The Edinburgh Cognitive and Behavioural ALS Screen (ECAS) for Japanese ALS and FTD patients

Abstract

Objective

Amyotrophic lateral sclerosis (ALS) patients might present with cognitive and behavioural abnormalities resembling frontotemporal dementia (FTD). The Edinburgh Cognitive and Behavioural ALS Screen (ECAS) was developed as an easy to administer cognitive screen for detecting these symptoms. The aim of the present study was to develop and validate a Japanese version of the ECAS.

Methods

In this single centre observational study, 35 ALS patients and 28 healthy controls were enrolled. Three patients in the ALS group fulfilled the criteria for behavioural variant FTD (ALS-FTD) and the rest were grouped as ALS without FTD. Participants were subjected to the Japanese version of the ECAS. ALS patients were also subjected to the Montreal Cognitive Assessment, Frontal Assessment Battery, ALS Functional Rating Scale-Revised, and respiratory function testing. Demographic and disease characteristics (e.g., sex, age at examination, and years of education) were also recorded.

Results

Internal consistency and correlations with general cognitive screenings were sufficient in the Japanese adaptation. Executive functions were the most commonly affected ECAS domain, followed by fluency and language. Compared to control subjects, ALS patients without FTD had low scores in the ECAS ALS-specific functions but not in ALS-nonspecific functions. Meanwhile ALS-FTD patients markedly underperformed both in the ECAS ALS-specific and ALS-nonspecific functions. Furthermore, the Japanese ECAS score correlated positively with years of education and negatively with age at onset.

Conclusion

The Japanese version of the ECAS is a valid and useful screening tool to identify multiple types of cognitive impairment in ALS patients.

Keywords:

• Amyotrophic lateral sclerosis
• frontotemporal dementia
• cognitive impairment
•  abnormalities

Introduction

A considerable number of amyotrophic lateral sclerosis (ALS) patients exhibit cognitive and/or behavioural abnormalities (1–3). These non-motor symptoms have received significant attention in recent years in relation to frontotemporal dementia (FTD), as FTD overlaps clinically, pathologically, and genetically with ALS (4–7). In ALS, executive functions are typically affected, but language and word fluency can also be compromised (8).

The Edinburgh Cognitive and Behavioural ALS Screen (ECAS) is a brief assessment tool designed specifically for the evaluation of patients with ALS. The screen includes ALS-specific functions (executive, language, and verbal fluency), ALS-nonspecific functions (memory and visuospatial functions), as well as measurements of behavioural abnormalities. The ECAS is less influenced by physical disabilities, i.e., answers can be provided in writing if patients are verbally impaired, and vice versa. The ECAS is useful for cognitive assessment in ALS patients with a sensitivity of 0.69–1.0 and specificity of 0.8–0.89 (9,10), but comprehensive neuropsychological assessment is still required for a definitive diagnosis in those exhibiting evidence of cognitive impairment.

Although the ECAS has been translated into various languages such as German/Swiss-German (11), Italian (12), and Chinese (13), a validated Japanese adaptation is not yet available. The purpose of the present study was to translate, adapt and validate a Japanese version of the ECAS to establish its use as a basic measure for clinical practice in Japan.

Subjects and methods

Participants

This single centre observational study was conducted from January 2017 to May 2019. In total, 35 patients (20 males and 15 females) with ALS including three ALS-FTD patients (one male and two females), and 28 healthy individuals (16 males and 12 females) were recruited (Table 1). All participants were native Japanese speakers. The ethical committees of Tottori University Hospital approved this study (No. 2511) and informed consent was obtained from all participants.

Table 1 Characteristics of ALS patients and controls.

