Frontal lobe-mediated behavioral changes in amyotrophic lateral sclerosis: Are they independent of physical disabilities?

Journal of the Neurological Sciences 309 (2011) 136–140

Contents lists available at ScienceDirect

Journal of the Neurological Sciences j o u r n a l h o m e p a g e : w w w. e l s ev i e r. c o m / l o c a t e / j n s

Frontal lobe-mediated behavioral changes in amyotrophic lateral sclerosis: Are they independent of physical disabilities? Tatsuhiro Terada a, b,⁎, Tomokazu Obi a, Miho Yoshizumi c, Toshiya Murai c, Hiroaki Miyajima b, Kouichi Mizoguchi a a b c

Department of Neurology, Shizuoka Institute of Epilepsy and Neurological Disorders, Urushiyama 886, Aoi-ku, Shizuoka 420-8688, Japan First Department of Medicine, Hamamatsu University School of Medicine, Handayama 1-20-1, Higashi-ku, Hamamatsu 431-3192, Japan Department of Psychiatry, Graduate School of Medicine, Kyoto University,Yoshida-Nihonmatsucho,Kyoto 606-8501, Japan

a r t i c l e

i n f o

Article history: Received 26 October 2010 Received in revised form 10 May 2011 Accepted 27 June 2011 Available online 23 July 2011 Keywords: Amyotrophic lateral sclerosis (ALS) Frontal Systems Behavior Scale (FrSBe) Frontal cognitive impairment Behavioral dysfunction Apathy Motor impairment Respiratory failure

a b s t r a c t Objective: Several studies have indicated that frontal cognitive impairment is present in patients with amyotrophic lateral sclerosis (ALS). However, it remains to be elucidated whether the behavioral change is a direct consequence of ALS pathology or the measurements are confounded by the physical impairments. We examined frontal lobe-mediated behavioral dysfunction in daily living in patients with ALS by using the family- and self-rating forms of the Frontal Systems Behavior Scale (FrSBe) and assessed the relationship between the scores and motor impairments or ventilatory status. Methods: We examined 24 patients with sporadic ALS, who were aged 65.7 ± 10.5 years with mean disease duration of 2.3 ± 1.7 years, Mini-Mental State Examination score of ≥ 24, normal Self-rating Depression Scale, no need of assistance in daily life, normal respiratory function, and normal arterial blood gas analytes. We examined the relationship between FrSBe scores and ALS Functional Rating Scale (ALSFRS), respiratory function, and arterial blood gas analytes. Results: The scores of family- and self-rating FrSBe were significantly higher after onset of ALS than before onset, most notably in apathy. The family-rating FrSBe scores after onset were not correlated with ALSFRS, respiratory function, or arterial blood gas analytes. Conclusion: The frontal-lobe-related behavioral dysfunction is present after the onset of ALS, but is independent of physical impairments. © 2011 Elsevier B.V. All rights reserved.

1. Introduction Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease characterized by a progressive degeneration of the first and second motor neurons, which results in paralysis of the limbs, the bulbar musculature, or both. Impairments due to ALS were once believed to be exclusively physical; however, many studies have now demonstrated frontal cognitive impairment in a substantial proportion of patients with ALS [1–3]. Furthermore, it has been suggested that cognitive deficits might occur in a continuum, ranging from subtle frontal cognitive dysfunction to frontotemporal lobar degeneration (FTLD). In a more recent study, 52% of the ALS subjects met the criteria for possible or probable FTLD [4]. These findings of FTLD in patients with ALS were confirmed in postmortem examinations that found 43-kDa transactivating responsive sequence DNA-binding protein

⁎ Corresponding author at: First Department of Medicine, Hamamatsu University School of Medicine, Handayama 1-20-1, Higashi-ku, Hamamatsu 431-3192, Japan. Tel.: + 81 53 435 2261; fax: + 81 53 434 9447. E-mail address: [email protected] (T. Terada). 0022-510X/$ – see front matter © 2011 Elsevier B.V. All rights reserved. doi:10.1016/j.jns.2011.06.049

