Amyotrophic Lateral Sclerosis and Frontotemporal Degeneration, 2015; 16: 40–45
Screening for cognitive impairment in a Chinese ALS population
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QIANQIAN WEI1, XUEPING CHEN1, ZHENZHEN ZHENG1, RUI HUANG1, XIAOYAN GUO1, BEI CAO1, THOMAS H. BAK2 & HUIFANG SHANG1 1Department of Neurology, West China Hospital, Sichuan University, Chengdu, Sichuan, China, and 2Centre for Cognitive Aging and Cognitive Epidemiology, The University of Edinburgh, Edinburgh, UK
Abstract Despite growing interest in cognitive impairment of ALS patients, there are only limited studies available that characterize cognitive deficits in the Chinese ALS population through highly sensitive and specific screening tools. The Chinese version of the Addenbrooke’s Cognitive Examination-revised (ACE-R) and mini-mental state examination (MMSE) were applied to evaluate cognitive function in 145 sporadic ALS patients and 50 healthy controls. The mean onset age was 50.72 ⫾ 12.38 years. Results showed that the prevalence of cognitive deficits was 14.48% and 30.34% based on the MMSE and ACE-R, respectively. Patients had a broad range of cognitive impairment domains, including language (26.21%), orientation/attention (24.13%), visuospatial ability (24.13%), memory (23.45%) and verbal fluency (22.76%). Logistic regression indicated that older age of onset, female gender and lower educational levels were potential determinants of cognitive deficits in ALS. Multiple regression analyses showed that the cognitive deficit during the baseline visit was not associated with the progression rate of ALS. In conclusion, cognitive impairment is common in Chinese ALS patients, but does not necessarily worsen the progression of ALS. ACE-R is superior to MMSE in detecting deficits in patients. Cognitive impairment in ALS patients may relate to age of onset, female gender and lower education level. Key words: Amyotrophic lateral sclerosis, Addenbrooke’s Cognitive Examination-revised, mini-mental state examination, cognitive impairment, cognitive screening
Introduction Studies have been increasingly suggesting that amyotrophic lateral sclerosis (ALS) is more than a motor neuron disease, and involves extramotor manifestations such as cognitive impairment in its different domains. Previous studies have reported that up to 50% of ALS patients suffered from cognitive impairment, predominantly in the realm of executive and language functions (1–3), with 10–15% meeting the diagnosis of ALS-frontotemporal dementia (ALS-FTD) (4,5). Verbal fluency, memory, visuospatial functions and social cognition have also been reported to be affected (6–9). Evidence from neuroimaging and pathological evaluations has deepened our understanding of the potential pathophysiological mechanism underlying cognitive impairment in ALS. Structural and functional neuroimaging studies have suggested that abnormalities
in the frontal lobe are highly associated with cognitive impairment in ALS (10,11). Neuropathological studies have indicated the involvement of the prefrontal cortex and its close association with ALS and FTD (12). Despite growing interest in the cognitive impairment of ALS patients, there are limited studies characterizing cognitive deficits in the Chinese ALS population. Yuan et al. investigated cognitive function in 22 Chinese ALS patients during the early stage, and showed that reduction of cognition could be influenced by the severity of bulbar symptoms and educational levels (13). Ji et al. showed there was no difference in cognitive function between bulbar-onset and spinal-onset patients (14). In summary, cognitive impairment is currently poorly characterized in Chinese ALS populations. An ideal cognitive screening instrument for ALS should be comprehensive, simple to administer,
Correspondence: H. Shang, Department of Neurology, West China Hospital, Sichuan University, 610041 Chengdu, Sichuan, China. Fax: ⫹ 86 028 85423550. E-mail: [email protected] (Received 7 April 2014 ; accepted 12 September 2014 ) ISSN 2167-8421 print/ISSN 2167-9223 online © 2014 Informa Healthcare DOI: 10.3109/21678421.2014.966311
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Screening for cognitive impairment in Chinese ALS patients assess a range of cognitive domains, and be sensitive to the initial stage of cognitive impairment. Although the mini-mental state examination (MMSE) is the most commonly used screening instrument for global cognition, the extent of its usefulness has been questioned, especially in milder forms of cognitive impairment (15–17). Limitations of MMSE restricted its use in cognitive screening in ALS patients (5). The Addenbrooke’s Cognitive Examinationrevised (ACE-R), a multidimensional test allowing not only an overall assessment of cognition but also a profile of different cognitive domains, which was developed as a brief cognitive assessment instrument and incorporates elements of MMSE, was initially used in the early detection of dementia and in distinguishing AD from FTD. It can be administered without trained personnel, and can be completed in approximately 15 min. The validation of different ACE-R versions has been performed in several countries (18–21), and it has been shown to be superior to the MMSE in the detection of cognitive dysfunction in patients with neurodegenerative diseases, such as Parkinson’s disease (PD) (22), Alzheimer’s disease (AD) (23), mild cognitive impairment (MCI) (24), multiple system atrophy (MSA) (25), progressive supranuclear palsy (PSP) (25), corticobasal degeneration (CBD) (25) and Huntington’s disease (HD) (26). ACE-R was also applied to facilitate recruitment of a non-demented ALS sample in a previous study (27). The Chinese version of ACE-R was a reliable assessment tool for screening for MCI and AD with the different cut-off scores of 86 and 68, respectively (20). This study aimed to investigate the spectrum and features of cognitive impairment in Chinese ALS patients by both MMSE and ACE-R. The associations of cognitive functions with a variety of diseasespecific factors and disease prognosis were further investigated in a large cohort of ALS patients. Patients and methods The study was conducted in a tertiary referral centre in the south-west of China (Department of Neurology, West China Hospital of Sichuan University). ALS patients were recruited from June 2012 to September 2013. All patients had clinical and electrophysiological evidence of combined upper and lower motor neuron involvement and fulfilled the El Escorial revised criteria for definite or probable ALS (28). The exclusion criteria were as follows: 1) severe dysarthria and hand weakness, or 2) patient met the criteria of ALS-FTD (29); 3) a history of other neurologic conditions that could affect assessment (brain injury, stroke, alcohol/substance related disorders, or experiencing depression or major psychiatric disease). Disease duration was defined as the time from first symptom onset to first evaluation of ACE-R. It was classified into spinal (upper limb, lower limb) and bulbar onset according to the site of