	ALS			Control
	Total	Without FTD	ALS-FTD
Number of patients (M/F)	35 (20/15)	32 (19/13)	3 (1/2)	28 (16/12)
Age at examination (years)	68.2 (7.4)	68.0 (7.6)	70.7 (5.5)	63.8 (12.7)
School education (years)*	11.9 (2.7)	12.2 (2.6)	9.0 (0.0)^†	13.0 (2.4)
Disease duration (months)	55.3 (6–593)	57.6 (7–593)	31.0 (6-47)
Onset of disease
Bulbar	9 (25.7%)	7 (21.9%)	2 (66.7%)
Cervical	13 (37.1%)	13 (40.6%)	0 (0%)
Thoracic	0 (0%)	0 (0%)	0 (0%)
Lumbar	13 (37.1%)	12 (37.5%)	1 (33.3%)
Bulbar involvement^a	23 (65.7%)	20 (62.5%)	3 (100%)
ALSFRS-R	33.3 (10.1)	33.2 (10.2)	34.7 (11.7)

ALSFRS-R: ALS Functional Rating Scale-Revised.

^a Bulbar involvement was defined as a score ≦ 11 on the 3 bulbar items of the ALSFRS-R.

Disease duration was expressed median month (range), other factors are expressed mean (SD).

*p < 0.05 among ALS without FTD, ALS with FTD and Control groups (Kruskal-Wallis test).

^†p < 0.05 vs Control (Mann-Whitney U test). This finding survives Bonferroni correction (adjusted p value = 0.017).

Patients with ALS were recruited from the Department of Neurology, Tottori University. The patients were diagnosed using the revised El Escorial criteria (probable or definite) (14). Diagnosis of behavioural variant FTD (bvFTD) was made according to the Rascovsky criteria (15) based on a comprehensive full neuropsychological assessment. Patients who met both the revised El Escorial and Rascovsky criteria were classified as ALS-FTD (8). No patients were diagnosed with Alzheimer’s disease (AD), ALS with progressive non-fluent aphasia, or ALS with semantic dementia, based on respective criteria (16,17). Patients with other neurological, psychiatric, or medical conditions that can affect cognition were excluded. None of the patients in this cohort received non-invasive positive pressure ventilation or tracheotomy positive pressure ventilation. In addition, no patient was noted as receiving alternative nutrition such as percutaneous endoscopic gastrostomy. Baseline characteristics (sex, age at onset, years of education, disease duration, site of onset, and presence or absence of bulbar involvement) were obtained for the patient group.

Spouses or friends of the ALS patients as well as other neurological disorder patients from the Department of Neurology, Tottori University were recruited as healthy controls. No participant in the healthy control group had any history of neurological or psychiatric disorders. Demographic characteristics (sex, age, and years of education) were obtained for the control group.

Japanese adaptation of the ECAS

After receiving permission from the original authors of the ECAS, we translated the English version of the ECAS (18) into Japanese according to the guidelines for translation (https://ecas.psy.ed.ac.uk/ecas-international/). The amended points in the Japanese version compared to the English version are listed in Supplementary Table 1. The scores for each section and the total score are unchanged from the original. During the translation, a picture in the “Naming” section and the story in the “Memory” section were adapted to the Japanese cultural environment. Specific amendments made to the spelling task for the Japanese version of the ECAS are detailed in Supplementary Table 2.

We then performed a back-translation by another bilingual specialist fluent in both Japanese and English. Normative data including cutoff scores (Table 2) were obtained according to the original report (18) and aforementioned guidelines. We selected phonetic fluency for the verbal fluency test in line with the original version. Standard scores for the verbal fluency test (written version) were produced from a sample of 28 healthy controls, and an additional 25 healthy controls were subjected to the spoken version of the verbal fluency test. From the data, corresponding conversion tables were created (Supplementary Table 3).

Table 2 Normative data for the Japanese version of ECAS.

Domain	Mean	SD	Min	Max	Cutoff score
Total ECAS score (max 136)	109.7	11.4	82	127	86.8
ALS-specific functions (max 100)	83.0	8.8	61	97	65.4
Executive functions (max 48)	38.9	4.7	30	47	29.4
Language functions (max 28)	25.9	2.1	20	28	21.6
Fluency (max 24)	18.3	4.2	10	24	9.8
ALS-nonspecific functions (max 36)	26.6	5.2	14	33	16.3
Memory functions (max 24)	14.7	5.0	3	21	4.7
Visuospatial functions (max 12)	18.3	4.2	10	24	9.8

Cutoff score: mean – 2 standard deviation (SD).

