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Brain Atrophy Is a Better Biomarker than Susceptibility for Evaluating Clinical Severity in Wilson Disease

Published Online:https://doi.org/10.1148/radiol.2021210106

See also the article by Dusek et al in this issue.

Dr Du is a professor of radiology at the University of California in San Diego. He is an investigator for the Academy for Radiology and Biomedical Imaging Research and a fellow of the American Institute for Medical and Biological Engineering. His research focuses on the development of techniques for morphologic and quantitative MRI. He also serves in NIH study sections and is the principal investigator for three NIH grants.

Dr Du is a professor of radiology at the University of California in San Diego. He is an investigator for the Academy for Radiology and Biomedical Imaging Research and a fellow of the American Institute for Medical and Biological Engineering. His research focuses on the development of techniques for morphologic and quantitative MRI. He also serves in NIH study sections and is the principal investigator for three NIH grants.

Dr Bydder is an emeritus professor of radiology at the University of California in San Diego. He was an author of the first MRI papers on multiple sclerosis (using inversion recovery sequences), clinical use of heavily T2-weighted spin-echo sequences, and contrast-enhanced MRI with gadopentetate dimeglumine. He and his colleagues first described the MRI features of Wilson disease, short inversion time inversion recovery and fluid-attenuated inversion recovery sequences, and susceptibility-weighted imaging.

Dr Bydder is an emeritus professor of radiology at the University of California in San Diego. He was an author of the first MRI papers on multiple sclerosis (using inversion recovery sequences), clinical use of heavily T2-weighted spin-echo sequences, and contrast-enhanced MRI with gadopentetate dimeglumine. He and his colleagues first described the MRI features of Wilson disease, short inversion time inversion recovery and fluid-attenuated inversion recovery sequences, and susceptibility-weighted imaging.

Wilson disease (WD) is an autosomal recessive genetic disorder caused by mutations in the ATP7B gene that result in defects in copper metabolism, with up to a 10-fold increase in free copper serum concentration compared with that in healthy control patients (1). Copper accumulates in the liver in the hepatic form of WD, and/or the brain in the neurologic form of WD, with the latter leading to neurologic and psychiatric symptoms. MRI has been used to demonstrate abnormalities in the brains of patients with WD since 1982 (2). In some cases, lenticular nucleus involvement was seen with MRI but not with CT, largely because of the high soft-tissue contrast available with MRI (3). MRI is the most sensitive neuroimaging technique for diagnosis, treatment monitoring, and outcome prediction in neurologic WD (4,5). The most prominent findings include T2 hyperintense lesions, T2 and T2* hypointense lesions, and brain atrophy (4). Although T2 hyperintense lesions are reversible, T2 and T2* hypointense lesions tend to progress despite anti-copper treatment (5). T2 hyperintense lesions can be detected with T2-weighted or fluid-attenuated inversion recovery sequences and are typically observed in the deep gray matter, brainstem, and white matter. The lesions often regress with treatment. They are assumed to reflect edema, demyelination, and gliosis caused by copper toxicity. T2 and T2* hypointense lesions can be detected with spin-echo and long echo time gradient-echo sequences and are usually observed in deep gray matter. The low signal intensities are attributed to iron and copper deposition, with iron being dominant. These tend to decrease T2* and to increase tissue susceptibility. Cu++ is weakly paramagnetic, and Cu+ is diamagnetic. Both forms are present in tissue. Quantitative susceptibility mapping is increasingly being used to evaluate iron accumulation in the brain in various neurologic diseases (6).

In this issue of Radiology, Dusek and colleagues (7) investigate associations between MRI measures, such as regional atrophy and susceptibility, and the neurologic severity of WD. Neurologic severity was evaluated using the Unified WD Rating Scale (UWDRS). A total of 29 participants with WD and 26 controls were recruited in their cross-sectional study. The imaging protocol included a high-resolution T1-weighted three-dimensional magnetization-prepared (inversion recovery) rapid acquisition with gradient-echo sequence, a T2-weighted fast spin-echo sequence, and a multi-echo gradient-recalled echo sequence. Regional volumes and mean susceptibilities in deep gray matter were measured with an automated multi-atlas segmentation pipeline that used dual susceptibility and T1 contrast. Whole-brain analysis was performed using deformation and surface-based morphometry. Parameters were statistically analyzed in the WD and control groups. Significant differences existed in regional volume, regional susceptibility, deformation-based morphometry metrics, and cortical thickness between the WD and control groups. Significant correlations were observed between UWRDS scores and volumes of the putamen (r = −20.63, P < .001), red nucleus (r = −20.58, P = .001), globus pallidus (r = −20.53, P = .003), and substantia nigra (r = −20.50, P = .006). Putamen volume was identified as the only stable factor showing moderate correlation with the Unified WD Rating Scale score (R2 = 0.35, P < .001) using a least absolute shrinkage and selection operator. Quantitative susceptibility mapping–derived susceptibilities did not show significant correlations with neurologic severity.

