Widespread White Matter Alterations Are Associated With Neurological Severity in Wilson Disease

278 

Abstract Submission 

Ann Carolin Hausmann¹, Silja Kannenberg¹, Christian Hartmann², Julian Caspers³, Christian Rubbert³, Alfons Schnitzler^1,2

¹Institute of Clinical Neuroscience & Medical Psychology, Medical Faculty, Heinrich-Heine-University, Duesseldorf, Germany, ²Department of Neurology, Medical Faculty, University Hospital Duesseldorf, Duesseldorf, Germany, ³Department of Diagnostic & Interventional Radiology, Medical Faculty, Heinrich-Heine-University, Duesseldorf, Germany

Ann Carolin Hausmann  
Institute of Clinical Neuroscience & Medical Psychology, Medical Faculty, Heinrich-Heine-University
Duesseldorf, Germany

Silja Kannenberg  
Institute of Clinical Neuroscience & Medical Psychology, Medical Faculty, Heinrich-Heine-University
Duesseldorf, Germany

Christian Hartmann  
Department of Neurology, Medical Faculty, University Hospital Duesseldorf
Duesseldorf, Germany

Julian Caspers  
Department of Diagnostic & Interventional Radiology, Medical Faculty, Heinrich-Heine-University
Duesseldorf, Germany

Christian Rubbert  
Department of Diagnostic & Interventional Radiology, Medical Faculty, Heinrich-Heine-University
Duesseldorf, Germany

Alfons Schnitzler  
Institute of Clinical Neuroscience & Medical Psychology, Medical Faculty, Heinrich-Heine-University|Department of Neurology, Medical Faculty, University Hospital Duesseldorf
Duesseldorf, Germany|Duesseldorf, Germany

Wilson disease (WD) is a rare metabolic disorder, leading to pathologic copper accumulation i.a. in the brain, which may cause neurological symptoms. Diffusion tensor imaging (DTI) derived white matter (WM) alterations have been proposed as neuroimaging biomarkers in patients with WD, which correlate with neurological severity [1,2]. However, evidence is yet sparse and inconclusive, often neglecting absolute measures of diffusion [3].

25 patients with WD (7 male; age: M=40.76±11.22 years; disease duration: M=244.56±101.04 months; on anticopper treatment) were examined with the Unified Wilson's Disease Rating Scale neurological subscale (UWDRS-N; M=7.04±9.62). Cranial 3T multi-shell diffusion MRI was acquired according to the Lifespan Human Connectome Project in Aging protocol and preprocessed with its minimal preprocessing pipeline [4]. DTI main indices fractional anisotropy (FA) and mean diffusivity (MD) as well as the absolute measures axial diffusivity (AD) and radial diffusivity (RD) were computed with FSL v.6.0 using DTIFIT. Voxel-wise statistical analyses were carried out using general linear models and permutation testing with 5000 permutations in Tract Based Spatial Statistics (TBSS, [5]), correcting for covariate effects of age and sex. Clusters of significant correlations between DTI parameters and UWDRS-N scores were identified at a threshold of p<.05 (family-wise error corrected) and by applying Threshold-Free Cluster Enhancement (TFCE) and overlaying them to the Johns Hopkins University WM tractography atlas.

TBSS analysis revealed a significant negative correlation between FA and UWDRS-N scores in the left corticospinal tract. Furthermore, significant positive correlations between MD and UWDRS-N scores were found in the following WM tracts: left corticospinal tract, bilateral genu of corpus callosum, right body of corpus callosum, bilateral anterior & superior corona radiata, bilateral anterior & posterior limb of internal capsule, right retrolenticular part of internal capsule, left external capsule, left superior longitudinal fasciculus, bilateral superior cerebellar peduncles, bilateral medial lemniscus and bilateral posterior thalamic radiation (see Fig.1). For AD, there were significant positive correlations with the neurological scores in: left anterior limb of internal capsule, left anterior & superior corona radiata as well as left superior fronto-occipital and longitudinal fasciculus. In addition, positive correlations with RD were found in: left corticospinal tract, right inferior cerebellar peduncle, bilateral medial lemniscus, left superior corona radiata, left superior longitudinal fasciculus, bilateral anterior thalamic radiation and unclassified WM tracts (see Fig.2).

Our analysis demonstrates significant correlations between alterations of all DTI indices and neurological impairment in manifold WM tracts of patients with WD, correcting for age and sex. Higher neurological severity was associated with higher MD, AD and RD in large interconnecting fibers, i.e., bilateral superior corona radiata and left superior longitudinal fasciculus, which are crucial for the transport of sensory and motor information throughout the brain. This may be supported by findings of increased diffusivities in the superior longitudinal fasciculus in WD patients relative to healthy controls [6]. Moreover, predominantly motor related WM tracts such as the left corticospinal tract, bilateral medial lemniscus and anterior limb of internal capsule were affected; for the latter, a positive association between MD and neurological scores has previously been reported in drug naive WD patients [2]. Overall, our results indicate the widespread loss of WM integrity in WD patients, presumably due to demyelination, edema and neuronal loss [7], which may contribute to observed sensory and motor impairments. All DTI derived WM changes seem to be promising neuroimaging biomarkers for residual neurological symptom severity in treated WD.

Neurodegenerative/ Late Life (eg. Parkinson’s, Alzheimer’s) ¹

Diffusion MRI Modeling and Analysis ²

Diffusion MRI

Degenerative Disease

DISORDERS

MRI

Neurological

White Matter

WHITE MATTER IMAGING - DTI, HARDI, DSI, ETC