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 »  Introduction
 »  Patients and Methods
 »  Results
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ORIGINAL ARTICLE
Year : 2010  |  Volume : 58  |  Issue : 5  |  Page : 708-713

Cognitive profile and structural findings in Wilson's disease: A neuropsychological and MRI-based study


1 Department of Mental Health and Social Psychology, National Institute of Mental Health and NeuroSciences (NIMHANS), Bangalore, Karnataka, India
2 Department of Neurology, National Institute of Mental Health and NeuroSciences (NIMHANS), Bangalore, Karnataka, India
3 Department of Neuroimaging and Interventional Radiology, National Institute of Mental Health and NeuroSciences (NIMHANS), Bangalore, Karnataka, India

Date of Acceptance29-Jul-2010
Date of Web Publication28-Oct-2010

Correspondence Address:
Shantala Hegde
Department of Mental Health and Social Psychology, Center for Cognition and Human Excellence, National Institute of Mental Health and NeuroSciences (NIMHANS), Bangalore - 560029, Karnataka
India
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DOI: 10.4103/0028-3886.72172

PMID: 21045492

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 » Abstract 

Background: Systematic studies on neuropsychological profile in patients with Wilson's disease (WD) are far and few. Aim: To examine the profile of cognitive deficits and their magnetic resonance imaging (MRI) findings in patients with WD. Patients and Methods: Twelve confirmed patients of WD (age at onset and evaluation, 13.7±11.2 and 21.7±5.3 years, respectively; M-F ratio, 7:5) on de-coppering therapy constituted the study sample. Battery of neuropsychological tests measuring mental speed, motor speed, sustained attention, focused attention, verbal category fluency, verbal working memory, response inhibition, planning, concept formation, set-shifting ability, verbal and visual learning and memory were administered. Phenotypic details and observations on MRI of brain carried out within six months of neuropsychological assessment were documented. Results: Neuropsychological assessment elicited cognitive deficits in multiple domains in all but one patient, who had normal MRI. Percentage of patients in the deficit range in various domains included: motor speed: 73%; verbal working memory, sustained and focused attention: 50%; verbal learning: 42%; visuo-constructive ability, verbal memory, mental speed: 33%-34%; verbal fluency, set-shifting ability, visual memory, verbal memory: 25%-27%; and verbal recognition: 17%. MRI was normal in three patients, and revealed variable abnormalities in the remaining: cerebral atrophy in 3; brainstem atrophy in 2; signal changes in basal ganglia in 9; and brainstem signal changes in 5. None had subcortical white matter changes. Two patients with normal MRI showed cognitive deficits. Conclusion: This study provides insight into the complex cognitive and brain changes observed on MRI in WD. Use of advanced MRI techniques in a larger cohort may improve understanding regarding functional and structural brain changes observed in similar disorders.


Keywords: Cognitive deficits, MRI, neuropsychology, Wilson′s disease


How to cite this article:
Hegde S, Sinha S, Rao SL, Taly AB, Vasudev M K. Cognitive profile and structural findings in Wilson's disease: A neuropsychological and MRI-based study. Neurol India 2010;58:708-13

How to cite this URL:
Hegde S, Sinha S, Rao SL, Taly AB, Vasudev M K. Cognitive profile and structural findings in Wilson's disease: A neuropsychological and MRI-based study. Neurol India [serial online] 2010 [cited 2014 Apr 21];58:708-13. Available from: http://www.neurologyindia.com/text.asp?2010/58/5/708/72172



 » Introduction Top


Wilson's disease (WD) is an inherited, monogenic, autosomal recessive disorder involving mutation on the APT7B gene leading to abnormal copper deposition in the liver and brain, particularly in the lenticular nuclei. [1],[2] The clinical manifestations of WD are rather varied and challenging. [1],[3] In his initial monograph, Wilson wrote "some form of mental change were observed in at least eight out of the twelve cases; its importance therefore must not be underestimated." [4] However, only a few studies have examined neuropsychological profile in WD. [5],[6],[7],[8],[9],[10],[11],[12],[13] Neurologically symptomatic patients show significant deficits in motor, memory and frontal executive functions and visuospatial processing. [8],[12] In contrast, the deficits in cognitive functions are minimal to nil in the asymptomatic patients. [12] Deficits chiefly involve the motor and mental speed; as well as higher cognitive functions such as reasoning, planning and problem solving and memory. [5],[6],[7],[8],[9],[10],[11],[12],[13]

