Original Paper Eur Neurol 2014;71:262–270 DOI: 10.1159/000357404

Received: November 20, 2012 Accepted: November 17, 2013 Published online: February 12, 2014

Cognitive Impairment in Native Chinese with Spinocerebellar Ataxia Type 3 Li Feng a Ding Bang Chen a Le Hou b Lin Huan Huang d Shu Yang Lu c Xiu Ling Liang a Xun Hua Li a a Department of Neurology, First Affiliated Hospital of Sun Yat-Sen University, b Department of Neurology, Guangzhou Psychiatric Hospital, and c Department of Psychology, Third Affiliated Hospital of Sun Yat-Sen University, Guangzhou, Guangdong, and d Department of Neurology, Shantou Central Hospital, Affiliated Shantou Hospital of Sun Yat-Sen University, Shantou, Guangdong, PR China

Key Words Spinocerebellar ataxia type 3 · Cerebellum · Cognition · Chinese

Abstract Background: Previous studies have shown cognitive impairment in patients with spinocerebellar ataxia type 3 (SCA3). However, there is a lack of data on Chinese patients with SCA3. Method: We investigated 22 native Chinese with SCA3 and 18 controls matched for age, education as well as mental status. Cognitive assessments were carefully carried out to measure verbal fluency, memory, attention, executive function, visuospatial and visuoconstructive functions. Results: The most common impairments of cognition in native Chinese with SCA3 were disruption of phonemic verbal fluency and frontal executive dysfunction. Deficits in semantic fluency were detected in about 31.8% patients. Impaired visuospatial function and verbal memory were also found in native Chinese with SCA3. The degree of ataxia, CAG repeat length and education were found to correlate with cognitive performance. Multivariate binary logistic regression suggested that an oculomotor disorder and depression are predictors of cognitive impairment. Conclusion: Native Chinese with SCA3 had cognitive impairment of frontal executive function, temporal and parietal functions. An oculomotor disorder might be an index of cognitive dysfunction. © 2014 S. Karger AG, Basel

© 2014 S. Karger AG, Basel 0014–3022/14/0716–0262$39.50/0 E-Mail [email protected] www.karger.com/ene

Introduction

The cerebellum was once believed to only participate in motor modulation. However, new information has since provided abundant evidence for its direct and indirect involvement in cognition. Currently, the concept of a Cerebellar Cognitive Affective Syndrome, which refers to deficits in language, visuospatial, affective and executive functions, has been accepted throughout the world [1–5]. Although spinocerebellar ataxia type 3 (SCA3) is characterized by prominent cerebellar ataxia and atrophy [6], recent pathological and imaging studies on SCA3 have described damage not only confined to the cerebellum, but also including the gray matter of the sensory system, the cerebello-thalamocortical motor loop, the basal gangliathalamocortical motor loop, the ingestion-related and precerebellar brain stem system, etc. [7]. Several studies have reported cognitive and psychiatric deficits in patients with SCA3, mainly in the domains of verbal and visual memory, verbal attention, verbal fluency, executive functioning, as well as visuospatial and visuoconstructive abilities [6, 8, 9]. Nevertheless, none of these cognitive impairments was found to correlate with CAG repeat length in SCA3 [10]. Meanwhile, whether the cognitive dysfunction is correlat-

Li Feng and Ding Bang Chen contributed to the study equally.

Xunhua Li Department of Neurology, First Affiliated Hospital of Sun Yat-Sen University, No. 58 Zhong Shan 2nd Road Guangzhou 510080, Guangdong (PR China) E-Mail lilysysu @ 126.com

