Japanese version of the ALS-FTD-Questionnaire (ALS-FTD-Q-J)

    Japanese version of the ALS-FTD-questionnaire (ALS-FTD-Q-J) Yasuhiro Watanabe, Emma Beeldman, Joost Raaphorst, Yuishin Izumi, Hiide Yoshino, Michihito Masuda, Naoki Atsuta, Satoru Ito, Tadashi Adachi, Yoshiki Adachi, Osamu Yokota, Masaya Oda, Ritsuko Hanashima, Mieko Ogino, Hiroo Ichikawa, Kazuko Hasegawa, Hideki Kimura, Toshio Shimizu, Ikuko Aiba, Hayato Yabe, Makoto Kanba, Kimiyoshi Kusumi, Tetsuya Aoki, Yu Hiroe, Hirohisa Watanabe, Kazutoshi Nishiyama, Masahiro Nomoto, Gen Sobue, Kenji Nakashima PII: DOI: Reference:

S0022-510X(16)30295-7 doi: 10.1016/j.jns.2016.05.036 JNS 14566

To appear in:

Journal of the Neurological Sciences

Received date: Revised date: Accepted date:

19 January 2016 18 April 2016 17 May 2016

Please cite this article as: Yasuhiro Watanabe, Emma Beeldman, Joost Raaphorst, Yuishin Izumi, Hiide Yoshino, Michihito Masuda, Naoki Atsuta, Satoru Ito, Tadashi Adachi, Yoshiki Adachi, Osamu Yokota, Masaya Oda, Ritsuko Hanashima, Mieko Ogino, Hiroo Ichikawa, Kazuko Hasegawa, Hideki Kimura, Toshio Shimizu, Ikuko Aiba, Hayato Yabe, Makoto Kanba, Kimiyoshi Kusumi, Tetsuya Aoki, Yu Hiroe, Hirohisa Watanabe, Kazutoshi Nishiyama, Masahiro Nomoto, Gen Sobue, Kenji Nakashima, Japanese version of the ALS-FTD-questionnaire (ALS-FTD-Q-J), Journal of the Neurological Sciences (2016), doi: 10.1016/j.jns.2016.05.036

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Japanese version of the ALS-FTD-questionnaire

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(ALS-FTD-Q-J)

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Yasuhiro Watanabe1), Emma Beeldman2), Joost Raaphorst3), Yuishin Izumi4), Hiide Yoshino5), Michihito Masuda6), Naoki Atsuta6), Satoru Ito1), Tadashi Adachi1), Yoshiki

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Division of Neurology, Department of Brain and Neurosciences, Faculty of Medicine, Tottori University, Yonago, Japan. Department of Neurology Academic Medical Centre, Amsterdam, the Netherlands. Department of Neurology, RadboudUMC, Nijmegen, the Netherlands． Department of Clinical Neuroscience, Institute of Biomedical Sciences, Tokushima University Graduate School, Tokushima, Japan. Yoshino Neurology Clinic, Ichikawa, Japan. Department of Neurology, Nagoya University Graduate School of Medicine, Nagoya, Japan. Department of Neurology, National Hospital Organization, Matsue Medical Center, Matsue, Japan. Department of Neuropsychiatry, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama, Japan. Department of Neurology, Vihara Hananosato Hospital, Miyoshi, Japan. Department of Neurology, Kitasato University School of Medicine, Kanagawa, Japan. Kitasato University, Department of Comprehensive Medicine, Division of Integrated Care and Whole Person Care, Kanagawa, Japan. Department of Neurology, Showa University Fujigaoka Hospital, Kanagawa, Japan. National Hospital Organization, Sagamihara National Hospital, Kanagawa, Japan. Department of Neurology, Tokyo Metropolitan Neurological Hospital, Tokyo, Japan. Department of Neurology, National Hospital Organization, Higashi Nagoya National Hospital, Noagoya, Japan. Department of Neurology and Clinical Pharmacology Ehime University Graduate School of Medicine, Ehime, Japan. Yodoe clinic, Yonago, Japan. Department of Neurology, San-in Rosai Hospital, Yonago, Japan. Akasaki Medical office, Kotoura, Japan. Division of Neuropsychiatry, Yowa Hospital, Yonago, Japan.