There are several studies describing the wide spectrum of magnetic resonance imaging (MRI) changes in WD. [14],[15],[16] However, there are very few studies correlating neuropsychological profile with MRI findings. [10] A recent study examined a large cohort of 67 patients with WD, both symptomatic and asymptomatic, and compared with healthy 50 normal controls. Based on MRI, they subdivided patients into those with predominantly basal ganglionic changes (putaminal changes) and those with multifocal MRI changes in the brain (involving basal ganglia, thalamus, brainstem, white matter and cerebral cortex). The authors concluded that "multifocal pathology was associated with more severe cognitive deficits than selective basal ganglia lesions but did not contribute significantly to memory impairment." However, the authors did not provide details of MRI changes in the cohort or the subgroups. [10] The aim of the present study was to examine the pattern of neuropsychological deficits and MRI changes in clinically stable patients of WD on treatment.


 » Patients and Methods Top


This cross-sectional study included 12 patients of established WD (Male-Female ratio, 7:5) treated and followed up regularly at the Department of Neurology, National Institute of Mental Health and Neurological Sciences, Bangalore, India. The investigator who assessed the patients on a battery of neuropsychological tests was blind to the MRI findings. Similarly the investigator who examined the MRI was blind to the findings on neuropsychological tests. The patients were screened for psychiatric symptoms using the Brief Psychiatric Rating Scale (BPRS), [17] and none of them had psychotic or depressive symptoms. All patients could take neuropsychological testing. The severity of WD was evaluated on neurological symptoms scores and CHU staging method. The disease severity ranged from very mild to moderate: mean neurological symptom score, 5.9±4.8; and CHU score, 1 or 2. All patients were on de-coppering therapy: d-Penicillamine and zinc sulfate eight patients; and zinc sulfate alone four patients. One patient was on trihexyphenidyl in addition to zinc sulfate and d-Penicillamine. Mean age of the group was 21.7±5.2 years (range, 18-32 years). All patients had formal education of 11±2 years. Mean age at onset was 13.7±11.2 years. Seven patients were employed in jobs such as agriculture or small industry, two patients were students, two were unemployed and one patient lived in a rehabilitation center. Detailed demographic and clinical characteristics of patients are given in [Table 1]. None of the patients spontaneously reported any form of cognitive deficits during the clinical interview.
Table 1: Demographic and clinical details of the patients

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Neuropsychological test battery

A comprehensive battery that included following domains and tests was: Sustained attention - Digit Vigilance Test [18] ; Focused attention - Color Trails tests 1 and 2 [19] ; Triads Test [20] ; Mental speed - Digit Symbol Substitution [21] ; Motor speed - Finger-Tapping Test [22] ; Category fluency - Animal Names Test [18] ; Verbal working memory - Verbal N-back 1 and 2 tests [23] ; Planning - Tower of London [24] ; Concept formation and set-shifting ability - Wisconsin Card-Sorting Test [25] ; Verbal learning and memory - Rey's Auditory Verbal Learning Test (AVLT) [26] ; and visuo-constructive ability, visual learning and memory - Rey's Complex Figure Test (RCFT). [27] The scores on the neuropsychological tests were compared with Indian normative data appropriate to those of the subject's gender, age and education. [20] The 15 th percentile score (1 SD below the mean) was taken as the cut off score. [20]


 » Results Top


The neuropsychological assessment took between 3 and 3.5 hours with adequate break when requested by the patient. On patient 1, Tower of London and Wisconsin Card-Sorting tests were not administered as the patient reported fatigue. On patient 12, Finger-Tapping Test could not be administered due to a technical problem with the apparatus. Eleven patients were tested using the Kannada version of the Auditory Verbal Learning Test, and one patient was tested using its English version. [17] These patients had an education of 11±2 years and had no difficulty in carrying out tests with instructions given in Kannada.