The Japanese version of the ECAS along with the normative data (version 1.05) and the guidelines for the administration and scoring of the ECAS (Japanese version 1.03) are posted on the official website for the Research Committee of CNS Degenerative Diseases, the Ministry of Health, Labour and Welfare of Japan (http://plaza.umin.ac.jp/neuro2/). Although the Japanese version of the ECAS also contains behavioural assessment, we focused on the ECAS cognitive functions in this study.

Other neuropsychological tests and clinical information

In addition to the Japanese version of the ECAS, subjects were also examined using a general cognitive screening, the Montreal Cognitive Assessment (MoCA) (19), and Frontal Assessment Battery (FAB) (20). Consistent with previous reports (21–23), for items that required manual dexterity, e.g., the first item of the MoCA and four of the six items of the FAB, a note was made when these tasks could not be performed, and we extrapolated the MoCA and FAB scores by considering the missing values. The corrected scores were calculated using the following formula: extrapolated score = (actual points scored/maximum attainable score for an individual patient) × maximum score of the test. With these extrapolated scores, the normal cutoff values of the FAB and MoCA could still be applied. For the FAB, this adjustment has demonstrated to be valid in patients with ALS and ALS-bvFTD (24).

The ALS Functional Rating Scale-Revised (ALSFRS-R) (25) and the vital capacity as a percentage of the predicted vital capacity (%VC) were also obtained.

Statistical analysis

The χ² test was conducted to assess categorical variables (sex, site of onset, presence or absence of bulbar involvement). Comparisons between the total ALS cohort and controls (age at examination, years of education, disease duration, ECAS scores) and between ALS patients with and without FTD (ALSFRS-R) were performed using the Mann-Whitney U test. Comparison of all three groups (ALS without FTD, ALS-FTD, and controls) was performed using the Kruskal-Wallis test. The Mann-Whitney U test was used for post hoc analysis.

We used Pearson’s correlation coefficient (r), Spearman’s correlation coefficient (rs), and Cronbach’s alpha coefficient (α) to determine the concordant validity and internal consistency of the scale.

Data analyses were performed using IBM SPSS Statistics version 25. A p-value of < 0.05 was considered statistically significant. Adjustment of the p values for multiple comparisons was performed using Bonferroni correction.

Results

Participants

No significant differences were noted between all ALS patients and controls, or among the three groups (ALS without FTD, ALS-FTD, and controls), in terms of sex and age (Table 1). Mean ages were 68.0 ± 7.6 years in the ALS without FTD group, 70.7 ± 5.5 years in the ALS-FTD, and 63.8 ± 12.7 years in the control group. Regarding disease duration, there was also no difference between the ALS patients and controls. However, significant differences were observed in disease duration among the three groups. The difference was still significant between ALS-FTD patients and controls after post hoc analysis with Bonferroni correction (Table 1).

There was no difference between ALS patients with and without FTD in terms of the onset site, bulbar involvement, and ALSFRS-R score.

Internal consistency and concordant validity

The Cronbach α coefficient of the Japanese ECAS was found to be 0.77, which was the same as the English version (α = 0.77); a coefficient of 0.7–0.8 is considered to be good to excellent.

The estimated MoCA and FAB scores exhibited moderate positive correlations with the total ECAS score (rs = 0.53 for the MoCA, p < 0.01; and rs = 0.59 for the FAB, p < 0.01). Moderate correlations were also noted between ALS-specific functions and the MoCA score (rs = 0.49, p < 0.05), between ALS-specific functions and the FAB score (rs = 0.49, p < 0.05), and between the ALS-nonspecific ECAS score and the FAB score (rs = 0.47, p < 0.05). The correlation between MoCA score and the ALS-nonspecific score was rs = 0.30, but did not reach statistical significance (p = 0.057).