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Adachi7), Osamu Yokota8), Masaya Oda9), Ritsuko Hanashima10), Mieko Ogino11), Hiroo Ichikawa12), Kazuko Hasegawa13), Hideki Kimura14), Toshio Shimizu14), Ikuko Aiba15), Hayato Yabe16), Makoto Kanba17), Kimiyoshi Kusumi18), Tetsuya Aoki19), Yu Hiroe20), Hirohisa Watanabe6), Kazutoshi Nishiyama10), Masahiro Nomoto16), Gen Sobue6), Kenji Nakashima1), and the ALS-FTD-Q-J research group.

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ABSTRACT

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Amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) share

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common clinical, genetic and neuropathological features. Some ALS patients have

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behavioral/personality changes, which could result in significant obstacles in the care provided by family members and caregivers. An easy screening tool would contribute greatly to the evaluation of these symptoms.

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We translated the ALS-FTD-Questionnaire, developed in the Netherlands, into

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Japanese (ALS-FTD-Q-J) and examined the clinimetric properties (internal consistency, construct and clinical validity). Patients with ALS and/or behavioral variant FTD

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(bvFTD) were evaluated alongside healthy controls in this multicenter study. All ALS

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patients, regardless of bvFTD status, were further evaluated by the frontal behavioral inventory (FBI) and for frontal/executive function, cognition, anxiety/depression, and

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motor functions.

Data from 146 subjects were analyzed: ALS (92), ALS-bvFTD (6), bvFTD (16), and

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healthy controls (32). The internal consistency of the ALS-FTD-Q-J was good (Cronbach α = 0.919). The ALS-FTD-Q-J showed construct validity as it exhibited a high correlation with the FBI (r = 0.79). However, correlations were moderate with anxiety/depression and low with cognitive scales, in contrast to the original report, i.e. a moderate correlation with cognition and a low correlation with anxiety/depression. The ALS-FTD-Q-J discriminated ALS patients from (ALS-)bvFTD patients and controls. Thus, the ALS-FTD-Q-J is useful for evaluating Japanese ALS/FTD patients.

Key words: amyotrophic lateral sclerosis; frontotemporal dementia; family members; caregivers; questionnaire; behavioral and personality abnormalities 2 / 20

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1. Introduction

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Recent genetic and neuropathological findings have shown that amyotrophic lateral

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sclerosis (ALS) shares common features with frontotemporal dementia (FTD), e.g.

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5-10% of ALS patients exhibit FTD and 32-45% of patients display mild cognitive impairment or behavioral changes[1-5]. The behavioral changes can be divided in three subgroups, i.e. apathy (lack of motivation and personal hygiene), disinhibition (loss of

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empathy, hypersexuality and childish behavior) and neuropsychiatric symptoms

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(hallucinations and obsessive compulsive behavior). The occurrence of (mild) behavioral changes in ALS can increase caregiver burden and can change the

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relationship between the patient and their loved-ones. Also, making choices about

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life-prolonging therapies, such as non-invasive respiratory support and a feeding tube becomes even more complicated when an ALS patient has behavioral changes or

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cognitive impairment. For the ALS practitioner, it is difficult to obtain accurate information about the presence of behavioral changes, because the questionnaires are

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not designed for ALS patients and cannot distinguish between apathy and lack of movement because of motor weakness. For a better understanding of patients’ behavior, a questionnaire has been developed specifically for ALS patients, the ALS-FTD-Q, which accounts for motor symptoms and dysarthria (Raaphorst J, et al. The ALS-FTD-Q: a new screening tool for behavioral disturbances in ALS. Neurology 2012) [6]. The presentation of behavioral changes might be different in ALS populations across the world, due to differences in cultural backgrounds. We already know that there is a large difference in genetic background. For example, the presence of disease-causing mutations in Caucasians and Asians (including Japanese) is entirely 3 / 20

