Predicting Development of Amyotrophic Lateral Sclerosis in Frontotemporal Dementia

Langenhove, Tim Van; Piguet, Olivier; Burrell, James R.; Leyton, Cristian E.; Foxe, David; Abela, M; Bartley, Lauren; Kim, Woojin Scott; Jary, Eve; Huang, Yue; Dobson‐Stone, Carol; Halliday, Glenda M.; Hodges, John R.

doi:10.3233/jad-161272

Cited by 18 publications

(13 citation statements)

References 36 publications

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“…Current evidence suggests that the risk of developing ALS declines with the duration of FTD symptoms and is unlikely after 5 years. 37 In any event, misclassifications would have the effect of masking rather than exaggerating differences between bvFTD and FTD-ALS, suggesting that identified differences are likely to be real.…”

Section: Discussionmentioning

confidence: 99%

Cognition and behaviour in frontotemporal dementia with and without amyotrophic lateral sclerosis

Saxon

Thompson

Harris

et al. 2020

J Neurol Neurosurg Psychiatry

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ObjectiveThe precise relationship between frontotemporal dementia (FTD) and amyotrophic lateral sclerosis (ALS) is incompletely understood. The association has been described as a continuum, yet data suggest that this may be an oversimplification. Direct comparisons between patients who have behavioural variant FTD (bvFTD) with and without ALS are rare. This prospective comparative study aimed to determine whether there are phenotypic differences in cognition and behaviour between patients with FTD-ALS and bvFTD alone.MethodsPatients with bvFTD or FTD-ALS and healthy controls underwent neuropsychological testing, focusing on language, executive functions and social cognition. Behavioural change was measured through caregiver interview. Blood samples were screened for known FTD genes.Results23 bvFTD, 20 FTD-ALS and 30 controls participated. On cognitive tests, highly significant differences were elicited between patients and controls, confirming the tests’ sensitivities to FTD. bvFTD and FTD-ALS groups performed similarly, although with slightly greater difficulty in patients with ALS-FTD on category fluency and a sentence-ordering task that assesses grammar production. Patients with bvFTD demonstrated more widespread behavioural change, with more frequent disinhibition, impulsivity, loss of empathy and repetitive behaviours. Behaviour in FTD-ALS was dominated by apathy. The C9ORF72 repeat expansion was associated with poorer performance on language-related tasks.ConclusionsDifferences were elicited in cognition and behaviour between bvFTD and FTD-ALS, and patients carrying the C9ORF72 repeat expansion. The findings, which raise the possibility of phenotypic variation between bvFTD and FTD-ALS, have clinical implications for early detection of FTD-ALS and theoretical implications for the nature of the relationship between FTD and ALS.

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Section: Discussionmentioning

confidence: 99%

Cognition and behaviour in frontotemporal dementia with and without amyotrophic lateral sclerosis

Saxon

Thompson

Harris

et al. 2020

J Neurol Neurosurg Psychiatry

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“…It is estimated that up to 50% of ALS patients show signs of behavioral dysfunction and/or subtle cognitive impairment, resembling dementia, and up to 15% of ALS patients reach the diagnostic criteria of FTD (referred to as ALS-FTD or FTD-ALS patients) [2][3][4]. Conversely, the same holds true for FTD [5,6]. At the genetic level, mutations in multiple genes contribute to the etiology of both ALS and FTD, as best represented by the C9orf72 repeat expansion, TBK1, VCP, and TARDBP mutations.…”

Section: Als and The Als-ftd Spectrummentioning

confidence: 99%

ALS Genes in the Genomic Era and their Implications for FTD

2018

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Amyotrophic lateral sclerosis (ALS) is a complex neurodegenerative disease, characterized genetically by a disproportionately large contribution of rare genetic variation. Driven by advances in massive parallel sequencing and applied on large patient-control cohorts, systematic identification of these rare variants that make up the genetic architecture of ALS became feasible. In this review paper, we present a comprehensive overview of recently proposed ALS genes that were identified based on rare genetic variants (TBK1, CHCHD10, TUBA4A, CCNF, MATR3, NEK1, C21orf2, ANXA11, TIA1) and their potential relevance to frontotemporal dementia genetic etiology. As more causal and risk genes are identified, it has become apparent that affected individuals can carry multiple disease-associated variants. In light of this observation, we discuss the oligogenic architecture of ALS. To end, we highlight emerging key molecular processes and opportunities for therapy.

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“…Behavioural abnormalities and/or signs of cognitive impairment including executive dysfunction, are observed in 50% of patients with ALS, while 15% of these subjects reach the diagnostic criteria for FTD [7][8][9][10]. Likewise, similar frequencies of motor disturbances are observed in FTD [11,12].…”

Section: Introductionmentioning

confidence: 95%

Monoaminergic and Kynurenergic Characterization of Frontotemporal Dementia and Amyotrophic Lateral Sclerosis in Cerebrospinal Fluid and Serum

et al. 2020

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Exploring the neurochemical continuum between frontotemporal dementia (FTD) and amyotrophic lateral sclerosis (ALS) with respect to monoamines and kynurenines in cerebrospinal fluid (CSF) and serum, may be useful to identify possible new research/therapeutic targets. Hence, we analysed monoamines and kynurenines in CSF and serum derived from patients with FTD (n = 39), ALS (n = 23), FTD-ALS (n = 4) and age-matched control subjects (n = 26), using reversed-phase ultra-high performance liquid chromatography (RP-UHPLC) with electrochemical detection (ECD) and liquid chromatography tandem mass spectrometry, respectively. We noted a shared dopaminergic disturbance in FTD and ALS when compared to CONTR, with significantly increased serum DA levels and decreased DOPAC concentrations, as well as decreased DOPAC/DA ratios in both disease groups. In CSF, significantly reduced DOPAC concentrations in FTD and ALS were observed as well. Here, a significant increase in DA levels and decrease in DOPAC/DA ratios was only found in FTD relative to CONTR. With respect to the kynurenine pathway (KP), we only found decreased HK/XA ratios, indicative for vitamin B6 status, in serum of ALS subjects compared to FTD. The dopaminergic commonalities observed in FTD and ALS might relate to a disturbance of dopaminergic nerve terminals in projection areas of the substantia nigra and/or ventral tegmental area, although these findings should first be confirmed in brain tissue. Lastly, based on the results of this work, the KP does not hold promise as a research/therapeutic target in FTD and ALS.

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Predicting Development of Amyotrophic Lateral Sclerosis in Frontotemporal Dementia

Abstract: FTD patients with a mixed bvFTD+PNFA phenotype and with a C9orf72 repeat expansion should be closely monitored for the possible development of ALS. The risk of developing ALS in FTD appears to decline with the duration of FTD symptoms.

Cited by 18 publications

References 36 publications

Cognition and behaviour in frontotemporal dementia with and without amyotrophic lateral sclerosis

Cognition and behaviour in frontotemporal dementia with and without amyotrophic lateral sclerosis

ALS Genes in the Genomic Era and their Implications for FTD

Monoaminergic and Kynurenergic Characterization of Frontotemporal Dementia and Amyotrophic Lateral Sclerosis in Cerebrospinal Fluid and Serum

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