ed with ataxia is still unclear. Burk et al. [11] reported that scores on digit span and verbal fluency tasks were weakly but significantly inversely correlated with scores for dysarthria. Kawai et al. [6] reported a significant correlation between category fluency and ataxia severity but without further analysis of details of ataxia. Conversely, Klinke et al. [12] found no correlation between ataxia and cognition in a sample of 15 in 2010 and Braga-Neto et al. [8] did not address this issue in 2012. Recently, Orsi et al. [13] reported the predictive effect of age and education on the neuropsychological performance in 33 subjects with SCAs. Although substantial research was carried out on cognitive dysfunction in patients with SCA3, there is a paucity of  data about the cognition of native Chinese speakers with SCA3. Chinese characters could provide more flexible  verbal stimuli due to their three-dimensional changes in phonemes, shapes and meanings. Ample evidence has demonstrated that the processing of alphabetic (e.g., English) versus ideographic (e.g., Chinese) languages may be fundamentally different, which was supported by functional MRI and electrophysiological studies in the different dominant hemispheres or in the processing pathways during cognition, reading, writing and learning of the two orthographic systems [14–18]. Kochunov et al. [19] found anatomical differences in the frontal, temporal and parietal gyri between Chinese and English speakers, which might be due to neural plasticity. Compared with English speakers, native Chinese have also been reported to behave differently in psychological and epidemiological studies [20– 23]. Thus, it is reasonable for native Chinese speakers with SCA3 to develop unique cognitive impairments that differ from those of their English-speaking counterparts. We investigated cognitive functioning in an ideographic language population of native Chinese patients with SCA3 for the first time. In the current study, we carefully administered a series of motor and neuropsychological tests to assess the degree of ataxia, verbal function, memory, attention, executive and visuospatial functions in our volunteers. We hypothesized that a unique presentation would be observed with neuropsychological assessments, which would reveal characteristic cognitive impairments in native Chinese speakers with SCA3.

Methods

Patients recruited received both clinical and genetic diagnosis of SCA3 in our Outpatient General Neurology Unit from 2010 to 2012. Exclusion criteria were as follows: presence of other neurological or psychiatric abnormalities which might affect cognition or the presence of any physical disabilities other than ataxia which might affect motor operation or movement. General information such as sex, age, education, handedness, onset age, disease duration and CAG copies was collected, as well as the SCA onset form, initial symptoms and family history. Twenty patients were excluded because their genetic tests did not yield the diagnosis of SCA3. Healthy controls were recruited via our Outpatient General Neurology Unit and were matched with patients for their age, education, and scores on the Self-Rating Anxiety Scale (SAS) and the Self-Rating Depression Scale (SDS). All controls met the following criteria: no complaints of impaired memory, no history of diseases or conditions that might affect cognition, no physical disability that might interrupt assessment and no administration of drugs which may affect cognition within 1 month. Additionally, none of these subjects had a family history of ataxia. Three subjects were excluded from the controls because they could not be matched for their SAS or SDS scores. All participants underwent the psychiatric and cognitive tests described below. All tests were administered in a fixed style and were evaluated by two examiners independently. Mental Status Participants all underwent the SAS and the SDS following neutral explanation from the two examiners [24–26]. Neurological Evaluation of Ataxia The International Cooperative Ataxia Rating Scale (ICARS), which is composed of separate assessments for gesture and gait (ICARS-1), kinetic functions (ICARS-2), speech disorders (ICARS-3) and oculomotor disorders (ICARS-4), was administered to evaluate the degree of ataxia in all patients [27, 28]. Healthy subjects were also tested as controls. Cognitive Measures Mini-Mental State Examination (MMSE) The MMSE was used as an assessment of general intellectual abilities [11, 29]. Verbal Function Verbal Fluency. Verbal fluency tests were designed to assess association fluency, which represents the function of the frontal lobe and the parietal lobe by phonemic test and semantic test, respectively [8]. Subjects were asked to name as many items (animals) as possible within 1 min to measure semantic fluency. Phonemic fluency was measured by requiring subjects to generate as many words as possible starting with a given letter (Chinese nouns starting with the Chinese character Dian, which means ‘electricity’) within 1 min [8]. Then, subjects were timed (T2) as they read aloud the items produced in the generation condition following a delay (T2). The Verbal Fluency Test-fluency index (VFT-fi), which represents the average time taken to think of each item, was calculated with the following formula [20, 30, 31]:

Participants All participants were native speakers of Chinese. Participants all provided written, informed consent, and all experimental procedures were approved by the Ethics Committee of the First Affiliated Hospital of Sun Yat-Sen University [No. (2012) 346].

