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Short report
Story of the ALS-FTD continuum retold: rather two distinct entities
  1. Dorothée E Lulé,
  2. Helena E A Aho-Özhan,
  3. Cynthia Vázquez,
  4. Ulrike Weiland,
  5. Jochen H Weishaupt,
  6. Markus Otto,
  7. Sarah Anderl-Straub,
  8. Elisa Semler,
  9. Ingo Uttner,
  10. Albert C Ludolph
  1. Department of Neurology, University of Ulm, Ulm, Germany
  1. Correspondence to Professor Dorothée E Lulé, Department of Neurology, Ulm University Hospital, Ulm D-89081, Germany; dorothee.lule{at}uni-ulm.de

Abstract

Objective To determine the evolution and profile of cognitive and behavioural deficits in amyotrophic lateral sclerosis (ALS) and behavioural variant frontotemporal dementia (bvFTD) to disentangle the development of FTD in ALS and vice versa.

Methods In a prospective design, cognitive and behavioural profiles of 762 patients with motor predominant ALS (flail arm/leg syndrome, primary lateral sclerosis, pseudobulbar palsy, ALS) and behavioural predominant FTD (bvFTD, ALS-FTD) were determined and caregivers of patients with ALS were asked on the evolution of behavioural symptoms. Data were compared with 49 healthy controls. Cognition was measured with the Edinburgh Cognitive and Behavioral ALS Screen.

Results Evolution and features of cognitive profile of patients with motor predominant ALS were distinctly different from patients with behavioural FTD with regard to number and degree of affected cognitive domains. Also, in ALS mostly minus symptoms evolved after physical symptom onset whereas in ALS-FTD plus and minus symptoms were reported with an onset before physical degradation.

Conclusion Evolution of cognitive and behavioural profile in patients with motor predominant ALS is distinctly different from those psychocognitive findings in patients with behavioural variant dementia. This may support the hypothesis that (possibly genetic) triggers decide in the preclinical phase on either motor or psychocognitive phenotypes.

  • cognitive neuropsychology
  • motor neuron disease
  • neuropsychology
  • frontotemporal dementia
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Introduction

In up to 50% of patients with amyotrophic lateral sclerosis (ALS) cognitive and behavioural manifestations are detected with typical impairment in primarily executive function and social cognition.1 There is considerable genetic and neuropathological evidence for an association of ALS with frontotemporal dementia (FTD), in particular in patients carrying C9ORF72 mutations.2 About 5%–10% of the patients suffer from frank ALS-FTD.1 Some consider ALS and FTD a continuum,3 yielding close attention on cognitive and behavioural alterations in ALS in the sense of dementia-like symptoms as these might significantly interfere with patient’s decision-making capacities in the course of the disease with respective clinical consequences for the patients and families.2 However, only few studies compared cognitive and behavioural phenotypes in motor predominant ALS and behavioural predominant FTD and therefore commonalities and differences in cognitive and behavioural phenotypes are not clear. Previous research reported on behavioural4 and neuropsychiatric symptoms5 in small and mostly heterogeneous ALS/FTD samples. In the study of De Silva and colleagues, patients with FTD-ALS presented with intermediate cognitive and behavioural impairment compared with ALS and FTD, and Mioshi et al reported on neuropsychiatric changes in ALS which evolve before motor symptoms similar to FTD, further supporting the concept of a continuum. However, clinical experience and previous studies suggest only very mild cognitive and behavioural alterations in patients with ALS1 with also distinct differences to those seen in dementia. Furthermore, there were no associations of these impairments seen to clinical decision-making.6 Furthermore, neuropathological data provide evidence for distinct entities with two different neuropathological spreading patterns of TDP43 pathology for ALS and FTD.7 8 Evolution of cognitive and behavioural profiles in motor predominant ALS compared with FTD subtypes is poorly understood but may be important to predict who may develop FTD in ALS and vice versa.

Methods

Participants

Overall, 762 patients with either motor or behavioural predominant ALS and FTD were consecutively included in this prospective study. They attended a specialised inpatient and outpatient clinic between December 2013 and January 2017 at the Department of Neurology, University Hospital Ulm. Of those, 611 patients were diagnosed with ALS, 38 with flail arm/leg syndrome (FA/L), 44 with primary lateral sclerosis (PLS), 20 with progressive bulbar palsy (PBP), 31 with ALS and FTD of the behavioural variant (ALS-bvFTD) and 18 with the bvFTD. Thus, patients presented with either motor (ALS, FA/L, PLS, PBP) or behavioural predominance (FTD, ALS-FTD). Diagnoses for ALS were performed according to the revised El Escorial criteria,9 for FTD according to the Rascovsky criteria10 and for ALS-FTD the combination of both. Interviewers were blinded to the actual diagnosis. Data were compared with 49 age, gender and education-matched healthy controls (online supplementary table 1). Participants with history of current comorbid neuropsychiatric or neurological illnesses (other than ALS/FTD) or with insufficient knowledge of German language were excluded.

