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

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 focused 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 6 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.

Neuroimaging Correlates of Cognitive Deficits in Wilson's Disease.

BACKGROUND: Cognitive impairment is common in neurological presentations of Wilson's disease (WD). Various domains can be affected, and subclinical deficits have been reported in patients with hepatic presentations. Associations with imaging abnormalities have not been systematically tested. OBJECTIVE: The aim was to determine the neuroanatomical basis for cognitive deficits in WD. METHODS: We performed a 16-item neuropsychological test battery and magnetic resonance brain imaging in 40 patients with WD. The scores for each test were compared between patients with neurological and hepatic presentations and with normative data. Associations with Unified Wilson's Disease Rating Scale neurological examination subscores were examined. Quantitative, whole-brain, multimodal imaging analyses were used to identify associations with neuroimaging abnormalities in chronically treated stable patients. RESULTS: Abstract reasoning, executive function, processing speed, calculation, and visuospatial function scores were lower in patients with neurological presentations than in those with hepatic presentations and correlated with neurological examination subscores. Deficits in abstract reasoning and phonemic fluency were associated with lower putamen volumes even after controlling for neurological severity. About half of patients with hepatic presentations had poor performance in memory for faces, cognitive flexibility, or associative learning relative to normative data. These deficits were associated with widespread cortical atrophy and/or white matter diffusion abnormalities. CONCLUSIONS: Subtle cognitive deficits in patients with seemingly hepatic presentations represent a distinct neurological phenotype associated with diffuse cortical and white matter pathology. This may precede the classical neurological phenotype characterized by movement disorders and executive dysfunction and be associated with basal ganglia damage. A binary phenotypic classification for WD may no longer be appropriate. © 2022 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.

Plasma Neurofilament Light as a Biomarker of Neurological Involvement in Wilson's Disease.

BACKGROUND: Outcomes are unpredictable for neurological presentations of Wilson's disease (WD). Dosing regimens for chelation therapy vary and monitoring depends on copper indices, which do not reflect end-organ damage. OBJECTIVE: To identify a biomarker for neurological involvement in WD. METHODS: Neuronal and glial-specific proteins were measured in plasma samples from 40 patients and 38 age-matched controls. Patients were divided into neurological or hepatic presentations and those with recent neurological presentations or deterioration associated with non-adherence were subcategorized as having active neurological disease. Unified WD Rating Scale scores and copper indices were recorded. RESULTS: Unlike copper indices, neurofilament light (NfL) concentrations were higher in neurological than hepatic presentations. They were also higher in those with active neurological disease when controlling for severity and correlated with neurological examination subscores in stable patients. CONCLUSION: NfL is a biomarker of neurological involvement with potential use in guiding chelation therapy and clinical trials for novel treatments. © 2020 University College London. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.

The BRadykinesia Akinesia INcoordination (BRAIN) Tap Test: Capturing the Sequence Effect.

BACKGROUND: The BRadykinesia Akinesia INcoordination (BRAIN) tap test is an online keyboard tapping task that has been previously validated to assess upper limb motor function in Parkinson's disease (PD). OBJECTIVES: To develop a new parameter that detects a sequence effect and to reliably distinguish between PD patients on and off medication. In addition, we sought to validate a mobile version of the test for use on smartphones and tablet devices. METHODS: The BRAIN test scores in 61 patients with PD and 93 healthy controls were compared. A range of established parameters captured number and accuracy of alternate taps. The new velocity score recorded the intertap speed. Decrement in the velocity score was used as a marker for the sequence effect. In the validation phase, 19 PD patients and 19 controls were tested using different hardware including mobile devices. RESULTS: Quantified slopes from the velocity score demonstrated bradykinesia (sequence effect) in PD patients (slope cut-off -0.002) with 58% sensitivity and 81% specificity (discovery phase of the study) and 65% sensitivity and 88% specificity (validation phase). All BRAIN test parameters differentiated between on and off medication states in PD. Differentiation between PD patients and controls was possible on all hardware versions of the test. CONCLUSION: The BRAIN tap test is a simple, user-friendly, and free-to-use tool for the assessment of upper limb motor dysfunction in PD, which now includes a measure of bradykinesia.