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Intrusion errors during verbal fluency task in amyotrophic lateral sclerosis

Abstract

Background

Numerous studies have noted the presence of a dysexecutive component of the ALS-FTD. The most widely replicated result refers to the significantly reduced verbal fluency of ALS patients when compared to healthy people. As ALS patients have motor alterations that interfere with production, qualitative studies have the advantage of being independent of the degree of motor disability and revealing patients’ cognitive state. This study examined the production differences between 42 ALS patients who presented with different degrees of dementia and motor impairment and 42 healthy people. Production processes were studied by extending the administration time of a letter fluency task to 2 minutes for the phonemic verbal fluency (PVF) and semantic verbal fluency (SVF) categories. This ensured that the qualitative aspects of verbal fluency were addressed, paying special attention to the new perseverations and intrusions, as well as any clinical correlates that may exist.

Results

The ALS patients produced a significantly lower number of responses in PVF (p = .017) and SVF (p = .008). The rest of the indicators for frontal lobe alteration also suggested the existence of a dysfunction. The most remarkable results were the number of intrusions on the PVF task, which was much higher in the ALS group (p = .002). However, the number of perseverations did not differ significantly.

Conclusions

This study highlights the value of intrusions in addressing cognitive deterioration in ALS patients. This deterioration seems to be independent of the degree of motor impairment and of behavioural alterations. Therefore, the value of the intromissions on the verbal fluency task was highlighted as an indicator of a new cognitive alteration, which can be easily evaluated, even retrospectively.

Introduction

ALS is a progressive neurodegenerative disease that produces muscle weakness and flaccidity, fasciculations and spasticity, in combination with breathing and swallowing problems [1]. It is a rare disease that has an incidence of 1–2.6 cases per 100 00 people/year, with an approximate prevalence of 6 cases per 100,000. Death usually occurs within 2 to 3 years from the onset of symptoms [2, 3].

About 3% -5% of patients with ALS are diagnosed with frontotemporal dementia (FTD) [4, 5]. Most cases of ALS-FTD present the behavioural variant of the disease, although there may also be a predominant impairment of language (i.e. primary progressive aphasia, or semantic dementia) [6, 7]. ALS-FTD usually presents with symptoms such as apathy, disinhibition, loss of empathy and repetitive behaviour [8].

In addition to behavioural changes, about 30% of ALS patients experience cognitive impairment [9], in areas such as language [10], memory [11], visuospatial function [12], and Theory of Mind [13]. However, the deterioration of executive functions is the most consistent finding [14]. While motor dysfunction is usually present in ALS patients, the most severe deficiencies are found in verbal fluency tasks [15, 16]. The verbal fluency task requires initiation processes, strategy formation, sustained attention, attentional changes, inhibition and working memory [17]. In the standard version of the task, participants are given 1 minute to produce as many words as they can beginning with a certain letter (phonetic fluency), or to name as many words as possible within a given category (semantic fluency). The participant's score is the correct number of words generated [1820]. However, it has been noted that extending the letter fluency task to 2 minutes can increase sensitivity to detect cognitive alterations [21].

The significant decrease in the number of words produced by patients with ALS led to the use of different approaches to understand the mechanisms involved in the generation of words. The strategies used by researchers such as Troyer and her colleagues may be of interest [22, 23]. These authors separated the compounds of verbal fluency into two main processes: clustering and switching. Clustering is the accumulation of words and is based on the storage of verbal memory, while switching is the process of changing from one group to another, and is based on the function of the frontal lobe. Switching relies on the executive functions, as change and the use of strategies are required [24]. Troyer's qualitative approach has been used previously in ALS and it has been shown that patients have a significantly decreased performance, caused by frontal degeneration [2527]. This approach has not been widely used but is of interest due to its independence from motor impairment, which can reduce the number of words generated.

Following the quality of the responses produced during the evaluation of verbal fluency, error patterns can be found, based on perseverations and intrusions. A perseveration error is the repetition of a previous response [28], while intrusion errors include all the words produced that do not belong to the required semantic field or do not begin with the required letter [29]. The appearance of these errors may suggest the presence of executive deterioration and has been described in patients with FTD [30], schizophrenia [31], Parkinson's disease [32], brain injury [33], Alzheimer's disease [3437], and progressive supranuclear palsy [38]. In most studies, intrusions have been studied by means of a verbal retrieval task.

