Cognition and behaviour in motor neurone disease - ResearchGate

Cognition and behaviour in motor neurone disease
Patricia Lillo and John R. Hodges
Neuroscience Research Australia, University of New
South Wales, Sydney, New South of Wales, Australia
Correspondence to Dr Patricia Lillo, Neuroscience
Research Australia, Barker St, Randwick, NSW 2031,
Australia
Tel: +612 9399 1803; e-mail: p.lillo@neura.edu.au
Current Opinion in Neurology 2010, 23:638–642
Introduction
Motor neurone disease (MND) has long been considered
a pure motor system disease, but recent evidence has led
to its reconceptualization as a multisystem disease [1].
Clinically, up to 50% of patients with MND have cognitive
impairment. Furthermore, 10–15% fulfil criteria
for frontotemporal dementia (FTD) which we have
designated MND-FTD [2]. A similar proportion of
patients with FTD develop MND (FTD-MND) [3].
Pathological findings also support this overlap: MND
patients and a subset of FTD cases have demonstrable
TAR DNA binding protein 43 (TDP-43) inclusions [4].
Here we review cognitive and behavioural changes in
patients with MND in the context of recent pathological
and genetic advances.
Pathological overlap with frontotemporal
dementia
A major advance has been the finding that TDP-43 is the
principal component in frontotemporal lobar degeneration
Purpose of review
Motor neurone disease has traditionally been considered a pure motor syndrome which
spares aspects of cognition and behaviour, although in recent years it has been
suggested that up to 50% of patients with motor neurone disease may develop frontal
dysfunction which, in some cases, is severe enough to reach criteria for frontotemporal
dementia. We review the cognitive and behavioural changes in motor neurone disease
emphasizing the recent advances.
Recent findings
A major advance in pathology has been the recent discovery of TDP-43 and FUS
inclusions as the key components in cases of motor neurone disease, frontotemporal
dementia–motor neurone disease and some cases with pure frontotemporal dementia.
In addition, mutations in TARDBP and FUS genes have been reported in recent years.
Longitudinal studies showed that progression of cognitive impairment over the course
of motor neurone disease appears to be mild and occurs only in a proportion of motor
neurone disease patients. The presence of cognitive impairment seems to be related to
a faster disease and a shorter survival.
Summary
Motor neurone disease is a multi-system disorder which overlaps with frontotemporal
dementia. Behavioural and cognitive changes appear to occur in a subset of patients
with motor neurone disease, but the cause of this variability remains unclear.
Keywords
amyotrophic lateral sclerosis, behavioural changes, cognitive impairment,
frontotemporal dementia, motor neurone disease
Curr Opin Neurol 23:638–642
ß 2010 Wolters Kluwer Health | Lippincott Williams & Wilkins
1350-7540
with ubiquitinated inclusions (FTLD-U), currently classified
as FTLD-TDP. The condition is found in those
patients who present with FTD but develop frank
MND (FTD-MND), approximately a half of those with
uncomplicated FTD and the majority of patients with
both sporadic and familial MND. TDP-43 is a nuclear
protein of 43 kDa, which participates in various critical
biological processes by binding DNA and RNA. Normally,
it is localized in nuclei of neurons and glial cells. Pathologically,
normal nuclear TDP-43 staining is absent, and
cytoplasmic and nuclear TDP-43 inclusions are detectable
[4]. Five patterns of TDP-43 aggregation are recognized.
Pure MND, type 5, is characterized by cytoplasmic
inclusions (skein-like or dense granular), affecting principally
the motor cortex, the spinal cord, basal ganglia and
thalamus. FTD-MND is usually associated with type 2,
which is characterized by neuronal cytoplasmic inclusions
in superficial and deep cortical layers involving the
temporal and frontal cortices, dentate gyrus, amygdala
and subcortical white matter [5 ]. As expected, the degree
of neuronal loss is more in FTD-MND than in pure MND
and affects primarily the anterior cingulate gyrus, substantia
nigra and amygdala [6,7].
1350-7540 ß 2010 Wolters Kluwer Health | Lippincott Williams & Wilkins DOI:10.1097/WCO.0b013e3283400b41
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In addition, another protein called FUS/TLS (fused in
sarcoma/translated into liposarcoma), a 526-amino-acid
DNA/RNA binding protein, has been very recently
identified in pathological cases of FTLD-U without
TDP-43 inclusions [8]. The disorder is characterized
by neuronal cytoplasmic and intra-nuclear inclusions
immunoreactive for FUS. This pattern has been also
been found in cases with pure MND, MND-FTD and
cases of behavioural variant FTD [9,10].
Genetics
There has been a recent explosion of knowledge in MND
and FTD genetics, although the exact relationship
between the identified genes and pathology remains
unclear. A prominent family history is present in around
5–10% of the patients with MND. It is interesting to
note that the Cu–Zn superoxide dismutase 1 (SOD1)
mutation, which accounts for 15–20% of autosomal dominant
familial cases, is characterized by lack of TDP-43
and FUS inclusions and an apparent absence of cognitive
involvement [9,11 ,12].