Verbal Memory. The Chinese Rey Auditory Verbal Learning Test (C-RAVLT) was chosen to evaluate transient (immediate re-

Cognitive Impairment in Native Chinese with SCA3

Eur Neurol 2014;71:262–270 DOI: 10.1159/000357404

VFT-fi = (60 – T2)/total number of nouns generated

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call) and delayed (20-min delayed recall) verbal memory. Outcome variables were the total number of correctly recalled words summed over the first five consecutive trials (C-RAVLT Total recall 1–5) and the number of correctly recalled words after a 20-min delay (C-RAVLT Delayed recall) [12, 31]. Considering the ceiling effect, scores for the total trails 1–3 (C-RAVLT Total recall 1–3) were also recorded in addition [20, 32]. Attention and Verbal Working Memory The Digit Span subset of the Wechsler Adult Intelligence Scale Revised was given to determine the verbal attention span (forward) and working memory (backward). The number of items correctly reproduced served as the outcome variables [8, 20]. Frontal Executive Function Trail-Making Test (TMT). The TMT Trails A and B were used as measurements of the speed of visual search, mental flexibility, attention resources, motor and sequencing ability. The time to complete the two parts was recorded separately for each test. Subtraction of Trail A from Trail B (Trail B – A) was used to eliminate possible bias resulting from the motor and sequencing elements. Moreover, a ratio score of the time taken to complete TMT-B to that taken to complete TMT A (TMT B/A ratio) was applied to determine the test revealing greater impairment [8, 20, 33]. Stroop Color-Word Test (SCWT) [20, 34]. The SCWT was administered as a general measure of cognitive flexibility, inhibitory control and executive function [35, 36]. The Chinese version of the SCWT was adopted for use in the present study [20]. Participants were instructed to read the words, name the colors and finally, to name the ink color which was incongruous with the printed words as quickly and accurately as possible in three sequential subtasks. The time taken to complete the three subtasks was recorded as Stroop I, Stroop II and Stroop III, respectively. The SCWT Interference Effect (SIE) served as the main outcome variable, which was defined with the following formula [31]: SIE = Stroop III – (Stroop I + Stroop II)/2. Color-Form Sorting Test. Participants were required to sort 12 items as ordered, according to their different colors and shapes. The test was used to detect whether concept formation and transitions were intact in these patients [37].

Table 1. Clinical characteristics of patients with SCA3 and controls Characteristic

SCA3 (n = 22)

Controls (n = 18)

p value

Male:female ratio Education, years Age at onset, years Age at examination, years Disease duration, years CAG repeat length Depression Anxiety

4:7 4:5 12.14±3.21 (9–16) 13.25±3.15 (9–16) 32±4.49 (25–40) –

0.833 0.416 –

37.05±6.10 (29–54)

36.78±12.03 (21–58)

0.806

5.15±3.62 (1–14) 74.57±3.34 (66–80) 40.36±10.37 38.4±8.75

– – 36.0±6.44 (19–59) 33.8±6.22 (14–48)

– – 0.272 0.295

Data are given as mean ± SD (range) unless otherwise indicated.

for categorical data. Additionally, the standard effect size and the percentage of impaired patients on each neuropsychological test are reported and a z score was calculated to express the impairments in the appropriate neuropsychological domains. Spearman’s correlations were used to determine any relationship between cognitive performance and clinical features of SCA3 patients. The independent variables included the disease duration, number of CAG repeats, ICARS and ICARS subscale scores, education and scores on the SAS and SDS, while the dependent variables were scores on each of the neuropsychological tests. Furthermore, a multivariate binary logistic regression model was used to explore predictors of cognitive impairment in SCA3 once a significant correlation was verified. Cognitive impairment was considered to be present if a given score in any of the designated cognitive domains was beyond the range of 1.5 standard deviations [44], or if scores were significantly different from controls in cases where published norms for the Chinese population were unavailable [45]; p < 0.05 was used to indicate a statistically significant difference.

