Study On Neuropsychology And Neuroimaging Characterization In Wilson’s Disease

Wilson’s disease (WD), also called hepatolenticular degeneration, is an unusual autosomal recessive genetic disorder in copper metabolism which is characterized by hepatic and neurological disease. The defective gene, ATP7B, encodes a hepatic copper-transporting protein, which plays a key role in human copper metabolism. The consequences of this disorder is related to copper deposition in different tissues, such as the brain, liver, kidneys, and cornea. Neurological and psychiatric symptoms might appear because of the copper stores in the brain. Among the WD patients, nearly half of them have psychiatric or neurological problems. The impaired social functioning is another important aspect of WD. This paper tries to study WD mainly from the point of the neuropsychology, such as attention network, theory of mind (ToM), empathy, and to explore the possible mechanism of impaired attention network, ToM and empathy through the study of multimodal magnetic resonance imaging. ObjectiveSection A:To investigate the characteristics of attention networks in patients with Wilson’s disease.Section B:To explore the cerebral gray matter, the connectivity in white matter fascicles and default mode network (DMN), fronto-parietal attention network (FPAN) based on multi-modal magnetic resonance imaging, and to investigate the neural mechanism of impaired attention network in patients with Wilson’s disease.Section C:To study the ToM and empathy in patients with Wilson’s disease and investigate the mechanism.Section D:To explore the whole brain network functional connectivity based on resting state fMRI, and to investigate the neural mechanism of impaired ToM and empathy in patients with Wilson’s disease.MethodsSection A:Attention Network Test (ANT) was performed in twenty-four WD patients and twenty-three healthy controls on the efficiency of three anatomically defined attentional networks:alerting, orienting, and executive control.All subjects underwent the neuropsychological background test.Section B:The subjects undergo multi-model MRI scan including resting-state BOLD-fMRI, DTI and3D MRI, the functional connectivity analysis was used to analyze the default mode network (DMN) and fronto-parietal attention network (FPAN); the voxel-based morphometry (VBM) was used to progress the gray matter volume data; the voxel-based analysis was used to analyze fractional anisotropy (FA) in all subjects.Then, we preliminary analyzing the correlation between the networks functional connectivity of DMN, FPAN and alerting efficiency in subjects. Section C:Twenty-four WD patients and twenty-three healthy controls completed the eyes task, Faux pas task, Theory-of-mind picture sequencing task (ToM-PST), interpersonal reactivity index Chinese version (IRI-C), All subjects complete the neuropsycho logical background test.Section D:The subjects underwent resting-state BOLD-fMRI and to investigate whole-brain network functional connectivity in WD patients, then preliminary analyzing the correlation between the whole-brain network functional connectivity and ToM, empathy scores in subjects.ResultsSection A:Compared with HCs, the overall mean RTs in the WD patients is longer (Z=18.82, p<0.001). The difference has statistical significance while the accuracy rates (Z=0.073, p=0.789) in two groups has no statistical significance Between WD patients and HC, we did find significant differences (Z=12.23,p=0.001) in baseline RT-adjusted alerting network scores. The differences between the groups for orienting and executive network scores were insignificant (Z=0.035, p=0.853; Z=1.028,p=0.316).Section B:Based on the research of VBM and compared with HCs, WD patients show significant reduction of gray matter volume not only in the common lenticular nucleus, caudate nucleus, thalamus, brainstem, but also in the cerebellum, frontal lobe, cingulate gyrus and insular lobe. On the base of VBA and DTI, WD patients show significantly decreased FA values in thalamus, corpus callosum, cingulate gyrus, mesencephalon, anterior cerebellar lobe, posterior cerebellar lobe, parahippocampal gyrus, and increased FA values in bilateral putamen area. Based on the BOLD-rsfMRI, WD patients show significantly abnormal functional connectivity of default mode network (DMN) and fronto-parietal attention network (FPAN). It is found that the L.IT-R.IT, PCC-vACC and L-DLPFC-R-vOC of functional connectivity strength is significantly correlated with alerting effect in all subjects. Section C:The WD patients were significantly impaired in the subcomponents of ToM-PST, such as understanding of the first order false belief(Z=-3.197, p<0.001),the second order false belief(Z=-3.997,p<0.001),the third order false belief(Z=-3.565, p=0.004) and understanding reciprocal(Z=-2.992,p<0.001) compared to HCs. The WD patients were significantly impaired in their ability on social-perceptual component in Eyes Task(Z=-3.453,p=0.001) compared to HCs, also WD patients were significantly impaired in their ability in Faux pas Task compared to HCs, including recognition of slip of the tongue(Z=-3.156,p=0.002), understanding of emotion (Z=-3.661,p<0.001)and understanding of intention(Z=-2.868,p=0.004).No significant difference was found on Control Questions in Eyes Task and Faux pas task(Z=-1.445, p=0.14; Z=-1.252,p=0.200).The personal distress (Z=-3.186,p=0.001), fantasy (Z=-2.632,p=0.008)and total empathy scores(Z=-3.261, p=0.001) were significantly lower in WD patients than HCs.Section D:Based on the whole-brain network functional connectivity and compared with HCs, the decrease strength of functional connectivity, such as CAU.L-CAU.R, CAU.L-PAL.L,CAU.L-PAL.R,CAU.L-PUT.R,CAU.L-THA.R,CAU.R-PAL.R,CAU.R-P UT.L,CAU.R-THA.L,CAU.R-THA.R,CAU-L-PUT.L,PAH.R-THA.R,PAL.L-PAL.R, PAL.R-THA.L,PCGR-CAU.R,PHG.R-SMGR,PUT.L-PUT.R,PUT.R-PAL.L,ROL.R-INS.L,ROL.L-ROL.R,ROL.R-AMYGR, shows a negative correlation relationship between ToM, empathy scores and those functional connectivity. Compared with HCs, the increase strength of functional connectivity, such as LINGL-PAL.L, CAU.L-ITGL, ORBmid.L-FFG.L, ORBsup.L-FFGL, ORBsup.R-FFGL,ROL.L-PAL.L,ROL.L-PUT.L, MFG.L-DCG.R,SFGdor.L-DCGR,SFGmed.L-ACGL,SFGmed.L-DCGR,SMGR-ANGL, shows a positive correlation between ToM, empathy scores and those functional connectivity. ConclusionsSection A:WD patients had impairment on the alerting domain of the attention network while the orienting and executive control domains are not impaired.Section B:There are abnormities in WD patients, cerebral gray matter and white matter volume as well as the functional connectivity in their DMN and FPAN. The resting-state brain functional connectivity of these abnormities might be one cause of lower alerting effect in WD patients.Section C:Both the ToM social-conceptual component and the ToM social-cognitive components were impaired in WD patients. Both cognitive empathy and affective empathy were impaired in WD patients.Section D:Abnormal whole-brain network functional connectivity was found in WD patients, this abnormal functional connectivity may be one of the main causes of damaged of ToM and empathy ability in WD patients.