(TDP-43) in ubiquitin-positive inclusions in both ALS and FTLD patients [5,6]. In ALS, impairments of executive functions such as logical thinking, strategy, problem solving, and planning are often observed in frontal lobe function tests [7–9]; however, the results of these tests only partially capture the complex frontal lobe functions [10], and the behavioral disturbances that are characteristic of FTLD may not be detected using neuropsychological test batteries [11]. Meanwhile, clinical researchers have noted behavioral dysfunction similar to FTLD in addition to cognitive disturbances in patients with ALS [10,12,13]. Therefore, our objective was to investigate frontal lobe-mediated neurobehavioral dysfunction in patients with ALS using an observerand self-rating behavioral assessment, the Frontal Systems Behavior Scale (FrSBe). The FrSBe is an assessment tool for frontal lobe-mediated behavioral dysfunction, and compensates for the shortcomings of neuropsychological tests in the assessment of real-life behavioral manifestations of frontal lobe dysfunction [11]. The FrSBe assesses social and daily behaviors and is composed of three subscales related to three frontal systems behavior syndromes: apathy, disinhibition, and executive dysfunction.

T. Terada et al. / Journal of the Neurological Sciences 309 (2011) 136–140

Previous studies using the FrSBe to assess patients with ALS did not adjust for the fact that muscle weakness, speech impairment, or respiratory failure can confound behavioral ratings [12,13]. As ALSrelated physical symptoms progress, the scores of neurobehavioral and neuropsychological tests might be biased by muscle weakness or dysarthria [14]. Moreover, it has been reported that fronto-temporal dysfunction in patients with ALS could be attributable to secondary effects associated with respiratory failure [15]. It therefore remains unclear whether the behavioral dysfunction and cognitive impairments are the direct consequences of ALS neuropathology. Therefore, in this study, we focused on non-demented patients in early-stage ALS. To avoid the confounding effects of motor impairments, we excluded severely physically impaired patients who received low scores on the ALS Functional Rating Scale (ALSFRS). Furthermore, we excluded patients with respiratory dysfunction by means of a respiratory function test and arterial blood gas analytes. We also investigated the correlations among the FrSBe, the ALSFRS, and ventilatory status, because the early clinical presentations were varied in the ALS patients, who may present with signs and symptoms affecting limited regions of the body or with restricted upper or lower motor neuron features.

2. Methods 2.1. Subjects Twenty-four subjects with sporadic ALS (11 men and 13 women; mean age ± SD, 65.7 ± 10.5 years, mean disease duration 2.3 ± 1.7 years) were recruited from Shizuoka Institute of Epilepsy and Neurological Disorders (SIEND) (Table 1). All subjects met the criteria for the diagnosis of probable ALS, probable ALS laboratory-supported, or definite ALS based on the El Escorial criteria [16]. Subjects whose MiniMental State Examination (MMSE) scores were less than 24 were excluded [17]. No subject had a history of head injury, psychiatric disease, or dementia. No subjects had tracheostomy, artificial ventilation, or percutaneous endoscopic gastrostomy. We excluded frontotemporal dementia with motor neuron disease type, which is characterized by behavioral changes due to progressive dementia prior to bulbar palsy, muscular weakness, and wasting [18–20]. All subjects underwent magnetic resonance imaging (MRI), and we excluded patients with cerebrovascular disease, hydrocephalus, brain tumor, and trauma. This study was reviewed and approved by the ethics committee of SIEND. All subjects gave informed consent to participate in the study.