The results of neuropsychological tests were compared with Indian norms, and scores below 15 th percentile were considered to be in the deficit range. One patient did not have any cognitive deficit, and his MRI was also normal. Two patients (patients 7 and 8) with normal MRI had cognitive deficits in four domains. Patient 7 had deficits in the domains of motor speed, focused attention, and visuo-constructive ability; and patient 8 had impaired focused attention, verbal working memory, set-shifting ability and verbal learning. The details of cognitive domains of each patient are given in [Table 2], and the percentages of patients in the deficit range in each of the cognitive domains are depicted in [Figure 1]. Barring the cognitive domain of planning as assessed by Tower of London Test (total number of problems solved with minimum moves), deficits were observed in all the other cognitive domains in varying degrees. More than 50% of the patients showed deficit in the domains of motor speed, sustained and focused attention and verbal working memory (level 2). In the domain of verbal learning, 42% of the patients were in the deficit range. In the domains of visuo-constructive ability, verbal memory and mental speed, 33% to 34% of the patients were in the deficit range. A quarter of the patients were in the deficit range in the domains of verbal fluency, verbal working memory (level 1), set-shifting ability, visual memory, and verbal memory. In the domain of verbal recognition, 17% of the patients were in the deficit range.
Table 2: Domains of cognitive deficits and MRI findings of the patients

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Figure 1: Percentage of patients in the deficit range in each of the cognitive domains assessed 1. mental speed (Digit Symbol Substitution Test); 2(a). motor speed (right), 2(b). motor speed (left) (Finger-Tapping Test); 3. sustained attention (Digit Vigilance Test); 4(a). focused attention (Color Trail Test 1), 4(b). (Color Trail Test 2); 5. category fluency (Animal Names Test); 6(a). verbal working memory (Verbal N-Back 1, Hits), 6(b). verbal working memory (Verbal N-Back 2, Hits); 7. planning (Tower of London Test, total number of problems solved with minimum moves); 8. concept formation and set-shifting ability (Wisconsin Card-Sorting Test, PR: perseverative response); 9(a). Visuo-constructive ability (Complex Figure Test, copy), 9(b). visual immediate memory (Complex Figure Test, immediate recall), 9(c). visual delayed memory (Complex Figure Test, delayed recall). 10(a). verbal learning (Auditory Verbal Learning Test, total score), 10(b). verbal immediate memory (Auditory Verbal Learning Test, immediate recall), 10(c). verbal delayed memory (Auditory Verbal Learning Test, delayed recall), 10(d). verbal recognition (Auditory Verbal Learning Test, recognitiontrial).

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MRI was normal in three patients and revealed various abnormalities in nine patients: cerebral atrophy in 3; brainstem atrophy in 2; basal ganglionic signal changes in 9; and brainstem signal changes in 5 [Figure 2]. There was no subcortical white matter involvement in any of the patients. An attempt was made to correlate the nature and severity of cognitive deficits with the MRI observations [Table 2]. Patients 1, 2, 4 and 6 had neuropsychological deficits in more than six domains, and all these patients had signal changes in putamen. The other patients, who had no involvement of the putamen, showed neuropsychological deficits in less than four domains. Patients 3, 9 and 10 had deficits in one of the neuropsychological domains and did not have involvement of putamen. Patients 7 and 8 had normal MRI and had deficits in four domains. Interestingly, all patients with putaminal changes had deficits in the domain of visual and verbal learning and memory [Figure 2].
Figure 2: MRI in patients with WD (a) T2W axial image showing hyperintense signal changes in bilateral putamen and thalami; (b) T1W axial sequence with hyperintensity of both pallidum; and (c) FLAIR axial sequence revealing midbrain tectal plate signal abnormality