It is not surprising to see a significant negative correlation between brain atrophy and neurologic severity in WD. Brain atrophy has been widely observed in various neurologic diseases (8). In multiple sclerosis, for example, the volumes of gray and white matter, as well as thalamic volume, correlate with disease severity. Hippocampal volume is related to cognitive function in Alzheimer disease. Whole-brain volume and the volume of gray matter are correlated with motor impairment in progressive supranuclear palsy. Reduced gray matter volume is also observed in the frontal lobe of patients with Parkinson disease without dementia, whereas significant gray matter atrophy is observed bilaterally in the occipital lobe of patients with Parkinson disease who have dementia. In their study, Dusek et al (7) found widespread atrophy in deep gray matter nuclei, the primary motor, premotor and visual cortices, as well as in white matter within the pons, mesencephalon, internal capsule, and adjacent lobes. Atrophy was most severe in central structures, with a nearly 30% reduction in the volume of putamen. This is the first study reporting the contribution of regional brain volume loss to overall neurologic severity, and it is a significant advancement compared with previous studies that focused on associations between global brain atrophy and clinical severity (8).

It is interesting to see nonsignificant correlations between tissue susceptibilities and neurologic severity. One would expect increased susceptibility because of significant brain iron accumulation in WD. Excessive iron accumulation is observed during the acute phase of WD, but this is often followed by a gradual iron decrease as a result of chronic anti-copper treatment. Increased cerebral iron levels can be observed in patients with WD throughout their adult lifespan, but the iron levels may not increase with clinical disease progression. The clinically nonsignificant correlation with susceptibility changes may reflect changes in iron concentration resulting from both the underlying disease and its treatment. They may also be complicated by myelin changes in WD. Oligodendrocytes are highly vulnerable to copper toxicity, and myelin may be the primary target in the disease in which total myelin loss in lobar and cerebellar white matter has been described. The magnetic susceptibility of myelin is difficult to measure, although a negative frequency shift induced by a diamagnetic myelin susceptibility is seen in white matter (9). A recent study of WD (5) shows iron accumulation in the basal ganglia and demyelination in the thalamus, with 3.0-T MRI more sensitive for detection of the former and 1.5-T MRI more sensitive for detection of the latter. A field-dependent study might help clarify the relative contributions of the presence of iron and demyelination in WD. Another option is to directly measure myelin changes using advanced MRI techniques, such as the short repetition time adiabatic inversion recovery prepared ultrashort echo time sequence (10). This technique can potentially map myelin density in both white and gray matter of the brain and thereby can facilitate quantitative assessment of contributions to clinical disability from the presence of iron and demyelination.

In conclusion, the authors conducted a systematic investigation of associations of regional brain atrophy and the presence of iron at MRI in patients with WD and permanent disability who have undergone long-term anti-copper treatment. Widespread brain atrophy and higher magnetic susceptibility were observed in multiple brain regions of patients with WD. Regional brain atrophy, especially putaminal volume, was found to be the best stable surrogate imaging marker of clinical severity. The results from this study are likely to be of value in the treatment of patients with WD. The nonsignificant correlation between susceptibility with neurologic severity may be due to different contributions to susceptibility resulting from iron and copper accumulation and removal, as well as myelin changes over the course of the disease. We hope follow-up studies will be conducted, ideally involving simultaneous assessment of regional brain atrophy, susceptibility, and demyelination to further improve the value of brain MRI in patients with WD.

Disclosures of Conflicts of Interest: J.D. disclosed no relevant relationships. G.M.B. disclosed no relevant relationships.

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Article History

Received: Jan 14 2021
Revision requested: Jan 19 2021
Revision received: Jan 19 2021
Accepted: Jan 20 2021
Published online: Mar 23 2021
Published in print: June 2021