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onset. The healthy control group consisted of 50 age-, gender- and education- matched subjects who were chose from the same region. None of the controls had any neurological diseases. During the baseline visit, the revised ALS functional rating scale (ALSFRS-R) was applied to assess the severity of the disease. Both the Chinese version of ACE-R (http://www.ftdrg.org) and MMSE were administered to all patients and controls by neurologists in a standardized manner. The ACE-R evaluates five cognitive domains including orientation/ attention (18 points), memory (26 points), verbal fluency (14 points), language (26 points) and visuospatial ability (16 points), and has a maximal total score of 100, with higher scores representing better cognitive function. Cognitive impairment was defined as a total score less than 1.5 standard deviations of the controls’ mean on the ACE-R, or a total score of less than 26 on the MMSE score (30). Patients have been followed with telephone or face to face in three-month intervals by our neurologists. Survival was defined as death, or tracheotomy, which was considered equivalent to death. The ALSFRS-R score was followed and evaluated by telephone or face to face. The rate of ALS progression was presented as the changes of ALSFRS-R per month (DALSFRS-R/m) (Formula: ALSFRS-R score at the last visit – ALSFRS-R score at the baseline visit/ month intervals between the assessments). Informed written consent was obtained from all participants and the study was approved by the Sichuan University Ethics Committee. Data analysis Comparisons of continuous variables between groups were conducted using Student’s t-test when the variables were normally distributed or the MannWhitney U-test when the variables did not meet the requirements for Student’s t-test. A χ2 test was used to compare categorical variables. Potential determinants of cognitive impairment (age of onset, gender, education, ALSFRS-R, site of onset, and disease duration) were studied by using binary logistic regression models. The association between cognitive deficit and the progression of ALS was conducted by multiple linear regression analysis. The changes of ALSFRS-R per month were used as dependent variables and the age of onset, gender, education, ALSFRS-R, cognitive status during the baseline visit, site of onset, and use of riluzole were employed as independent variables. Data analysis was performed using SPSS 18.0 statistical software. p ⬍ 0.05 was considered to be statistically significant. Results Of the 269 patients diagnosed with ALS, 10 patients with FTD, 29 with severe dysarthria, 21 with severe
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Q. Wei et al. Table I. Normative data of healthy controls on the ACE-R.
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Variables Age (Years) Gender (M/F) Education (Years) ACE-R total score (Max 100) Orientation/attention (Max 18) Memory (Max 26) Verbal fluency (Max 14) Language (Max 26) Visuospatial ability (Max 16)
Mean (SD) 50.41 27/23 9.99 86.94 17.64 23.38 10.38 20.90 14.46
(10.08) (3.54) (8.16) (0.75) (2.33) (2.24) (3.87) (1.71)
Range
Cut-off score
30 –73 – 2 –19 70 –100 14 –18 18 –26 5 –14 13 –26 9 –16
– – – 74/75 16/17 19/20 7/8 15/16 11/12
M: male; F: female; Max: maximum score; SD: standard deviation. Cut-off was based on 1.5 SD from the controls’ mean. A score less than this value indicated impairment.
hand weakness, and 20 with severe anxiety and depression were excluded due to incomplete ACE-R assessment. Forty-four patients who refused to perform the ACE-R assessment were also excluded. Finally, a total of 145 ALS patients were included in the analyses. The demographic variables of healthy controls and cut-off scores on ACE-R are presented in Table I. Cognitive deficit was defined as a total score ACE-R less than 75. Based on the MMSE scores, 21 patients (14.48%) had cognitive impairment. However, the prevalence of cognitive deficit was 30.34% (44/145) according to ACE-R scores. Patients with a total score of more than 75 had significantly higher scores in every domain of ACE-R. The most frequent cognitive deficit domain was language (26.21%) followed by orientation/attention (24.13%), visuospatial ability (24.13%), memory (23.45%), and verbal fluency (22.76%) (Figure 1). A significantly higher prevalence of cognitive deficits was found in female patients than in male patients (39.34% vs. 23.81%, p ⫽ 0.045), but there was no difference among bulbar-onset, upper limb-onset and lower limb-onset groups (33.33%, 27.5%, 34.09%, respectively, p ⫽ 0.709) (Table II). Patients with cognitive impairment had significantly older
age of onset and lower educational levels (p ⫽ 0.027 and p ⬍ 0.001, respectively) (Table II) than patients without cognitive impairment. There were no differences in ALSFRS-R, onset form and disease duration between patients with and without cognitive impairment (Table II). Education level revealed no difference between male and female patients (p ⫽ 0.345) or between the spinal form and bulbar form groups (p ⫽ 0.858). The logistic regression model indicated that older age of onset (OR: 1.051, 95% CI 1.000–1.103, p ⫽ 0.048), female gender (OR: 3.220, 95% CI 1.019–10.174, p ⫽ 0.046) and lower educational level (OR: 0.554, 95% CI 0.429–0.716, p ⬍ 0.001) were the potential independent determinants of cognitive impairment in ALS (Table III). Of 145 patients, 122 were alive while 16 patients were deceased by the end of our study. Seven patients were lost to follow-up. In nine patients the interval between the assessments was less than three months. Finally, a total of 113 patients were included in the multiple linear regression analysis to investigate the association between cognitive function and disease progression. Age of onset, gender, educational level, ALSFRS-R and cognitive status during the baseline
Figure 1. The frequencies of abnormal performances in ACE-R total score and in individual cognitive domains.