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different. In Europe, a large percentage of FTD patients have a family history of the

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disease (29% in the UK [7], 43% in the Netherlands [8]) while familial cases are quite

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rare in Japan. Also, the hexanucleotide repeat expansion in C9orf72 was only found in

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2.8% - 3.4% [9,10] of familial ALS cases in Japan, in 0.4% [9,11] of sporadic ALS cases and in 0% of FTD cases [12]. In comparison, in Caucasian individuals, the repeat expansion was seen in 23.5 - 39.3% [13,14] of familial ALS cases, 7.0% [13] of

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sporadic ALS cases, and in 6.0% [13] of sporadic FTD cases.

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We do expect that some aspects of behavior are comparable between the Caucasian and Asian population, e.g., hunger and abnormal eating behavior. Meanwhile, certain

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elements of behavior may be influenced by cultural backgrounds, such as individualism

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in the West versus collectivism in the East. Further, is the ALS-FTD-Q suitable for accurate evaluation of Japanese ALS/FTD patients, or is there a need to develop a new

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questionnaire for the evaluation of Japanese patients? In this cross-sectional, multicenter study, we investigated the validity of the ALS-FTD-Q in a Japanese ALS and bvFTD

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cohort.

2. Subjects and methods 2.1. Questionnaire: ALS-FTD-Q-J The ALS-FTD-Q is a proxy-based questionnaire for a close relative or primary caregiver of ALS/FTD patients [6]. With approval of the authors, the English ALS-FTD-Questionnaire was translated into Japanese and then back-translated into English. The consistency between the original English version and the back-translated version was carefully examined by a language expert and final adjustments in the Japanese version were made after a pilot study in patients with ALS. The questionnaire 4 / 20

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consists of 25 statements about behavioral, cognitive and psychiatric symptoms, with a

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more behavioral disturbances and the maximum score is 100.

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4-point rating scale in each item (0, 1, 3, or 4 points per item). A higher score indicates

2.2. Subjects

Three groups of patients and control subjects were enrolled into this study from 18

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neurology and psychiatry facilities in Japan. Patients with ALS were diagnosed by the

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revised El Escorial criteria (possible，probable or definite) [15] including ALS with otherwise normal cognition or ALS with cognitive or behavioral changes but without meeting the criteria for bvFTD. The diagnosis of bvFTD was according to the Neary

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criteria [16] and Rascovsky criteria [17]. Patients with ALS with Alzheimer’s disease, ALS with progressive non-fluent aphasia and ALS with semantic dementia were

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excluded from this study. Patients who met the revised El Escorial and the Neary criteria were grouped as ALS-bvFTD. Subjects without any medical history of

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neurological or psychiatric disease were included as controls.

2.3. Procedure

The ethical committees of the participating hospitals approved the study. Written informed consent was obtained from all subjects. Disease onset was defined as the first sign of muscle weakness (ALS) or first behavioral change (bvFTD). Bulbar involvement was defined as a score ≦11 on the 3 bulbar items of the ALS Functional Rating Scale-Revised (ALSFRS-R). Aside from initial onset, family information related to ALS and/or FTD history was collected. If available, genetic information was gathered. The upright vital capacity as percent of predicted (%VC) was also included in the 5 / 20

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analyses.

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The proxy assessed the behavior of the patient with the ALS-FTD-Q and the FBI, a

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24-item scale measuring frontal lobe-mediated behavior [18]. All ALS patients,

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regardless of bvFTD status, were administered the following: Montreal Cognitive Assessment (MoCA) [19]; Frontal Assessment Battery (FAB) [20]; letter ([i], [re], [si] in Japanese) fluency [21], a measure of executive function with correction for

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speech/motor dysfunction by calculating the mean thinking time per word in seconds

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(fluency index) (written or spoken versions were used, depending on disability); Hospital Anxiety and Depression Scale (HADS) [22]; and ALSFRS-R [23] as obtained

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by physicians or clinical psychologists. In line with the original report, for items that

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require manual dexterity, e.g., the first item of the MoCA and 4 out of 6 items of the FAB, a note was made when these tasks could not be performed. We recorded the score

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obtained and the highest obtainable score. The highest obtainable score is the maximum score of all items that were performed. Extrapolated scores of the MoCA and FAB were

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used for analyses according to the formula: extrapolated score = score obtained × maximum scale score/highest obtainable score for this patient. A higher extrapolated score indicated a better performance.