Table 1 Demographic and clinical characteristics of the amyotrophic lateral sclerosis (ALS) patients. All ALS patients Age (years) Men/women (number) Disease duration (years) ALS functional rating scale (/48) Mini-Mental State Examination (/30) Self-rating Depression Scale (/100)a Respiratory function test Forced vital capacity (L) % forced vital capacity (%) Arterial blood gas analytes pCO2 (Torr) pO2 (Torr) HCO3 (mEq/L) Base Excess (mEq/L)

137

2.2. ALS-related physical assessment We classified all subjects by using the classification of ALS severity in activities of daily living developed by the Committee of the Intractable Degenerative CNS Disease, the Ministry of Health and Welfare of Japan [21]. This is evaluated by interview and clinical observation. All subjects met the criteria for classification grade 1 (patients who report no difficulty in work and everyday life) or 2 (patients who report difficulties with work, but can eat a meal, excrete, or move themselves alone, and do not need assistance in everyday life). And, all subjects were able to do activities of daily living. Potential subjects with grades 3 (patients who cannot take at least one action of eating meal, excreting, or moving with one self alone, and need assistance in everyday life), 4 (patients who complain about difficulty in breathing caused by deteriorating respiratory function and dysphagia), or 5 (patients who take tracheostomy, percutaneous endoscopic gastrostomy, or are bedridden) were excluded. All subjects completed the revised ALSFRS [22]. Subjects having at least one subscore less than 3 were excluded. Consequently, the speech subscore of the participants was 4 (normal speech processes) or 3 (detectable speech disturbance intelligible without repeating), cutting food and handling utensils subscore was 4 (normal eating habits) or 3 (somewhat slow and clumsy, but no help needed), dyspnea subscore was 4 (no dyspnea), orthopnea subscore was 4 (no orthopnea), and respiratory insufficiency subscore was 4 (no use of biphasic positive airway pressure or invasive mechanical ventilation by intubation or tracheostomy). 2.3. Behavioral assessments The FrSBe is a 46-item behavior rating scale for frontal lobemediated behavioral dysfunction. We used two forms of the standardized Japanese version of the FrSBe [23]: a self-rating form to be completed by the patient, and a family rating form to be completed by a spouse who has regular contact with the patient. Each item consists of a 5-point scale (1, almost never; 2, seldom; 3, sometimes; 4, frequently; 5, almost always), and a total score and three subscales for apathy (14 items), disinhibition (15 items), and executive dysfunction (17 items) are calculated. The patient's current behavior (current ratings), as well as the patient's behavior before the onset of the disease (retrospective ratings) were scored. Raw FrSBe scores were linearly transformed to generate standardized T scores. In a larger sample of healthy participants, this standardization was set so that the mean T score corresponds to 50 and the standard deviation to 10, with higher scores indicating more severe impairments [23]. In addition, we administered the Self-rating Depression Scale (SDS) which is a self-report measure of depressive symptoms. We excluded patients with an SDS score above 60, reflecting obvious depression [24] (Table 1).

Normal range

2.4. Respiratory function

65.7 ± 10.5 (44–87) 11/13 2.3 ± 1.7 (1–4) 40.2 ± 2.1 (38–47) 27.4 ± 2.2 (24–30) 45.2 ± 9.3 (24–59) 2.82 ± 0.75 (1.70–4.14) 96.3 ± 15.1 (82.7–129.8)

N80

41.1 ± 3.6 (38.1–44.1) 91.0 ± 9.0 (78.9–107.6) 27.4 ± 1.6 (25.0–30.4) 3.2 ± 1.8 (0.6–6.5)

35–45 70–100 22–26 − 2–+2

Data are presented as mean ± SD (range). a SDS; A score of SDS N 60 indicates depression. Higher scores reflect greater symptoms of depression.

Even in the early stages of ALS, we sometimes observe subtle respiratory insufficiency that does not have explicit impact on the patient's activities of daily living. Therefore, we evaluated the ventilatory status with a respiratory function test (forced vital capacity and FVC%, adjusted for each subject's gender, age, and height) and arterial blood gas analytes (pCO2, pO2, HCO3, and Base Excess). Subjects with reduced vital capacity (FVC% b80), hypoxemia (pO2 b 70 mmHg), or hypercarbia (pCO2 N 45 mmHg) were excluded (Table 1). 2.5. Statistical analysis The data were analyzed using the Statistical Package for Social Sciences version 16 (SPSS Inc, Chicago, IL, USA). We used T scores of