Screening for cognitive impairment in Chinese ALS patients
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Table II. Clinical and cognitive features of ALS patients based on the ACE-R scores. All patients (n ⫽ 145)
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Variables
50.72 ⫾ 12.38 Age of onset (Years) a (Mean ⫾ SD) Gender (M/F) 84/61 Education (years) (Mean ⫾ SD) 9.27 ⫾ 3.78 ALSFRS-R (Mean ⫾ SD) 41.72 ⫾ 4.63 80/44/21 Onset form (UL/LL/Bulbar) b Disease duration (months) (Mean ⫾ SD) 13.88 ⫾ 8.15 MMSE scores (Mean ⫾ SD) 27.71 ⫾ 2.27 ACE-R total scores (Mean ⫾ SD) 79.66 ⫾ 12.92
ACE-R ⱕ 74 (n ⫽ 44) 54.15 ⫾ 11.54 20/24 6.06 ⫾ 2.78 41.91 ⫾ 4.45 22/15/7 14.97 ⫾ 8.55 25.82 ⫾ 2.70 63.30 ⫾ 8.88
ACE-R ⱖ 75 (n ⫽ 101)
p -value
49.22 ⫾ 12.49 0.027* 64/37 0.045* 10.67 ⫾ 3.27 ⬍ 0.001* 0.843 41.64 ⫾ 4.72 58/29/14 0.709 0.315 13.40 ⫾ 7.97 28.53 ⫾ 1.43 ⬍ 0.001* 86.69 ⫾ 6.33 ⬍ 0.001*
M: male; F: female; ALSFRS-R: Amyotrophic Lateral Sclerosis Functional Rating Scale-revised; MMSE: Mini-Mental State Examination; UL: upper limb; LL: lower limb; ACE-R: Addenbrooke’s Cognitive Examination-revised; SD: Standard Deviation; * significant difference. a Mann-Whitney U -tests, except for the age of onset ( t- tests); SD: standard deviation. b χ2 test.
visit, site of onset and taking riluzole were not associated with DALSFRS-R/m (Table IV). Discussion This was the largest longitudinal study to explore the frequency of cognitive deficits and the relationship between cognitive deficits, and the progression and survival of ALS in a Chinese population. In the current study, the prevalence of cognitive impairment was as high as 30.34% based on ACE-R, and 14.48% based on MMSE, which is consistent with previous studies (5,31). Our findings suggest that ACE-R is superior to MMSE in screening cognitive impairment in ALS patients, and MMSE usefulness is limited, especially in milder forms of cognitive impairment. Due to its broader range of cognitive domains, ACE-R may be a more reliable bedside test to detect cognitive impairment in ALS patients. However, 20% of patients with severe motor impairment and severe dysarthria were excluded in the current study, which indicates that the limitations of ACE-R are used to screen the cognition of patients during the late stage. Wide ranges of cognitive impairment domains including ‘Language’, ‘Orientation/attention’, ‘Visuospatial ability’, ‘Memory’, and ‘Verbal fluency’ domains were found in the current study, which was consistent with previous results (8,32). Language disturbance was the most frequent cognitive deficit Table III. Determinants of cognitive impairment based on cutoff score of ACE-R (⬍ 75).
domain in the current study, which was supported by the study by Taylor et al. (3). However, in future studies we have to undertake additional tasks to confirm that language is the most common domain with deficits. The prevalence of visuospatial deficits was high in our study, which was inconsistent with a previous study (9). The following may be explanations for the differences: 1) The visuospatial domain in ACE-R required the subject to copy a pentagon and cube and to draw a clock. The executive impairments may impact on the visuospatial domain; 2) The study also asked the subject to identify four capital letters, which might not conform to Chinese reading habits. After we removed the test ‘to identify four letters’, the prevalence of visuospatial deficits (18.62%) was decreased and was the domain affected least. These two causes might exaggerate performance decrements. Massman et al. found poor recall but intact recognition in ALS patients (31), and Mantovan et al. reported deficits in delayed memory and recognition (6), which were also agreement with our results. Verbal fluency deficits in ALS patients in the current study were also supported by the study of Abrahams et al. (7). Our findings, together with the above-listed findings, suggested that cognitive impairment in ALS was not a universal feature, and its manifestations may be more heterogeneous than previously recognized (8). Aspects of cognitive impairment in ALS should be refined into more sophisticated and complicated processes. Table IV. Multiple linear regression analysis for the determinants of D ALSFRS-R/m.
Multivariate analyses Variables Clinical variables
p -value
Odds ratio (95% CI) p -value
Age of onset (Years) 1.051 (1.000 –1.103) 0.048* Gender (M/F) 3.220 (1.019 –10.174) 0.046* Education (Years) 0.554 (0.428 – 0.716) ⬍ 0.001* ALSFRS-R – – Onset form (bulbar/spinal onset) – – Disease duration – –
Age of onset Gender Education ALSFRS-R Clinical onset Medication with riluzole Cognitive status
0.673 0.525 0.952 0.266 0.610 0.237 0.305
ALSFRS-R: Amyotrophic Lateral Sclerosis Functional Rating Scale-revised; * significant difference.
