Motor neuron dysfunctions in the frontotemporal lobar degeneration spectrum: A clinical and neurophysiological study

Cerami, Chiara; Marcone, Alessandra; Crespi, Chiara; Iannaccone, Sandro; Marangoni, Claudio; Dodich, Alessandra; Giusti, Mariana; Zamboni, Michele; Golzi, V.; Cappa, Stefano F.

doi:10.1016/j.jns.2015.02.039

Cited by 19 publications

(16 citation statements)

References 40 publications

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“…Interestingly, FTD patients can also develop motor neuron disease (MND), including amyotrophic lateral sclerosis (ALS) (Cerami et al . ). ALS is a devastating neurodegenerative disease characterized by the progressive loss of upper and lower spinal motor neurons.…”

Section: An Introduction To C9‐ftd/alsmentioning

confidence: 97%

“…This degeneration results in cognitive deficits that commonly manifest as changes in personality and behavior and language alterations. Interestingly, FTD patients can also develop motor neuron disease (MND), including amyotrophic lateral sclerosis (ALS) (Cerami et al 2015). ALS is a devastating neurodegenerative disease characterized by the progressive loss of upper and lower spinal motor neurons.…”

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confidence: 99%

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Insights into the pathogenic mechanisms of Chromosome 9 open reading frame 72 (C9orf72) repeat expansions

Todd

Petrucelli

2016

Journal of Neurochemistry

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The identification of a hexanucleotide repeat expansion in a non-coding region of C9orf72 as a major cause of both frontotemporal dementia (FTD) and amyotrophic lateral sclerosis (ALS) drastically changed the field of research on both of these conditions. Yet, despite the vast amount of work aimed at elucidating the molecular mechanisms underlying the role of this repeat in disease, the exact pathomechanisms are still unclear. A reduction in the expression of the C9orf72 gene is observed in patients, but a gain-of-function model is now preferred. The hexanucleotide repeat expansion forms RNA foci in the central nervous system (CNS) of repeat-positive FTD and ALS patients, and these foci are believed to sequester RNA-binding proteins (RBPs) and impair their function in RNA processing. At the same time, the repeat undergoes repeat-associated non-ATG translation to produce dipeptide repeat proteins that also form inclusions in the patient CNS. Studies from cells and flies suggest that these proteins may also be an important factor in the disease. Finally, the hexanucleotide repeat also induces the mislocalization and aggregation of TAR DNA-binding protein 43 (TDP-43) through an as yet unknown mechanism. This review covers the different potential pathogenic factors that have been put forth for C9orf72-repeat-associated FTD and ALS (C9-FTD/ALS), while highlighting some remaining questions.

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Section: An Introduction To C9‐ftd/alsmentioning

confidence: 97%

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confidence: 99%

Insights into the pathogenic mechanisms of Chromosome 9 open reading frame 72 (C9orf72) repeat expansions

Todd

Petrucelli

2016

Journal of Neurochemistry

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“…There is growing evidence supporting amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) as extreme points of a disease spectrum. Although these two neurodegenerative diseases are characterized by extremely different spectra of symptoms, a partial clinical overlap is common (Lillo and Hodges, 2009;Cerami et al, 2015;Devenney et al, 2015). It has been estimated that 12-20% of patients with a diagnosis of FTD, especially those diagnosed as behavioral variant of FTD (bvFTD), can develop motor neuron dysfunction and are then diagnosed as ALS (Lomen-Hoerth et al, 2002;Burrell et al, 2011).…”

Section: Introductionmentioning

confidence: 99%

Comparison of Gray Matter Atrophy in Behavioral Variant Frontal Temporal Dementia and Amyotrophic Lateral Sclerosis: A Coordinate-Based Meta-Analysis

Chen

Xiao

et al. 2020

Front. Aging Neurosci.

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Background: There is growing evidence supporting behavioral variant frontotemporal dementia (bvFTD) and amyotrophic lateral sclerosis (ALS) as extreme points of a disease spectrum. The aim of this study was to delineate the common and different patterns of gray matter atrophy associated with bvFTD and with ALS by pooling together the results of previous voxel-based morphometry (VBM) studies. Methods:We retrieved VBM studies that investigated gray matter atrophy in bvFTD patients vs. controls and in ALS patients vs. controls. Stereotactic data were extracted from those studies and subsequently tested for convergence and differences using activation likelihood estimation (ALE). A behavioral analysis using the BrainMap database was performed to assess the functional roles of the regions affected by bvFTD and/or ALS.Results: Our study demonstrated a convergence of gray matter atrophy in the frontolimbic structures that involve the bilateral anterior insula and anterior cingulate cortex. Comparing the pattern of GM atrophy in bvFTD and ALS patients revealed greater atrophy in the frontomedial cortex, bilateral caudate, left anterior insula, and right thalamus in those with bvFTD and a higher degree of atrophy in the right motor cortex of those with ALS. Behavioral analysis revealed that the pattern of the affected regions contributed to the dysfunction of emotional and cognitive processing in bvFTD patients and the dysfunction of motor execution in ALS patients. Conclusion:Our results revealed a shared neural basis between bvFTD and ALS subjects, as well as a specific and distinct neural signature that underpinned the clinical manifestations of those two diseases. Those findings outlined the role of the frontomedial-caudate circuit in the development of bvFTD-like deficits in ALS patients.

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“…Clinical manifestations of FTD include changes in behavior and personality, accompanied by language alterations. Importantly, a fraction of FTD patients also develop motoneuron diseases, including ALS 5 , suggesting that they are part of a unique pathological spectrum 6 .…”

Section: Introductionmentioning

confidence: 99%

Disulfide cross-linked multimers of TDP-43 and spinal motoneuron loss in a TDP-43A315T ALS/FTD mouse model

Bargsted

Medinas

Traub

et al. 2017

Sci Rep

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Tar DNA binding protein 43 (TDP-43) is the principal component of ubiquitinated protein inclusions present in nervous tissue of most cases of both amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). Previous studies described a TDP-43A315T transgenic mouse model that develops progressive motor dysfunction in the absence of protein aggregation or significant motoneuron loss, questioning its validity to study ALS. Here we have further characterized the course of the disease in TDP-43A315T mice using a battery of tests and biochemical approaches. We confirmed that TDP-43 mutant mice develop impaired motor performance, accompanied by progressive body weight loss. Significant differences were observed in life span between genders, where females survived longer than males. Histopathological analysis of the spinal cord demonstrated a significant motoneurons loss, accompanied by axonal degeneration, astrogliosis and microglial activation. Importantly, histopathological alterations observed in TDP-43 mutant mice were similar to some characteristic changes observed in mutant SOD1 mice. Unexpectedly, we identified the presence of different species of disulfide-dependent TDP-43 aggregates in cortex and spinal cord tissue. Overall, this study indicates that TDP-43A315T transgenic mice develop key features resembling key aspects of ALS, highlighting its relevance to study disease pathogenesis.

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Motor neuron dysfunctions in the frontotemporal lobar degeneration spectrum: A clinical and neurophysiological study

Cited by 19 publications

References 40 publications

Insights into the pathogenic mechanisms of Chromosome 9 open reading frame 72 (C9orf72) repeat expansions

Insights into the pathogenic mechanisms of Chromosome 9 open reading frame 72 (C9orf72) repeat expansions

Comparison of Gray Matter Atrophy in Behavioral Variant Frontal Temporal Dementia and Amyotrophic Lateral Sclerosis: A Coordinate-Based Meta-Analysis

Disulfide cross-linked multimers of TDP-43 and spinal motoneuron loss in a TDP-43A315T ALS/FTD mouse model

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