Abstract

Although executive functions in sporadic non-demented amyotrophic lateral sclerosis (ALS) patients are mostly affected, it remains unclear whether executive measures can differentiate between patients with bulbar and spinal ALS forms. Thirty spinal and 18 bulbar-onset ALS patients (ALS-s and ALS-b, respectively) as well as 47 demographically related healthy controls were examined in executive processes (Trail Making Test-part B [TMT-(B-A)]; Stroop Neuropsychological Screening Test [SNST]; Similarities subtest of the Wechsler Adult Intelligence Scale [WAIS Similarities]; Wisconsin Card Sorting Test [WCST]). ALS subgroups were similar with regard to demographic characteristics and disease duration; yet, ALS-b showed greater disease severity compared with ALS-s patients (p = .006). Both ALS-s and ALS-b patients were significantly inferior to healthy controls on TMT-(B-A) (p < .001), SNST (p = .009 and p = .02, respectively) and WAIS Similarities (p = .031 and p = .021, respectively), whereas ALS-s performed significantly worse than controls on the WCST perseverative responses (p = .005). However, neuropsychological measures did not significantly differ between ALS subgroups (p > .05). Despite the fact that ALS-b patients may present greater disease severity, specific executive impairments that are present early in the course of ALS seems to be independent of the site of onset.

Introduction

Amyotrophic lateral sclerosis (ALS) is the most common adult-onset motor neuron disease. It is a progressive neurodegenerative disorder primarily involving motor neurons in the cerebral cortex, brainstem, and spinal cord (Brooks, Miller, Swash, & Munsat, 2000) and is characterized by motor deficits, bulbar palsy, and respiratory insufficiency. Until fairly recently, cognitive impairment has not been considered as a component of ALS. However, formal psychometric testing has demonstrated that 33%–51% of ALS patients develop cognitive dysfunction (Ringholz et al., 2005), even in the early stages of the disease (Hanagasi et al., 2002), with 15% of patients manifesting features of frontotemporal dementia (Massman et al., 1996; Ringholz et al., 2005). Furthermore, cognitive impairment in ALS is associated with a greater distribution and load of neuropathological features, suggesting a disease continuum (Kato, Hayashi, & Yagishita, 1992; Wilson, Grace, Munoz, He, & Strong, 2001).

Many neuropsychological studies have reported executive dysfunction in ALS patients (Abe et al., 1997; Abrahams, Leigh, & Goldstein, 2005; Hanagasi et al., 2002; Irwin, Lippa, & Swearer, 2007; Paulus et al., 2002; Phukan, Pender, & Hardiman, 2007; Ringholz et al., 2005; Štukovnik, Zidar, Podnar, & Repovs, 2010), with the most consistent finding being impaired verbal fluency (Abrahams et al., 2000, 2005; Hanagasi et al., 2002; Kew et al., 1993; Rippon et al., 2006; Röttig et al., 2006; Strong, 2008). Attention deficits have been commonly reported in ALS (Abe et al., 1997; Frank, Haas, Heinze, Stark, & Munte, 1997; Hanagasi et al., 2002; Massman et al., 1996; Paulus et al., 2002), though there has been disagreement with regard to impaired memory function (Frank et al., 1997; Hanagasi et al., 2002; Iwasaki, Kinoshita, Ikeda, Takamiya, & Shiojima, 1990; Strong et al., 1999).

