Review

Cognitive impairment in amyotrophic lateral sclerosis

Julie Phukan, Niall P Pender, Orla Hardiman
Lancet Neurol 2007;
6: 9941003
Department of Neurology
(J Phukan MB, O Hardiman MD)
and Department of Psychology
(N P Pender PhD), Beaumont
Hospital, Dublin, Ireland
Correspondence to:
Julie Phukan, Department of
Neurology, Beaumont Hospital,
Dublin 9, Ireland
juliephukan@yahoo.co.uk

Amyotrophic lateral sclerosis (ALS) is a motor neuron disease that has sporadic and inherited forms. ALS is the most
common neurodegenerative disorder of young and middle-aged adults, and few treatments are available. Although
the degeneration predominantly aects the motor system, cognitive and behavioural symptoms have been described
for over a century, and there is evidence that ALS and frontotemporal dementia overlap clinically, radiologically,
pathologically, and genetically. Cognitive decline in ALS is characterised by personality change, irritability, obsessions,
poor insight, and pervasive decits in frontal executive tests. This presentation is consistent with the changes to
character, social conduct, and executive function in frontotemporal dementia. We highlight genetic, imaging, and
neuropathological evidence that non-motor systems are aected in ALS and explain the importance of recent
discoveries. We review studies of cognitive impairment in ALS and common neuropsychological test results. We also
provide advice about clinical assessment of frontotemporal dysfunction in patients with ALS, and suggest future
research. Understanding of cognitive impairment in ALS will improve care for patients and their families and provide
valuable insights into the pathogenesis of neurodegeneration.

Introduction
Amyotrophic lateral sclerosis (ALS) is a degenerative
motor neuron disease that has age-dependent onset and
duration. Although the causes of ALS are not well
understood, recent studies support the view that ALS is a
complex genetic disorder.1 About 10% of ALS cases are
familial, with a Mendelian pattern of inheritance. A fth
of these cases are associated with mutations in the
superoxide dismutase 1 gene (SOD1).2 The remaining
90% of ALS cases are classed as sporadic, although there
is accumulating evidence that subpopulations of patients
with sporadic ALS have common inherited susceptibility
genes.1,3,4
ALS was traditionally believed to spare cognitive
functions, but is now known to involve a range of
cognitive impairments. Most patients with ALS have
mild cognitive impairment with subtle executive decits,
and 5% have a clinical subtype of frontotemporal lobar
degeneration (FTLD) called frontotemporal dementia.5,6
FTLD, which was originally described as Picks disease,
is the second most common cause of progressive
cognitive impairment after Alzheimers disease. The
three forms of FTLD were dened by consensus criteria
in 1998 (table 1).7 The form most frequently described in
patients with ALS is frontal variant frontotemporal
dementia (fvFTD); the other two forms are non-uent
progressive aphasia, which is characterised by language
impairment, and semantic dementia, which is
characterised by loss of conceptual knowledge.
The behavioural changes associated with fvFTD dier
according to which neuroanatomical pathways are most
severely aected.8 Some patients become disinhibited,
fatuous, purposelessly overactive, and easily distracted,
with socially inappropriate behaviour and little concern
for others. Pathological changes in these patients are
conned to orbitomedial frontal and anterior temporal
regions. Other patients become bland, apathetic, inert,
mentally rigid, and perseverative, and lack volition and
mental eort. In these patients, pathological changes
extend throughout the frontal lobes, including the
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dorsolateral frontal cortex. A third group of patients

presents with stereotyped, ritualistic behaviour that is
associated with substantial changes to the striatum.
These patients also have variable cortical involvement,
often with pathology of the temporal lobe rather than the
frontal lobe. In ALS, the most common recognised form
of cognitive impairment is frontal dysexecutive syndrome.
This syndrome refers most closely to the second of the
three aforementioned groups.