To our knowledge, the presence and value of intrusions and perseverations within the verbal fluency task have not been previously evaluated in ALS. Given the emphasis on frontal dysfunction in ALS-FTD, the objective of this study is to evaluate the usefulness of a verbal fluency response test in a sample of ALS, and to compare the results with the healthy population, as well as with the related clinical variables. According to the hypothesis posed here, patients with ALS will be less able to inhibit irrelevant information, so they will produce more intrusion and perseverance errors. In addition, it is held that these errors will not be related in a statistically significant way to the degree of motor alteration, but rather to a greater severity of behavioural changes.

Methods

Forty-two patients diagnosed with definite or probable ALS according to the El Escorial criteria for [39] were recruited from the Motor Neuron Disease Units. In addition, forty-two healthy volunteers were recruited, matched according to sex, age and years of education. Prior to commencing the neuropsychological evaluations, the purpose of the research was explained to all participants, and then each person was asked to sign the consent form to ensure that they were a willing participant in the research. The informed consent form was approved by the research program’s human subjects board. Also, 42 unrelated healthy volunteer controls matched for sex, age and years of education were recruited through public advisements in hospitals. The exclusion criteria for both groups were having suffered brain injury or stroke, psychological problems and/or severe psychiatric disorders, or alcohol/substance abuse, critical levels of anxiety and/or depression at the time of the evaluation based on the HADS cutoff score, in addition to non-acceptance of informed consent. Two volunteers with ALS were excluded due to previous ischemic strokes.

A clinical trial was conducted on the ALS group using the Spanish version of the ALS-Revised Functional Rating Scale (ALSFRS-R) [40], peak cough flow, and other clinical variables such as age of onset, duration of illness, and rate of disease progression. The rate of disease progression is calculated as = (48 –ALSFRS-R at time of diagnosis) / duration from onset to diagnosis (months) [41]. In addition, the Frontal Behaviour Inventory (FBI) [42] was administered. The FBI incorporates symptoms of habitual behaviour of FTD, according to the criteria set by Lund and Manchester [43]. This is a Likert-type questionnaire aimed at carers on 24 categories of negative uninhibited behaviour. This test provides cut-off points to determine the severity of the behavioural alteration (none, mild, moderate and severe) and ensure face and contextual validity, with high inter-rater reliability (Cohen's kappa = 0.9) and internal consistency (Cronbach's alpha = 0.9) [44]. In addition, phonological verbal fluency (PVF) (letters P, M and R for the Spanish version) and semantic verbal fluency (SVF) (animals) were evaluated. In this case, participants had 2 minutes for each letter in PVF and SVF. For PVF, the use of proper nouns or words that began with a letter different from the one provided was considered to be an intrusion. The qualitative aspects of verbal fluency were evaluated according to the criteria of Troyer et al. [22]. Repetitions and intrusions were excluded if there were clustering and switching. The presence of language disorders was assessed using the Boston Naming Test (BNT) [45]. In addition, the emotional state of all participants was assessed using the Hospital Anxiety and Depression Scale (HADS) [46].

All patients were included after informed written consent forms approved by the research program’s human subjects board. Also, caregivers were consulted to determine whether participants were able to consent. The firm of consent was obtained from patients or their caregivers, in case of severe motor impairment. The controls were informed written consent by themselves, as set forth by the Declaration of Helsinki and its subsequent amendments. Full approval for the study was obtained from the Hospital Ethics Committee.

The data were analysed using the statistical package for the social sciences (SPSS), version 20. The assumptions of normality and homogeneity for parametric tests were examined for the variables using the Shapiro-Wilk test. The comparisons between groups were made using the Mann-Whitney and Kruskal-Wallis tests. Spearman correlations and discriminant function analyses were used to examine the relationships between neuropsychological scores and clinical measures. All standard and raw scores were transformed into z-scores. All the tests were two-tailed and the statistical significance was established at p = .005.

Results

The clinical and control groups did not differ in age, sex and years of education (Table 1).

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Table 1. Demographic and clinical characteristics of the ALS and control groups.

https://doi.org/10.1371/journal.pone.0233349.t001

With respect to neuropsychological measures, the ALS group had significantly poorer performance in the BNT and PVF tests, together with a greater number of intrusions and switching. With respect to SVF, fewer words and fewer clusters were produced (Table 2). Strikingly, in both groups a statistically significant correlation was found between the number of words in PVF and the number of perseverations. However, the greater number of words in the ALS group was related to more perseverations (r = .414, p = .006), whereas this trend was reversed in the control group (r = -.376, p = .014). That is, fewer words were related in a statistically significant manner to more perseverations.