ALSFRS-R: Amyotrophic Lateral Sclerosis Functional Rating Scale-revised.
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Q. Wei et al.
In the current study we found that older age of onset and female patients were likely to develop cognitive impairment more than younger age of onset and male patients, and multivariable analysis revealed that older age of onset, female gender, and lower educational levels were potential independent determinants of cognitive impairment. These results are consistent with the accepted views that cognitive decline is more universal in the general elderly population and increases with age (33), and that females have higher risk for cognitive decline than males (34). Furthermore, a meta-analysis reported that visual memory impairment in ALS patients was related to age (35). Studies from other degenerative diseases such as mild AD (21) and PD patients with MCI (36) showed that level of education could significantly affect the performance on the ACE-R. Therefore, educational level should be considered when using ACE-R to detect cognitive impairment in ALS patients. However, in the current study, no difference in educational level between male and female patients further supported that female gender was the determinant for cognition impairment independent of education level. Our study found that site of onset, disease duration and ALSFRS-R were not the determining factors for cognitive impairment in ALS. The relationship between cognitive deficits and motor function should be viewed with caution. A meta-analysis (35) and a study by Sterling et al. (37) also confirmed that cognitive deficits did not relate to bulbar onset. However, Gordon et al. found that bulbar onset was potentially associated with cognitive impairment (4). Therefore, a prospective study with a larger sample size and a follow-up study would provide more insight into cognitive impairment related to motor deficits of ALS patients. Our results showed that cognitive status did not contribute to the progression of ALS (DALSFRSR/m), which was inconsistent with results from previous studies (4, 38, 39). Gordon et al. found that severe cognitive impairment (but not mild cognitive impairment) was associated with poor survival (4). Elamin et al. found executive dysfunction specifically affected motor progression and survival (38). Oh et al. reported that ALS patients with cognitive impairment had shorter survival (39). Our result can be partly explained by the short follow-up and limited number of deceased patients. In addition, simple cognitive assessments but not tasks focused on frontal executive function were used during the cognition evaluation. Further prospective studies are required to verify the association between cognition and survival in ALS patients. This study should be interpreted with consideration of several limitations. First, cognitive deficits in ALS patients are defined by an ACE-R score of less than 75. However, due to the complexity of cognitive impairment, a hierarchical approach might be required using a combination of several cognitive screens
and/or behavioural questionnaires to define cognitive impairment in ALS patients. Patients with FTD, severe dysarthria and hand weakness were excluded, which might lead to a selection bias that could underestimate the prevalence of severe cognitive impairment. Conclusions Cognitive impairment is common in Chinese ALS patients but does not necessarily worsen the progression of ALS. ACE-R is a reliable and valid cognitive screening instrument, and it is superior to MMSE in detecting cognitive impairment in ALS patients. Ages of onset, gender and education level were potential independent determinants for cognitive impairment. Acknowledgements We thank the patients and their families for their participation in this study. Declaration of interest: The authors report no confl icts of interest. The authors alone are responsible for the content and writing of the paper. References 1. Abrahams S, Leigh P, Goldstein L. Cognitive change in ALS: a prospective study. Neurology. 2005;64:1222–6. 2. Bak TH, Hodges JR. The effects of motor neuron disease on language: further evidence. Brain Lang. 2004;89:354–61. 3. Taylor LJ, Brown RG, Tsermentseli S, Al-Chalabi A, Shaw CE, Ellis CM, et al. Is language impairment more common than executive dysfunction in amyotrophic lateral sclerosis? J Neurol Neurosurg Psychiatry. 2013;84:494–8 4. Gordon PH, Delgadillo D, Piquard A, Bruneteau G, Pradat PF, Salachas F, et al. The range and clinical impact of cognitive impairment in French patients with ALS: a cross-sectional study of neuropsychological test performance. Amyotroph Lateral Scler. 2011;12:372–8. 5. Ringholz G, Appel S, Bradshaw M, Cooke N, Mosnik D, Schulz P. Prevalence and patterns of cognitive impairment in sporadic ALS. Neurology. 2005;65:586–90. 6. Mantovan MC, Baggio L, Dalla Barba G, Smith P, Pegoraro E, Soraru G, et al. Memory deficits and retrieval processes in ALS. Eur J Neurol. 2003;10:221–7. 7. Abrahams S, Leigh PN, Harvey A, Vythelingum GN, Grise D, Goldstein LH. Verbal fluency and executive dysfunction in amyotrophic lateral sclerosis (ALS). Neuropsychologia. 2000;38:734–47. 8. Phukan J, Elamin M, Bede P, Jordan N, Gallagher L, Byrne S, et al. The syndrome of cognitive impairment in amyotrophic lateral sclerosis: a population based study. J Neurol Neurosurg Psychiatry. 2011;83:102–8. 9. Abrahams S, Newton J, Niven E, Foley J, Bak TH. Screening for cognition and behaviour changes in ALS. Amyotroph Lateral Scler Frontotemporal Degener. 2014;15:9–14. 10. Abrahams S, Goldstein L, Simmons A, Brammer M, Williams S, Giampietro V, et al. Word retrieval in amyotrophic lateral sclerosis: a functional magnetic resonance imaging study. Brain. 2004;127:1507–17. 11. Abrahams S, Goldstein LH, Suckling J, Ng V, Simmons A, Chitnis X, et al. Frontotemporal white matter changes in amyotrophic lateral sclerosis. J Neurol. 2005;252:321–31.
