibility in the deep gray matter nuclei of patients with WD, and total susceptibility should be an additional metric for total metal content assessment. Mean bulk susceptibility and total susceptibility of deep gray matter nuclei may be helpful for the early diagnosis of WD.

Project description:Deep Brain Stimulation (DBS) is a neurosurgical procedure consisting in the stereotactic implantation of stimulation electrodes to specific brain targets, such as deep gray matter nuclei. Current solutions to place the electrodes rely on rectilinear stereotactic trajectories (RTs) manually defined by surgeons, based on pre-operative images. An automatic path planner that accurately targets subthalamic nuclei (STN) and safeguards critical surrounding structures is still lacking. Also, robotically-driven curvilinear trajectories (CTs) computed on the basis of state-of-the-art neuroimaging would decrease DBS invasiveness, circumventing patient-specific obstacles. This work presents a new algorithm able to estimate a pool of DBS curvilinear trajectories for reaching a given deep target in the brain, in the context of the EU's Horizon EDEN2020 project. The prospect of automatically computing trajectory plans relying on sophisticated newly engineered steerable devices represents a breakthrough in the field of microsurgical robotics. By tailoring the paths according to single-patient anatomical constraints, as defined by advanced preoperative neuroimaging including diffusion MR tractography, this planner ensures a higher level of safety than the standard rectilinear approach. Ten healthy controls underwent Magnetic Resonance Imaging (MRI) on 3T scanner, including 3DT1-weighted sequences, 3Dhigh-resolution time-of-flight MR angiography (TOF-MRA) and high angular resolution diffusion MR sequences. A probabilistic q-ball residual-bootstrap MR tractography algorithm was used to reconstruct motor fibers, while the other deep gray matter nuclei surrounding STN and vessels were segmented on T1 and TOF-MRA images, respectively. These structures were labeled as obstacles. The reliability of the automated planner was evaluated; CTs were compared to RTs in terms of efficacy and safety. Targeting the anterior STN, CTs performed significantly better in maximizing the minimal distance from critical structures, by finding a tuned balance between all obstacles. Moreover, CTs resulted superior in reaching the center of mass (COM) of STN, as well as in optimizing the entry angle in STN and in the skull surface.

Project description:Huntington disease (HD) is a fatal progressive neurodegenerative disorder for which only symptomatic treatment is available. A better understanding of the pathology, and identification of biomarkers will facilitate the development of disease-modifying treatments. HD is potentially a good model of a neurodegenerative disease for development of biomarkers because it is an autosomal-dominant disease with complete penetrance, caused by a single gene mutation, in which the neurodegenerative process can be assessed many years before onset of signs and symptoms of manifest disease. Previous MRI studies have detected abnormalities in gray and white matter starting in premanifest stages. However, the understanding of how these abnormalities are related, both in time and space, is still incomplete. In this study, we combined deep gray matter shape diffeomorphometry and white matter DTI analysis in order to provide a better mapping of pathology in the deep gray matter and subcortical white matter in premanifest HD. We used 296 MRI scans from the PREDICT-HD database. Atrophy in the deep gray matter, thalamus, hippocampus, and nucleus accumbens was analyzed by surface based morphometry, and while white matter abnormalities were analyzed in (i) regions of interest surrounding these structures, using (ii) tractography-based analysis, and using (iii) whole brain atlas-based analysis. We detected atrophy in the deep gray matter, particularly in putamen, from early premanifest stages. The atrophy was greater both in extent and effect size in cases with longer exposure to the effects of the CAG expansion mutation (as assessed by greater CAP-scores), and preceded detectible abnormalities in the white matter. Near the predicted onset of manifest HD, the MD increase was widespread, with highest indices in the deep and posterior white matter. This type of in-vivo macroscopic mapping of HD brain abnormalities can potentially indicate when and where therapeutics could be targeted to delay the onset or slow the disease progression.

Dataset Information

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

Publications

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

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