A possible spectrum of ALS and dementia

Although ALS is predominantly a disease of motor
system degeneration, cognitive and behavioural
symptoms have been described for over a century, and an
association between ALS and frontal lobe dementia was
postulated as early as 1932.9 Many authors have since
suggested that ALS and frontotemporal dementia form a
clinical and pathological spectrum. This idea remains
controversial, but there is no doubt that ALS and
frontotemporal dementia have clinical, radiological,
pathological, and genetic overlap.
A clinical phenotype of cognitive decline in ALS has
been characterised by personality change, irritability,
obsessions, poor insight, and pervasive decits on frontal
executive tests.10 This presentation is consistent with the
character change, altered social conduct, and executive
decits in patients with frontotemporal dementia. Some
patients with ALS show more subtle frontal executive
decits that involve verbal uency, attention, and working
memory.
Imaging correlates of cognitive decline in ALS include
atrophy of the frontal lobe and hypometabolism in the
cortex, particularly in frontotemporal regions and the
anterior cingulate gyrus.1113 These ndings suggest that
neurons other than motor neurons, particularly those
along the thalamofrontal association pathway, are aected
in some patients who have ALS without dementia.
Imaging studies have also implicated dysfunction of the
dorsolateral prefrontal cortex in some patients with ALS
who have associated cognitive impairments.1416
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Review

Neuropathological topography

Cognitive symptoms

Behavioural changes

Neurological ndings

Frontal variant
frontotemporal
dementia

Frontal atrophy more severe than

temporal atrophy. Particularly aected:
right dorsolateral and prefrontal cortex,
and left premotor cortex

Executive dysfunction (eg, verbal uency and

attention)

Distractibility, disinhibition, decline in

personal hygiene, hyperorality,
compulsions, perseveration, apathy,
and submissiveness

Frontal release signs and primitive

reexes, motor neuron disease, and
possible extrapyramidal features (PSP
or CBD)

Non-uent
progressive
aphasia

Asymmetric atrophy of left hemisphere.

Particularly aected: left frontal, insular,
anterior parietal, superior temporal, and
perisylvian cortex

A disorder of expressive language. Non-uent

spontaneous speech with agrammatism,
phonemic paraphasias, and anomia. Impaired
executive function and working memory

Behavioural changes are typically seen Supranuclear gaze disturbance, axial

late in the course of this illness. Possible rigidity, alien limb, and focal
social withdrawal and depression
dystonias

Semantic
dementia

Temporal atrophy more severe than

frontal atrophy. Particularly aected:
insula, amygdala, and anterior
hippocampus

Impaired understanding of word meaning and

object identity, uent but empty spontaneous
speech, semantic paraphasias, long-term
memory loss, and perceptual disorder (eg,
prosopagnosia, associative agnosia, or both)

Emotional withdrawal, depression,

mental rigidity, and compulsions

Neurological ndings emerge late in

the course of this illness

PSP=progressive supranuclear palsy. CBD=corticobasal degeneration.

Table 1: Variants of frontotemporal lobar dementia

Few studies have reported neuropathological correlates

of cognitive decline in well characterised clinical cohorts
of patients with ALS. Findings from such studies include
frontal and temporal lobar atrophy with neuronal loss,
supercial linear spongiosis, and ubiquitinated taunegative
and
synuclein-negative
intraneuronal
inclusions.1719 These ndings are similar to those in
patients with frontotemporal dementia who have
ubiquitin-positive, tau-negative, and synuclein-negative
pathology (FTLDU). Ubiquitinated inclusions in both
ALS and FTLDU contain deposits of TAR DNA-binding
protein (TARDBP, also known as TDP43).20 Some patients
with typical clinical features of frontotemporal dementia
also have clinical and pathological degeneration of the
anterior horn of the spinal cord.7 Conversely, postmortem studies show that cells in the anterior horn
degenerate and have typical ALS inclusions in some
patients with frontotemporal dementia who had no
apparent clinical features of ALS during life.21
The link between frontotemporal dementia and ALS is
also supported by accumulating genetic evidence of
mechanistic overlaps between ALS and other types of
neurodegeneration (table 2). For example, mutations in
the progranulin gene (GRN) cause non-tau, chromosome
17-linked ALS with frontotemporal dementia,29 and
another locus for ALS with frontotemporal dementia has
been identied on chromosome 9p.32,33 The chromatinmodifying protein 2B gene (CHMP2B) and the dynactin 1
gene (DCTN1)28,34 are also mutated in some families who
have ALS and frontotemporal dementia.
The pathogeneses of ALS and frontotemporal dementia
are unknown, but the functional similarities between
some of the implicated geneseg, GRN and the
angiogenin gene (ANG)might provide some clues.
Loss-of-function mutations in ANG have been associated
with classic ALS in populations that include Irish,
Scottish, Scandinavian, US, and German patients3,35
(Ludolph AC, personal communication). Both angiogenin
and progranulin promote angiogenesis; angiogenin is
part of an RNAse superfamily, and progranulin is an
http://neurology.thelancet.com Vol 6 November 2007