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Screening for cognitive impairment in a Chinese ALS population
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QIANQIAN WEI1, XUEPING CHEN1, ZHENZHEN ZHENG1, RUI HUANG1, XIAOYAN GUO1, BEI CAO1, THOMAS H. BAK2 & HUIFANG SHANG1 1Department of Neurology, West China Hospital, Sichuan University, Chengdu, Sichuan, China, and 2Centre for Cognitive Aging and Cognitive Epidemiology, The University of Edinburgh, Edinburgh, UK
Abstract Despite growing interest in cognitive impairment of ALS patients, there are only limited studies available that characterize cognitive deficits in the Chinese ALS population through highly sensitive and specific screening tools. The Chinese version of the Addenbrooke’s Cognitive Examination-revised (ACE-R) and mini-mental state examination (MMSE) were applied to evaluate cognitive function in 145 sporadic ALS patients and 50 healthy controls. The mean onset age was 50.72 ⫾ 12.38 years. Results showed that the prevalence of cognitive deficits was 14.48% and 30.34% based on the MMSE and ACE-R, respectively. Patients had a broad range of cognitive impairment domains, including language (26.21%), orientation/attention (24.13%), visuospatial ability (24.13%), memory (23.45%) and verbal fluency (22.76%). Logistic regression indicated that older age of onset, female gender and lower educational levels were potential determinants of cognitive deficits in ALS. Multiple regression analyses showed that the cognitive deficit during the baseline visit was not associated with the progression rate of ALS. In conclusion, cognitive impairment is common in Chinese ALS patients, but does not necessarily worsen the progression of ALS. ACE-R is superior to MMSE in detecting deficits in patients. Cognitive impairment in ALS patients may relate to age of onset, female gender and lower education level. Key words: Amyotrophic lateral sclerosis, Addenbrooke’s Cognitive Examination-revised, mini-mental state examination, cognitive impairment, cognitive screening
Introduction Studies have been increasingly suggesting that amyotrophic lateral sclerosis (ALS) is more than a motor neuron disease, and involves extramotor manifestations such as cognitive impairment in its different domains. Previous studies have reported that up to 50% of ALS patients suffered from cognitive impairment, predominantly in the realm of executive and language functions (1–3), with 10–15% meeting the diagnosis of ALS-frontotemporal dementia (ALS-FTD) (4,5). Verbal fluency, memory, visuospatial functions and social cognition have also been reported to be affected (6–9). Evidence from neuroimaging and pathological evaluations has deepened our understanding of the potential pathophysiological mechanism underlying cognitive impairment in ALS. Structural and functional neuroimaging studies have suggested that abnormalities
in the frontal lobe are highly associated with cognitive impairment in ALS (10,11). Neuropathological studies have indicated the involvement of the prefrontal cortex and its close association with ALS and FTD (12). Despite growing interest in the cognitive impairment of ALS patients, there are limited studies characterizing cognitive deficits in the Chinese ALS population. Yuan et al. investigated cognitive function in 22 Chinese ALS patients during the early stage, and showed that reduction of cognition could be influenced by the severity of bulbar symptoms and educational levels (13). Ji et al. showed there was no difference in cognitive function between bulbar-onset and spinal-onset patients (14). In summary, cognitive impairment is currently poorly characterized in Chinese ALS populations. An ideal cognitive screening instrument for ALS should be comprehensive, simple to administer,
Correspondence: H. Shang, Department of Neurology, West China Hospital, Sichuan University, 610041 Chengdu, Sichuan, China. Fax: ⫹ 86 028 85423550. E-mail: [email protected] (Received 7 April 2014 ; accepted 12 September 2014 ) ISSN 2167-8421 print/ISSN 2167-9223 online © 2014 Informa Healthcare DOI: 10.3109/21678421.2014.966311
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Screening for cognitive impairment in Chinese ALS patients assess a range of cognitive domains, and be sensitive to the initial stage of cognitive impairment. Although the mini-mental state examination (MMSE) is the most commonly used screening instrument for global cognition, the extent of its usefulness has been questioned, especially in milder forms of cognitive impairment (15–17). Limitations of MMSE restricted its use in cognitive screening in ALS patients (5). The Addenbrooke’s Cognitive Examinationrevised (ACE-R), a multidimensional test allowing not only an overall assessment of cognition but also a profile of different cognitive domains, which was developed as a brief cognitive assessment instrument and incorporates elements of MMSE, was initially used in the early detection of dementia and in distinguishing AD from FTD. It can be administered without trained personnel, and can be completed in approximately 15 min. The validation of different ACE-R versions has been performed in several countries (18–21), and it has been shown to be superior to the MMSE in the detection of cognitive dysfunction in patients with neurodegenerative diseases, such as Parkinson’s disease (PD) (22), Alzheimer’s disease (AD) (23), mild cognitive impairment (MCI) (24), multiple system atrophy (MSA) (25), progressive supranuclear palsy (PSP) (25), corticobasal degeneration (CBD) (25) and Huntington’s disease (HD) (26). ACE-R was also applied to facilitate recruitment of a non-demented ALS sample in a previous study (27). The Chinese version of ACE-R was a reliable assessment tool for screening for MCI and AD with the different cut-off scores of 86 and 68, respectively (20). This study aimed to investigate the spectrum and features of cognitive impairment in Chinese ALS patients by both MMSE and ACE-R. The associations of cognitive functions with a variety of diseasespecific factors and disease prognosis were further investigated in a large cohort of ALS patients. Patients and methods The study was conducted in a tertiary referral centre in the south-west of China (Department of Neurology, West China Hospital of Sichuan University). ALS patients were recruited from June 2012 to September 2013. All patients had clinical and electrophysiological evidence of combined upper and lower motor neuron involvement and fulfilled the El Escorial revised criteria for definite or probable ALS (28). The exclusion criteria were as follows: 1) severe dysarthria and hand weakness, or 2) patient met the criteria of ALS-FTD (29); 3) a history of other neurologic conditions that could affect assessment (brain injury, stroke, alcohol/substance related disorders, or experiencing depression or major psychiatric disease). Disease duration was defined as the time from first symptom onset to first evaluation of ACE-R. It was classified into spinal (upper limb, lower limb) and bulbar onset according to the site of