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Table 2. Comparison between control group and ALS group on verbal fluency and its components.

https://doi.org/10.1371/journal.pone.0233349.t002

Regarding the clinical characteristics of the ALS group, the number of years of education was significantly correlated to the number of intrusions (r = -.351, p = .023) and PVF switches (r = .387, p = .011). In addition, motor impairment was related to PVF score (r = .346, p = .025), and SVF (r = .375, p = .014), and SVF clusters (r = .399, p = .009). Furthermore, those participants with bulbar onset did not differ from those with spinal onset in none of the cognitive measures.

Once the statistically significant differences were identified in the non-parametric analysis between the ALS and the control group, a stepwise discriminant function analysis was performed to establish five discriminant variables between the ALS and the control group (see Table 2). The final model indicates that there are two discriminant variables: PVF score and intrusions (Wilk’s Lambda = .835, χ2 = 14.626, p = .001). The classification table indicates that 70.2% of the subjects were correctly classified. In the ALS group, nine patients (21.4%) performed as the control group in the PVF score and in the number of intrusions. A comparative analysis was performed between the subgroup of ALS patient comparing the clinical variables and differences in the age at disease onset (U = 114.5, p = .043) and in the disease progression rate (U = 92.5, p = .008) were found.

With respect to behaviour, the total FBI score was significantly correlated to the number of switches produced in PVF (r = -.324, p = .036) and to their clusters (r = -.305, p = .049), and to SVF (r = -.358, p = .020). When applying the cut-off points of the FBI test, those with severe alterations showed a significantly lower number of words in PVF and their switches, as well as in the SVF score (Table 3). In addition, those ALS patients without behavioural alterations did not differ in the PVF score from the control group (U = 186, p = .063), neither in the SVF score (U = 170.5, p = .170).

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Table 3. Differences in verbal production according to the degree of behavioural impairment.

https://doi.org/10.1371/journal.pone.0233349.t003

Discussion

This study was conducted with the purpose of evaluating the qualitative components of verbal fluency in patients with ALS, paying special attention to the errors committed while performing the task. Despite our baseline hypotheses, ALS patients did not differ in a statistically significantly manner in perseverations in non-semantic phonetic modalities. However, the ALS group produced a remarkably higher number of intrusions. In addition, the data suggest that these errors were independent of other clinical characteristics of the disease, such as the severity of motor impairment and the disease onset type, even though they were linked to a more severe progression and a late onset of the disease. In this sense, although some previous studies had linked the bulbar onset with greater cognitive deficits [47, 48], the present study suggests that there are not differences regarding the verbal fluency compounds. However, a negative relationship was found between the motor alteration and the quantity and quality of the responses produced. Given that verbal fluency has been described as the most sensitive test to detect frontal alterations of ALS and FTD [49, 50], studying the underlying aspects of production was of interest. In line with previous studies [5153], the dysexecutive component of the ALS-FTD complex was also reflected in the switches and clusters [25, 26].

A novelty was that this study used 2 minutes instead of the usual 1 minute in the study of verbal fluency. Because ‘automatic’ production occurs during the first 30 seconds of the task, the extension of time allows the voluntary activation search strategies to be studied [54]. This methodology allowed an overview analysis of the pathological motor component of the disease. Although there are ways to accommodate for the range of motor impairment, such as that proposed by Abrahams [55], some patients cannot write or say words quickly [56], and deficits can be exacerbated. The 2-minute task has also made it possible to notice some effects in the production pattern. For example, the PVF score was positively related to the number of perseverances. However, this pattern was reversed in the healthy population. It seems that those people who have a greater ability to generate words, based perhaps on a significantly higher number of years of education, were not exempt from executive errors that caused perseverance to occur. In contrast, the scarcity of words in some people may have not allowed this phenomenon to unfold and, it may have been more difficult to record for this reason. In this line, patients with more years of education produced significantly fewer intrusions. It has previously been pointed out that cognitive reserve plays a role as a protective factor against dementia in ALS [57, 58]. Continuing with the clinical factors, it has been observed that a significant relationship exists between motor alteration and verbal fluency: patients with more severe alterations produced significantly fewer words, particularly in the semantic task. According to Abrahams et al. [59], the participation of temporal regions can cause deficits in semantic processing, and also result in in confrontational naming deterioration. Therefore, it is not surprising that the ALS group in this study exhibited significant impairment in confrontational naming in.

