The frontotemporal syndrome in amyotrophic lateral sclerosis
An interim analysis for a new cognitive screening instrument
The aim of this study is to provide an interim analysis, evaluating the diagnostic accuracy and the psychometric qualities of the ALS-FTD-Cog. The ALS-FTD-Cog is a screening instrument, designed to detect cognitive impairment associated with Amyotrophic Lateral Sclerosis (ALS).
This cognitive impairment (in combination with behavioural impairment) is known as the Frontotemporal Syndrome (FTS) and occurs in 30-50% of ALS patients. 70 ALS-patients, 35 healthy control participants and fourteen patients with frontotemporal dementia (positive control participants) participated in this study. The outcomes of the ALS-FTD-Cog were compared with a
reference standard; a full neuropsychological investigation. In our sample, 14 ALS patients (21%) had FTS. The ALS-FTD-Cog identified these patients with 77% sensitivity and 80% specificity. The reliability varies from acceptable (.7) when calculated in all participants to very low (.2) when
calculated in only the ALS patient group. When measured in all subjects, a principal component analysis shows that the ALS-FTD-Cog is a unidimensional measure. However, in only ALS
patients the screening outcomes cluster together in a more ambiguous way, suggesting two subscales with low (.3 and .4) reliability. It is important to emphasize that this is an interim analysis, probably lacking the statistical power to draw clear conclusions about the diagnostic
accuracy of the ALS-FTD-Cog. However, this study thoroughly analyses the current test outcomes, and identifies important areas for further research concerning the ALS-FTD-Cog. The
main objective is not only enhancing the quality of care for FTS patients but also gain a more thorough understanding of the underlying processes in ALS.
Name: Anoek Appelboom Supervisor (daily): Rosanne Govaarts
Supervisor (AMC): Ben Schmand Word count: 4250 10-07-2016
2 Contents
Introduction P. 3
Methods P. 6
Results P. 11
Conclusion and discussion P. 16
3 Introduction
Traditionally, amyotrophic lateral sclerosis (ALS) has been described as a motor neuron disease, selectively targeting the primary motor neuron in the central and peripheral nervous system and causing motor symptoms throughout the body. However, as pointed out by Strong et al. in 1999, a more accurate definition is one of a “multisystem disease”, causing cognitive and behavioural impairment besides the “classic” motor impairment. This cognitive and behavioural impairment is known as the frontotemporal syndrome (FTS), and is caused by frontotemporal lobar degeneration, typically found in frontotemporal dementia (FTD) (Lomen-Hoerth C, Anderson T, 2002; Strong et al., 2009).
FTS develops in 30-50% of ALS patients (Beeldman et al., 2015; Montuschi et al., 2014; J. Phukan et al., 2012). In 5-15% of the ALS patients, the symptoms become more severe and meet the criteria of FTD, mostly the behavioural variant (Montuschi et al., 2014; Phukan et al., 2012; Ringholz et al., 2005). A recent meta-analysis showed that the cognitive profile of ALS patients is characterized by deficits in fluency, language, social cognition, executive functions and verbal memory (Beeldman et al., 2015). Possible behavioural changes are apathy or impulsivity, loss of insight, social disinhibition and hyperorality (Grossman, Woolley-Levine, Bradley, & Miller, 2007)
FTS has an adverse effect in the patient as well as its environment. However, early detection of FTS may be a challenge, as there are individual differences in how the disease progresses, leading to different presentations of ALS and FTS (Rowland & Shneider, 2001). FTS in ALS patients is associated with shorter survival time, this may be due to biological factors or to the cognitive and behavioural symptoms of FTS, resulting in a decreased adherence to therapeutic interventions or life-prolonging therapies, like non-invasive ventilation. Furthermore, it may negatively influence quality of life of partners and caregivers (Merrilees, Klapper, Murphy, Lomen-Hoerth, & Miller, 2010; Olney et al., 2005).