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onset. The healthy control group consisted of 50 age-, gender- and education- matched subjects who were chose from the same region. None of the controls had any neurological diseases. During the baseline visit, the revised ALS functional rating scale (ALSFRS-R) was applied to assess the severity of the disease. Both the Chinese version of ACE-R (http://www.ftdrg.org) and MMSE were administered to all patients and controls by neurologists in a standardized manner. The ACE-R evaluates five cognitive domains including orientation/ attention (18 points), memory (26 points), verbal fluency (14 points), language (26 points) and visuospatial ability (16 points), and has a maximal total score of 100, with higher scores representing better cognitive function. Cognitive impairment was defined as a total score less than 1.5 standard deviations of the controls’ mean on the ACE-R, or a total score of less than 26 on the MMSE score (30). Patients have been followed with telephone or face to face in three-month intervals by our neurologists. Survival was defined as death, or tracheotomy, which was considered equivalent to death. The ALSFRS-R score was followed and evaluated by telephone or face to face. The rate of ALS progression was presented as the changes of ALSFRS-R per month (DALSFRS-R/m) (Formula: ALSFRS-R score at the last visit – ALSFRS-R score at the baseline visit/ month intervals between the assessments). Informed written consent was obtained from all participants and the study was approved by the Sichuan University Ethics Committee. Data analysis Comparisons of continuous variables between groups were conducted using Student’s t-test when the variables were normally distributed or the MannWhitney U-test when the variables did not meet the requirements for Student’s t-test. A χ2 test was used to compare categorical variables. Potential determinants of cognitive impairment (age of onset, gender, education, ALSFRS-R, site of onset, and disease duration) were studied by using binary logistic regression models. The association between cognitive deficit and the progression of ALS was conducted by multiple linear regression analysis. The changes of ALSFRS-R per month were used as dependent variables and the age of onset, gender, education, ALSFRS-R, cognitive status during the baseline visit, site of onset, and use of riluzole were employed as independent variables. Data analysis was performed using SPSS 18.0 statistical software. p ⬍ 0.05 was considered to be statistically significant. Results Of the 269 patients diagnosed with ALS, 10 patients with FTD, 29 with severe dysarthria, 21 with severe
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Q. Wei et al. Table I. Normative data of healthy controls on the ACE-R.
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Variables Age (Years) Gender (M/F) Education (Years) ACE-R total score (Max 100) Orientation/attention (Max 18) Memory (Max 26) Verbal fluency (Max 14) Language (Max 26) Visuospatial ability (Max 16)
Mean (SD) 50.41 27/23 9.99 86.94 17.64 23.38 10.38 20.90 14.46
(10.08) (3.54) (8.16) (0.75) (2.33) (2.24) (3.87) (1.71)
Range
Cut-off score
30 –73 – 2 –19 70 –100 14 –18 18 –26 5 –14 13 –26 9 –16
– – – 74/75 16/17 19/20 7/8 15/16 11/12
M: male; F: female; Max: maximum score; SD: standard deviation. Cut-off was based on 1.5 SD from the controls’ mean. A score less than this value indicated impairment.
hand weakness, and 20 with severe anxiety and depression were excluded due to incomplete ACE-R assessment. Forty-four patients who refused to perform the ACE-R assessment were also excluded. Finally, a total of 145 ALS patients were included in the analyses. The demographic variables of healthy controls and cut-off scores on ACE-R are presented in Table I. Cognitive deficit was defined as a total score ACE-R less than 75. Based on the MMSE scores, 21 patients (14.48%) had cognitive impairment. However, the prevalence of cognitive deficit was 30.34% (44/145) according to ACE-R scores. Patients with a total score of more than 75 had significantly higher scores in every domain of ACE-R. The most frequent cognitive deficit domain was language (26.21%) followed by orientation/attention (24.13%), visuospatial ability (24.13%), memory (23.45%), and verbal fluency (22.76%) (Figure 1). A significantly higher prevalence of cognitive deficits was found in female patients than in male patients (39.34% vs. 23.81%, p ⫽ 0.045), but there was no difference among bulbar-onset, upper limb-onset and lower limb-onset groups (33.33%, 27.5%, 34.09%, respectively, p ⫽ 0.709) (Table II). Patients with cognitive impairment had significantly older
age of onset and lower educational levels (p ⫽ 0.027 and p ⬍ 0.001, respectively) (Table II) than patients without cognitive impairment. There were no differences in ALSFRS-R, onset form and disease duration between patients with and without cognitive impairment (Table II). Education level revealed no difference between male and female patients (p ⫽ 0.345) or between the spinal form and bulbar form groups (p ⫽ 0.858). The logistic regression model indicated that older age of onset (OR: 1.051, 95% CI 1.000–1.103, p ⫽ 0.048), female gender (OR: 3.220, 95% CI 1.019–10.174, p ⫽ 0.046) and lower educational level (OR: 0.554, 95% CI 0.429–0.716, p ⬍ 0.001) were the potential independent determinants of cognitive impairment in ALS (Table III). Of 145 patients, 122 were alive while 16 patients were deceased by the end of our study. Seven patients were lost to follow-up. In nine patients the interval between the assessments was less than three months. Finally, a total of 113 patients were included in the multiple linear regression analysis to investigate the association between cognitive function and disease progression. Age of onset, gender, educational level, ALSFRS-R and cognitive status during the baseline
Figure 1. The frequencies of abnormal performances in ACE-R total score and in individual cognitive domains.