Supplemental material

Cognition and behaviour

Cognition was measured with the German version11 of the Edinburgh Cognitive and Behavioral ALS Screen12 by a trained psychologist, addressing cognitive domains of language, verbal fluency, executive functions (ALS-specific functions) and memory and visuospatial functions (ALS non-specific functions). Age and education adjusted cut-offs were used.13 Behavioural changes were assessed in 464 patients by caregiver interviews12 on disinhibition, apathy, loss of sympathy/empathy, perseverative/stereotyped behaviour, hyperorality/altered eating behaviour and psychotic symptoms.

Statistics

Statistics were performed using Statistical Package for the Social Sciences (SPSS, V.21.0; IBM). Numbers of cognitive and behavioural domains between groups were calculated with Χ² test, for the latter following Ward hierarchical cluster analysis. Cognitive performance between groups (ALS, PLS, PBP, FA/L, ALS-FTD, FTD; first and/or second motor neuron (MN) vs second MN only) was calculated with analysis of covariance and post hoc Scheffé, corrected for age as patient groups differed significantly in age (F=3.4; p<0.001). Statistics was done in a blinded way regarding the actual diagnosis of patients. Threshold of p<0.05 was adopted for statistical significance.

Results

The cognitive profile of patients of the motor predominant ALS entity was different from patients of the behavioural predominant FTD entity with regard to degree of cognitive impairment in all cognitive domains and number of affected cognitive domains (Χ²=214.08, df=30; p<0.001, eta=0.42; table 1, figure 1), indicating two distinct clusters in Ward cluster analysis (cluster 1 ALS entity: ALS, FA/L, PLS, PBP; cluster 2 FTD entity: ALS-FTD, FTD; Χ²=107.10, df=5, eta=0.38; p<0.001). Extra motor involvement in the behavioural domain was thus closely linked to cognitive impairments, whereas motor predominant patients all had a similar cognitive profile.

Figure 1

Cognitive impairment in ALS and FTD. Top row: numbers of cognitive domains for which patients presented with cognitive deficits in the ECAS (max 5: language, verbal fluency, executive functions, memory, visuospatial function) according to age and gender-adjusted norms. For patients with motor neuron disease, 75% presented with no cognitive deficits or with deficits in one subdomain only. Less than 12% of the patients of the FTD entity presented with none or with deficits in one domain only. Bottom row: mean cognitive performance in the ECAS total score for patients of the ALS and FTD entity. ALS, amyotrophic lateral sclerosis; bvFTD, frontotemporal dementia of the behavioural variant; ECAS, Edinburgh Cognitive and Behavioral ALS Screen; FA/L, flail arm/leg syndrome; FTD, frontotemporal dementia; PBP, progressive bulbar palsy; PLS, primary lateral sclerosis.

Table 1

Comparison of severity of cognitive impairments

More cerebral area involvement in the motor system (eg, ALS/PBP/PLS vs flail arm) was not associated with increased frequency and severity of cognitive impairment, although on the descriptive level, there was a trend for patients with FA/L (second MN) to have less severity of impairments in executive functions compared with those with first MN involvement (ALS, PBP, PLS) and the level was comparable to healthy controls (figure 1, table 1A).

Also, single minus symptoms (mostly apathy) were present in the motor predominant ALS group whereas in the behavioural predominant FTD group both plus (mostly disinhibition) and minus symptoms were reported (Χ²=217.2, df=40, eta=0.4; p<0.001; table 1). In the ALS groups, changes in behaviour (mostly apathy) evolved mostly at the time or within 1 year after symptom onset (92%), whereas in patients with ALS-FTD, changes in behaviour were described to have evolved more likely before motor symptoms evolved (64%; Χ²=31.6, df=8; p<0.001). Especially apathy evolved before motor symptoms in the ALS-FTD group (Χ²=11.0, df=2; p=0.004), whereas the other behavioural changes (plus and minus) randomly evolved either before or during motor symptoms, but rarely after. Mean latency of motor symptoms after behavioural changes was 8.0 years (SD 10.3).

Table 2

Comparison of behavioural alterations

In the ALS group, 39% were ALS with cognitive impairments (ALSci; ALS: 39%, FA/L: 29%, PLS: 48%, PBP: 35%) and 17% were ALS with behavioural impairments (ALSbi; ALS: 17%, FA/L: 21%, PLS: 18%, PBP: 10%) according to new Strong criteria,3 whereas in the ALS-FTD group, 88% qualified for ALSci and 100% for ALSbi.