4 FTS, Strong et al. stated that ALS patients are suspected to have mild FTS when they score one standard deviation below the normal mean on an executive measure (Strong et al., 2009). These consensus criteria emphasize the role of executive tests. However, later research shows that it is also possible for clinically distinct FTS patients to be executively intact but fall short on other cognitive domains (Phukan et al., 2012).
Cognitive measures that are used nowadays may vary from a full neuropsychological assessment to the administration of a verbal fluency task only (Abrahams, Newton, Niven, Foley, & Bak, 2014). A neuropsychological assessment is time consuming and it may be too fatiguing for some patients, whereas the use of one fluency task leaves out other important cognitive domains. (Lomen-Hoerth et al., 2003; Phukan et al., 2012). Newly developed alternatives are short (10 min) screening instruments, providing a quick scan for multiple cognitive domains (Abrahams et al., 2014; Floris et al., 2012; Woolley et al., 2010). These instruments are useful, but normative data lack the extensive norm groups that are necessary for valid clinical decisions. Also, an instrument that provides a more thorough evaluation of cognitive performance is currently not available.
Given the abovementioned shortcomings of currently available cognitive assessments, a new screening instrument, the ALS-FTD-Cog, is under development at the Academic Medical Centre in Amsterdam. It consists of parallel versions of well-known and validated
neuropsychological tests, raising the face validity of the screening instrument. The selection of the tests is based on the consensus criteria stated by Strong et al. (2009) and previous research
(Beeldman et al., 2015; Phukan et al., 2012), selectively targeting the cognitive deficits of FTS; language, social cognition, executive functioning and memory. Compared to a neuropsychological assessment, it is designed to be faster and more suitable for bedside testing. Furthermore, the tests are not affected by (or control for) impairment caused by ALS, such as muscle weakness and slowness or loss of speech.
5 The aim of this study is to provide an interim analysis, evaluating the diagnostic accuracy and the psychometric qualities of the ALS-FTD-Cog. It is important to note that the emphasis lies on developing a valid and reliable screening instrument. This is investigated in healthy control participants, ALS and FTD patients, by comparing the outcomes the ALS-FTD-Cog to the golden standard, i.e. an extensive neuropsychological assessment.
6 Methods
Participants
Patients were recruited from the Dutch ALS centre (an expertise centre, based in the Academic Medical Centre and the University Medical Centre Utrecht). To participate in the study, patients had to meet the following inclusion criteria: (a) diagnosis of sporadic or familial ALS, in terms of the El Escorial criteria; possible, (probable-) laboratory supported or definite ALS (Brooks, Miller, Swash, & Munsat, 2000), (b) with a disease duration (time since symptom onset) of less than 12 months, (c) patients had to be 18 years or older, (d) have a fluent knowledge of the Dutch language, and (e) have a proxy (this might be partner, family member or close friend) who spoke Dutch and was willing to fill in several questionnaires. Excluded were patients who (a) were considered incompetent (e.g. in case of unaccountability for consent) by their treating physicians or (b) had other neurological or psychiatric conditions that might affect cognitive functioning. FTD patients were recruited from the Dutch Alzheimer centre, based in the VU University Medical Centre. Healthy control participants were recruited from the social environment of the patients.
Participation was on voluntary basis. The medical ethical committee approved the study. Written informed consent was obtained from all participants at inclusion. Participants received both the neuropsychological assessment and the screening with a two week interval, this interval was chosen to limit both practice effects in parallel tests and effects of possible cognitive
degeneration between the two test moments. To further avoid practice effects, the order of the tests was counterbalanced. In consultation with the patient, half of the participants was assigned to complete the neuropsychological assessment before the screening and vice versa. The
neuropsychological assessment (±1.5 – 2 hours) was conducted at a hospital nearby the patient. To minimize strain on the patient, the screening (± 30 minutes) was conducted during a home visit. All tests were conducted by formally trained test assistants or neuropsychologists. The
ALS-FTD-7 Cog and the neuropsychological assessment were never administered by the same person to limit the effect of observer bias.