Screening for cognitive impairment in Chinese ALS patients
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Table II. Clinical and cognitive features of ALS patients based on the ACE-R scores. All patients (n ⫽ 145)
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Variables
50.72 ⫾ 12.38 Age of onset (Years) a (Mean ⫾ SD) Gender (M/F) 84/61 Education (years) (Mean ⫾ SD) 9.27 ⫾ 3.78 ALSFRS-R (Mean ⫾ SD) 41.72 ⫾ 4.63 80/44/21 Onset form (UL/LL/Bulbar) b Disease duration (months) (Mean ⫾ SD) 13.88 ⫾ 8.15 MMSE scores (Mean ⫾ SD) 27.71 ⫾ 2.27 ACE-R total scores (Mean ⫾ SD) 79.66 ⫾ 12.92
ACE-R ⱕ 74 (n ⫽ 44) 54.15 ⫾ 11.54 20/24 6.06 ⫾ 2.78 41.91 ⫾ 4.45 22/15/7 14.97 ⫾ 8.55 25.82 ⫾ 2.70 63.30 ⫾ 8.88
ACE-R ⱖ 75 (n ⫽ 101)
p -value
49.22 ⫾ 12.49 0.027* 64/37 0.045* 10.67 ⫾ 3.27 ⬍ 0.001* 0.843 41.64 ⫾ 4.72 58/29/14 0.709 0.315 13.40 ⫾ 7.97 28.53 ⫾ 1.43 ⬍ 0.001* 86.69 ⫾ 6.33 ⬍ 0.001*
M: male; F: female; ALSFRS-R: Amyotrophic Lateral Sclerosis Functional Rating Scale-revised; MMSE: Mini-Mental State Examination; UL: upper limb; LL: lower limb; ACE-R: Addenbrooke’s Cognitive Examination-revised; SD: Standard Deviation; * significant difference. a Mann-Whitney U -tests, except for the age of onset ( t- tests); SD: standard deviation. b χ2 test.
visit, site of onset and taking riluzole were not associated with DALSFRS-R/m (Table IV). Discussion This was the largest longitudinal study to explore the frequency of cognitive deficits and the relationship between cognitive deficits, and the progression and survival of ALS in a Chinese population. In the current study, the prevalence of cognitive impairment was as high as 30.34% based on ACE-R, and 14.48% based on MMSE, which is consistent with previous studies (5,31). Our findings suggest that ACE-R is superior to MMSE in screening cognitive impairment in ALS patients, and MMSE usefulness is limited, especially in milder forms of cognitive impairment. Due to its broader range of cognitive domains, ACE-R may be a more reliable bedside test to detect cognitive impairment in ALS patients. However, 20% of patients with severe motor impairment and severe dysarthria were excluded in the current study, which indicates that the limitations of ACE-R are used to screen the cognition of patients during the late stage. Wide ranges of cognitive impairment domains including ‘Language’, ‘Orientation/attention’, ‘Visuospatial ability’, ‘Memory’, and ‘Verbal fluency’ domains were found in the current study, which was consistent with previous results (8,32). Language disturbance was the most frequent cognitive deficit Table III. Determinants of cognitive impairment based on cutoff score of ACE-R (⬍ 75).
domain in the current study, which was supported by the study by Taylor et al. (3). However, in future studies we have to undertake additional tasks to confirm that language is the most common domain with deficits. The prevalence of visuospatial deficits was high in our study, which was inconsistent with a previous study (9). The following may be explanations for the differences: 1) The visuospatial domain in ACE-R required the subject to copy a pentagon and cube and to draw a clock. The executive impairments may impact on the visuospatial domain; 2) The study also asked the subject to identify four capital letters, which might not conform to Chinese reading habits. After we removed the test ‘to identify four letters’, the prevalence of visuospatial deficits (18.62%) was decreased and was the domain affected least. These two causes might exaggerate performance decrements. Massman et al. found poor recall but intact recognition in ALS patients (31), and Mantovan et al. reported deficits in delayed memory and recognition (6), which were also agreement with our results. Verbal fluency deficits in ALS patients in the current study were also supported by the study of Abrahams et al. (7). Our findings, together with the above-listed findings, suggested that cognitive impairment in ALS was not a universal feature, and its manifestations may be more heterogeneous than previously recognized (8). Aspects of cognitive impairment in ALS should be refined into more sophisticated and complicated processes. Table IV. Multiple linear regression analysis for the determinants of D ALSFRS-R/m.
Multivariate analyses Variables Clinical variables
p -value
Odds ratio (95% CI) p -value
Age of onset (Years) 1.051 (1.000 –1.103) 0.048* Gender (M/F) 3.220 (1.019 –10.174) 0.046* Education (Years) 0.554 (0.428 – 0.716) ⬍ 0.001* ALSFRS-R – – Onset form (bulbar/spinal onset) – – Disease duration – –
Age of onset Gender Education ALSFRS-R Clinical onset Medication with riluzole Cognitive status
0.673 0.525 0.952 0.266 0.610 0.237 0.305
ALSFRS-R: Amyotrophic Lateral Sclerosis Functional Rating Scale-revised; * significant difference.