Cognitive impairment in ALS is thought to be associated with disease severity, with progression of impairment over time (Rippon et al., 2006). Together with other factors, such as older age and shorter delay to diagnosis, cognitive impairment is also considered to have a negative effect on survival (Czaplinski, Yen, & Appel, 2006; Mandrioli et al., 2006; Rusin et al., 2010). However, there are studies that failed to find any associations between disease severity and cognitive impairment and report that cognitive impairments do not progress in parallel with motor decline (Abrahams et al., 1997, 2000; Schreiber et al., 2005). In addition, the prognostic effect of the site of disease onset on cognitive functions has been addressed in studies. Patients with ALS can present with two main symptoms, namely a quivering of the lip or a change in speech, as seen in those with a bulbar onset (ALS-b), and stumbling or weakness of grasp, in those with a spinal onset (ALS-s). Some authors have suggested that ALS-b patients show cognitive impairments (Abrahams et al., 1997; Lomen-Hoerth et al., 2003); yet, there are studies that have failed to support this relationship (Frank et al., 1997; Massman et al., 1996; Ringholz et al., 2005; Rippon et al., 2006; Štukovnik et al., 2010) or have indicated that the absence of bulbar signs is not a definite predictor of intact cognition (Strong et al., 1999). In general, bulbar involvement carries a poor prognosis with shorter life expectancy compared with spinal involvement (Haverkamp, Appel, & Appel, 1995; Jablecki, Berry, & Leach, 1989; Mandrioli, Faglioni, Nichelli, & Sola, 2006; Norris et al., 1993). The topography of motor neuron degeneration in patients with ALS-b could result in more extensive disruption of cognitive pathways due to more extensive degeneration, with this occurring in the cortex where the fronto-cortical representation area of bulbar structures is large and close to prefrontal structure (Ellis et al., 2001; Schreiber et al., 2005). In a recent meta-analytic study, the magnitude of difference between ALS-s and ALS-b patients' cognitive performance was small in tests of immediate verbal memory, visual memory, and executive functions, when more than 40% of the total ALS group had bulbar onset (Raaphorst, De Visser, Linssen, De Haan, & Schmand, 2009).

Cognitive functions in sporadic non-demented ALS patients remain relatively unexplored and it is still unclear whether the frequency of cognitive impairment is higher and more prominent in ALS-b patients. The purpose of the present study was to determine the effect of site of ALS onset on executive performance by comparing ALS-s and ALS-b patients, in order to specifically identify any cognitive sub-processes that could differentiate the two ALS forms.

Methods

Participants

Sixty-two consecutive ALS patients (40 men) were selected from the data set of the Neuropsychological Laboratory. All patients underwent clinical assessment, including full neurological examination, and were diagnosed with sporadic ALS according to the modified El Escorial diagnostic criteria for ALS (Brooks et al., 2000). Patients were subsequently referred for neuropsychological assessment as part of their routine clinical care. The patients' disease severity was quantified using the ALS Functional Rating Scale (ALSFRS; Cedarbaum & Stambler, 1997), with a higher score being representative of a better functional status. Inclusion criteria for the present study were the following: (i) absence of a history of other neurological conditions affecting cognition, such as stroke or traumatic brain injury, (ii) no serious mental illness (e.g., major depression, schizophrenia), (iii) no family history of ALS, (iv) absence of psychoactive drugs or other medication that could affect mental status, (v) absence of dementia (absence of significant reduction in activities of daily living based on patients' and caregivers' self-reports and a Mini-Mental State Examination [MMSE] >26), (vi) absence of severe motor deficits (upper extremities, dysarthria) that could interfere with neuropsychological performance. Based on these criteria, 14 patients were excluded (1 ALS-s patient with a history of traumatic brain injury; 1 ALS-s patient with familial history of the disease; and 12 patients [ALS-s/ALS-b = 8/4] with MMSE <26 including four ALS-s patients with severe motor impairment of both upper and lower limbs and two ALS-b patients with severe dysarthria], and the final group included 48 patients (33 men/15 women), with mean age and education of 60.29 years (range: 20–79 years) and 9.69 years (range: 4–18 years), respectively. The mean disease duration was 21.02 months (range: 3–96 months) and the mean disease severity score was 27.48 (range: 20–34). Depending on the site of onset (spinal vs. bulbar), the rest of the 48 patients (33 men) were subdivided into ALS-s (n = 30) and ALS-b (ALS-b, n = 18) groups. We also included a group of 47 unrelated healthy volunteer controls. Both patients and healthy controls had a Beck Depression Inventory score <10 and a Hospital Anxiety and Depression Scale (Anxiety Subscale) <11. Table 1 displays demographic characteristics for controls and ALS subgroups, as well as clinical characteristics for ALS patients. The retrospective analysis of the data was approved by the ethical committee of our institution.

Table 1.

