Review article
Cognitive change in motor neurone disease/amyotrophic lateral sclerosis (MND/ALS)

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Abstract

A motor neuronopathy complicating frontotemporal dementia (FTD) has been recognised and designated FTD/motor neurone disease (MND). FTD is characterised by profound character change and altered social conduct, and executive deficits, reflecting focal degeneration of the frontal and temporal neocortex. The motor neuronopathy comprises bulbar palsy and limb amyotrophy. The major histological change is typically of microvacuolation of the cerebral cortex, with atrophy of the bulbar neurones and anterior horn cells of the spinal cord. Ubiquitinated inclusion bodies occur in large pyramidal cortical neurones and in surviving cranial nerve nuclei and anterior horn cells. Evidence is emerging that some patients with classical MND/amyotrophic lateral sclerosis (ALS), who are thought not to be demented, develop cognitive deficits in the realm of frontal executive functions. Moreover, frontal lobe abnormalities have been demonstrated by neuroimaging. The findings point to a link between FTD/MND and cMND/ALS and suggest that a proportion of patients with cMND/ALS go on to develop FTD. Patients with cMND/ALS may not be equally vulnerable. The hypothesis is that patients who present with bulbar palsy and amyotrophy, rather than corticospinal and corticobulbar features, may be most susceptible to the development of FTD.

Introduction

Classical motor neurone disease/amyotrophic lateral sclerosis (cMND/ALS) has traditionally been assumed to spare cognitive functions. However, there are many historical references to behavioural disorder in MND, and descriptive terms have been applied, ranging from schizophrenia to dementia. A variety of factors compound the interpretation of cognitive abilities, including motor slowing, lack of control of facial and bulbar emotional expression, and the secondary effects of depression, sedative drug intake and hypoventilation. Nevertheless, evidence is accruing from neuropsychological analysis and functional imaging procedures that a proportion of patients with cMND/ALS do have cognitive impairment that is not explicable purely in terms of these confounding variables. Specific dysfunction of the anterior cerebral cortex appears to underlie these mental changes.

A theoretically relevant development in this regard is the observation that a motor neuronopathy arises in a proportion of patients with established frontotemporal dementia (FTD), in which there is degeneration of the frontal and temporal neocortex. This syndrome of FTD/MND is important in that it has potential, in view of its attenuated course, to shed light on the evolution of symptoms in FTD. It points to the earliest neuropsychological deficits and corresponding anatomical changes which precede the spread of pathology and secondary degenerative processes that occur over the course of FTD. Moreover, FTD/MND may have a bearing on understanding of the cognitive changes that arise in cMND/ALS.

This paper addresses the nature of cognitive change in both FTD/MND and cMND/ALS and examines their relationship to neurological findings and type and distribution of pathological change in the brain and spinal cord. Comparisons ought to help to elucidate the nature of the relationship between FTD/MND and cMND/ALS and suggest clues as to why some patients with cMND/ALS appear to develop cognitive impairment, whereas others do not.

Section snippets

FTD/MND

An association between dementia and MND/ALS has been recognized since the early part of the twentieth century [1], and is now well established [2], [3], [4], [5], [6], [7]. The term ‘ALS dementia’ has commonly been adopted to designate the clinical syndrome. Documented clinical information has typically pointed to impairments in frontal lobe function, with reports of character change and behavioural alterations such as social disinhibition being common [4], [5], [8], [9], [10], [11], [12], [13].

Brain-behaviour relationships in FTD and FTD/MND

The pattern of dementia in FTD and FTD/MND is indistinguishable [24]. However, FTD/MND carries out a more localised experiment upon the brain, which can be attributed to its attenuated course: patients with FTD/MND develop bulbar palsy and typically die within 3 years from respiratory failure, whereas patients with FTD may survive as long as 10 or even 15 years. The premature death of patients with FTD/MND may provide clues to the sites of initial change in FTD and the primary structures

Cognitive change in cMND/ALS

Patients with cMND/ALS have difficulty expressing their thoughts and feelings and controlling the emotional aspects of their behaviour because of pseudobulbar and bulbar palsy [27], [28], [29], complicating behavioural analysis. Nevertheless families often comment on alterations in the personality of the patient. Therapists may note a lack of initiative and compliance in occupational and physical therapy, distinguishing patients with cMND/ALS from those with other peripheral neurological and

Memory in cMND/ALS

Memory deficits in cMND/ALS have been demonstrated most consistently on free recall tasks. These have been attributed by some [35] to retrieval failure and inefficient use of learning strategies secondary to frontal lobe dysfunction. Impairments on a visual but not verbal recognition task [35] has also been interpreted in terms of frontal lobe dysfunction on the basis of the greater attentional demands of the visual task. Evidence of deficits in selective attention but not memory function in

Language in MND/ALS

In cMND/ALS several studies have demonstrated impaired performance on language tasks [34], [36], [39], [48], [49], [50], [51], [52], [53], [54]. Most often reported is impoverished word generation, measured by verbal fluency tasks [30], [32], [33], [35], [36], [37], [38], [40], but abnormalities may also be present in other domains, such as sentence comprehension [34], [49] and verb processing [53]. Interestingly, language features largely point to frontal lobe dysfunction. There is evidence,

The relationship beween cMND/ALS and FTD

Functional imaging using SPECT has elicited abnormalities in the frontal and anterior temporal cortices in cMND/ALS, mirroring the pattern of abnormality found in FTD and FTD/MND, albeit to lesser degree [34]. Moreover, frontal lobe abnormalities on imaging can be identified in some patients for whom cognitive deficits cannot be elicited. It has been argued above that orbital frontal cortex represents an early site of pathological change in FTD. Patients with the disinhibited, orbitotemporal

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