Results

Visual Spatial Function Clock Drawing Test (CDT) [38]. The CDT was used to screen for visuospatial and visuoconstructive disabilities. Two independent scoring systems, the Watson scoring system [39, 40] and the AD Cooperative Study scoring system [41], were both adopted to measure the performance of each subject. Given the motor dysfunctions observed in the SCA3 patients, the time taken to complete the drawing task was not included. Bender-Gestalt Test. The Bender-Gestalt test was administered mainly to evaluate visuomotor integration skills. The total score was determined using the scoring system of Bakar and Bakar [42] and Lacks and Newport [43].

Participants SCA3 patients (n  = 22) and controls (n  = 18) were matched for age, education and scores on the SAS and SDS. All participants were right-handed. The demographic characteristics of all subjects are shown in table 1. There were no significant differences in sex, age at examination, educational level, SDS or SAS scores between the two groups.

Data Analysis Data analysis was performed using the Statistical Package for the Social Science version 17.0. Independent t tests or MannWhitney U tests were used to assess differences between patients and controls according to the data distribution. A χ2 test was used

Ataxia Rating Scale The ICARS was used to assess the degree of ataxia in the SCA3 group (table 2). The total and subscale scores are as follows: total scores (maximum points, 100) 28.14  ± 9.40 (mean ± SD); ICARS-1 (gesture and gait,

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Eur Neurol 2014;71:262–270 DOI: 10.1159/000357404