important signal for cell survival. In the endothelium,

angiogenin regulates activity of vascular endothelial
growth factor (VEGF) and insulin-like growth factor 1
(IGF1),36 both of which have neuroprotective properties.37,38
These families of angiogenic and hypoxia-responsive
proteins might be interesting from both mechanistic and
potentially therapeutic perspectives.
On the basis of genetic evidence, both ALS and
frontotemporal dementia seem to be clinically
heterogeneous. Accordingly, there might be a clinical
pathological spectrum of neurodegeneration in only a
subset of both conditions. For example, there is emerging
pathological evidence that motor neuron degeneration
associated with deposition of TARDBP is linked to a
dierent pathogenic mechanism from that associated
with mutations in SOD1,39 particularly in mice.40 Although
subject to further clarication, this result is consistent
with the nding that dementia is uncommon in families
with ALS who have mutations in SOD1.41,42 However,
whether all patients who have ALS with frontotemporal
dementia have a distinct pathological signature remains
to be determined.

Patterns of cognitive impairment in ALS

Although there is a clear link between some forms of
ALS and frontotemporal dementia, the frequency,
severity, and progression of cognitive impairment in
otherwise classic ALS remain unclear. The most
consistently reported cognitive changes in ALS relate to
dysfunction in components of the executive system
(eg, verbal uency and attention), whereas abnormalities
in memory and language are less well characterised.
Table 3 summarises some of these ndings.

Executive function
Executive functions are traditionally thought of as higherlevel mental processes that control and organise other
cognitive processes.51 They are a heterogeneous set of
skills that facilitate problem solving and responses to
novelty. Executive functions are also implicated in
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Review

Studies

Population

Clinical manifestations

Neuropathology

DDPAC

Tau pathology

FTD and later motor syndrome (not typical ALS)

No distinctive features (tau negative and

ubiquitin negative)

16 families in USA

ALS, FTD, or both

Undened

Occurs mainly in North America

owing to founder eect

Autosomal dominant inclusion body myopathy, Pagets disease

of bone, and FTD

Ubiquitin pathology (cytoplasmic and

nuclear)

Large North American kindred

LMN disease with vocal cord paralysis; normal cognition

Undened

Munch, 2004

2 family members with classical

ALS, 2 with FTD

FTD and ALS segregate as separate traits

Undened

17q21.32 (GRN)

Baker, 200629
Cruts, 200630
Snowden, 200631

North America and Scandinavia

Progressive change in personality, behaviour, and language (eg,

PNFA) in the sixth and seventh decades of life, followed by
impairment of executive function, memory retrieval decit with
or without motor neuron disease, rigidity, bradykinesia, and
semantic language abnormalities

FTDU-type cytoplasmic inclusions and

intranuclear pathology

9p13.2-21.3

Vance, 200632

1 large family in the Netherlands Motor symptoms followed by personality and behavioural
abnormalities in the fourth to seventh decades of life

UMN and LMN degeneration, and

ubiquitinated inclusions in anterior horn
cells and granular layer of hippocampus

9p

Morita, 200633

1 family in Scandinavia

Ubiquitin pathology only (cytoplasmic

and nuclear)

17q21-22 (MAPT)

Wilhelmsen, 199422 1 large family in North America

3p12 (CHMP2B)

Brown, 199523

1 large family in Denmark

9q21-22

Hosler, 200024

9p13.3-12 (VCP)