A second gene now linked to both familial and sporadic
MND is the TAR DNA binding protein (TARDBP) gene
on chromosome 1p36.22, designated ALS10. It is present
in 1–3% of MND cases, and over 30 mutations have been
identified with an autosomal dominant pattern of inheritance.
Two cases presenting with FTD-MND have been
reported; one with language deficits and the other with
behavioural impairment. Only one sporadic case with
pure FTD with a TARDBP mutation has, so far, been
reported [11 ,13].
The third group, classified as ALS6, have mutations in
the fused sarcoma/translocation in liposarcoma gene
(FUS/TLS), on chromosome 16q12. Dominant and recessive
mutations have been identified in familial and
sporadic MND cases, and one case of sporadic FTD
[11 ,12,14].
Other mutations linked to MND cases with FTD are
missense mutations in angiogenin (ANG) gene and
mutations in the p150 subunit of dynactin 1 (DCTN1)
gene. In addition, two mutations reported in FTD
cases, affecting chromatin-modifying protein 2B
(CHMP2B) and progranuline (PGRN) genes, although
uncommon, have been found in cases with FTD and
MND [12].
There are clearly more genes to be identified which are
likely to be more common than some of the known
mutations. A significant number of families in which
some members have MND, FTD or both have been
linked to chromosome 9, but the gene responsible
remains elusive [15].
Cognition and behaviour in motor neurone disease Lillo and Hodges 639
Development of motor neurone disease in
patients with frontotemporal dementia
Approximately, 15% of the patients with FTD develop
frank MND in the course of the disease [3,16]. This
clinical syndrome has a fairly consistent pattern in which
rapidly evolving behavioural and cognitive symptoms are
followed after a period of 1–2 years later (sometimes up
to 7 years) by bulbar and other signs of motor dysfunction
[17,18 ]. The presentation may be with either behavioural
or language impairment, but usually both are
present from the start.
The behavioural changes include poor insight, lack of
empathy, obsessions and tendency to eat sweet food and
hoard things. Periods of apathy alternate with irritability
and disinhibition. The language impairment is characterized
by a progressive nonfluent aphasia, leading to
mutism [17]. A detailed case study of five patients with
marked aphasia in association with MND documented a
selective deficit in verb processing involving both production
and comprehension. These patients were shown
to have pathological involvement of Broca’s area [19].
Neuropsychological assessment often reveals prominent
frontal/executive dysfunction. Although psychotic
symptoms appear to be infrequent in FTD, remarkably,
delusionshavebeenreportedinupto50%ofpatients
with the FTD-MND phenotype. Recent reports have
focused attention on the presence of delusions in early
stages of the disease, which have been described as
persecutory type, phantom boarder syndrome, erotomania,
bodily invasion and delusional pregnancy [18 ,20 ].
The course of the disease, with survival from diagnosis of
2–3 years, is certainly shorter than in cases with pure
FTD [18 ].
Executive dysfunction
The greatest body of literature on cognition in MND has
related to executive function and by implication to prefrontal
lobe abilities [2,21–24] (Table 1). Although estimates
of the prevalence of such deficits range from 10 to
70%, in the largest study to date subtle cognitive impairment
was found in 50% of 279 patients with sporadic
MND [2].
Table 1 Summary of cognitive and behavioural changes in
patients with motor neurone disease
Deficits caused by cognitive impairment Behavioural changes
Attention Apathy
Verbal fluency Irritability
Working memory Lack of empathy
Planning/organizing Disinhibition
Mental shifting Compulsions
Stereotyped behaviours
Data from [21–27,28 ].
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640 Degenerative and cognitive diseases
The most prominent deficit reported has been reduction
in verbal fluency, which is evident in the letter fluency
test [24,25]. This impairment has been associated with
dysfunction of anterior cingulate gyrus and middle and
inferior frontal gyri as demonstrated by functional MRI
[25]. Written rather verbal fluency has been examined in
patients with significant dysarthria [24]. Attention (verbal
series attention test and paced auditory serial addition
test), working memory (reverse digit span test), planning
(Tower of Hanoi) and cognitive flexibility (Wisconsin
card sorting test) may also be impaired [21–24]. As
impaired performance on neuropsychological assessment
can be confounded by motor dysfunction, a recent study
assessed executive function with a motor-free test. In this
study, the performance of MND patients and controls
was compared using the Medication Scheduling Task,
which includes planning, multitasking, mental set shifting
and delaying response components. The participants
were asked to assemble a daily safe scheme for the
administration of the medication. Despite correction
for motor disability, MND patients performed worse than
the control group [26].
Behavioural symptoms
A range of behavioural symptoms that parallel those
found in FTD have been reported although, as with
cognitive dysfunction, estimates of prevalence vary considerably.
Apathy has been consistently found to be the
most common feature. For instance, one study reported
apathy in 55% of MND patients, which correlated with
deficits in verbal fluency but not with physical disability,
mood disturbances or respiratory function [27]. A study
on 225 MND patients, which used the Frontal Systems
Behaviour Scale (FrSBe) designed to evaluate apathy,
executive dysfunction and disinhibition, showed an
elevation in the total FrSBe score in a quarter of cases
and over a third of cases had impairment in at least one
behavioural domain. Patients with cognitive impairment
had greater behavioural changes, although the two
domains were partially independent [28 ]. Finally, two
informant-based behavioural interview surveys showed
that patients with MND may also present indiscriminate
eating, gluttony, compulsions and behavioural stereotypes
[29,30] (see Table 1).