It has been previously pointed out that altered processes of working memory, attention and inhibition could be responsible for the difficulty in satisfactorily performing the verbal fluency task [60, 61]. As these are alterations have been described previously in ALS, this finding does not come as a surprise. Some studies have suggested that the cognitive processes responsible for perseverations in SVF are based on the right hemisphere [62]. The atrophy of this hemisphere has been identified as a major biomarker in cognitive impairment in ALS [6365].

Surprisingly, no statistically significant difference was observed between the levels of behavioural alteration observed in ALS. These seem to be relatively independence of the behavioural and cognitive measures in the sample evaluated; only people with severe behavioural alterations showed a significantly lower number of switches, and a smaller number of clusters in SVF. These findings are similar to those reported by Schmolck, Schulz and York [27]. It is believed that phonemic fluency invokes prefrontal and frontal functions due to the strategic processes required to search for the word [66, 67], whereas semantic fluency is usually located in the left anterior temporal lobe, where representations are classified by meaning [68]. This anatomical difference is also expressed in the results obtained here, where the score in SVF and clusters decrease in those patients with ALS that has been classified as having a severe alteration.

This study highlights the value of intrusions in the dysexecutive syndrome of ALS. As was seen previously, the patients without alterations in behaviour did not differ from the healthy population in the number of words produced, although they seemed to have a great tendency to generate intrusions. Intrusions only occurred during the PVF task, but not during the SVF task. In our opinion, there is a greater dependence on the executive domain that triggered these errors. Another explanation could be the greater number of trials during the phonological task (three) in contrast to the semantics task (only one). It has been noted that memory is frequently altered in patients with ALS [6972], and this alteration may cause a failure in the suppression of incorrect responses. Therefore, the very noticeable presence of intrusions during the evaluation of verbal fluency could be a sign to distinguish patients with ALS with severe behavioural impairment. Notably, the discriminant function analysis indicated that it is the variable that best differentiated people from ALS from healthy controls. Nevertheless, the great number of predictors involved in the analysis could affect negatively to the statistical power and forces this result to be considered with caution.

Some previous studies have pointed to the lack of association between the severity of dementia and the number of perseverations [73]. Taking into account the role of inhibition responses in perseverations [74, 75], a greater number of perseverations were expected. Some authors have suggested that inhibitory processes are necessary in verbal fluency tasks to suppress previously generated responses [60]. In this sense, the intuitive rule of not repeating a word can be understandable, in contrast to the explicit command not to use proper nouns. Therefore, this rule demands a greater load on cognitive resources than monitoring previous words. The inhibition response can also be important in the number of total words generated, as it may prevent strong responses and consider those words that are less likely to be produced [75]. Because of this, it is possible that the fewer words generated by the control group may be the consequence of a weaker executive functioning that produces repetitions. In this sense, although repetitive and persistent behaviour is a usual characteristic of people with FTD [76], it seems that this repetitive characteristic is independent of repetition (understood as an alteration dependent on executive processes), which could be more linked to processes involved in monitoring the task, and not so much to a disinhibition problem.

Limitations

There are several limitations in this study that can be addressed in future research. Firstly, the evaluation of 2 minutes per letter may require considerable effort in ALS patients, especially those with significant bulbar or respiratory impairment. Secondly, this study did not include any complementary measure for testing executive functions and did not apply complementary measure for testing cognitive status in ALS as ECAS [77] nor other instrument which can be useful for distinguish patients cognitively impaired as MoCA or FAB [78]. Additionally, this study did not possess additional neuroimaging data that can support the findings. Thirdly, there were significant differences between the ALS and control groups in the Boston Naming Test result, so there may be specific language impairment in ALS patients. Future research should address these limitations, and also review those records in order to retrospectively study the importance of intrusions in the cognitive deterioration of patients with ALS.