Kovach, 200125
Watts, 200426

2p13 (DCTN1)

Puls, 200327

Point mutation
(Arg1101Lys) in DCTN1

28

5 died of ALS with mild or minimal cognitive impairment, and

9 had FTD without motor neuron involvement

MAPT=the microtubule-associated protein tau gene. DDPAC=disinhibiton-dementia-Parkinson-amyotrophy complex. FTD=frontotemporal dementia. CHMP2B=the chromatin-modifying protein 2B gene. VCP=
the valosin-containing protein gene. DCTN1=the dynactin 1 gene. LMN=lower motor neuron. GRN=the progranulin gene. PNFA=progressive non-uent aphasia. FTDU=frontotemporal dementia with ubiquitinonly (ie, tau-negative and synuclein-negative) pathology. UMN=upper motor neuron.

Table 2: Loci and genes associated with familial ALS and cognitive impairment

behavioural regulation, response initiation, motivation,

and elements of memory functioning.52
Impaired verbal uency, a sensitive indicator of damage
to frontal or striatofrontal areas that are involved in
intrinsic initiation of responses, has been reported in
almost all studies of cognitive impairment in ALS.11,45,46,53
Both letter uency and category uency, which require
rapid generation of words, can be disturbed. Simultaneous
eects on both types of uency implicate dysfunction in
components of the executive system, whereas a
disproportionate reduction in category uency would
suggest broader semantic impairment.
Tests of verbal uency are sensitive, but they depend on
verbal or written responses and the results can be
confounded by motor impairments in ALS. However,
modications to control for the speed of response can
allow patients with upper limb disabilities, and consequent
writing disabilities, to be assessed meaningfully. For
example, Abrahams and colleagues54 calculated a verbal
uency index using the time patients took to copy words
they had written previously in uency tests (the average
time taken to think of each word was estimated as the
total time allowed for the test minus the time taken to
copy all words generated, divided by the total number of
words generated).
Although deciencies in verbal uency are commonly
believed to result from executive dysfunction, true
language dysfunction might also contribute to decits in
verbal uency in ALS. A functional MRI study55 has
shown abnormal activation of the inferior frontal gyrus
and Brocas area during verbal uency and naming tasks
in patients who have sporadic ALS without aphasia or
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dementia. Cerebral structures involved in language

seemed to be aected before naming decits had become
clinically signicant. Further investigations of the
executive system are needed to identify clearly the nature
and range of decits in patients who have sporadic ALS
without aphasia or dementia.
The Wisconsin card-sorting test is an established
measure of rule shifting and mental exibility. This test
is often used to measure executive function, but it can be
less reliable than tests of verbal uency in patients with
ALS. David and Gillham43 and Gallasi and colleagues56
have reported impaired executive function in patients
with ALS using the Wisconsin card-sorting test, but this
nding has not been conrmed in further studies.11,12,15
The computerised Tower of Hanoi is another test used to
measure the executive functions of planning and working
memory (a complex component of the executive system
that also involves many other cognitive processes). This
complex test is closely based on the three-dimensional
Tower of London tests, and was used by Abrahams and
co-workers46 to assess patients whose ALS included
pseudobulbar palsy. Planning times on complex trials were
shorter for these patients than for controls, and the patients
with ALS and pseudobulbar palsy were more likely to fail
to solve these trials than were other patients with ALS and
controls.
Impairments in the attentional system are often
associated with damage to the frontal lobes, and
attention decits have been reported in ALS.45,57
Evaluation of attention is important, because
disinhibited-type patients might have near-normal
results in traditional tests of frontal executive function
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Review

Neuropsychological test performance that showed impairment

Neuropsychological test performance in the normal range

Gallassi,
198518

Patients (n)
22

Verbal uency (COWA), verbal reasoning, visual attention (Barrage test),

short-term verbal memory (Reys), short-term visual recall

Long-term verbal memory (Reys), memory spans (verbal and spatial)

