Elsevier

The Lancet

Volume 388, Issue 10047, 27 August–2 September 2016, Pages 919-931
The Lancet

Review
The frontotemporal dementia-motor neuron disease continuum

https://doi.org/10.1016/S0140-6736(16)00737-6Get rights and content

Summary

Early reports of cognitive and behavioural deficits in motor neuron disease might have been overlooked initially, but the concept of a frontotemporal dementia-motor neuron disease continuum has emerged during the past decade. Frontotemporal dementia-motor neuron disease is now recognised as an important dementia syndrome, which presents substantial challenges for diagnosis and management. Frontotemporal dementia, motor neuron disease, and frontotemporal dementia-motor neuron disease are characterised by overlapping patterns of TAR DNA binding protein (TDP-43) pathology, while the chromosome 9 open reading frame 72 (C9orf72) repeat expansion is common across the disease spectrum. Indeed, the C9orf72 repeat expansion provides important clues to disease pathogenesis and suggests potential therapeutic targets. Variable diagnostic criteria identify motor, cognitive, and behavioural deficits, but further refinement is needed to define the clinical syndromes encountered in frontotemporal dementia-motor neuron disease.

Introduction

Reports of dementia in patients with motor neuron disease have appeared intermittently in the literature since 100-year-old descriptions of emotional lability in bulbar-onset cases. Gradually, the more specific association with frontotemporal dementia was recognised,1 and pathological and genetic discoveries have reinforced the overlap between frontotemporal dementia and motor neuron disease. We now know that frontotemporal dementia-motor neuron disease—ie, where both frontotemporal dementia and motor neuron disease are present—is an important dementia syndrome that presents a unique set of diagnostic and management challenges. In this Review we assess current knowledge of the pathology, genetics, disease models, and clinical features of frontotemporal dementia-motor neuron disease. Diagnostic criteria are explained and challenges to effective management are outlined.

Section snippets

Genetics

Familial clusters of frontotemporal dementia, motor neuron disease, and frontotemporal dementia-motor neuron disease have been recognised for many decades and associated with loci on chromosome 17,2 chromosome 9q, and most recently at chromosome 9p.3 This work led to the discovery of the chromosome 9 open reading frame 72 (C9orf72) hexanucleotide GGGGCC repeat expansion (figure 1),4, 5 which is a frequent cause of familial motor neuron disease and frontotemporal dementia, and especially

Putative pathogenic mechanisms

C9orf72 is an alternatively spliced gene encoded by 11 exons (figure 1), with two alternately spliced non-coding exons 1a and 1b, resulting in three major transcripts that encode two protein variants (481 and 222 aminoacids long). The expanded repeat is located in the proximal regulatory gene region, upstream of one transcript (exon 1b) and in the first intron of the two other transcripts (figure 1).4 Studies of fibroblasts derived from patients with motor neuron disease who are C9orf72

Pathology

In motor neuron disease and frontotemporal dementia the populations of susceptible neurons differ substantially, particularly the upper and lower motor neurons in motor neuron disease and frontal and anterior or medial temporal neurons in frontotemporal dementia. The pattern of neuronal loss associates best with clinical phenotypes. Initially regarded as distinct, the phosphorylated form of TDP-43 was identified as the major protein accumulating in susceptible regions in a large proportion of

Modes of presentation

Several population-based and retrospective cohort studies have examined the development of cognitive dysfunction and frank frontotemporal dementia-motor neuron disease in patients with motor neuron disease. About 10–15% of patients with motor neuron disease met criteria for a diagnosis of frontotemporal dementia at baseline,57, 58, 59 but milder cognitive impairment without dementia might be detected in a higher proportion of patients. Executive impairment is noted in about 20–25% of cases58, 59

Executive and language function

Cognitive studies in motor neuron disease have focused on executive deficits, particularly in bulbar-onset cases. Executive abilities help with decision making, motivation, and inhibitory control. Verbal fluency tests, often adapted to control for dysarthria,65 are robust measures of executive dysfunction in motor neuron disease and frontotemporal dementia-motor neuron disease. Executive deficits can affect day-to-day abilities—eg, patients with motor neuron disease were shown to be impaired on

Imaging

In the past 5 years, the number and sophistication of neuroimaging studies in motor neuron disease has substantially increased. Several techniques including voxel-based morphometry, cortical thickness analyses, diffusor tensor imaging, and to a lesser extent functional techniques (eg, functional MRI or PET) have been used, but several limitations must be recognised.82 Most studies have used only single modalities for small numbers of patients, with subgroup (eg, limb-onset vs bulbar-onset motor

Diagnostic criteria

Diagnostic criteria for motor neuron disease were devised before cognitive and behavioural disturbances were fully realised and need to be revised to incorporate these clinical features. Separate criteria for the classification of cognitive and behavioural changes in motor neuron disease have been developed, but have not been validated in population-based studies. The criteria include categories for frontotemporal dementia-motor neuron disease, motor neuron disease with behavioural features,

Management

Management of frontotemporal dementia-motor neuron disease presents a unique set of challenges and evidence-based guidelines are not available. Additionally, most behavioural clinics are ill equipped to deal with motor impairments and cognitive and behavioural deficits might hamper management of motor neuron disease. The burden of disease in frontotemporal dementia-motor neuron disease is substantial79 and effective therapies are desperately needed.

No specific therapies exist to manage abnormal

Conclusions: current controversies

Despite intense research efforts and crucial pathological and genetic discoveries, much remains uncertain in frontotemporal dementia-motor neuron disease. One of the most striking features of frontotemporal dementia-motor neuron disease is the substantial clinical heterogeneity and variability in disease prognosis. Some patients develop motor neuron disease years after the onset of frontotemporal dementia, whereas others might present with simultaneous onset of cognitive and motor symptoms with

Search strategy and selection criteria

We searched PubMed, MEDLINE, and Google Scholar for articles about frontotemporal dementia-motor neuron disease published in English between Jan 1, 1950, and April 1, 2015. We used the search terms “frontotemporal dementia”, “motor neurone disease”, “amyotrophic lateral sclerosis”, “dementia”, “cognition”, “behaviour”, “TDP-43”, and “C9orf72”. Existing studies of frontotemporal dementia-motor neuron disease have focused on small clinic-based cohorts, often derived from single frontotemporal

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