References

  1. 1. Van Deerlin VM, Leverenz JB, Bekris LM, Bird TD, Yuan W, Elman LB, et al. TARDBP mutations in amyotrophic lateral sclerosis with TDP-43 neuropathology: a genetic and histopathological analysis. Lancet Neurol. 2008 May;7(5):409–16.
  2. 2. Al-Chalabi A, Hardiman O. (2013). The epidemiology of ALS: a conspiracy of genes, environment and time. Nat Rev Neurol.y 2013; Nov;9(11):617–28.
  3. 3. Talbott EO, Malek AM, Lacomis D. (2016). The epidemiology of amyotrophic lateral sclerosis. In Aminoff MJ, Boller F, Dick F. Swaab DF. Handbook of clinical neurology. New York: Elseveir (pp. 225–238).
  4. 4. Phukan J, Elamin M, Bede P, Jordan N, Gallagher L, Byrne S, et al. The syndrome of cognitive impairment in amyotrophic lateral sclerosis: a population-based study. J Neurol Neurosurg Psychiatry. 2012; Jan;83(1):102–8.
  5. 5. Raaphorst J, Beeldman E, De Visser M, De Haan RJ, Schmand B. A systematic review of behavioural changes in motor neuron disease. Amyotroph Lateral Scler. 2012; Oct;13(6):493–501.
  6. 6. Murphy JM, Henry RG, Langmore S, Kramer JH, Miller BL, Lomen-Hoerth C. Continuum of frontal lobe impairment in amyotrophic lateral sclerosis. Arch Neurol. 2007; Apr;64(4):530–4.
  7. 7. Saxon JA, Harris JM, Thompson JC, Jones M, Richardson AMT, Langheinrich T, et al. Semantic dementia, progressive non-fluent aphasia and their association with amyotrophic lateral sclerosis. J Neurol Neurosurg Psychiatry. 2017; Aug;88(8):711–712.
  8. 8. Rascovsky K, Hodges JR, Knopman D, Mendez MF, Kramer JH, Neuhaus J, et al. Sensitivity of revised diagnostic criteria for the behavioural variant of frontotemporal dementia. Brain. 2011; Sep;134(Pt 9):2456–77.
  9. 9. Goldstein LH, Abrahams S. Changes in cognition and behaviour in amyotrophic lateral sclerosis: nature of impairment and implications for assessment. Lancet Neurol 2013;12:368–380.
  10. 10. Taylor LJ, Brown RG, Tsermentseli S, Al-Chalabi A, Shaw CE, Ellis CM, et al. Is language impairment more common than executive dysfunction in amyotrophic lateral sclerosis? J Neurol Neurosurg Psychiatry. 2013; May;84(5):494–8.
  11. 11. Elamin M, Bede P, Byrne S, Jordan N, Gallagher L, Wynne B, et al. Cognitive changes predict functional decline in ALS: a population-based longitudinal study. Neurology. 2013; Apr 23;80(17):1590–7.
  12. 12. Leslie FV, Hsieh S, Caga J, Savage SA, Mioshi E, Hornberger M, et al. Semantic deficits in amyotrophic lateral sclerosis. Amyotroph Lateral Scler Frontotemporal Degener. 2015; Mar;16(1–2):46–53.
  13. 13. Girardi A, MacPherson SE, Abrahams S. Deficits in emotional and social cognition in amyotrophic lateral sclerosis. Neuropsychology. 2011 Jan;25(1):53–65.
  14. 14. Kew JJ, Goldstein LH, Leigh PN, Abrahams S, Cosgrave N, Passingham RE, et al. The relationship between abnormalities of cognitive function and cerebral activation in amyotrophic lateral sclerosis. Brain. 1993; Dec;116 (Pt 6):1399–423.
  15. 15. Abrahams S, Leigh PN, Harvey A, Vythelingum GN, Grisé D, Goldstein LH. Verbal fluency and executive dysfunction in amyotrophic lateral sclerosis (ALS). Neuropsychologia. 2000; 38(6):734–47.
  16. 16. Raaphorst J, de Visser M, Linssen WH, de Haan RJ, Schmand B. The cognitive profile of amyotrophic lateral sclerosis: a meta-analysis. Amyotroph Lateral Scler. 2010;11(1–2):27–37.
  17. 17. Pettit LD, Bastin ME, Smith C, Bak TH, Gillingwater TH, Abrahams S. Executive deficits, not processing speed relates to abnormalities in distinct prefrontal tracts in amyotrophic lateral sclerosis. Brain. 2013 Nov;136(Pt 11):3290–304.
  18. 18. Lezak MD. Neuropsychological assessment (3rd Ed.). New York: Oxford University Press, 1995.
  19. 19. Spreen O. Strauss EA. compendium of neuropsychological tests. New York: Oxford University Press, 1998.