We then confirmed the frequency of ECAS scores below the cutoffs presented in Table 2 among ALS patients. Among ALS patients without FTD, executive functions were the most commonly affected domain with 43.8% of patients performing below the cutoff, followed by fluency (21.9%), language (15.6%), memory (15.6%), and visuospatial functions (3.1%). Approximately one-third (34.4%) of patients had cognitive impairments according to the ECAS total score, while 37.5% of the patients were below the cutoff for ALS-specific functions. Further, 15.6% of ALS patients without FTD scored below the cutoff for ALS-nonspecific functions.

However, 100% of ALS-FTD patients scored below the cutoff for all items; total ECAS, ALS-specific and ALS-nonspecific functions, and all subcategories (executive, language, fluency, memory, and visuospatial functions).

Comparison of patients and controls

The ALS patients achieved significantly lower scores in executive functions, language, fluency, ALS-specific functions, and the total ECAS score (all p < 0.01) than did controls (Table 3). However, no differences in memory, visuospatial functions, and ALS-nonspecific functions were noted between these groups (Table 3).

Table 3 ECAS scores and ECAS time of ALS patients and controls.

	ALS			Control
	Total	without FTD	ALS-FTD
Total ECAS score***	87.5 (22.6)^††	92.2 (17.0)^†††	37.7 (8.5)^†††,¶¶¶	104.7 (15.6)
ALS-specific functions***	64.5 (16.6)^†††	67.9 (12.8)^†††	28.7 (6.4)^†††,¶¶¶	80.5 (10.7)
Executive functions***	28.6 (9.3)^†††	30.3 (7.7)^†††	11.0 (5.3)^†††,¶¶	37.3 (6.5)
Language functions***	22.7 (4.0)^††	23.7 (2.7)^††	13.0 (2.0)^†††,¶¶¶	25.4 (2.3)
Fluency**	13.2 (6.7)^††	14.0 (6.3)^†	4.7 (4.2)^†††,¶	16.1 (6.2)
ALS-nonspecific functions*	23.0 (7.7)	24.3 (6.6)	9.0 (3.6)^†††,¶¶	24.3 (6.9)
Memory functions	11.8 (6.8)	12.7 (6.4)	2.0 (2.0)^(†,¶¶)	12.4 (6.8)
Visuospatial functions***	11.2 (1.5)	11.6 (0.7)	7.0 (1.7)^†††, ¶¶¶	11.9 (0.4)
ECAS time**	32.5 (7.4)^†††	32.4 (6.9)^†††	33.3 (13.3)	25.6 (5.9)

*p < 0.05, **p < 0.01, ***p < 0.001 among ALS without FTD, ALS with FTD and Control groups (Kruskal-Wallis test).

^†p < 0.05, ^††p < 0.01, ^†††p < 0.001 vs Control (Mann-Whitney U test).

^¶p < 0.05, ^¶¶p < 0.01, ^¶¶¶p < 0.001 vs ALS without FTD (Mann-Whitney U test).

Except for the comparisons with ^†, all statistically significant findings survive Bonferroni correction (adjusted p value = 0.017). As memory functions did not reach significance in Kruskal-Wallis test, the results of post hoc analysis in parenthesis.

When we compared the scores among ALS without FTD, ALS-FTD, and controls; significant differences were observed in executive functions (p < 0.001), language (p < 0.001), fluency (p < 0.01), visuospatial functions (p < 0.001), ALS-specific functions (p < 0.001), ALS-nonspecific functions (p < 0.05), and the total ECAS score (p < 0.001). Post hoc analyses revealed that the differences between ALS without FTD and controls were similar to those between all ALS patients and controls (Table 3).

Post hoc comparison between ALS-FTD and controls revealed significant differences in executive functions, language, fluency, visuospatial functions, ALS-specific and -nonspecific functions, and the total ECAS score (Table 3). This tendency was also observed in the comparison of ALS patients with and without FTD. In both comparisons, the differences in fluency did not survive Bonferroni correction (Table 3).

We also found significant differences in the mean implementation time of the ECAS between all ALS patients and controls (p < 0.001), and between ALS without FTD and controls (p < 0.001) (Table 3).