138

T. Terada et al. / Journal of the Neurological Sciences 309 (2011) 136–140

The total score and each of the three subscales of the self-rating FrSBe were within the normal range before onset, as was the total score of the self-rating FrSBe after onset. Only the apathy subscale was outside of the normal range, at 66.1 ± 15.3 (Table 2, top). Two-way ANOVAs of the total score as well as the three subscales, demonstrated significant main effects of time (before onset vs. after onset), with significantly higher current ratings compared with retrospective ratings. The main effects of rater (family rating form vs. self rating form), as well as the time × rater interactions were not significant (Table 2, bottom).

the FrSBe in the analyses. Changes in behavior with the onset and progression of the disease were assessed by two-way (time, before or after; rater, self- or family-rating form) analysis of variance (ANOVA) performed on each subscore of the FrSBe. Correlations of the FrSBe subscores with clinical and neuropsychological ratings were investigated using Spearman correlation coefficients. Statistic significance was set at P b 0.05. All data are presented as mean ± 1 standard deviation (SD), unless indicated otherwise. 3. Results

3.3. Behavioral ratings and ALS-related physical variables

3.1. Demographic and ALS-related clinical factors

No significant correlation was found between the current family FrSBe ratings and ALS-related factors, including disease duration, ALSFRS, or ventilatory status (forced vital capacity, FVC%, pCO2, pO2, HCO3, and Base Excess). The scores of the current family FrSBe ratings were also not significantly correlated to MMSE or SDS. In the case of the current self ratings, the apathy subscale was significantly inversely correlated with the ALSFRS, and significantly positively correlated with the SDS. A significant inverse correlation was also noted between the disinhibition subscale and disease duration. No other significant correlations were found.

Demographic and ALS-related clinical factors are presented in Table 1. The number of men and women was about equal. The mean ALSFRS score was 40.2 ± 2.1, the mean MMSE score was 27.4 ± 2.2, and the mean SDS score was 45.2 ± 9.3. All of the subjects were right handed. 3.2. Behavioral ratings and cognitive function The mean total score and three subscales of the family-rating FrSBe before ALS onset were within the range of mean ± 1 SD of normative data (termed the “normal range” for simplicity). The total score of the family-rating FrSBe after onset was also within the normal range. However, the apathy subscale of the family-rating FrSBe after onset was 61.9 ± 10.3, which is above the normal range. The other subscales of the family-rating FrSBe after onset (disinhibition and executive dysfunction) were within the normal range (Table 2, top).

4. Discussion The aim of this study was to investigate frontal lobe-mediated behavioral dysfunction in patients with sporadic ALS without dementia, and to ascertain the relationship between behavioral dysfunction and ALS-related physical and cognitive variables.

Table 2 The frontal systems behavioral scale (FrSBe) ratings. Family rating form

FrSBe total score Apathy Disinhibition Executive dysfunction

Self rating form

Before onset

After onset

Before onset

After onset

44.3 ± 8.2 46.7 ± 8.6 43.4 ± 7.6 43.4 ± 8.4

53.9 ± 10.1 61.9 ± 10.3 48.7 ± 7.9 50.0 ± 10.9

44.8 ± 7.1 45.4 ± 7.1 44.9 ± 6.1 45.6 ± 8.3

55.0 ± 10.3 66.1 ± 15.3 49.6 ± 9.3 49.6 ± 11.9

Data are presented as mean ± SD Statistics (two-way ANOVAs) for the FrSBe results

FrSBe total score

Apathy

Disinhibition

Executive dysfunction

Main effect of rater (family rating form vs. self rating Error Main effect of time (before onset vs. after onset) Error Interaction (rater × time) Error Main effect of rater (family rating form vs. self rating Error Main effect of time (before onset vs. after onset) Error Interaction (rater × time) Error Main effect of rater (family rating form vs. self rating Error Main effect of time (before onset vs. after onset) Error Interaction (rater × time) Error Main effect of rater (family rating form vs. self rating Error Main effect of time (before onset vs. after onset) Error Interaction (rater × time) Error

Values enclosed in parentheses represent mean square errors. ⁎ P b 0.05.