Feng/Chen/Hou/Huang/Lu/Liang/Li

Table 2. Comparison between SCA3 patients and controls

Items

SCA3 mean

Controls SD

%

p

ES

mean

SD

%

– – – – –

– – – – –

– – – – –

– – – – –

ICARS ICARS-1 ICARS-2 ICARS-3 ICARS-4

28.14 12.93 9.28 2.36 3.57

9.40 6.45 2.33 1.39 0.76

100 100 100 100 100

– – – – –

MMSE

28.14

1.66

10

29

1.20

0

0.213

0.59

Verbal fluency Phonemic pVFT-fi Semantic sVFT-fi

7.8 7.72 15.71 3.0

1.32 2.48 3.67 1.23

100 – 31.8 –

13.2 4.15 21.61 1.86

1.35 1.49 5.76 0.87

5.56 – 0 –

0.008 0.008 0.003 0.021

1.37a 0.79 1.08a 0.88a

C-RAVLT Total recall 1–3 Total recall 1–5 Delayed recall

19.75 40.41 8.89

7.41 11.30 3.16

45.4 59.1 27.3

26.38 51.63 12.88

5.85 9.52 2.30

0 0 0

0.023b 0.007b 0.003b

0.90a 0.93a 1.16a

Digit Span Forward Backward

7.86 4.14

0.86 1.10

40.9 31.8

8.62 6.12

1.50 2.10

22.2 0

0.093 0.012b

0.81 1.18a

TMT Trail A Trail B Trail B – A

59.12 207.80 150.11

10.86 63.23 60.61

81.25 90.1 –

49.30 124.02 45.13

14.90 55.23 14.97

33.3 50.0 –

0.149 0.047b 0.006b

0.78 1.17a 1.48a

SCWT Stroop I Stroop II Stroop III SIE

21.66 22.71 45.49 21.66

12.85 8.54 9.37 12.85

63.6 63.6 100 –

15.42 17.73 28.72 12.14

4.99 4.65 6.77 5.44

18.2 27.3 27.3 –

0.076 0.212 0.001b 0.026b

0.91 0.75 1.37a 0.88

CFST

12.00

0.00

0

12.00

0.00

0

1.000

0

CDT 5 scores Watson

3.66 3.78

1.21 2.29

70.6 55.6

4.61 0.67

0.42 1

11.1 0

0.033b 0.001b

0.84a 1.27a

Bender-Gestalt test

6.25

1.94

–

0.78

0.64

–

0.004b

2.66a

Scores are gained from standardized protocols. Statistical significance was set at p < 0.05. ICARS subscales: ICARS-1 = gesture and gait; ICARS-2 = kinetic function; ICARS-3 = speech disorders; ICARS-4 = oculomotor disorder. % = Percentage of neuropsychologically impaired patients; pVFT-fi = phonemic Verbal Fluency Testfluency index; sVFT-fi = semantic Verbal Fluency Test-fluency index; CFST = Color-Form Sorting Test; ES = effect size. a A significant difference between SCA3 and the control group can be interpreted as a large effect. b  Significant difference between SCA3 and control group.

maximum 34) 12.93 ± 6.45; ICARS-2 (kinetic function, maximum 52) 9.28 ± 2.33; ICARS-3 (speech disorders, maximum 8) 2.36 ± 1.39; ICARS-4 (oculomotor disorder, maximum 6) 3.57 ± 0.76. Patients with SCA3 displayed apparent dysfunctions in oculomotor function, gesture and gait.

Neuropsychological Assessment Comparisons, effect sizes and percentages of impaired subjects in each neuropsychological test for both the SCA3 patients and the controls are presented in table 2. A deviation of SCA3 patients from controls in multiple neuropsychological domains is illustrated with z scores in figure 1.

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General Intelligence Performance on the MMSE revealed no significant differences between SCA3 patients and controls.

SCA3 Control

Z score

1 0 –1 –2

-B

ST CF

ST

T CD

D

-F

Z score

4 2

b

0

ro St

ro St

op

op

B

op

T-

ro St

TM

III

II

I

Eur Neurol 2014;71:262–270 DOI: 10.1159/000357404

ST

6

A

266

D

8

T-

Frontal Executive Function Trail-Making Test. The time needed to complete Trail A in patients and controls did not differ significantly between the two groups, but it took significantly more time for SCA3 patients to finish Trail B (207.8 ± 63.23 s for patients; 124.02 ± 55.23 s for controls). The Trail B – A subtraction score revealed more difficulties in accomplishing the task for SCA3 patients (150.11 ± 60.61 s for patients; 54.13 ± 14.97 s for controls), which indicated possible deficits in attention and visual searching ability. Lower Trail B/A ratios (3.66 ± 1.16) in patients with SCA3 demonstrated possible impairments in executive functions, such as mental flexibility and attention resourcing, especially in complicated task. Stroop Color-Word Test. The time taken to complete the first two subtasks (Stroop I and II) did not differ sig-

FT

10

TM

Attention and Working Memory The performance of subjects on the Digit Span test (forward) indicated no significant degradation in attention but significantly impaired working memory (backward, SCA3: 4.14 ± 1.1; controls: 6.12 ± 2.1) in native Chinese speakers with SCA3.

pV

–3

FT ay sV el D TVL l RA ta CTo TVL RA

a

C-

Verbal Function Verbal Fluency. Patients with SCA3 generated 7.8 ± 1.32 nouns in the phonemic test and 15.71 ± 3.67 nouns in the semantic test, while controls had 13.2 ± 1.35 and 21.61 ± 5.76 nouns, respectively. The time taken for patients to generate one word was 7.72 ± 2.48 s in the phonemic test (phonemic VFT-fi) and 3.0 ± 1.23 s in the semantic test (semantic VFT-fi), while controls took 4.15 ± 1.49 s for one word in the phonemic test and 1.86 ± 0.87 s in the semantic test. Phonemic and semantic fluency were both significantly impaired in SCA3 patients. Furthermore, the VFT-fi indicated that phonemic and semantic fluency were equally affected in Chinese patients with SCA3 (p = 0.336). Verbal Memory. The total recall in trails 1–3 and 1–5 for SCA3 patients was 19.75 ± 7.41 and 40.41 ± 11.3, respectively, while 26.38 ± 5.85 and 51.63 ± 9.52 for controls, respectively. Delayed recall scores were 8.89 ± 3.16 for patients and 12.88 ± 2.3 for controls. Both the CRAVLT total recall in trails 1–3 and 1–5 demonstrated declines in transient memory in SCA3 subjects, while lower scores on the C-RAVLT delayed recall suggested impaired long-term memory.