Memory
A majority of the studies assessing memory have shown
greater impairment of immediate recall than with recognition
tasks, suggesting a retrieval disturbance secondary
to prefrontal dysfunction [21,31]. A recent meta-analysis
of studies to date concluded that some aspects of memory
are consistently impaired, notably immediate and
delayed visual memory and immediate verbal memory.
The pattern is in keeping with frontal lobe dysfunction,
but involvement of temporal lobe structures could not be
discounted because of the effect size [32 ].
Language
Language assessment presents particular problems in
patients with dysarthria, but even allowing for this it
seems that significant aphasia occurs in a proportion of
patients with MND and may be more common in
patients with bulbar onset disease [33]. The most commonly
identified deficits have been reduced speech
output and anomia [17,34]. Some patients develop significant
aphasia designated progressive nonfluent aphasia
with agrammatism in production and impaired syntactic
comprehension. Interestingly, a higher order disturbance
of motor speech, apraxia of speech, has been reported in
patients with bulbar onset disease, frequently associated
with spastic or mixed spastic–flaccid dysarthria [35].
Emotional processing
The fact that emotion processing is severely and consistently
compromised in patients with FTD [36] has understandably
led a number of investigators to study this
aspect of social cognition in MND. Impaired recognition
of emotional faces was found in a group of bulbar MND
patients [37]. A selective deficit in the recognition of
threat stimuli through faces has also been reported, which
parallels that seen in patients with amygdala damage [38].
Longitudinal studies
A key question unanswered from cross-sectional studies
is whether cognitive dysfunction remains confined to a
subset of patients with MND whose condition worsens
over time or alternatively whether all patients with MND
eventually develop cognitive or behavioural changes.
Longitudinal studies have found cognitive dysfunction
early in the course of the disease, on the basis of verbal
fluency deficits [39] particularly in those with bulbar
onset disease [40], although this has not been a universal
finding [41,42 ].
Progression of cognitive impairment over the course of
MND appears to be mild. Older patients, and those with
more rapidly progressing disease, may be more predisposed
to cognitive impairment, which, in turn, contributes
to a shorter survival [42 ].
Neuroimaging
The principal role of neuroimaging in MND has been to
exclude alternative diagnoses, although in more recent
years new techniques have been used to assess the
integrity of both the motor system and the extra motor
regions.
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Structural MRI has established that those with subtle
cognitive or behavioural impairment showed grey matter
loss in frontal, parietal and limbic regions [43 ]. As
expected, patients with MND-FTD have atrophy of
frontotemporal lobes and hyperintensity of subcortical
white matter in medial anterior temporal lobe, similar to
that seen in patients with pure FTD [44,45].
A comparison of MND and MND-FTD patient groups
using voxel-based morphometry showed a similar pattern
of grey matter atrophy involving bilateral motor and
premotor cortices, superior, middle and inferior frontal
gyri, superior temporal gyri, temporal poles and left
posterior thalamus that was, as predicted, greater in
the MND-FTD group [46].
Functional MRI (fMRI) studies have shown reduced
activation of the middle and inferior frontal gyri and
anterior cingulate gyrus in MND patients during letter
fluency tasks [29]. Deficits on word fluency and confrontation
naming have been shown to correlate with
impaired activation of the prefrontal region (Broca area),
temporal, parietal and occipital lobes [29,43 ].
A few recent studies have examined the relationship
between social processing and regions of brain activation
using fMRI. One study demonstrated that patients with
MND presenting altered sensitivity to social–emotional
clues had an increased response in the right supramarginal
area [47]. Another showed that impaired emotional
process in ALS patients was related to right hemisphere
dysfunction [48].
Conclusion
Recent advances in genetics and pathology have led to
the concept of MND as a multisystem disorder which
overlaps with frontotemporal dementia. The assessment
of patients with MND is challenging, due to the motor
disability and the variability of the clinical phenotype. It
appears that changes in behaviour and cognition, notably
executive function, language and emotional processing,
occurs only in a subset of patients, but the cause of this
variability in the clinical phenotype remains unclear.
Acknowledgements
The study was supported by the Australian Research Council
Federation Fellowship, FF0776229 (Prof. Hodges) and CONICYT
scholarship (Government of Chile) (Dr Lillo).
J.R.H. serves on editorial boards of Aphasiology, Cognitive Neuropsychiatry,
and Cognitive Neuropsychology; receives royalties from
publication of Cognitive Assessment for Clinicians (Oxford University
Press, 2007) and Frontotemporal Dementia Syndromes (Cambridge
University Press, 2007) and receives fellowship support from the
Australian Research Council Federation.
Thanks to Dr James Burrell, MBBS (Hons), for his assistance with
proofreading.
Cognition and behaviour in motor neurone disease Lillo and Hodges 641
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