form)

form)

form)

form)

df

F score

η2

P value

1 23 1 23 1 23 1 23 1 23 1 23 1 23 1 23 1 23 1 23 1 23 1 23

0.52 (105.71) 52.90⁎

0.034

0.48

0.78

0.001

0.069

0.31

0.028

0.52

0.75

0.001

0.19

0.083

0.090

0.24

0.52

0.001

0.001

0.94

0.047

0.41

0.46

0.003

0.001

0.99

(25.7) 1.11 (14.1) 0.43 (106.15) 44.53⁎ (100.17) 3.45 (36.32) 1.48 (64.41) 16.37⁎ (16.94) 0.006 (9.07) 0.73 (108.22) 12.90⁎ (36.25) 0.001 (20.80)

T. Terada et al. / Journal of the Neurological Sciences 309 (2011) 136–140

The significant differences between current and retrospective FrSBe ratings, together with the lack of statistical differences between family and self ratings, indicate that behavioral changes in social and daily activities after the onset of the disease were recognized by both the patients with ALS and their family members. Among the three behavioral domains evaluated by the FrSBe (apathy, disinhibition, and executive dysfunction), behavioral change was most clearly observed in apathy. There are important potential confounders in the assessment of premorbid behaviors using the FrSBe. Retrospective ratings can be influenced by current behavior and may be viewed as more normal than it actually was, due to recall bias [11]. However, in our study, the retrospective scores were within the range of mean ± 1 SD of the normative data, suggesting that these ratings are authentic. When assessing real-life behaviors of ALS patients, motor impairments should be taken into consideration. Even mild muscle weakness or speech impairments pose a problem for the assessment of social and daily behaviors. In the FrSBe, some of the items inquire about changes in physical abilities. In ALS patients, these changes can either be caused by frontal lobe pathology or by motor impairments. Even in patients who do not need assistance in everyday life, the ratings might be biased by the existence and severity of muscle weakness or speech impairments. Therefore, in this study, we excluded patients who needed assistance in everyday life, and, in addition, assessed the correlations of the FrSBe scores with the motor impairments in patients whose motor impairments are within the milder range. As results, we did find behavioral change in patients with minimal motor impairments, and we did not find significant correlation of the current family FrSBe ratings with disease duration or the ALSFRS. Thus, we suspect that behavioral dysfunction cannot be explained by motor impairments alone. ALS has been associated with obvious cognitive atrophy or reductions in blood flow or metabolism in frontal cortex [25,26]. The presence of widespread TDP-43 pathology in multiple brain areas outside the pyramidal motor system suggests that ALS is a disease of multiple-system neurodegeneration with multiple-system TDP-43 proteinopathy [27–29]. Because of the strong associations between ALS and FTLD, knowing whether or not an ALS patient has cognitive impairment brings important considerations for the clinical management of these patients. The previous studies using FrSBe may have included patients with the frontotemporal dementia with motor neuron disease type [12,13]. In contrast, in our current study, we excluded subjects with obvious depression or dementia, and we did not find significant correlation of the current family FrSBe ratings with SDS or MMSE. Thus, our results can be interpreted that behavioral disturbances in ALS would emerge in the subjects with minimal depression or dementia. Reduced vital capacity, hypoxia, hypercarbia can cause cognitive impairments in several ways, such as by chronic intermittent hypoxia [15]. In patients with ALS, significant oxygen desaturation can occur, particularly nocturnally, even in individuals with seemingly adequate vital capacities. However, previous studies of behavioral changes in ALS have not taken ventilatory status into account in detail. We therefore excluded patients with apparent respiratory failure, as detected by the ALSFRS, from this study, and no subjects in this study had pulmonary dysfunction, hypoxemia, or hypercarbia. Moreover, we did not find correlation between the scores on the family- or selfrating FrSBe and ventilatory status, retrospectively. Thus, consistent with previous report that indicated that there was no significant correlation between FrSBe and forced vital capacity [12], our results indicate that respiratory insufficiency is an unlikely explanation for the behavioral changes demonstrated in this study. Although our results are showing obvious behavioral change in early stage of ALS patients, we should be cautious about ascribing these behavioral changes to frontal lobe dysfunction. As is well known, behavioral changes in frontal lobe damage are more likely to be