Demographic and clinical characteristics (mean ± SD) of ALS patients and controls

 ALS-s ALS-b Controls p-value 
n (M/F) 30 (22/8) 18 (11/7) 47 (34/13) ns 
Age 59.43 (11.79) 61.72 (10.21) 59.57 (11.03) ns 
Education 9.63 (3.89) 9.78 (4.26) 9.87 (3.70) ns 
Disease's duration 21.19 (19.41) 20.76 (18.48) — ns 
ALSFRS 29.50 (3.40) 24.78 (3.60) — .006 
Full IQ 95.67 (10.90) 96.78 (10.95) 101.57 (10.83) ns 
 ALS-s ALS-b Controls p-value 
n (M/F) 30 (22/8) 18 (11/7) 47 (34/13) ns 
Age 59.43 (11.79) 61.72 (10.21) 59.57 (11.03) ns 
Education 9.63 (3.89) 9.78 (4.26) 9.87 (3.70) ns 
Disease's duration 21.19 (19.41) 20.76 (18.48) — ns 
ALSFRS 29.50 (3.40) 24.78 (3.60) — .006 
Full IQ 95.67 (10.90) 96.78 (10.95) 101.57 (10.83) ns 

Notes: Age and education are expressed in years, disease's duration is expressed in months, and full IQ is expressed in z-scores. Values are present by mean (SD). M/F = men/women; ALS-s = amyotrophic lateral sclerosis spinal onset; ALS-b = amyotrophic lateral sclerosis bulbar-onset; ALSFRS = Amyotrophic Lateral Sclerosis Functional Rating Scale; ns = non-significant.

Neuropsychological Assessment

Executive functions were evaluated using the following tests: Trail Making Test-part B (TMT-(B-A); Zalonis et al., 2008), Stroop Neuropsychological Screening Test (SNST; Zalonis et al., 2009), Wechsler Adult Intelligence Scale (WAIS) Similarities subtest (Kokkevi, Repapi, Adamou, & Stefanis, 1979; Wechsler, 1955), and Wisconsin Card Sorting Test (WCST; Heaton, Chelune, Talley, Kay, & Curtiss, 1993). The derived difference score (part B–part A) was used in TMT in order to remove the speed element from test evaluation and have a better index for the cognitive processes related to TMT-B. Moreover, the interference score was examined in the SNST, without further adjustments for effects of oromotor impairment (i.e., dysarthria), since ALS patients did not differ from healthy controls on the time needed to read the first part of the SNST, nor was there a significant difference between the ALS groups. As for the WCST, the number of categories (WCST-C) completed, the percent of errors (WCST-E), and the percent of preservative responses (WCST-PR) made, as well as the percent of conceptual level responses (WCST-CLR) achieved, were included for the purpose of the study. WAIS Information and Vocabulary subtests were also used as indicators of a general cognitive impairment (in addition to the Full-Scale IQ), since they are two tests that do not require executive functions.

Statistical Analysis

A retrospective analysis of the neuropsychological data available on our sample was carried out using SPSS v.15.0 and the significance level was set to α = 5%. Between-group differences on demographic data and ALS clinical characteristics were analyzed using univariate analysis of variance and χ2 test. Assumptions for normality (Kolmogorov–Smirnov test) were not significantly violated, and parametric statistics were applied in the subsequent analyses. Comparisons were made using univariate analysis of variance to detect meaningful between-group differences (ALS-s, ALS-b, controls) on the neuropsychological tests. The overall α level of 5% was used with an adjustment for multiple comparisons according to the following formula: α = 0.05/(kx + 1), with k representing the number of tests and x representing the number of significant results (Röttig et al., 2006).

Results

Demographic and Clinical Data

Our patients (total group) and controls did not differ in age, years of education, and gender distribution (p > .05). Moreover, there were no significant differences in demographic characteristics between ALS subgroups (ALS-s and ALS-b) or between controls and each ALS subgroup. With respect to the general intellectual level (full IQ), as measured using the WAIS, post hoc comparisons between controls, ALS-s, and ALS-b groups did not reached significance (p > .05). ALS subgroups did not differ in mean disease duration (p > .05) and the majority of patients were at the medium stage of the disease (81.5% of ALS-s and 88.2% of ALS-b patients had <24 months of disease duration). ALS-s patients had a higher ALSFRS (at p < .006) compared with ALS-b patients.