  20. 20. Shao Z, Janse E, Visser K, Meyer AS. What do verbal fluency tasks measure? Predictors of verbal fluency performance in older adults Front Psychol. 2014 Jul 22;5:772. eCollection 2014
  21. 21. Holtzer R, Goldin Y, Donovick PJ. Extending the administration time of the letter fluency test increases sensitivity to cognitive status in aging. Exp Aging Res. 2009 Jul-Sep;35(3):317–26.
  22. 22. Troyer AK, Moscovitch M, Winocur G, Alexander MP, Stuss D. Clustering and switching on verbal fluency: The effects of focal frontal-and temporal-lobe lesions. Neuropsychologia. 1998 Jun;36(6):499–504.
  23. 23. Troyer AK. Normative data for clustering and switching on verbal fluency tasks. J Clin Exp Neuropsychol. 2000 Jun;22(3):370–8.
  24. 24. Troyer AK, Moscovitch M, Winocur G, Alexander MP, Stuss D. Clustering and switching on verbal fluency: The effects of Neuropsychologia. 1998 Jun;36(6):499–504.
  25. 25. Stukovnik V, Zidar J, Podnar S, Repovs G. Amyotrophic lateral sclerosis patients show executive impairments on standard neuropsychological measures and an ecologically valid motor-free test of executive functions. J Clin Exp Neuropsychol. 2010 Dec;32(10):1095–109.
  26. 26. Lepow L, Van Sweringen J, Strutt AM, Jawaid A, MacAdam C, Harati Y, et al. Frontal and temporal lobe involvement on verbal fluency measures in amyotrophic lateral sclerosis. J Clin Exp Neuropsychol. 2010 Nov;32(9):913–22.
  27. 27. Schmolck H, Schulz P York M. Overview of Cognitive Function in ALS, with Special Attention to the Temporal Lobe: Semantic Fluency and Rating the Approachability of Faces. Intech Open 2012 Jan.
  28. 28. McNamara P, Albert ML. Neuropharmacology of verbal perseveration. Semin Speech Lang. 2004 Nov;25(4):309–21.
  29. 29. Raboutet C, Sauzeon H, Corsini MM, Rodrigues J, Langevin S, N'kaoua B. Performance on a semantic verbal fluency task across time: Dissociation between clustering, switching, and categorical exploitation processes. Journal of Clinical and Experimental Neuropsychology. 2010;32(3):268–280. J Clin Exp Neuropsychol. 2010 Mar;32(3):268–80.
  30. 30. Lavenu I, Pasquier F, Lebert F, Pruvo JP, Petit H. Explicit memory in frontotemporal dementia: the role of medial temporal atrophy. Dement Geriatr Cogn Disord. 1998 Mar-Apr;9(2):99–102.
  31. 31. Flavia Galaverna, Bueno Adrián M., Morra Carlos A., Roca María, Torralva Teresa. Analysis of errors in verbal fluency tasks in patients with chronic schizophrenia. Eur. J. Psychiat. [Internet]. 2016 Dic; 30(4): 305–320
  32. 32. Scholtissen B, Dijkstra J, Reithler J, Leentjens AF. Verbal fluency in Parkinson's disease: results of a 2‐min fluency test. Acta Neuropsychiatr. 2006 Feb;18(1):38–41.
  33. 33. Fischer-Baum S, Miozzo M, Laiacona M, Capitani E. Perseveration during verbal fluency in traumatic brain injury reflects impairments in working memory. Neuropsychology. 2016 Oct;30(7):791–9.
  34. 34. Doubleday EK, Snowden JS, Varma AR, Neary D. Qualitative performance characteristics differentiate dementia with Lewy bodies and Alzheimer's disease. J Neurol Neurosurg Psychiatry. 2002 May;72(5):602–7.
  35. 35. Pasquier F, Lebert F, Grymonprez L, Petit H. Verbal fluency in dementia of frontal lobe type and dementia of Alzheimer type. J Neurol Neurosurg Psychiatry. 1995 Jan;58(1):81–4.
  36. 36. McDowd J, Hoffman L, Rozek E, Lyons KE, Pahwa R, Burns J, et al. Understanding verbal fluency in healthy aging, Alzheimer’s disease, and Parkinson’s disease. Neuropsychology. 2011 Mar;25(2):210–25.
  37. 37. Pekkala S, Albert ML, Spiro A 3rd, Erkinjuntti T. Perseveration in Alzheimer’s disease. Dement Geriatr Cogn Disord. 2008;25(2):109–14.
  38. 38. Gainotti G, Marra C, Villa G, Parlato V, Chiarotti F. Sensitivity and specificity of some neuropsychological markers of Alzheimer disease. Alzheimer Dis Assoc Disord. 1998 Sep;12(3):152–62.