139

recognized by caregivers than the patients [30]. Thus in case of typical frontal lobe dysfunction, we should expect discrepancies between family- and self- ratings in the FrSBe. But we did not find such differences. Moreover, this is in the self-rating version, in which we found significant a correlation of apathy with the ALSFRS score. This would suggest the apathetic feelings in our patients are not necessarily symptoms mediated by frontal lobe dysfunction, but are mediated by some other processes. As is indicated above, neither physical impairment, respiratory dysfunction, depression nor dementia offers a single reasonable explanation. In addition, the self-rating apathy score did not correlate with the disease duration. One possibility is that the combinations of some these factors, even though they may be mild if assessed singly, might have caused subjective feeling of apathy in our subjects. Another possibility would be psychosocial impact of disease notification. In conclusion, in this study, even the patients with early and relatively normal-functioning ALS had behavioral dysfunction characteristic of apathy which was not due to motor impairments or respiratory failure. Neurobehavioral assessments are important for identifying cognitive dysfunction as an early feature in patients with ALS, and the FrSBe were revealed to provide useful information about real-life behavioral changes. As this study is a cross-sectional study and the sample size was relatively small, further studies are needed to confirm our preliminary findings. Acknowledgment This research was supported by a grant from the National Hospital Organization Headquarters Center for support of Clinical Research. References [1] Abrahams S, Goldstein LH, Al-Chalabi A, Pickering A, Morris RG, Passingham RE, et al. Relation between cognitive dysfunction and pseudobulbar palsy in amyotrophic lateral sclerosis. J Neurol Neurosurg Psychiatry 1997;62:464–72. [2] Neary D, Snowden JS, Mann DM. Cognitive change in motor neurone disease/ amyotrophic lateral sclerosis (MND/ALS). J Neurol Sci 2000;180:15–20. [3] Rippon GA, Scarmeas N, Gordon PH, Murphy PL, Albert SM, Mitsumoto H, et al. An observational study of cognitive impairment in amyotrophic lateral sclerosis. Arch Neurol 2006;63:345–52. [4] 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. [5] Neumann M, Sampathu DM, Kwong LK, Truax AC, Micsenyi MC, Chou TT, et al. Ubiquitinated TDP-43 in frontotemporal lobar degeneration and amyotrophic lateral sclerosis. Science 2006;314:130–3. [6] Arai T, Hasegawa M, Akiyama H, Ikeda K, Nonaka T, Mori H, et al. TDP-43 is a component of ubiquitin-positive tau-negative inclusions in frontotemporal lobar degeneration and amyotrophic lateral sclerosis. Biochem Biophys Res Commun 2006;351:602–11. [7] Evdokimidis I, Constantinidis TS, Gourtzelidis P, Smyrnis N, Zalonis I, Zis PV, et al. Frontal lobe dysfunction in amyotrophic lateral sclerosis. J Neurol Sci 2002;195: 25–33. [8] Santhosh J, Bhatia M, Sahu S, Anand S. Quantitative EEG analysis for assessment to ‘plan’ a task in amyotrophic lateral sclerosis patients: a study of executive functions (planning) in ALS patients. Brain Res Cogn Brain Res 2004;22:59–66. [9] 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. [10] Murphy J, Henry R, Lomen-Hoerth C. Establishing subtypes of the continuum of frontal lobe impairment in amyotrophic lateral sclerosis. Arch Neurol 2007;64:330–4. [11] Grace J, Stout JC, Malloy PF. Assessing frontal lobe behavioral syndromes with the frontal lobe personality scale. Assessment 1999;6:269–84. [12] Grossman AB, Woolley-Levine S, Bradley WG, Miller RG. Detecting neurobehavioral changes in amyotrophic lateral sclerosis. Amyotroph Lateral Scler 2007;8: 56–61. [13] Witgert M, Salamone AR, Strutt AM, Jawaid A, Massman PJ, Bradshaw M, et al. Frontal-lobe mediated behavioral dysfunction in amyotrophic lateral sclerosis. Eur J Neurol 2010;17:103–10. [14] Iwasaki Y, Kinoshita M, Ikeda K, Takamiya K, Shiojima T. Neuropsychological dysfunctions in amyotrophic lateral sclerosis: relation to motor disabilities. Int J Neurosci 1990;54:191–5. [15] Kim SM, Lee KM, Hong YH, Park KS, Yang JH, Nam HW, et al. Relation between cognitive dysfunction and reduced vital capacity in amyotrophic lateral sclerosis. J Neurol Neurosurg Psychiatry 2007;78:1387–9.