2

Fig. 1. Neuropsychological impairment of native Chinese patients

with SCA3. Derivations of SCA3 patients in respective neuropsychological domains from controls are expressed by z scores. a Tests of which the lower score indicates dysfunction. sVFT = Semantic Verbal Fluency Test; pVFT = phonemic Verbal Fluency Test; DSTF = Digit Span forward; DST-B = Digit Span backward; CFST = Color-Form Sorting Test. b Tests of which the higher score indicates impairment.

nificantly between both groups, but the time taken on Stroop III (45.49 ± 9.37 s for patients; 28.72 ± 6.77 s for controls) was significantly longer for patients. The SIE (21.66 ± 12.85 for patients; 12.14 ± 5.44 for controls) was also worse for patients with significant difference. We suggested that native Chinese speakers with SCA3 presented more disturbances in the incongruent condition than controls. Color-Form Sorting Test. Both SCA3 patients and controls did well in this task and no significant differences were found. Feng/Chen/Hou/Huang/Lu/Liang/Li

Visuospatial Function Participants’ performance on the CDT, evaluated by both the AD Cooperative Study method (3.66 ± 1.21 for patients; 4.61 ± 0.42 for controls) and the Watson scoring system (3.78 ± 2.29 for patients; 0.67 ± 1.0 for controls), indicated deficits in visuospatial abilities in Chinese with SCA3. Performance on the Bender-Gestalt test also revealed impairments in visuoconstructive and planning abilities in patients (6.25 ± 1.94 for patients; 0.78 ± 0.64 for controls). Statistical Analysis All neuropsychological tests that showed significant performance differences between patients and controls had large effect sizes (table  2). Spearman’s correlations were applied for the correlation study (table 3). The degree of ataxia correlated with C-RAVLT total recall 1–3, C-RAVLT delayed recall, phonemic fluency, visuospatial and planning abilities. Education positively correlated with attention but negatively correlated with long-term verbal memory. Visuoconstructive and planning abilities were both negatively correlated with depression and CAG repeat lengths, while ataxia correlated with phonemic verbal fluency, verbal memory, SIE, and visuospatial abilities. The MMSE score was negatively correlated with the degree of anxiety although it did not significantly differ between patients and controls. All significant correlations were verified with multivariate binary logistic regression (table 4). However, only the severity of an oculomotor disorder and the education level were predictive of cognitive impairments in native Chinese speakers with SCA3.

Table 3. Correlation study

Items

Correlated factors

MMSE Verbal fluency: phonemic Verbal fluency: VFT-fi C-RAVLT: Total recall 1–3 C-RAVLT: 20-min recall Digit Span: forward SCWT: SIE CDT: 5 scores CDT: Watson Bender-Gestalt test

ICARS-1 and 2 (–), SAS (–) ICARS-2 (–) ICARS-2 (+) ICARS-1 (+) ICARS-4 (–), Education (–) Education (+) ICARS-4 (+) ICARS-1 and 3 (–) ICARS-3 (+) CAG (–), SDS (–)

ICARS subscales: ICARS-1 = gesture and gait; ICARS-2 = kinetic function; ICARS-3 = speech disorders; ICARS-4 = oculomotor disorder. Results of other tests listed in table 2 were not correlated with any of the variables assessed. Statistical significance was set at p < 0.05. (+) = Positive correlation; (–) = negative correlation.