2.4. Clinimetric evaluation and statistics Internal consistency refers to the statistical coherence of the scale items and can be measured by Cronbach α coefficient, which is based on the weighted average correlation of items within a scale. Internal consistency is considered to be good if α ≧ 0.80. We calculated corrected item–total correlations, which represent the correlation of a single items with the sum of all other scale items. Correlations of ≧ 0.30 were 6 / 20

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considered sufficient.

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Construct validity was assessed by the correlation of the ALS-FTD-Q-J with the FBI

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(the other frontal behavioral score) and other modalities, i.e. cognitive, affective and

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motor functions. Associations between the ALS-FTD-Q scores and the other measures were expressed as Spearman rank correlation coefficients (r). Construct validity is considered to be substantial when coefficients are equal to 0.7 and above.

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Differences between ALS-FTD-Q scores and patient characteristics in relation to the

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various subgroups were analyzed using the Mann-Whitney U test. To reduce the influence of age and sex, we included these variables in the statistical analysis as

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covariates (analysis of covariance or ANCOVA). We obtained the HADS score only

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from patients with ALS symptoms, the analysis the HADS covariate was limited between ALS and ALS-bvFTD. Analyses were performed using PASW statics, version

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3. Results

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18 (IBM SPSS).

3.1. ALS-FTD-Q-J

After a pilot examination in 5 ALS patients we concluded the ALS-FTD-Q-J had any ambiguous nor unintelligible parts in the whole sentence. The final version of the ALS-FTD-Q-J was posted at 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/pdffiles/ALS-FTD-Q-J.pdf).

3.2. Participants Ninety-two patients with ALS without bvFTD, 22 bvFTD patients (including 6 7 / 20

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patients with ALS-bvFTD) and 32 healthy control subjects were enrolled in this study

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(Table 1). The mean age of onset was 67.7 years in ALS patients, 67.2 in ALS-bvFTD

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patients and 67.1 in bvFTD patients. There were 4 ALS patients with a familial or

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genetic form of ALS (one patient had a father with bvFTD, another had a cousin with ALS, and the remaining two patients had a mutation without a family history, i.e. a SOD1 mutation (L126S) and a pathogenic OPTN E478G mutation [24]. In the

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ALS-bvFTD group, 3 patients presented with motor symptoms (ALS-FTD) and 3

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patients presented with behavioral changes (FTD-ALS). The age of onset (years, mean±SD), disease duration {months, median (range)} were 69.7±5.9 and 13.0 (7-47)

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in ALS-FTD patients; and 64.7±6.8 and 37.0 (23-37) in FTD-ALS patients. ALSFRS-R

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(mean±SD) were 30.3±13.9 in ALS-FTD patients and 33.3±9.6 in FTD-ALS patients. In the analyses of 98 ALS patients with/without bvFTD, the mean (SD) age at the

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time of examination was 67.7 ± 10.1, 59.2% were male the median disease duration was 21.0 months (range 3-360 months), and the mean ALSFRS-R score was 37.0 (range

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7-48). Bulbar involvement was seen in 68.7% of patients and 73.5% of patients had limb onset ALS.