The Effect of Site of ALS Onset on Neuropsychological Performance

Disease duration or severity score (ALSFRS) was not included as covariates, since the ALS-s and ALS-b groups did not differ in disease duration and no significant correlations were emerged between severity index (ALSFRS) and neuropsychological scores either within the total sample of ALS patients or within ALS-s and ALS-b subgroups. Furthermore, ALS patients did not differ from healthy controls on the time needed to read the first part of the SNST (controls = 61.53 [2.50]; ALS = 62.42 [2.78]; p = .119, ns), and there was not significant difference between ALS-s and ALS-b (ALS-s = 61.96 [2.59]; ALS-b = 63.20 [3.01]; p = .319, ns). Three ALS-s and two ALS-b patients were not administered the TMT, whereas five ALS-s and three ALS-b patients were not administered the SNST. Table 2 represents neuropsychological performance (raw scores) of ALS-s and ALS-b subgroups and controls and summarizes levels of significance concerning the comparisons of the three groups by means of univariate analysis of variance applied on neuropsychological tests.

Table 2.

Neuropsychological performance of ALS-s and ALS-b patients and controls

 Groups
 
 
Cognitive tests ALS-s ALS-b Controls Statistics (p-value) 
TMT-(B-A) 177.30 (19.80) 249.12 (25.72) 78.38 (15.05) <.001a 
SNST 62.24 (4.23) 61.73 (5.47) 78.27 (3.16) .003b 
WAIS similarities 7.93 (0.65) 7.39 (0.83) 10.06 (0.52) .007c 
WCST-C 3.17 (0.30) 3.44 (0.38) 3.91 (0.27) .184 
WCST-E 48.17 (2.70) 43.56 (3.43) 40.31 (2.46) .105 
WCST-PR 37.07 (2.95) 31.39 (3.75) 24.11 (2.69) .007d 
WCST-CLR 35.86 (3.5) 40.83 (4.54) 45.89 (3.25) .123 
WAIS information 11.83 (2.89) 11.44 (2.68) 12.51 (2.47) .287 
WAIS vocabulary 10.20 (2.02) 10.44 (1.65) 11.02 (2.03) .183 
 Groups
 
 
Cognitive tests ALS-s ALS-b Controls Statistics (p-value) 
TMT-(B-A) 177.30 (19.80) 249.12 (25.72) 78.38 (15.05) <.001a 
SNST 62.24 (4.23) 61.73 (5.47) 78.27 (3.16) .003b 
WAIS similarities 7.93 (0.65) 7.39 (0.83) 10.06 (0.52) .007c 
WCST-C 3.17 (0.30) 3.44 (0.38) 3.91 (0.27) .184 
WCST-E 48.17 (2.70) 43.56 (3.43) 40.31 (2.46) .105 
WCST-PR 37.07 (2.95) 31.39 (3.75) 24.11 (2.69) .007d 
WCST-CLR 35.86 (3.5) 40.83 (4.54) 45.89 (3.25) .123 
WAIS information 11.83 (2.89) 11.44 (2.68) 12.51 (2.47) .287 
WAIS vocabulary 10.20 (2.02) 10.44 (1.65) 11.02 (2.03) .183 

Notes: ALS-s = amyotrophic lateral sclerosis spinal onset; ALS-b = amyotrophic lateral sclerosis bulbar-onset; TMT-(B-A) = Trail Making Test part B–part A (s); SNST = Stroop Neuropsychological Screening Test; WAIS = Wechsler Adult Intelligence Scale; WCST-C = Wisconsin Card Sorting Test categories completed; WCST-E = Wisconsin Card Sorting Test percent errors; WCST-PR = Wisconsin Card Sorting Test percent preservative responses; WCST-CLR = Wisconsin Card Sorting Test percent conceptual level responses. Values are expressed as the mean (standard error of mean). Statistically significant post hoc comparisons indicate that controls performed significantly better than ALS-s and ALS-b.

aALS-s and ALS-b, both at p < .001.

bALS-s (p = .009) and ALS-b (p = .02).

cALS-s (p = .031) and ALS-b (p = .021).dALS-s (p = .005).