  39. 39. 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 Dec;1(5):293–9.
  40. 40. Campos TS, Rodríguez-Santos F, Esteban J, Vázquez PC, Mora Pardina JS, Carmona AC. Spanish adaptation of the revised amyotrophic lateral sclerosis functional rating scale (ALSFRS-R). Amyotroph Lateral Scler. 2010 Oct;11(5):475–7.
  41. 41. Kimura F. Fujimura C. Ishida S. Nakajima H., Furutama D. Uehara H., et al. et al. Progression rate of ALSFRS-R at time of diagnosis predicts survival time in ALS. Neurology, 2006, vol. 66, no 2, p. 265–267.
  42. 42. Kertesz A, Davidson W, Fox H. Frontal Behavioral Inventory: Diagnostic Criteria for Frontal Lobe Dementia. Can J Neurol Sci. 1997 Feb;24(1):29–36.
  43. 43. Englund B, Brun A, Gustafson L, Passant U, Mann D, Neary D, et al. Clinical and neuropathological criteria for frontotemporal dementia. J Neurol Neurosurg Psychiatry. 1994 Apr;57(4):416–8.
  44. 44. Kertesz A, Nadkarni N, Davidson W, Thomas AW. The Frontal Behavioral Inventory in the differential diagnosis of frontotemporal dementia. J Int Neuropsychol Soc. 2000 May;6(4):460–8.
  45. 45. Kaplan EF, Goodglass H, Weintraub S. The Boston Naming Test. Philadelphia: Lea & Febiger;1978
  46. 46. Zigmond AS, Snaith RP. The hospital anxiety and depression scale. Acta psychiatrica scandinavica. Acta Psychiatr Scand. 1983 Jun;67(6):361–70.
  47. 47. Sterling LE, Jawaid A, Salamone AR, Murthy SB, Mosnik DM, McDowell E, et al. Association between dysarthria and cognitive impairment in ALS: A prospective study. Amyotrophic Lateral Sclerosis, 2010;11(1–2):46–51.
  48. 48. Bak TH, Chandran S. What wires together dies together: verbs, actions and neurodegeneration in motor neuron disease. Cortex. 2012;48(7):936–944.
  49. 49. Roberson ED, Hesse JH, Rose KD, Slama H, Johnson JK, Yaffe, et al. Frontotemporal dementia progresses to death faster than Alzheimer’s disease. Neurology. 2005 Sep 13;65(5):719–25.
  50. 50. Vicioso BA. Dementia: When is it not Alzheimer disease? American Journal of the Medical Sciences. 2002;324(2):84–95.
  51. 51. Strong MJ. The syndromes of frontotemporal dysfunction in amyotrophic lateral sclerosis. Amyotroph Lateral Scler. 2008 Dec;9(6):323–38.
  52. 52. Abrahams S, Leigh PN, Harvey A, Vythelingum GN, Grise D, Goldstein LH. Verbal fluency and executive dysfunction in amyotrophic lateral sclerosis (ALS). Neuropsychologia. 2000;38(6), 734–747.
  53. 53. 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 Mar;63(3):345–52.
  54. 54. Fernaeus SE, Almkvist O. Word production: Dissociation of two retrieval modes of semantic memory over time. J Clin Exp Neuropsychol. 1998 Apr;20(2):137–43.
  55. 55. Abrahams S, Leigh PN, Harvey A, Vythelingum GN, Grisé D, Goldstein LH. Verbal fluency and executive dysfunction in amyotrophic lateral sclerosis (ALS). Neuropsychologia. 2000;38(6):734–47.
  56. 56. Lakerveld J, Kotchoubey B, Kübler A. function in patients with late stage amyotrophic lateral sclerosis. J Neurol Neurosurg Psychiatry. 2008 Jan;79(1):25–9.
  57. 57. Montuschi A, Iazzolino B, Calvo A, Moglia C, Lopiano L, Restagno G. Cognitive correlates in amyotrophic lateral sclerosis: a population-based study in Italy. J Neurol Neurosurg Psychiatry. 2015 Feb;86(2):168–73.
  58. 58. Placek K, Ternes K, Olm C, Massimo L, Woo J, Elman L, et al. Cognitive Reserve Is Protective of Cognition and Frontal Grey Matter in Amyotrophic Lateral Sclerosis. Neurology Apr 2016, 86 (16 Supplement) P6.245
  59. 59. Abrahams S, Goldstein LH, Simmons A, Brammer M, Williams SC, Giampietro V, et al. Word retrieval in amyotrophic lateral sclerosis: a functional magnetic resonance imaging study. Brain. 2004 Jul;127(Pt 7):1507–17