Clinical features and cognitive measures

We next investigated the correlations between clinical features and cognitive measures in the ALS without FTD patients (Table 4). The clinical features consisted of onset age, disease duration, years of education, ALSFRS-R score, and %VC. The cognitive measures consisted of the ECAS total score, ALS-specific and -nonspecific ECAS scores, MoCA score, and FAB score. Years of education was highly correlated (rs ≥ 0.5) with the total ECAS score, ALS-specific ECAS score, and MoCA score and moderately correlated (0.3≤rs < 0.5) with the FAB score. Onset age was moderately negatively correlated with the total ECAS score, ALS-specific ECAS score, MoCA score, and FAB score.

Table 4 Correlations between neuropsychological tests and clinical features in ALS without FTD.

Characteristics	Total ECAS		ALS-specific ECAS		ALS-nonspecific ECAS		MoCA		FAB
	rs	p	rs	p	rs	p	rs	p	rs	p
Age at onset	−0.39	0.029*	−0.41	0.023*	−0.20	0.266	−0.38	0.063*	−0.46	0.025*
Disease duration	−0.17	0.333	−0.05	0.782	−0.31	0.086	0.15	0.463	−0.06	0.756
School education	0.45	0.013**	0.51	0.004**	0.15	0.394	0.55	0.007**	0.39	0.055
ALSFRS-R	−0.01	0.939	−0.02	0.897	0.11	0.534	0.10	0.636	0.11	0.591
%VC	0.26	0.151	0.19	0.298	0.30	0.098	0.15	0.469	0.42	0.045*

ALSFRS-R: ALS Functional Rating Scale-Revised; %VC: Predicted Vital Capacity.

*p < 0.05, **p < 0.01.

Discussion

Validation of the Japanese version of the ECAS

The Japanese ECAS exhibited good internal consistency similar to the English counterpart (18). The Japanese version also exhibited good convergent validity; the MoCA and FAB scores were highly correlated with the total ECAS score. These findings are comparable to other language versions of the ECAS (11–13). According to the cutoff value for the total ECAS score (Table 2), 34.4% of patients had cognitive impairment. Further, 37.5% of patients were considered to have impaired ALS-specific functions, while only 15.6% of patients were considered to be impaired in ALS-nonspecific functions. In contrast, 100% of ALS-FTD patients were considered to be markedly impaired in ALS-nonspecific functions. These tendencies were also observed in a Spanish cohort evaluated using the ECAS (26).

Various versions of the ECAS had been validated against standardized screening measures: the MoCA and FAB for the German/Swiss-German (11), Italian (12), and Chinese (13) versions, or against a comprehensive full neuropsychological assessment (9,10). The present study used the MoCA and FAB for validation. There are some limitations in the use of these screening instruments in ALS patients. The MoCA was first developed to detect mild cognitive impairment by assessing short-term memory, visuospatial abilities, attention, concentration and working memory, time and place orientation, executive function, and language (19). The FAB, designated to assess frontal lobe function, did not evaluate language, memory, or visuospatial ability (20). As such, neither test was specifically designed for ALS patients and neither separately assess ALS-specific and -nonspecific functions. Further, both tests require dexterity, which can be impaired in ALS patients. Consequently, validation studies using such screening measures are less reliable than those employing a full comprehensive assessment.

Comparison between groups and relation to clinical features

In the comparison of ECAS scores between all ALS patients and controls, there were significant differences in terms of the ALS-specific scores and all subcategory scores as well as the total ECAS scores, while no differences were found in the scores of ALS-nonspecific functions and the related subcategories (Table 3). These overall tendencies were also observed when we compared ALS patients without FTD and controls. However, post hoc comparison of ALS-FTD and controls revealed significant differences in executive functions, language, fluency, visuospatial functions, ALS-specific and ALS-nonspecific functions, and total ECAS scores. This tendency was also observed in the comparison of ALS patients with and without FTD, suggesting that ALS-FTD patients exhibited impairment in a broad range of domains compared to ALS without FTD patients.