Materials
The neuropsychological assessment was an extended test battery, based on the cognitive domains and tests that proved sensitive for FTS in previous literature (Table 1) (Strong et al., 2009). The selected subtests were not affected by, or are corrected for, motor impairment and dysarthria. Therefore, this battery was considered similar to the neuropsychological assessment administered on ALS patients in clinical practice.
The ALS-FTD-Cog consisted of the five following subtests: The Faux-Pas Recognition Task (Stone, Baron-Cohen, & Knight, 1998), the Rey Auditory Verbal Learning Test (RAVLT), Boston Naming Test (BNT), letterfluency and prose recall (Rivermead Behavioural Memory Test (RBMT) Stories), see table I. The Faux-Pas Recognition Task is a test for social abilities, the other four subtests are parallel version of those used in the full neuropsychological assessment (see table I). Fluency was only corrected for slowness of speech in patients that experienced bulbar
impairment. Abnormal test scores per participant were calculated using the same standards as the neuropsychological assessment.
The Hospital Anxiety & Depression Scale (HADS) is a 14 item questionnaire to assess feelings of anxiety and depression in patients on a 4 point Likert scale (0-3). Examples of items are “I feel tense or wound up” (anxiety scale) and “I still enjoy the things I used to enjoy (depression)”. The revised ALS-Functional Rating Scale (ALS-FRS-R) is a 13 item rating scale, assessing impairment in ALS. An example item is “speech”, ranging from 0 (normal speech) to 5 (loss of useful speech).
8 Table I Subtests of the neuropsychological assessment battery.
Subtests per cognitive domain
Executive functions
(modified) Wisconsin Card Sorting Test (mWCST) (Heaton, 1993) Antisaccade test
Verbal fluency: letter (D, A, T) (Arthur Lester Benton, Hamsher, & Sivan, 1994) Memory
Rey Auditory Verbal Learning Test (RAVLT) (Rey, 1941)
Rivermead Behavioural Memory Test Story a+b (prose recall)(Wilson, Cockburn, Baddeley, & Hiorns, 1989) Visual Association Test (VAT) (Lindeboom, Schmand, Tulner, Walstra, & Jonker, 2002)
Wechsler Adult Intelligence Scale IV Letter – Number Sequencing (WAIS IV-LNS) (Wechsler, 2008) Language
Boston Naming Test (BNT) (Goodglass & Kaplan, 1983)
Wechsler Adult Intelligence Scale III Similarities (WAIS III similarities) (Wechsler, 1997) Dutch Adult Reading Test (DART) (Schmand, Lindeboom, & Van Harskamp, 1992) Visual-spatial perception
Judgement of Line Orientation (JOLO) (Arthur L Benton, Hamsher, Varney, & Spreen, 1983) Social perception
Ekman 60 Faces Test, subtest of Facial Expressions of Emotion: Stimuli and Tests (FEEST) (Young, 2002) Questionnaires
Hospital Anxiety and Depression Scale (HADS) (Zigmond & Snaith, 1983) ALS-Functional Rating Scale Revised (ALS-FRS-R)
ALS-FTD-Questionnaire (ALS-FTD-Q)
Subtests of the full neuropsychological assessment, the reference standard. Subtest are displayed per cognitive domain, and based on test that proved sensitive for FTS by previous literature.
Criteria for FTS
Cognitive impairment
Cognitive impairment was measured using the reference standard, the full
neuropsychological assessment. As described in the introduction, the proposed consensus criteria from 2009 were adjusted. A low subtest score was defined as two or more standard deviations below the norm (T<30, or <2nd percentile). Mild FTS was defined as two low scores on any
subtests, severe FTS was defined as three or more low scores on any subtests. Normative data was absent for the Antisaccade test, our healthy participants served as the norm group.
9 Behavioural impairment
The ALS-FTD-Questionnaire measured behavioural impairment. It was filled in by a proxy of the patient. It consists of 25 items as “your partner becomes irritated or angry more easily” on a 4 point Likert scale. A total score of ≥22 indicated mild behavioural change, a total score of ≥29 indicated severe behavioural change (Raaphorst et al., 2012).