140

T. Terada et al. / Journal of the Neurological Sciences 309 (2011) 136–140

[16] Beghi E, Balzarini C, Bogliun G, Logroscino G, Manfredi L, Mazzini L, et al. Reliability of the El Escorial diagnostic criteria for amyotrophic lateral sclerosis. Neuroepidemiology 2002;21:265–70. [17] Tombaugh TN, McIntyre NJ. The mini-mental state examination: a comprehensive review. J Am Geriatr Soc 1992;40:922–35. [18] Mitsuyama Y. Presenile dementia with motor neuron disease in Japan: clinicopathological review of 26 cases. J Neurol Neurosurg Psychiatry 1984;47:953–9. [19] Neary D, Snowden JS, Mann DM, Northen B, Goulding PJ, Macdermott N. Frontal lobe dementia and motor neuron disease. J Neurol Neurosurg Psychiatry 1990;53:23–32. [20] Clinical and neuropathological criteria for frontotemporal dementia. The Lund and Manchester Groups. J Neurol Neurosurg Psychiatry 1994;57:416–8. [21] Ohashi Y, Tashiro K, Itoyama Y, Nakano I, Sobue G, Nakamura S, et al. Study of functional rating scale for amyotrophic lateral sclerosis: revised ALSFRS (ALSFRS-R) Japanese version. No To Shinkei 2001;53:346–55. [22] Cedarbaum JM, Stambler N, Malta E, Fuller C, Hilt D, Thurmond B, et al. The ALSFRS-R: a revised ALS functional rating scale that incorporates assessments of respiratory function. BDNF ALS Study Group (Phase III). J Neurol Sci 1999;169:13–21. [23] Yoshizumi M, Ueda K, Murai T. Reliability, validity, and standardization of Japanese version of the Frontal Systems Behavioral Scale. Seishin Igaku 2007;49:137–42.

[24] Holmes CB, Fouty HE, Wurtz PJ, Burdick BM. Zung Self-Rating Depression Scale scores of psychiatric outpatients by age and sex. Psychol Rep 1988;62:259–62. [25] Abe K, Fujimura H, Toyooka K, Hazama T, Hirono N, Yorifuji S, et al. Single-photon emission computed tomographic investigation of patients with motor neuron disease. Neurology 1993;43:1569–73. [26] Chang JL, Lomen-Hoerth C, Murphy J, Henry RG, Kramer JH, Miller BL, et al. A voxel-based morphometry study of patterns of brain atrophy in ALS and ALS/FTLD. Neurology 2005;65:75–80. [27] Geser F, Brandmeir NJ, Kwong LK, Martinez-Lage M, Elman L, McCluskey L, et al. Evidence of multisystem disorder in whole-brain map of pathological TDP-43 in amyotrophic lateral sclerosis. Arch Neurol 2008;65:636–41. [28] Geser F, Martinez-Lage M, Robinson J, Uryu K, Neumann M, Brandmeir NJ, et al. Clinical and pathological continuum of multisystem TDP-43 proteinopathies. Arch Neurol 2009;66:180–9. [29] Geser F, Martinez-Lage M, Kwong LK, Lee VM, Trojanowski JQ. Amyotrophic lateral sclerosis, frontotemporal dementia and beyond: the TDP-43 diseases. J Neurol 2009;256:1205–14. [30] Woolley SC, Moore DH, Katz JS. Insight in ALS: awareness of behavioral change in patients with and without FTD. Amyotroph Lateral Scler 2010;11:52–6.