Motor function and behaviour across the ALS-FTD spectrum

Silva, Dinuksha De; Hsieh, Sharpley; Caga, Jashelle; Leslie, Felicity; Kiernan, Matthew C.; Hodges, John R.; Mioshi, Eneida; Burrell, James R.

doi:10.1111/ane.12471

Cited by 22 publications

(23 citation statements)

References 28 publications

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“…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.…”

Section: Discussionsupporting

confidence: 67%

“…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.…”

Section: Discussionmentioning

confidence: 88%

“…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.…”

Section: Introductionmentioning

confidence: 99%

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Story of the ALS-FTD continuum retold: rather two distinct entities

Lulé

Aho-Özhan

Vázquez

et al. 2018

J Neurol Neurosurg Psychiatry

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ObjectiveTo 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.MethodsIn 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.ResultsEvolution 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.ConclusionEvolution 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.

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Section: Discussionsupporting

confidence: 67%

Section: Discussionmentioning

confidence: 88%

Section: Introductionmentioning

confidence: 99%

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Story of the ALS-FTD continuum retold: rather two distinct entities

Lulé

Aho-Özhan

Vázquez

et al. 2018

J Neurol Neurosurg Psychiatry

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“…There were no significant correlations between the severity of behavioural profiles, disease length, progression rate or functional decline, confirming that, while physical disability may contribute to milder degrees of behavioural impairment, it is unlikely to be a major determinant of overall behavioural changes 21. Not even the type of motor onset contributed to presence of behavioural features 3 19.…”

Section: Discussionmentioning

confidence: 87%

Cortical correlates of behavioural change in amyotrophic lateral sclerosis

Consonni

Cappa

Bella

et al. 2018

J Neurol Neurosurg Psychiatry

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BackgroundBehavioural changes in amyotrophic lateral sclerosis (ALS) are heterogeneous. The study aim was to identify the behavioural profiles of non-demented patients with ALS and their neuroimaging correlates and to elucidate if they are comparable to those reported in studies of the behavioural-variant of frontotemporal dementia (bvFTD).MethodsBehavioural changes of 102 non-demented patients with ALS were assessed through the Frontal Behavioural Inventory (FBI), a 24-item scale assessing different behavioural modifications, mainly chosen from the core clinical features of FTD. Principal component analysis (PCA) was used to detect distinct clusters of behavioural changes based on FBI subscores. The cortical thinning related to each behavioural profile was analysed in 29 patients with ALS. Cronbach’s α was used to test the reliability of bvFTD-related FBI clustering in our cohort.ResultsSixty patients with ALS had FBI score≥1. PCA identified three phenotypic clusters loading on disinhibited/hostile, dysexecutive and apathetic FBI subscores. Imaging analyses revealed that the thinning of bilateral orbitofrontal cortex was related to apathy, the right frontotemporal and cingular cortex to the disinhibited/hostile profile and the left precuneus cortex to the dysexecutive behaviours. The bvFTD-associated aggressive profile reliably applied to our cohort.ConclusionsIn non-demented patients with ALS, different behavioural profiles could be identified. The right frontotemporal and cingular cortex thinning was the hallmark of the behavioural profile mostly overlapping that described in bvFTD. Our findings provide the unbiased identification of determinants relevant for a novel stratification of patients with ALS based on their behavioural impairment, which might be useful as proxy of cognitive decline.

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“…The presence of frontotemporal impairment in ALS predicts a shorter survival time (8) and behavioural and functional impairment may decline independently of motor function (9,10).…”

mentioning

confidence: 99%

Molecular basis of ALS and FTD: implications for translational studies / Molekularna osnova ALS-a i FTD-a: implikacije za translacijska istraživanja

Liščić

2015

Archives of Industrial Hygiene and Toxicology

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Amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) are neurodegenerative disorders, related by signs of deteriorating motor and cognitive functions, and short survival. The cause is unknown and no effective treatment currently exists. For ALS, there is only a drug Riluzole and a promising substance arimoclomol. The overlap between ALS and FTD occurs at clinical, genetic, and pathological levels. The majority of ALS cases are sporadic (SALS) and a subset of patients has an inherited form of the disease, familial ALS (FALS), with a common SOD1 mutation, also present in SALS. A few of the mutant genes identified in FALS have also been found in SALS. Recently, hexanucleotide repeat expansions in C9ORF72 gene were found to comprise the largest fraction of ALS-and FTD-causing mutations known to date. TAR DNA-binding protein 43 , encoded by the TARDBP gene, has been identified as the pathological protein of FALS, SALS and, less frequently, FTD. The less frequent TDP-43 pathology in other forms of familial FTD has been linked to a range of mutations in GRN, FUS/TLS, rarely VCP, and other genes. TDP-43 and FUS/TLS have striking structural and functional similarities, most likely implicating altered RNA processing as a major event in ALS pathogenesis. The clinical overlap of the symptoms of FTD and ALS is complemented by overlapping neuropathology, with intracellular inclusions composed of microtubule-associated protein tau, TDP-43 and less frequently FUS, or unknown ubiquitinated proteins. Furthermore, new therapeutic approaches continue to emerge, by targeting SOD1, TDP-43 or GRN proteins. This review addresses new advances that are being made in our understanding of the molecular mechanisms of both diseases, which may eventually translate into new treatment options. KEY WORDS: dementia; FTLD; FUS/TLS; genetics; motor neuron disease; TDP-43; C9ORF72 nucleotide repeat expansions; TARDBP Liščić RM, Molecular basis of ALS and FTD: Implications for translational studies Arh Hig Rada Toksikol 2015;66:285-290 Amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) are related neurodegenerative disorders, which are characterised by decline in motor and cognitive functions, and short survival. ALS is clinically characterised by signs of upper and lower motor neuron degeneration and its progressive spread of signs within a region or to other regions in a time frame, as defined by the revised El Escorial criteria (1). Both diseases have fatal outcome within a few years' time (1). The cause is unknown and no effective treatment currently exists. There is a drug Riluzole, which slightly prolongs survival in patients with ALS (2), and a Phase II/III randomised, placebo-controlled trials of arimoclomol (BRX-345) in familial ALS with SOD-1 mutation (NCT00706147; www.clinicaltrials.gov). The substance arimoclomol may reduce the levels of protein aggregates in motor nerves, a possible cause of ALS, by boosting expression of chaperons Hsp 70 and Hsp 90 which help newly synthesised proteins properly fol...

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Motor function and behaviour across the ALS-FTD spectrum

Cited by 22 publications

References 28 publications

Story of the ALS-FTD continuum retold: rather two distinct entities

Story of the ALS-FTD continuum retold: rather two distinct entities

Cortical correlates of behavioural change in amyotrophic lateral sclerosis

Molecular basis of ALS and FTD: implications for translational studies / Molekularna osnova ALS-a i FTD-a: implikacije za translacijska istraživanja

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