Motor neuron disease-frontotemporal dementia: a clinical continuum

Abstract

Overlap between motor neuron disease (MND) and frontotemporal dementia (FTD) occurs at clinical, genetic and pathological levels, and has been recently strengthened through the discovery of the C9orf72 genetic expansion. MND is now considered to be a multisystem disorder in which cognitive involvement may be present and, in some cases, may evolve to frank FTD. Identifying cognitive features in MND can be challenging, while, similarly, motor dysfunction in FTD may be overlooked. As such, the present review aims to decipher the variety of overlapping clinical features across the MND–FTD continuum.

Keywords:

• behavior
• C9orf72
• clinical continuum
• cognition
• Frontotemporal dementia
• genetics
• motor neuron disease
• neuroimaging
• neurophysiology

Acknowledgements

We would like to acknowledge the Sydney Brain Bank for providing the images of TDP-43 pathology used in Figure 1.

Financial & competing interests disclosure

This work was supported by funding to Forefront, a collaborative research group dedicated to the study of frontotemporal dementia and motor neuron disease, from the National Health and Medical research Council of Australia program grant (#1037746) and the Australian Research Council Centre of Excellence in Cognition and its Disorders Memory Node (#CE110001021). E Devenney is supported by a PhD fellowship funded by the University of New South Wales and MND Association UK. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.

No writing assistance was utilized in the production of this manuscript.

Key issues

• Motor neuron disease (MND) is now considered to be a multisystem disorder encompassing motor, cognitive and behavioral changes. MND and frontotemporal dementia (FTD) overlap at clinical, genetic and pathological levels with some patients satisfying criteria for both diseases.

• Verbal fluency is a robust measure of executive dysfunction in MND. Language, social cognition and behavioral changes are also prevalent and should be sought.

• Co-existence of both disorders has a detrimental impact on survival.

• The C9orf72 expansion has cemented the concept of an MND–FTD continuum with one or both diseases present in affected pedigrees, although the presentation can be clinically variable. It is the commonest genetic abnormality in familial MND–FTD, although other genes have also been reported, including TARDBP and UBQLN2.

• GRN and MAPT mutations are found primarily in cases of FTD, while SOD-1 is almost entirely exclusive to the MND end of the spectrum.

• Consensus criteria have been developed for the diagnosis of MND–FTD in the research setting.

• Neuroimaging techniques may evolve to aid patient phenotyping across the MND–FTD continuum.

• Riluzole remains the only approved disease-modifying drug for MND and has shown modest improvements in life expectancy.

• Ongoing drug trials targeted at pathology, genetic and immunological processes offer hope for the future in MND–FTD.

Notes

bvFTD: Behavioral variant frontotemporal dementia; FTLD: Frontotemporal lobar degeneration.

PPA: Primary progressive aphasia; PPA-sv: Primary progressive aphasia semantic variant; PPA-G: Primary progressive aphasia non-fluent variant; PPA-lv: Primary progressive aphasia logopenic variant.

ALS: Amyotrophic lateral sclerosis; EMG: Electromyography; LMN: Lower motor neurone; UMN: Upper motor neurone.