3.3. Clinimetric analyses The ALS-FTD-Q-J score showed substantial internal consistency (Chronbach α = 0.92) and 20 of the 25 items showed an item-total score correlation ranging between 0.30 and 0.8. The items below 0.30 were hypersexuality (0.12), suspicious behavior (0.08), spatial disorientation (0.27), visual or auditory hallucinations (0.12) and temporal disorientation (0.27). In the original study, the ALS-FTD-Q correlated highly with another behavioral 8 / 20

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measure (FBI) (r = 0.79), moderately with measures of frontal functions (FAB) (r =

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0.37) and global cognitive function according to the Mini Mental State Examination

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(MMSE) (r = 0.32), and poorly with anxiety/depression (HADS) and motor impairment

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(ALSFRS-R) (r = 0.18 for both) (Table 2). In comparison, our version correlated highly with the FBI (r = 0.70), moderately with HADS (r = 0.36), and poorly with measures of frontal functions (FAB) (r = 0.13), global cognitive functioning (MoCA) (r = 0.07) and

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motor function (ALSFRS-R) (r = 0.28) (Figure 1 and Table 2). Although respiratory

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function was not included in the original report, the ALS-FTD-Q was moderately correlated with %VC (r = 0.40) (Figure 1 and Table 2).

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The ALS-FTD-Q-J discriminated between ALS patients (9.5 ± 8.7; mean ± SD) and

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ALS-bvFTD patients (31.3 ± 7.4) (p < 0.001); between ALS patients and bvFTD patients (48.9 ± 14.0) (p < 0.0001); and between ALS patients (9.5 ± 8.7; mean ± SD)

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and controls (4.4 ± 4.1) (p < 0.01) (Figure 2). When correcting for age and sex, the differences remained (ALS vs ALS-bvFTD, ALS vs bvFTD, ALS-bvFTD vs control,

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and bvFTD vs control: p < 0.0005; ALS vs control: p = 0.003; and ALS-bvFTD vs bvFTD: p = 0.011).

4. Discussion and conclusion This multicenter study showed that the ALS-FTD-Q-J can be a useful tool for screening behavioral disturbances in ALS/FTD patients. Since there are few ALS centers in Japan and each facility independently practices with a relatively small number of ALS/FTD patients, this research was performed in a multicenter manner. We included as many patients as possible during a relatively short period, and this method also contributed to minimizing regional, institutional, and examiners’ biases. The majority of 9 / 20

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Japanese ALS/FTD patients are sporadic cases, and demographic and clinical

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information from this study indicates that our results would represent the overall picture

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of Japanese ALS/FTD patients. The Japanese patients were older (6.3 years for ALS

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patients, 7.0 years for ALS-bvFTD patients and 3.7 years for bvFTD patients) compared to the original study. The internal consistency of the ALS-FTD-Q-J was satisfactory, and it also showed construct validity as the ALS-FTD-Q-J showed a high correlation with

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the FBI. The ALS-FTD-Q-J could also differentiate with statistical significance among

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patients with ALS, FTD, and healthy control subjects similar to the original report. Other than behavioral/personality changes seen in ALS/FTD patients, cognitive

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impairments are easy to measure and to compare among different nations or cultural

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backgrounds. There already exist many batteries with different language versions such as MMSE and MoCA. Languages, in contrast, show so much diversity. For example,

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some languages use characters which have a meaning (ideograms), while other languages use letters which do not have a meaning (phonograms). FTD patients

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sometimes can be affected ideogrammatic linguistic abilities [25] those are never noticed in phonogramatic language groups. For the precise understanding of language disability of FTD, therefore, it is necessary to use test batteries that optimize the respective languages backgrounds. As for behavior/character measurements, this item is still comparable between different cultures and languages, as we confirmed in this study using the ALS-FTD-Q-J, for example. There were, however, some intriguing differences in the clinimetric analyses between the Netherland and Japanese studies. First, among 25 items in the ALS-FTD-Q, the number of a single item showed poor correlation with the sum of all of other items was 5 in the present study, while 2 in the original cohort. Five items were hypersexuality, suspicious, spatial disorientation, visual or auditory 10 / 20

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hallucination, and temporal disorientation. The two items that showed poor correlation

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in the Dutch cohort were hypersexuality (0.20) and euphoria (0.26), of which

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hypersexualitiy is in agreement with our findings (0.12). The item euphoria however

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showed good correlation with the rest of items in the Japanese study (0.61) as opposed to the Dutch study. Second, the ALS-FTD-Q-J was unexpectedly more correlated to the anxiety/depression measure. In contrast, the original report found that the questionnaire

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correlated to frontal functions and global cognitive functioning. Although further

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investigations are necessary, we might take a close account of anxiety/depression symptoms, whether cause or result, if behavioral abnormalities are seen in Japanese

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ALS patients. Third, the behavioral abnormalities do not necessarily parallel cognitive

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decline in Japanese ALS patients, in contrast to the Netherland cohort. To pin down the factor(s) underlying such differences, e.g., genetic factors such as the repeat expansion

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in c9orf72, would be intriguing.