ALSFRS-R: Amyotrophic Lateral Sclerosis Functional Rating Scale-revised.
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Q. Wei et al.
In the current study we found that older age of onset and female patients were likely to develop cognitive impairment more than younger age of onset and male patients, and multivariable analysis revealed that older age of onset, female gender, and lower educational levels were potential independent determinants of cognitive impairment. These results are consistent with the accepted views that cognitive decline is more universal in the general elderly population and increases with age (33), and that females have higher risk for cognitive decline than males (34). Furthermore, a meta-analysis reported that visual memory impairment in ALS patients was related to age (35). Studies from other degenerative diseases such as mild AD (21) and PD patients with MCI (36) showed that level of education could significantly affect the performance on the ACE-R. Therefore, educational level should be considered when using ACE-R to detect cognitive impairment in ALS patients. However, in the current study, no difference in educational level between male and female patients further supported that female gender was the determinant for cognition impairment independent of education level. Our study found that site of onset, disease duration and ALSFRS-R were not the determining factors for cognitive impairment in ALS. The relationship between cognitive deficits and motor function should be viewed with caution. A meta-analysis (35) and a study by Sterling et al. (37) also confirmed that cognitive deficits did not relate to bulbar onset. However, Gordon et al. found that bulbar onset was potentially associated with cognitive impairment (4). Therefore, a prospective study with a larger sample size and a follow-up study would provide more insight into cognitive impairment related to motor deficits of ALS patients. Our results showed that cognitive status did not contribute to the progression of ALS (DALSFRSR/m), which was inconsistent with results from previous studies (4, 38, 39). Gordon et al. found that severe cognitive impairment (but not mild cognitive impairment) was associated with poor survival (4). Elamin et al. found executive dysfunction specifically affected motor progression and survival (38). Oh et al. reported that ALS patients with cognitive impairment had shorter survival (39). Our result can be partly explained by the short follow-up and limited number of deceased patients. In addition, simple cognitive assessments but not tasks focused on frontal executive function were used during the cognition evaluation. Further prospective studies are required to verify the association between cognition and survival in ALS patients. This study should be interpreted with consideration of several limitations. First, cognitive deficits in ALS patients are defined by an ACE-R score of less than 75. However, due to the complexity of cognitive impairment, a hierarchical approach might be required using a combination of several cognitive screens
and/or behavioural questionnaires to define cognitive impairment in ALS patients. Patients with FTD, severe dysarthria and hand weakness were excluded, which might lead to a selection bias that could underestimate the prevalence of severe cognitive impairment. Conclusions Cognitive impairment is common in Chinese ALS patients but does not necessarily worsen the progression of ALS. ACE-R is a reliable and valid cognitive screening instrument, and it is superior to MMSE in detecting cognitive impairment in ALS patients. Ages of onset, gender and education level were potential independent determinants for cognitive impairment. Acknowledgements We thank the patients and their families for their participation in this study. Declaration of interest: The authors report no confl icts of interest. The authors alone are responsible for the content and writing of the paper. References 1. Abrahams S, Leigh P, Goldstein L. Cognitive change in ALS: a prospective study. Neurology. 2005;64:1222–6. 2. Bak TH, Hodges JR. The effects of motor neuron disease on language: further evidence. Brain Lang. 2004;89:354–61. 3. Taylor LJ, Brown RG, Tsermentseli S, Al-Chalabi A, Shaw CE, Ellis CM, et al. Is language impairment more common than executive dysfunction in amyotrophic lateral sclerosis? J Neurol Neurosurg Psychiatry. 2013;84:494–8 4. Gordon PH, Delgadillo D, Piquard A, Bruneteau G, Pradat PF, Salachas F, et al. The range and clinical impact of cognitive impairment in French patients with ALS: a cross-sectional study of neuropsychological test performance. Amyotroph Lateral Scler. 2011;12:372–8. 5. Ringholz G, Appel S, Bradshaw M, Cooke N, Mosnik D, Schulz P. Prevalence and patterns of cognitive impairment in sporadic ALS. Neurology. 2005;65:586–90. 6. Mantovan MC, Baggio L, Dalla Barba G, Smith P, Pegoraro E, Soraru G, et al. Memory deficits and retrieval processes in ALS. Eur J Neurol. 2003;10:221–7. 7. Abrahams S, Leigh PN, Harvey A, Vythelingum GN, Grise D, Goldstein LH. Verbal fluency and executive dysfunction in amyotrophic lateral sclerosis (ALS). Neuropsychologia. 2000;38:734–47. 8. Phukan J, Elamin M, Bede P, Jordan N, Gallagher L, Byrne S, et al. The syndrome of cognitive impairment in amyotrophic lateral sclerosis: a population based study. J Neurol Neurosurg Psychiatry. 2011;83:102–8. 9. Abrahams S, Newton J, Niven E, Foley J, Bak TH. Screening for cognition and behaviour changes in ALS. Amyotroph Lateral Scler Frontotemporal Degener. 2014;15:9–14. 10. Abrahams S, Goldstein L, Simmons A, Brammer M, Williams S, Giampietro V, et al. Word retrieval in amyotrophic lateral sclerosis: a functional magnetic resonance imaging study. Brain. 2004;127:1507–17. 11. Abrahams S, Goldstein LH, Suckling J, Ng V, Simmons A, Chitnis X, et al. Frontotemporal white matter changes in amyotrophic lateral sclerosis. J Neurol. 2005;252:321–31.
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