Discussion

Patients of either motor predominant ALS or behavioural predominant FTD entities presented with a distinct cognitive and behavioural profile with regard to onset, frequency and extent of impairments, expanding previous findings of differences in cognitive and behavioural patterns between those groups.4 The pattern of onset follows the prominence of the feature: in the motor predominant ALS entity motor symptoms evolve before behavioural changes, and in the FTD entity behavioural symptoms evolve before potential motor symptoms. Especially apathy seems to be an early indicator of FTD if it evolves before motor symptoms. In ALS, the behavioural changes such as apathy evolve after diagnosis and may in some cases be interpreted as a reactive episode to the devastating diagnosis.

Those patients with a motor predominant clinical phenotype have minor cognitive and behavioural dysfunctions in single cognitive tasks only which become evident in clinical tests only and which are distinctly different from what we see in patients with a clinical bvFTD phenotype. Thus, ALS and FTD do not represent one entity in the sense that a single patient, for example, with ALS necessarily changes into a patient with FTD and vice versa, which is in line with the fact that cognitive performance does not necessarily decline in the course of ALS.14 This has major clinical implications as these minor cognitive impairments in ALS do not interfere with medical decision-making6 and thus have mostly no impact on the daily living of patients with ALS, whereas for patients with ALS with full-blown behavioural phenotype of bvFTD (ALS-bvFTD), the interference can be expected.

The split pathway of motor and psychocognitive predominance is in complete agreement with the published neuroanatomical studies describing two different neuropathological spreading patterns with opposing directions for ALS (from precentral to anterior regions) and FTD (from frontotemporal to posterior regions).7 8

The distinct features of psychocognitive findings in predominant patients with ALS and FTD raise questions with regard to causation. Genetic factors such as C9ORF are not sufficient to distinguish between ALS and FTD predominant phenotypes but it might be hypothesised that additional (genetic) triggers probably exist. It can be speculated that these triggers evolve early (possibly decades) before symptom onset and decide on either motor or psychocognitive phenotypes. Once a pathway has been activated by the trigger, a stereotypic pattern seems to evolve as has been shown in the current study.

It is a limitation of the study that only screening instruments of cognition were used but these seem to provide similar results as extensive neuropsychological tests.15 Furthermore, patients were clinically predefined as belonging to either the ALS or the FTD entity but interviewers were blinded to the actual diagnosis and cognitive screening was therefore unbiased. Future longitudinal studies need to address distinct features of motor (ALS) and cognitive/behavioural (FTD) dominant phenotypes more closely.

Concluding, cognitive and behavioural symptoms in motor predominant ALS develop in a different pattern compared with the behavioural predominant FTD entity, suggesting two different entities of cognitive phenotypes in ALS and FTD groups (and for the commonly used phrasing ‘ALS-FTD’, the terminology ‘FTD-ALS’ might be even more appropriate, as suggested by others already4). Thus, the presented data imply the hypotheses that causative pathways are probably triggered early in the preclinical phase and decide on either motor or psychocognitive phenotypes. Future work needs to focus on possible triggers which set the course of either phenotype in ALS and FTD.

Acknowledgments

We thank Jürgen Keller, Sarah Böhm, Olga Helczyk and Markus Loose for support in ECAS data collection and all the patients for giving their valuable time.

References

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Footnotes

  • Contributors DEL designed the study, analysed the data and wrote the manuscript. IU assisted in interpretation of the data and revised the manuscript for intellectual content. HEAAO, CV, UW, JHW, MO, SAS, ES and ACL edited the manuscript for intellectual content.

  • Funding This is an EU Joint Programme–Neurodegenerative Disease Research (JPND) Project (‘NEEDSinALS’ 01ED1405 and PreFrontALS 01ED1512). The project is supported through the following organisations under the aegis of JPND—www.jpnd.eu, for example, Germany, Bundesministerium für Bildung und Forschung (BMBF, FKZ), Sweden, Vetenskaprådet Sverige, Poland, Narodowe Centrum Badań i Rozwoju (NCBR). This work was additionally funded by the Deutsche Forschungsgemeinschaft (DFG, LU 336/13-2), the Bundesministerium für Bildung und Forschung (FTLDc O1GI1007A, MND-Net 01GM1103A) and the foundation of the state Baden-Württemberg (D.3830), Boehringer Ingelheim Ulm University BioCenter (D.5009) and Thierry Latran Foundation.

  • Disclaimer The funding sources played no role in the preparation of this manuscript.

  • Competing interests None declared.

  • Patient consent Obtained.

  • Ethics approval The study was approved by the Ethics Committee of the University of Ulm (19/12).

  • Provenance and peer review Not commissioned; externally peer reviewed.

  • Data statement Data sharing requests are made in writing through DEL (dorothee.lule@uni-ulm.de) and require a formal data sharing agreement. Data sharing agreements must include details on how the data will be stored, who will have access to the data and intended use of the data, and agreements as to the allocation of intellectual property.

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