After controlling for multiple comparisons (pcorrected < 0.0125), a significant main effect was observed for TMT-(B-A) (F = 19.20; p < .001), SNST (F = 6.21; p = .003), WAIS Similarities (F = 5.31; p = .007), and WCST-PR (F = 5.32; p = .007). Post hoc comparisons indicated that controls were superior to both ALS subgroups (p < .001) on TMT-(B-A) and to ALS-s (p = .009) and ALS-b (p = .02) on SNST. With respect to the WAIS Similarities, significant between-group differences were observed between controls and ALS-s patients (p = .031) and ALS-b (p = .021). In WCST-PR, controls performed significantly better than ALS-s patients (p = .005). None of the differences between ALS-s and ALS-b subgroups reached significance (p > .05). Furthermore, there were no significant differences on the non-executive tests of WAIS Information (F = 3.08; p > .05) and Vocabulary (F = 1.73; p > .05). After controlling for the ALSFRS score (univariate analysis of covariance), our analyses between ALS-s and ALS-b subgroups did not change. Table 3 shows the percent of patients within each ALS subgroup that falls ≤−1, >−1 and ≤−1.5, >−1.5 and ≤−2, or more standard deviations below the mean of the control group for each neuropsychological test.

Table 3.

Percent of patients within each ALS subgroup that falls ≤ −1, > −1 and ≤ −1.5, > −1.5 and ≤ −2 or more standard deviations below the mean of the control group for each neuropsychological test

 Standard deviations bellow healthy participants' mean for each test
 
 ≤−1
 
>−1 and ≤−1.5
 
>−1.5 and ≤−2
 
>−2
 
Cognitive tests ALS-s ALS-b ALS-s ALS-b ALS-s ALS-b ALS-s ALS-b 
TMT-(B-A) 44.44 37.50 7.41 6.25 3.70 0.00 44.44 56.25 
SNST 40.00 40.00 16.00 20.00 20.00 13.33 24.00 26.67 
WAIS Similarities 56.67 38.89 6.67 5.56 20.00 38.89 16.67 16.67 
WCST-C 63.33 61.11 23.33 33.33 3.33 5.56 10.00 0.00 
WCST-E 66.67 66.67 10.00 16.67 13.33 16.67 10.00 0.00 
WCST-PR 53.33 61.11 6.67 16.67 3.33 5.56 36.67 16.67 
WCST-CLR 56.67 77.78 16.67 16.67 16.67 5.56 10.00 0.00 
 Standard deviations bellow healthy participants' mean for each test
 
 ≤−1
 
>−1 and ≤−1.5
 
>−1.5 and ≤−2
 
>−2
 
Cognitive tests ALS-s ALS-b ALS-s ALS-b ALS-s ALS-b ALS-s ALS-b 
TMT-(B-A) 44.44 37.50 7.41 6.25 3.70 0.00 44.44 56.25 
SNST 40.00 40.00 16.00 20.00 20.00 13.33 24.00 26.67 
WAIS Similarities 56.67 38.89 6.67 5.56 20.00 38.89 16.67 16.67 
WCST-C 63.33 61.11 23.33 33.33 3.33 5.56 10.00 0.00 
WCST-E 66.67 66.67 10.00 16.67 13.33 16.67 10.00 0.00 
WCST-PR 53.33 61.11 6.67 16.67 3.33 5.56 36.67 16.67 
WCST-CLR 56.67 77.78 16.67 16.67 16.67 5.56 10.00 0.00 

Notes: ALS-s = amyotrophic lateral sclerosis spinal onset; ALS-b = amyotrophic lateral sclerosis bulbar-onset; TMT-(B-A) = Trail Making Test part B–part A (s); SNST = Stroop Neuropsychological Screening Test; WAIS = Wechsler Adult Intelligence Scale; WCST-C = Wisconsin Card Sorting Test categories completed; WCST-E = Wisconsin Card Sorting Test percent errors; WCST-PR = Wisconsin Card Sorting Test percent preservative responses; WCST-CLR = Wisconsin Card Sorting Test percent conceptual level responses. Values represent the percent of patients.

Discussion

Our goal was to determine the effect of site of ALS onset on executive performance by comparing ALS-s and ALS-b patients, in order to specifically identify any cognitive sub-processes that could differentiate the two ALS forms. Our results suggest that non-demented ALS-s and ALS-b patients have an equivalent level of performance with regard to their general intellectual abilities and a group of commonly used executive measures.