  60. 60. Azuma T. Working memory and perseveration in verbal fluency. Neuropsychology. 2004 Jan;18(1):69–77.
  61. 61. Rosen VM, Engle RW. The role of working memory capacity in retrieval. J Exp Psychol Gen. 1997 Sep;126(3):211–27.
  62. 62. Pakhomov SVS, Eberly LE, Knopman DS. Recurrent perseverations on semantic verbal fluency tasks as an early marker of cognitive impairment. J Clin Exp Neuropsychol. 2018 Oct;40(8):832–840.
  63. 63. Murphy JM, Henry RG, Langmore S, Kramer JH, Miller BL, Lomen-Hoerth C. Continuum of frontal lobe impairment in amyotrophic lateral sclerosis. Arch Neurol. 2007 Apr;64(4):530–4.
  64. 64. Tanaka M, Kondo S, Hirai S, Sun X, Yamagishi T, Okamoto K. Cerebral blood flow and oxygen metabolism in progressive dementia associated with amyotrophic lateral sclerosis. J Neurol Sci. 1993 Dec 1;120(1):22–8.
  65. 65. Wicks P, Turner MR, Abrahams S, Hammers A, Brooks DJ, Leigh PN, et al. Neuronal loss associated with cognitive performance in amyotrophic lateral sclerosis: an [11C]- flumazenil PET study. Amyotroph Lateral Scler. 2008 Feb;9(1):43–9.
  66. 66. Leggio MG, Silveri MC, Petrosini L, Molinari M. Phonological grouping is specifically affected in cerebellar patients: a verbal fluency study. J Neurol Neurosurg Psychiatry. 2000 Jul;69(1):102–6.
  67. 67. Martin A, Wiggs CL, Lalonde F, Mack C. Word retrieval to letter and semantic cues: A double dissociation in normal subjects using interference tasks. Neuropsychologia. 1994 Dec;32(12):1487–94.
  68. 68. Pihlajamäki M, Tanila H, Hänninen T, Könönen M, Laakso M, Partanen K, et al. Verbal fluency activates the left medial temporal lobe: a functional magnetic resonance imaging study. Ann Neurol. 2000 Apr;47(4):470–6.
  69. 69. Christidi F, Zalonis I, Smyrnis N, Evdokimidis I. Selective attention and the three-process memory model for the interpretation of verbal free recall in amyotrophic lateral sclerosis. J Int Neuropsychol Soc. 2012 Sep;18(5):809–18.
  70. 70. Frank B, Haas J, Heinze HJ, Stark E, Münte TF. Relation of neuropsychological and magnetic resonance findings in amyotrophic lateral sclerosis: evidence for subgroups. Clin Neurol Neurosurg. 1997 May;99(2):79–86.
  71. 71. Massman PJ, Sims J, Cooke N, Haverkamp LJ, Appel V, Appel SH. Prevalence and correlates of neuropsychological deficits in amyotrophic lateral sclerosis. J Neurol Neurosurg Psychiatry. 1996 Nov;61(5):450–5.
  72. 72. Ringholz GM, Appel SH, Bradshaw M, Cooke NA, Mosnik DM, Schulz PE. Prevalence and patterns of cognitive impairment in sporadic ALS. Neurology. 2005 Aug 23;65(4):586–90.
  73. 73. Shindler AG, Caplan LR, Hier DB. Intrusions and perseverations. Brain Lang. 1984 Sep;23(1):148–58.
  74. 74. Matías-Guiu JA, Cabrera-Martín MN, Valles-Salgado M, Rognoni T, Galán L, Moreno-Ramos T, et al. Inhibition impairment in frontotemporal dementia, amyotrophic lateral sclerosis, and Alzheimer’s disease: clinical assessment and metabolic correlates. Brain Imaging Behav. 2019 Jun;13(3):651–659.
  75. 75. Chiappe DL, Chiappe P. The role of working memory in metaphor production and comprehension. Journal of Memory and Language. 2007;56(2):172–188.
  76. 76. Rascovsky K, Hodges HR, Knopman D, Mendez MF, Kramer JH, Neuhaus J, et al. Sensitivity of revised diagnostic criteria for the behavioural variant of frontotemporal dementia. Brain. 2011 Sep;134(9):2456–2477. Published online 2011 Aug 2.
  77. 77. Abrahams S, Newton J, Niven E, Foley J, Bak TH. Screening for cognition and behaviour changes in ALS. Amyotroph Lateral Scler Frontotemporal Degener. 2014; 15:9–14.
  78. 78. Barulli MR, Fontana A, Panza F. Copetti M., Bruno S. Tursi M. et al. Frontal assessment battery for detecting executive dysfunction in amyotrophic lateral sclerosis without dementia: A retrospective observational study. BMJ Open. 2015;5(9):e007069.