Statistical methods
In verbal fluency tasks, index scores were used to control for slowness of speech. The verbal fluency index was calculated by the time needed for word generation (60 seconds) minus the time needed for reading, divided by the number of words generated. It was a measure for the average thinking time per word, consequently it was a more accurate measure for cognitive functioning (Beeldman et al., 2014).
Before the statistical analysis, assumptions such as normality were checked. If the data failed to meet the assumptions, non-parametric tests were used. The first part of the results consist of the demographic and clinical characteristics of the participants. Differences between the ALS patient group and the healthy control participants or the FTD / ALS-FTD patient group were calculated using independent t-tests and Mann-Whitney tests. As a possible covariate, the
correlation between the neuropsychological test outcomes and feelings of anxiety and depression was checked using Kendall’s tau. Secondly, the performance of the ALS-FTD-Cog in comparison to the reference standard (the full neuropsychological assessment) was assessed. A receiver
operator characteristics curve (ROC curve), was plotted using the number of abnormal subtests of the ALS-FTD-Cog and the dichotomous outcome of the neuropsychological assessment (positive or negative for FTS). This analysis provided the optimal cut-off for the ALS-FTD-Cog. The diagnostic odds ratio indicated the chance of an FTS patient getting the correct diagnosis (true positive). Two principal component analyses (PCA) were conducted, one on all participants and
10 one on ALS patients only. A Cronbach’s alpha reliability analysis was conducted on all
components. This reliability analysis assessed how the ALS-FTD-Cog measured the latent variable; FTS. Statistical analysis of the data were executed with SPSS 23. The statstical analysis was
11 Results
Sample
A total of 119 participants were included, 70 ALS, fourteen ALS-FTD patients and 35 healthy control participants. ALS patients had a mean age of 61.0 years (SD=9.9) and a median disease duration of 9 months (interquartile range 6-12). The level of education was assessed with Verhage’s categorization, which ranges from 1 (below primary school) to 7 (academic degree). The median level of education was 5 (interquartile range = 5 – 6), ranging from 2 (n=5) to 7 (n=11) (see table II). There was no significant difference in the median level of education between ALS patients and healthy control participants (Mdn = 5), H (1) = 2.547, p > .05 (Kruskal – Wallis test).
Values are median (range) unless stated otherwise. * = p<.05. All groups are compared to the ALS patient group using independent t-tests or Mann-Whitney tests. 1 HADS = Hospital Anxiety & Depression Scale 2 Disease duration and time to diagnosis are in months. 3 ALS-FRS-R = ALS Functional Rating Scale Revised 4 Forced vital capacity (FVC) is the amount of air exhaled during three seconds. FVC, ALS-FRS-R and bulbar onset in FTD / ALS – FTD patients is based on 5 ALS-FTD patients.
Thirty-six patients (52.9%) experienced bulbar impairment; the scores of these patients were corrected for slowness of speech. Behavioural impairment in ALS was measured with the ALS-FTD-Q. Sixteen proxies (23.5%) reported behavioural changes (ALSFTDQ≥22), of which eight (11.8%) reported severe behavioural changes (ALSFTDQ≥29).
One FTD and six ALS patients report feelings of anxiety and/or depression (total HADS Table II. Demographic and clinical characteristics of participants.
ALS Healthy control FTD / ALS – FTD
Total (N) 68 35 18 Male sex (N (%)) 46 (68) 15* (43) 15 (83) Age (mean (SD)) 61.7 (10) 58.4 (10) 67.6 (46) HADS1 Anxiety 4 (12) 3* (7) 4.5 (12) HADS1 Depression 3 (14) 1* (9) 4 (10) Bulbar onset (N (%)) 21 (35) - 2 (40) Disease duration2 8.5 (9) - 23* (159)
ALS-FRS-R score3 (mean (SD)) 39 (5) - 40 (9)
12 score, cutoff 18). The total HADS score was significantly non-normal (D (109) = 0.137, p < .001). Outcomes of the questionnaire on anxiety and depression did not covariate with the outcomes of the neuropsychological assessment (τ = .076, p >.05) or de ALS-FTD-Cog (τ = .098, p >.05).