Table 4. Multivariate binary logistic regression

Dependent variables

Independent variables

p value

Coefficient

Occurrence of cognitive impairment

Duration CAG Education ICARS ICARS-1 ICARS-2 ICARS-3 ICARS-4 SDS SAS

0.986 0.878 0.002a 0.973 0.926 0.982 0.136 0.001a 0.051 0.973

– – –5.022 – – – – –5.318 –1.190 –

a Statistical

significance was set at p < 0.05.

Discussion

There are three major findings of our study on cognitive impairment in native Chinese with SCA3. First, it revealed the impairment of phonemic fluency and executive dysfunction, including interruption inhibition, attention resources, generation process, visual searching and sequencing abilities, etc. Second, disrupted verbal memory and visuospatial function have been detected. Third, the degree of ataxia and CAG repeat length were both found to be correlated with cognitive impairment, while only education and oculomotor dysfunction were suggestive of cognitive impairment. Impaired executive function has been reported in previous studies [8, 10]. In the current study, 100% of subjects with SCA3 displayed impairment in the SCWT

Stroop III and significantly impaired SIE, which indicated the disruption of cognitive flexibility and inhibitory control [8]. Theoretically, Stroop interference arises primarily from response competition between the color and the word at the output stage, but not from initial stimulus identification or the evaluation stage [46]. It has been demonstrated that during the SCWT, robust activation occurred in the anterior cingulated cortex, prefrontal cortex, motor cortex, inferior temporal gyrus as well as the superior and inferior parietal cortices [16, 47]. In native Chinese speakers with SCA3, the involvement of frontal and parietal lobes might participate in the development of a greater Stroop effect because these areas are needed

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to control irrelevant information inference and to make an appropriate judgment [16]. Intriguingly, Braga-Neto et al. [8] failed to find similar change in the SCWT. This inconsistency might be explained by differences in visual word recognition between ideographic and alphabetic systems. The faster the irrelevant stimulus is analyzed, the greater the Stroop interference is [48]. A strictly visual form-to-meaning process during the recognition of Chinese characters is faster than the English processing transition from orthographic forms to phonological forms then to meaning [49, 50]. Thus, greater interference was observed for Chinese characters than for English words in healthy native speakers [51]. Another significant executive dysfunction has been detected by TMT. Attention resources, simple motor and spatial skills, visual searching and sequencing abilities are all needed to complete both Trail A and B in the TMT. Additionally, Trail B requires extra cognitive effort due to the need for mental flexibility and divided attention [33, 52]. Subjects with SCA3 exhibited apparent disturbance in TMT-B with the percentage of impaired subjects up to about 90%. We further assessed the two subsets with index Trail B – A, controlling for the motor and searching requirements of the task, to discover significant impairments in aforementioned executive functions. Moreover, a TMT B/A ratio score less than 2 demonstrates relatively greater impairment on TMT-A, whereas a ratio score greater than 3 suggests relatively greater impairment on TMT-B [33]. Therefore, relatively greater impairments in TMT-B suggested that SCA3 patients have more difficulties in handling complicated tasks, which resulted from the involvement of the frontal cortex [8]. Phonemic verbal fluency has been reported to be impaired in SCA3 in a series of studies [8, 10, 12]. It has been reported that greater activation was found in the left precentral and inferior frontal gyrus for phonemic fluency [53]. Thus it is supposed that phonemic fluency is associated with frontal lobe involvement and sensitive to executive dysfunction [54]. The impairment of phonemic fluency that was found in our study confirmed the results of previous studies. Consistent with the SWCT and TMT, the most impaired domain in Chinese patients with SCA3 was the frontal cortex. Given the prominent frontal dysfunction has already been described in patients with SCA including SCA3 [13], the anatomic connection between cerebellum and frontal lobe may play a role in frontal dysfunction, particularly attention, memory and executive deficits. Furthermore, the impairment on not only phonemic but also semantic verbal fluency was also observed in the 268