ALS is identified as a multisystem disease (Wilson et al., 2001), involving areas in association cortices, in addition to the motor cortex, and consequently affecting cognition. Problems in visual attention, cognitive flexibility, inhibition of response alternatives, planning, and problem solving have been identified as ALS-related executive impairments and attributed to frontal lobe dysfunction (Abrahams et al., 2005; Evdokimidis et al., 2002; Frank et al., 1997; Ludolph et al., 1992; Massman et al., 1996; Neary, Snowden, & Mann, 2000). In line with previous studies (Abrahams et al., 1997; Frank et al., 1997; Kilani et al., 2004; Rusin et al., 2010; Štukovnik et al., 2010), our patients showed deficient divided and selective attention as evidenced by their impaired performance on TMT-(B-A) and SNST. Previous studies have mentioned either impaired (i.e., Abrahams et al., 1997; Evdokimidis et al., 2002; Massman et al., 1996; Neary et al., 1990) or normal (i.e., Abrahams et al., 2005; Kew et al., 1993; Ludolph et al., 1992) performance in the WCST. Perseverative responses observed in the WCST have been considered as the “strongest predictor of both brain damage and involvement of frontal areas” (Golden, Espe-Pfeifer, & Wachsler-Felder, 2000) and can be used as a measure of cognitive flexibility and set-shifting. In our small sample, we observed that the ALS-s patients performed significantly worse than healthy participants in the WCST-PR measure. We also found that while abstract verbal reasoning (WAIS Similarities) was impaired in the ALS group relative to controls, fund of knowledge and verbal expression (WAIS Information, Vocabulary) did not differ between ALS-s, ALS-b, and healthy controls. Thus, our patients' impaired performance can be interpreted as executive impairment.

Our findings contradict general findings of worse performance of ALS-b patients when compared with ALS-s patients. It is interesting to note that in our ALS patients without dementia, the presence of executive impairment was independent of the presence of overall functional impairment. Thus, despite the fact that ALS-b patients showed greater disease severity, this was not associated with significantly greater executive impairment. Our findings are in line with those of the large study of Massman and colleagues (1996) which did not confirm any associations between bulbar onset and cognitive impairment. Other studies also have supported an absence of strong correlation between site of onset and cognitive impairment (Frank et al., 1997; Portet, Cadilhac, Touchon, & Camu, 2001; Ringholz et al., 2005).

Strengths of the present study are the inclusion of non-demented ALS patients diagnosed according to well-established EL Escorial clinical criteria (Brooks et al., 2000), with spared voluntary speech and relatively intact physical abilities, and none with severe dysarthria, as well as the inclusion of a group of healthy participants with similar demographic characteristics. Although these exclusions may limit the generalizability of the findings, they minimize the likelihood that motor involvement interfered with performance on the neuropsychological exam. We also provided detailed description of patients' clinical characteristics, presenting mean test scores and standard deviations for both patient and control groups. Some drawbacks were not avoided and are suggestive of potential topics for feature research. Limitations of the study include its retrospective analysis, the small and unequal sample size of the ALS subgroups and the relatively limited scope of the cognitive battery. In regard to the latter, including tasks that assess episodic memory and other aspects of working memory may offer additional insights into the cognitive deficits associated with ALS and potential differences among the subgroups.

In summary, our ALS patients exhibit deficient divided attention and difficulties on tasks of selective attention, inhibition, verbal abstract reasoning, cognitive flexibility, and set shifting. Nevertheless, none of the administered executive measures discriminated patients with spinal from the bulbar-onset form of the disease, despite the fact that ALS-b patients showed greater disease severity. As long as executive functions are intact, a person with considerable cognitive loss can still continue to be independent and productive (Lezak, 1995). Given that executive functions may not be completely unitary (Miyake et al., 2000), it is necessary to systematically administer multiple executive tasks to understand the nature of spared and impaired executive processes. The present findings highlight the importance of comprehensive neuropsychological assessment in patients with ALS, well-controlled for motor or speech difficulties, since a definite conclusion about clinical profiles related to spinal or bulbar onset may not be reached.

Conflict of Interest

None declared.

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