Reference standard
The outcomes of the neuropsychological assessment showed that 59 (79.4%) ALS patients had no cognitive impairment, seven (10.3%) had mild and seven (10.3%) severe FTS.
Table III: Mean test scores of the reference standard (neuropsychological assessment)
ALS Healthy control ALS-FTD / FTD Wisconsin Card Sorting Test 45.5 (8.2) 49.0* (7.2) 36.8* (10.0) Rey Auditory Verbal Learning Test 52.8 (11.7) 52.7 (10.5) 33.5* (11.6) RBMT stories (prose recall) 50.1 (10) 51.9 (9.6) 30.1* (17.5) WAIS Letter-Number Sequencing 51.0 (9.5) 53.4 (8.7) 40.1* (11.6) WAIS Similarities 49.5 (11.4) 55.7* (8.7) 37.1* (10.5) Dutch Adult Reading Test (IQ (SD)) 104.1 (15.6) 107.3 (16.3) 97.4 (21.6) Judgment Of Line Orientation (percentile (SD)) 62.1 (19.6) 69.4 (9.8) 48.6 (27.9) Visual Association Test (percentile (SD)) 46.5 (25.1) 45.5 (23.5) 25.7* (28.2) Boston Naming Test (z-score (SD)) -0.1 (1.7) 0.4 (1.1) -3.8* (5.9) Ekman 60 Faces Test (z-score (SD)) -1.1 (1.5) -0.4* (1.1) -4.3* (2.4) Letter Fluency (z-score (SD)) 0.5 (0.7) 0.8* (0.3) -2.8* (4.0) Anti-saccade Test (no. correct (SD)) 16.2 (4.0) 18.2* (1.1) 12.1* (7.3) All scores are T-scores unless stated otherwise. WCST T-score is based on total no. of errors. All memory T-scores (RAVLT, prose recall) are delayed recall scores, not corrected for immediate recall. * = p<.05. All groups are compared to the ALS patient group using independent t-tests or Mann-Whitney tests. All letter fluency scores are corrected using the verbal fluency index. Norm scores on the Judgment of Line
Orientation and Dutch Adult Reading Test are often labeled as “higher than” a certain percentile (e.g. >49). The specific percentile (e.g. 49) is used for this table, true values may be higher.
13 Table IV subtests of the full neuropsychological assessment on which
two or more FTS patients obtained abnormal scores
Test name N (%)
Antisaccade 10 (71.4)
Ekman 60 faces 9 (64.3)
Boston Naming Test 5 (35.7)
WAIS III Similarities 4 (28.6)
Letter fluency 2 (14.3)
WCST 2 (14.3)
0))
JOLO 2 (14.3)
RBMT Stories (prose recall) 2 (14.3)
Total 14 (100)
Table IV shows the subtests that proved sensitive for FTS in the neuropsychological assessment by displaying the number of FTS patients that obtained abnormal scores.
ALS-FTD-Cog
Figure 1 shows a ROC curve of all participants. The area under the curve is .840. The ALS-FTD-Cog discriminates with 77.4% sensitivity and 80% specificity using the optimal cutoff of one abnormal test. The diagnostic odds ratio in ALS patients is 7.0, indicating that the odds of a (possible) FTS patient getting a positive test result (“true positive”), is seven times higher than a person without FTS (“false positive”).
14 .
In order to explore the underlying structure of the ALS-FTD-Cog, an unrotated principal component analysis (PCA) was conducted on the five subtests of the ALS-FTD-Cog, on all subjects. The sample adequacy for the analysis was verified by the Kaiser-Meyer-Olkin measure (KMO=.773). Bartlett’s test of sphericity showed that the correlations between the subtest outcomes were sufficiently large for PCA (χ² (10) = 107.068, p < .001). Only the first component was associated with an eigenvalue greater than 1 (Kaiser’s criterion), this explained 49% of the variance. Table V shows the unrotated factor loadings, suggesting that all items represent the same factor: the frontotemporal syndrome. Reliability, calculated using Cronbach’s alpha, was mediocre when the analysis was carried out on all subjects (α = .7) and very low when carried out only on ALS patients (α = .2).