In conclusion, the ALS-FTD-Q is a valid method for screening for behavioral

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changes in the Japanese ALS/FTD population. This study showed that the ALS-FTD-Q can distinguish between ALS and ALS-bvFTD patients and can therefore be used for behavioral evaluation in the individual ALS patient. Due to the cross-sectional study design, we cannot comment on the progression of behavioral changes during the disease course of ALS. A longitudinal study is needed to reveal the natural history of behavioral changes in ALS, and to elucidate the factors associated with the development of these behavioral changes.

Acknowledgements This work was supported by Grants-in-Aid from the Research Committee of CNS 11 / 20

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Degenerative Diseases, the Ministry of Health, Labour and Welfare of Japan.

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References

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[1] Lomen-Hoerth C, Murphy J, Langmore S, Kramer JH, Olney RK, Miller B. Are amyotrophic lateral sclerosis patients cognitively normal? Neurology. 2003;60:1094-7. [2] Ringholz GM, Appel SH, Bradshaw M, Cooke NA, Mosnik DM, Schulz PE.

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Prevalence and patterns of cognitive impairment in sporadic ALS. Neurology. 2005;65:586-90.

MA

[3] Beeldman E, Raaphorst J, Klein Twennaar M, de Visser M, Schmand BA, de Haan RJ. The cognitive profile of ALS: a systematic review and meta-analysis update. J

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Neurol Neurosurg Psychiatry. 2015.

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[4] Lillo P, Mioshi E, Zoing MC, Kiernan MC, Hodges JR. How common are

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behavioural changes in amyotrophic lateral sclerosis? Amyotroph Lateral Scler. 2011;12:45-51.

[5] Phukan J, Elamin M, Bede P, Jordan N, Gallagher L, Byrne S, et al. The syndrome

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of cognitive impairment in amyotrophic lateral sclerosis: a population-based study. J Neurol Neurosurg Psychiatry. 2012;83:102-8. [6] Raaphorst J, Beeldman E, Schmand B, Berkhout J, Linssen WH, van den Berg LH, et al. The ALS-FTD-Q: a new screening tool for behavioral disturbances in ALS. Neurology. 2012;79:1377-83. [7] Ratnavalli E, Brayne C, Dawson K, Hodges JR. The prevalence of frontotemporal dementia. Neurology. 2002;58:1615-21. [8] Stevens M, van Duijn CM, Kamphorst W, de Knijff P, Heutink P, van Gool WA, et al. Familial aggregation in frontotemporal dementia. Neurology. 1998;50:1541-5.

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[9] Tomiyama H. C9orf72 in Japanese amyotrophic lateral sclerosis (ALS). Rinsho

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Shinkeigaku. 2013;53:1074-6.

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[10] Konno T, Shiga A, Tsujino A, Sugai A, Kato T, Kanai K, et al. Japanese

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amyotrophic lateral sclerosis patients with GGGGCC hexanucleotide repeat expansion in C9ORF72. J Neurol Neurosurg Psychiatry. 2013;84:398-401.

[11] Ogaki K, Li Y, Atsuta N, Tomiyama H, Funayama M, Watanabe H, et al. Analysis

MA

Neurobiol Aging. 2012;33:2527 e11-6.

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of C9orf72 repeat expansion in 563 Japanese patients with amyotrophic lateral sclerosis.

[12] Ogaki K, Li Y, Takanashi M, Ishikawa K, Kobayashi T, Nonaka T, et al. Analyses

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of the MAPT, PGRN, and C9orf72 mutations in Japanese patients with FTLD, PSP, and

TE

CBS. Parkinsonism Relat Disord. 2013;19:15-20. [13] Majounie E, Renton AE, Mok K, Dopper EG, Waite A, Rollinson S, et al.