Many reports have indicated that the ECAS total score was notably correlated with years of education (10,27,28) and age at onset (13,27,28). In the present study, ALS-FTD patients had significantly fewer years of education than controls (9.0 ± 0.0 vs 13.0 ± 2.4, p < 0.05) (Table 1). This must be a crucial influential factor explaining why ALS-FTD patients showed lower ECAS performance compared to other groups. In the ALS without FTD patients, however, the ECAS total score was also strongly positively correlated with years of education (Table 4). Regarding age at onset, the ECAS total score was negatively correlated with age at onset (Table 4); i.e., the older the age at onset, the lower the ECAS score.

We recently reported that lower MoCA and FAB scores were associated with higher age at onset (23). In this report, we speculated that age-related brain changes, independent from ALS/FTD pathology (e.g., nonspecific cognitive impairment by aging or subclinical AD pathology), might in part contribute to this observation, as we could not analyze ALS-specific and ALS-nonspecific domains separately (23). However, the present study clearly indicated that the ALS-specific score of the ECAS was moderately negatively correlated with age at onset (rs = −0.36) (Table 4) while the ALS-nonspecific score of the ECAS did not (rs = −0.19). Although inconclusive, we believe that ALS/FTD-specific pathology could contribute to the negative correlation between age of onset and cognitive performance.

To date, over 20 different language versions of the ECAS have been developed (https://ecas.psy.ed.ac.uk/ecas-international/). However, caution should be applied regarding the differences among the various language versions of the ECAS. For example, in control subjects, the total ECAS score (mean ± standard deviation) and impairment cutoff score are 118.5 ± 6.6 and 105 for the English version (18) and 104.7 ± 15.6 and 86.8 for the Japanese version, respectively (Tables 1 and 2). These scores in the Japanese version are similar to those in the Chinese version (106.2 ± 12.2 and 81, respectively) (13). Multiple independent factors likely contribute to these differences, and many reports have stressed that both age and education are influential (12,27,28). Regardless of these differences, the benefits still greatly outnumber the limitations in the ability to compare and verify the cognitive status of patients with ALS among the different language communities using the ECAS.

Limitations

Given that the present study was conducted for the purposes of validating the cognitive domain of the ECAS, we only evaluated cognitive function. We used two cognitive screening tools (MoCA and FAB), rather than a standardized neuropsychological battery, as a gold standard for the validation study. To date, there is little evidence that this is a valid procedure with which to extrapolate scores for the missing components of MoCA, and that the same cutoff scores can be used for abnormality. Further, a small sample was used to standardize the test; and years of education were not corrected among ALS without FTD, ALS-FTD, and controls.

Future studies should focus on revealing the natural history of cognitive and behavioural abilities and elucidating the factors that contribute to the progression of cognitive and behavioural symptoms.

Conclusion

The Japanese version of the ECAS is a valid measure, effective, and an easy to apply tool for screening both ALS-specific and -nonspecific cognitive impairments in ALS and ALS-FTD patients.

Acknowledgments

The authors would like to thank all of the ALS patients and their caregivers for participating in this study. The authors also thank Professors Sharon Abrahams and Thomas H. Bak for providing guidance during the translation and performance testing.

We would like to thank Dr. Shan Ye (Department of Neurology, Peking University Third Hospital) for providing the Chinese version of the ECAS (13) and Dr. Shenghong Pu (Neuropsychiatry, Tottori University) for translating the “Spelling” section of the Chinese version of the ECAS into Japanese, and for the detailed explanation of the enquiries.

We would like to thank Editage (www.editage.com) for English language editing.

Declaration of interest

The authors report no conflicts of interest. The authors alone are responsible for the content and writing of this article.

Additional information

Funding

This work was supported by Grants-in Aid from the Research Committee of CNS Degenerative Diseases, Research on Policy Planning and Evaluation for Rare and Intractable Diseases, Health, Labour and Welfare Sciences Research Grants, the Ministry of Health, Labour and Welfare, Japan.