A second PCA with orthogonal rotation (varimax) was conducted in this sample. The adequacy of this sample was mediocre (KMO=.468). Correlations between subtests were sufficiently large, according to Bartlett’s test of sphericity (χ² (10) = 28.224, p < .001). The first
Figure I: the Receiver Operater Characteristics curve of the ALS-FTD-Cog
Figure 1 shows the ROC curve of the ALS-FTD-Cog based on the number of abnormal subtest scores in comparison with the dichotomous outcome of the neuropsychological assessment (positive or negative for FTS). The green reference line has an area under the curve of .5 and indicates a random test (e.g. flipping a coin). The closer the curve follows the left-hand border and the top border of the ROC space, the more accurate the test. The blue line indicates the performance of the ALS-FTD-Cog.
15 two components were associated with an eigenvalue greater than 1 (Kaiser’s criterion), explaining 56% of the total variance. The rotated factor loadings are displayed in table V. The subtests that cluster together suggest that component 1 represents word generation, and component 2 represents memory.
Table V: Factor loadings of the ALS-FTD-Cog
Subtests (T-scores) All subjects ALS patients
Component 1 Component 2 Verbal Fluency .766 .836 .200 Faux-pas task .556 .006 -.369 RBMT .764 -.161 .776 BNT .493 .726 -.261 RAVLT .738 .474 .704 Eigenvalue 2.3 1.8 1.6 % of variance 45.3 36.6 24.3 Cronbach’s α .7 .3 .4
Table V displays the factor loadings of the principal component analysis of the ALS-FTD-Cog. Factor loadings derived from all subjects are unrotated. The factor loadings in the ALS patient’s column were rotated using orthogonal (varimax) rotation. Factor loadings in bold clustered together in components. As shown, the ALS-FTD-Cog was a unidimensional measure when tested in all participants. In only ALS patients, the underlying structure of the ALS-FTD-Cog broke down in two components.
To check whether the test environment influenced the test outcomes, a Wilcoxon signed-rank test was executed. This showed that participants obtained significantly lower scores on the BNT (z = -3.29, p < .05, r = -.3) and RBMT (z = -4.023, p < .001, r = -0.4) in the ALS-FTD-Cog in comparison to parallel versions in the full neuropsychological assessment. On the RAVLT and the letterfluency (T-scores, not corrected using the verbal fluency index), there was no significant difference (z = -1.671, p > .05, z = -.977, p > .05).
16 Conclusion and Discussion
The aim of this study was to provide an interim analysis, evaluating the diagnostic accuracy and the psychometric qualities of a cognitive screening instrument. The ALS-FTD-Cog is a
cognitive screening instrument with a strong theoretical foundation, tested in a relatively large population of ALS patients, healthy control participants, ALS-FTD - and FTD patients. The ALS-FTD-Cog was compared to the reference standard, which encompasses a full neuropsychological assessment. The results show that 21% of our ALS patient population had cognitive impairment, based on the extensive neuropsychological assessment. It has been estimated that 30 – 50% of ALS patients suffer from cognitive impairment (Phukan et al., 2012; Phukan, Pender, & Hardiman, 2007; Strong et al., 2009). The difference in incidence of the reported FTS compared to the incidence recorded here, may be a consequence of the study population, in which a relatively short disease duration was prominent.
The ALS-FTD-Cog identified FTS patients with fair (.77) sensitivity and high (.80) specificity, using a cutoff value of 1 abnormal test. The area under the curve (.84) is well above chance (.5 (Metz, 1978)). The reliability of the ALS-FTD-Cog varies from very low (.2) in the ALS patient group, to acceptable (.7) in all participants. The extracted principal components indicate that frontotemporal impairment, tested with the ALS-FTD-Cog, is distinguishable in ALS and FTD patients, compared to the healthy control group. Within the ALS patient group, these larger patterns break down in a more ambiguous way. This possibly results from the fact that the frontotemporal syndrome is complex, with impairment across multiple domains and in multiple gradations. Another explanation may be that the ALS subgroup is smaller, and therefore more prone to noise due to a decrease in statistical power.