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 » Discussion Top


Our findings are similar to the findings in the previous studies which reported cognitive deficits in multiple domains. [5],[6],[7],[8],[9],[10],[11],[12],[13] Motor speed was the most frequently impaired domain (73%) but did not seem to have significant effect on the performance on other neuropsychological tests. This is evident as no patient had deficit on test measuring planning and a timed test involving motor execution. Similar to the findings of earlier studies, we found deficits in the frontal executive functions such as sustained and focused attention, mental speed, verbal working memory, category fluency, set-shifting ability, as well as verbal and visual learning and memory, indicating the involvement of frontal and subcortical structures. On the Complex Figure Test, as well as on Rey's Auditory Verbal Learning Test assessing visual and verbal learning and memory, the deficits were relatively higher in the learning trials than the memory trial, indicating a possible deficit in the information-processing and encoding ability. In a previous study on a cohort of 67 WD patients, Seniow et al. reported similar findings using the same test and attributed these abnormalities to the involvement of frontostriatal circuits, as noted in other subcortical diseases such as Parkinson's disease and supra-nuclear palsy. [10]

In the present study, we attempted to correlate the MRI findings with profile of cognitive deficits. Patients with signal changes in the putamen had cognitive deficits in more than six domains, while those without signal changes in the putamen had involvement of less than four domains. Interestingly, a deficit in visual and verbal learning was noted in all the patients with signal changes in putamen. Similar findings were observed in a study wherein WD patients with signal changes in the putamen in comparison with controls not only had lower IQ scores assessed using the Wechsler-Bellevue Intelligence Test but also impaired verbal and visual learning as assessed on Auditory Verbal Learning Test and Benton's Visual Memory Test. [10] Over the past one and half decade, there is growing evidence of brain imaging studies showing involvement of basal ganglia and cerebellum in mental imagery [28],[29],[30] ; sensory processing [31] ; and higher cognitive functions such as planning, [32],[33] attention, [34] language [35] and learning. [28],[36] Both the basal ganglia and the cerebellum have connections with the cerebral cortex. [37] Anatomical studies have shown that the projections from the basal ganglia and the cerebellum through the thalamus to the cortex constitute multiple `parallel' channels. [29],[38],[39],[40] The target cortical areas are also the prefrontal, [29] temporal and parietal cortices. [38]

It is noteworthy that two patients with normal MRI had cognitive deficits in more than one domain. One of them (patient 8) did have signal alterations in the caudate, putamen and thalami in his initial MRI carried out eight years ago. However, detailed cognitive assessment was not performed then. Also, it is interesting to note that one patient without basal ganglionic involvement showed impairment in cognitive functions. One of the patients with hepatic involvement and without any apparent neurological manifestation had T1W pallidal hyperintensity and slowing of motor speed, which reflects the involvement of basal ganglia in mediating motor control.

Despite the limitations of small sample size without subgroups of WD, this study has provided details of the cognitive deficits and the MRI findings and examined the correlation between the two. Among previous studies, the one by Medalia et al. has examined neuropsychological profile and computerized tomography (CT) of 19 neurologically symptomatic and 12 neurologically asymptomatic patients with WD and compared them with those of 15 healthy controls; however, they did not provide the CT correlates of neuropsychological deficits [6] ; and the other by Seniow et al., who have examined a larger cohort (n= 67), however, has not provided details of MRI observations. [10] The present study therefore has both clinical as well as theoretical implications. Studies with a homogenous cohort with newer MRI technique such as the diffusion tensor imaging and functional MRI may provide better insight into the understanding of the intricate connection between basal ganglia and cortical structures and their role in cognitive functions. Patients with WD, unlike other basal ganglionic disorders, have distinct and perceptible MRI changes and therefore provide unique opportunity to explore substrate for cognitive deficits. Cognitive studies in a larger cohort of WD patients with discrete structures like thalami, caudate, putamen or white matter being affected will provide better understanding of the role of basal ganglia and cerebellar structures in higher cognitive functions.

 
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    Tables

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