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Frequency of the C9orf72 hexanucleotide repeat expansion in patients with amyotrophic lateral sclerosis and frontotemporal dementia: a cross-sectional study. Lancet Neurol.

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2012;11:323-30.

[14] DeJesus-Hernandez M, Mackenzie IR, Boeve BF, Boxer AL, Baker M, Rutherford NJ, et al. Expanded GGGGCC hexanucleotide repeat in noncoding region of C9ORF72 causes chromosome 9p-linked FTD and ALS. Neuron. 2011;72:245-56. [15] Brooks BR, Miller RG, Swash M, Munsat TL. El Escorial revisited: revised criteria for the diagnosis of amyotrophic lateral sclerosis. Amyotroph Lateral Scler Other Motor Neuron Disord. 2000;1:293-9. [16] Neary D, Snowden JS, Gustafson L, Passant U, Stuss D, Black S, et al. Frontotemporal lobar degeneration: a consensus on clinical diagnostic criteria. Neurology. 1998;51:1546-54. 13 / 20

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[17] Rascovsky K, Hodges JR, Knopman D, Mendez MF, Kramer JH, Neuhaus J, et al.

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Sensitivity of revised diagnostic criteria for the behavioural variant of frontotemporal

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dementia. Brain. 2011;134:2456-77.

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[18] Kertesz A, Davidson W, Fox H. Frontal behavioral inventory: diagnostic criteria for frontal lobe dementia. Can J Neurol Sci. 1997;24:29-36.

[19] Nasreddine ZS, Phillips NA, Bedirian V, Charbonneau S, Whitehead V, Collin I, et

NU

al. The Montreal Cognitive Assessment, MoCA: a brief screening tool for mild

MA

cognitive impairment. J Am Geriatr Soc. 2005;53:695-9. [20] Dubois B, Slachevsky A, Litvan I, Pillon B. The FAB: a Frontal Assessment

D

Battery at bedside. Neurology. 2000;55:1621-6.

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[21] Suga M, Uetsuki M, Takizawa R, Araki T, Kasai K. Phonological fluency is uniquely impaired in Japanese-speaking schizophrenia patients: Confirmation study.

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Psychiat Clin Neuros. 2011;65:672-5. [22] Zigmond AS, Snaith RP. The hospital anxiety and depression scale. Acta Psychiatr

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Scand. 1983;67:361-70.

[23] Cedarbaum JM, Stambler N. Performance of the Amyotrophic Lateral Sclerosis Functional Rating Scale (ALSFRS) in multicenter clinical trials. J Neurol Sci. 1997;152 Suppl 1:S1-9. [24] Ito H, Nakamura M, Komure O, Ayaki T, Wate R, Maruyama H, et al. Clinicopathologic study on an ALS family with a heterozygous E478G optineurin mutation. Acta Neuropathol. 2011;122:223-9. [25] Suh MK, Kim EJ, Lee BH, Seo SW, Chin J, Kang SJ, et al. Hanja (Ideogram) alexia and agraphia in patients with semantic dementia. Neurocase. 2010;16:146-56.

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Figure legends Fig. 1. Boxplot with ALS-FTD-Q score by diagnosis.

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*p ≦ 0.0001, **p < 0.001, ***p < 0.01(= 0.0055), ****p < 0.05(= 0.0148),

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Mann-Whitney U test.

ALS-FTD-Q: amyotrophic lateral sclerosis – frontotemporal dementia – questionnaire, ALS: amyotrophic lateral sclerosis, bvFTD: behavioral variant of frontotemporal

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dementia.

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Fig. 2. Correlations of ALS-FTD-Q with ALSFRS-R, FAB, MoCA, HADS, FAB, FBI, and %VC.

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Respective blue dots indicate ALS cases and red dots indicate ALS-bvFTD cases.