The FTD-Cog is added to a series of cognitive screening instruments, like the ALS-Cognitive Behavioural Screen (ALS-CBS), Edinburgh ALS-Cognitive and Behavioural ALS Screen (ECAS) and Frontal Assessment Battery (FAB) (Abrahams et al., 2014; Floris et al., 2012; Woolley
17 et al., 2010). The difference is that the ALS-FTD-Cog has extensive norm groups and is designed to detect FTS (not only full blown FTD). Furthermore, the ALS-FTD-Cog is a relevant addition to short (10 min) screening instruments, as it gives a more thorough understanding of the cognitive strengths and weaknesses in the patient.
In order to be used in clinical practice, it should be stressed that a practical screening instrument should have higher sensitivity than specificity. With the present cut-off of one abnormal subtest, sensitivity and specificityare about equal; this is a limitation of the ALS-FTD-Cog. Ultimately, the ALS-FTD-Cog should discriminate patients with possible early FTS. These patients should be followed over time, monitoring the cognitive status and making early
intervention possible to mitigate the consequences of FTS.
It should also be mentioned that four out of five ALS-FTD-Cog subtests had parallel versions in the reference standard. Essentially, the methodological design allowed an incorporation bias. This possibly raised the validity of the screening in this interim analysis. It is of primary importance that the FTD-Cog is also validated using other related instruments, e.g. the ALS-FTD-Q questionnaire for behavioural impairment, or another screening instrument for FTS.
Another discussion point may be the use of home visits to validate the ALS-FTD-Cog. Testing the patient at home may either enhance or lower test performance. It presumably makes people more at ease or less tired, but it is also more prone to environmental noise. This is
consistent with the findings in this study; it was found that participants score significantly different in three out of four parallel tests. However, home visits raised the feasibility for patients this study. This is of great importance and a responsibility of any research in this study population. Taking into account the negligible effect sizes of the differences in test performance, we conclude that these findings do not reflect fundamental problems in the ALS-FTD-Cog.
The complex cognitive profile of the syndrome was described by Beeldman et al. in 2015 and Phukan et al. in 2012, showing that mild impairment may occur in the domains of executive functioning, but also language, visual spatial abilities and memory. While the ALS-FTD-Cog
18 measures multiple important domains (e.g. social cognition, executive functions and memory), all tasks have a strong verbal component. A possible adjustment to improve the psychometric qualities of the ALS-FTD-Cog may be the addition of more visual-spatial tasks such as the Judgment of Line Orientation. The Anti Saccade task, provided that the normative data is improved, should also be considered because of its short administration time and executive involvement. Another adjustment may be to change the impact that every subtest score has on the total outcome, and increasing the impact of sensitive tests.
Although these possible adjustments are relevant to consider, all conclusions and theories are based on an interim analysis in seventy patients. To meet the calculated study population for sufficient statistical power, 110 ALS patients and 36 FTD or ALS-FTD patients should be included in the study. The population size is important in various analyses, it is possible that the problems with the ALS-FTD-Cog decrease when the number of participants increases.
It is important to note that, like FTD, the diagnosis of FTS should never be based on the outcome of the ALS-FTD-Cog or any neuropsychological test alone. These measures should be complemented with behavioural and anamnestic information to make an informed clinical decision. In case of low premorbid intelligence or non-fluent Dutch speakers, test outcomes should be interpreted with caution.
This study contributes to a new set of cognitive tests, specifically designed for cognitive impairment in ALS patients. The development of new cognitive instruments, as well as the
implementation of these tests in treatment protocols, is an important challenge in future empirical research. This is a first step to enable early identification of cognitive impairment in ALS, leading to the possibility of not only enhancing the quality of care for these patients but also gain a more thorough understanding of the underlying processes in ALS.
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