Eur Neurol 2014;71:262–270 DOI: 10.1159/000357404

current study, which was different from the results of previous studies in an alphabetic system [8, 10]. The semantic fluency task was associated with the involvement of left parietal (middle frontal gyrus) and temporal lobes (fusiform gyrus) [53]. Compared to English reading, reading Chinese characters leads to a greater activation of the left fusiform gyrus [18], which is also the area intensively involved in semantic fluency tasks [53]. Thus we speculate on greater reliance upon the left fusiform gyrus when dealing with Chinese characters in the semantic task. Damage in this area, which was compensable for English patients, might lead to more prominent deficits in semantic fluency for Chinese-speaking patients than for native English speakers [18]. Compromised visuospatial function and verbal memory have been reported in SCA3 patients in several neuropsychological studies [6, 8, 10]. In our study, we confirmed previous results in a smaller proportion but still significantly more than that of controls by using the CDT to screen for visuospatial impairment and the BenderGestalt test for visuoconstructive and planning abilities. It might also be attributed to parietal dysfunction. CDT performance has been considered to be related to cerebellar metabolism [55]. Poor performance on the CDT correlates with activity in the bilateral inferior parietal lobes, premotor cortex and cerebellum [56]. Results from the Bender-Gestalt test provided evidence supporting visuospatial dysfunctions in SCA3 patients, which might also be attributed to impairment in parietal lobes. Meanwhile, interrupted verbal memory supported the impairment in the temporal lobe. Additionally, it has been reported that depression is pervasive among patients with SCA3 and it contributes to a poorer performance in cognition [9, 10, 57]. Nevertheless, scant data is available on conditions that control for depression and anxiety. Given the effects of mental status on cognition [9, 58], we added scores on the SAS and SDS to the demographic matching items for the control group to guarantee refined results. Moreover, considering the inevitable existence of movement disorders in patients with SCA3, we made some methodological improvements according to the literature. Nevertheless, we timed subjects with standard measurements as required in most tasks. Indexes such as the VFT-fi, TMT B – A and TMT B/A were introduced to eliminate the effects of ataxia or dysarthria. Only tests of visuospatial and visuoconstructive functions (the CDT) were not timed as required. The reason for these methodological alterations lies in the fact that ataxia is known to affect the completion of these tasks; meanwhile the total time taken is not essential. The untimed method Feng/Chen/Hou/Huang/Lu/Liang/Li

has been applied in previous studies and this methodological alteration helps to gain refined data [6, 30, 59]. Statistical analysis elucidated a correlation between CAG repeat length and visuoconstructive ability, as well as between the degree of ataxia and visuospatial function. The correlation between CAG repeat length and cognitive impairment has not been reported before and the correlation between ataxia severity and cognition is still controversial [6, 10–12]. There should be more multicenter studies based upon larger data samples or metaanalyses to elucidate their relationships. The mechanism of these correlations is still unknown, which may result from the wide involvement of the brain in SCA3. Furthermore, regression analysis revealed a relationship between the score on the ICARS-4 and cognitive impairments on the basis of the correlation between ICARS-4 score and both verbal memory and SIE score. The ICARS-4 is usually interpreted as an assessment of oculomotor disorder, which might be due to the impairment of multiple areas including the frontal lobes, cerebellum and brain stem. The oculomotor dysfunction, one of the characteristics of

cerebellar ataxia, might also be one of the predictors of cognitive impairment. Limitations of the current study include the absence of  neuroimaging data. The lack of some norms in the Chinese population makes it difficult to define the accurate proportion of impaired patients on some subjects. The current study confirmed the impairment of executive function and phonemic fluency, the percentage of which is all above 90%. Structurally all of these cognitive dysfunctions have the involvement of the frontal lobe in common. Disruption of semantic fluency in a native Chinese population, which was a unique finding, indicated the impairment of the parietal lobe along with visuospatial dysfunction. Consistent with previous findings, we detected interrupted verbal memory, which reveals temporal lobe involvement. The degree of ataxia and CAG repeat length were both correlated with cognition. Also oculomotor disorder was found to be suggestive of cognitive impairment as well as ataxia. Whether these particular neural network deficits are associated with the unique pictographic nature of Chinese should be tested in future studies.

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