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The ALS-FTD-Q correlate well with the Frontal Behavioral Inventory (FBI) (r = 0.70),

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moderately with the vital capacity as percent of predicted (%VC) (r = 0.40) and the Hospital Anxiety and Depression Scale (HADS) (r = 0.36), and poorly with the ALS Functional Rating Scale-Revised (ALSFRS-R) (r = 0.28), the Frontal Assessment

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Battery (FAB) (r = 0.13), and the Montreal Cognitive Assessment (MoCA) (r = 0.07).

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Table 1 Demographic and clinical characteristics of control subjects and patients with ALS

(n = 92)

(n = 6)

mean 67.7 (10.2) 55/37

Limb/bulbar onset, n

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Bulbar involvement, %

65.2

subjects

(n = 16)

(n = 32)

67.2 (6.9)

67.1 (8.4)

62.1 (8.6)

3/3

10/6

14/18

3/3

D

Sex, M/F

Negative control

bvFTD

NU

y,

ALS-bvFTD

MA

Age, (SD)

ALS

SC R

Positive control

IP

T

and/or bvFTD

TE

83.3 30 (7-47)

ALSFRS-R, mean (SD)

26.8 (8.2)

CE P

Disease duration, 21.0 (3-360) mo, median (range)

AC

33.7 (9.7)

76.0 (25-880)

Abbreviations: ALS = amyotrophic lateral sclerosis; ALSFRS-R = ALS functional rating scale – Revised; ALS-FTD-Q = amyotrophic lateral Ssclerosis – frontotemporal dementia – questionnaire; bvFTD = behavioral variant of frontotemporal dementia. * Bulbar involvement was defined as a score ≦ 11 on the 3 bulbar items of the ALSFRS-R. ** The maximum score if the ALSFRS-R is 48 and indicates no motor dysfunction.

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ACCEPTED MANUSCRIPT

Table 2 Test scores and correlations of ALS-FTD-Q wht other measures of behavioral, cognitive, affective, and motor functions in patients with ALS

(range)

ALS-FTD-Qa

98

8.0 (0-34)

94

5.0 (0-28)

Frontal behavioral symptoms

0.70*

0.79

14.0 (0-18)

-0.13c,d

-0.37

9.0 (4-25)

0.08

0.30

NU

FBI

Fluencye

91

D

96

TE

Cognitive functions

24.0 (2-30)

-0.07c,d

-0.32

AC

MMSE

95

CE P

MoCA

MA

Frontal/executive functions

FAB

Original reportb

T

Correlation with

IP

ALS-FTD-Q

test score, median

SC R

No.

Affective functions

HADS

98

9.0 (0-34)

0.36*

0.18

ALSFRS-R

98

37.0 (7-48)

-0.28*,c

-0.18

%VC

84

82.7 (16.5-136.4)

-0.40*,c

Motor functions

ALS: Amyotrophic Lateral Sclerosis; ALS-FTD-Q: Amyotrophic Lateral Sclerosis-Frontotemporal Dementia-Questionnaire; FBI: Frontal Behavioral Inventory; FAB: Frontal Assessment Battery; MoCA: Montreal Cognitive Assessment; MMSE: Mini-Mental State Examination HADS: Hospital Anxiety and Depression Scale;

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ACCEPTED MANUSCRIPT

ALSFRS-R: ALS Functional Rating Scale-Revised; %VC: Vital Capacity Percentage; * p < 0.01.

T

a Correlation values are expressed as Spearman correlation coefficients ( r).

IP

b Raaphorst J, et al. Neurology 79, 1377-83, 2012.

c Negative as higher scores on the FAB, MoCA, MMSE, ALSFRS-R, and %VC indicate better

SC R

performance.

d Extrapolated scores of the MoCA and FAB were used, corrected for missed items due to motor impairment.

TE

D

MA

NU

e Fluency represents the letter fluency index.

CE P

Highlights

We established a screening tool for behavioral symptoms for Japanese ALS/FTD cases.

AC

The tool was efficacious for Japanese patients same as the original English version. Combining other measures, the tool revealed some characteristics of Japanese ALS/FTD.

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