David, 198643

14

Set shifting (WCST), episodic memory (VPAL), picture recall

Attention (digit span), visual recall (RCFT), prose recall

Neary, 199044

Verbal uency (letter and category), set shifting (WCST and WBT), intelligence
(WAIS-R), interpretation of proverbs, episodic memory (VPAL)

Visuoperception (Money road map), intelligence (KBF), memory (Warrington

memory test), delayed verbal recall

Kew, 199316
Kew, 199315

12
16

Verbal uency (written), free picture recall, recall memory (KOLT)

Cognitive inhibition (Stroop), recognition memory, visuoperceptual battery, set

shifting (WCST), episodic memory (VPAL)

Ludolph,
199211

18

Verbal uency

Set shifting (WCST), cognitive inhibition (Stroop), visual recall (RCFT), attention
(digit span), naming (modied test), visual concentration (d2 test)

Massman,
199645

146

Verbal uency (COWA), immediate free recall (CVLT), continuous recognition

memory (CRMT, major deciency in some patients), attention (VSAT), set
shifting (WCST)

Delayed verbal recognition memory (CVLT), visuoperception (Benton JLO),

confrontation naming (BNT)

Abrahams,
199746

52

Verbal uency (written), executive function and intrinsic generation (RMJT;

noted in pseudobulbar palsy only), planning and working memory (CTH), set
shifting (WCST), word recognition memory test, Stroop negative priming
(trend towards signicance)

Episodic memory (VPAL), recall memory (KOLT)

Rakowicz,
199847

18

Verbal uency, attention (reverse digit span), conceptual semantic processing

(pyramids and palm trees test), syntactic comprehension (TROG), MMSE,
confrontation naming (graded naming test)

Attention (forward digit span), picture naming, word-picture matching

Moretti,
200248

14

Verbal uency (letter), set shifting (WCST), cognitive inhibition (Stroop),

Intellectual ability (RSPM, WAIS-R, KBF), attention (digit span), story retrieval,
attention (PASAT), interpretation of proverbs, bilingual, aphasia testB, MMSE past events retrieval, visuoperception (JLO)

Abrahams,
200549

20

Verbal uency (written and spoken), computerised sentence-completion task

Ringholz,
200550

279

Confrontation naming (graded naming test), uency (category and design),

attention (PASAT, letter span), set shifting (WCST), episodic memory (VPAL),
recognition memory test, recall memory (KOLT), visuoperception (Benton JLO),
object decision, position discrimination

Verbal uency, VSAT, visual recall, logical memory (verbal recall), confrontation Visuoperceptual ability (Benton facial recognition test), MMSE (except severely
naming (BNT)
impaired patients), cognitive inhibition (Stroop)

COWA=controlled oral word association test. WCST=Wisconsin card-sorting test. VPAL=verbal paired associate learning. RCFT=Rey complex gure test. WBT=Weigls block task. KBF=Kohs block gures.
WAIS-R=Weschler adult intelligence scale. KOLT=Kendrick object learning task. CVLT=California verbal learning test. CRMT=continuous recognition memory test. VSAT=verbal series attention test. JLO=judgment
of line orientation. BNT=Boston naming test. RMJT=random movement joystick test. CTH=computerised Tower of Hanoi test. TROG=test for the reception of grammar. MMSE=mini mental state examination.
PASAT=paced auditory serial addition test. RSPM=Ravens standard progressive matrices.

Table 3: Neuropsychological test performance in ALS

but show impaired responses in tests of selective

attention.58 Rakowicz and Hodges47 reported a consistent
and signicant reduction in reverse digit span in
patients with ALS. In the digit-span test, patients must
repeat strings of numbers forwards and backwards, and
the sequences become progressively more dicult until
nine digits are read aloud. Poor reverse digit span often
indicates impaired working memory rather than pure
attentional impairments.

Memory
There has been disagreement about memory decits in
ALS. Studies of cognition have shown that memory
impairments in patients with ALS usually involve
immediate recall. Decits in delayed recall are highly
variable, which suggests that the abnormality lies in the
encoding of information rather than in the speed of
forgetting.10 These results are consistent with current
theories that encoding is an executive component of
memory and involves a neuronal circuit that arises in the
left frontal lobe.59
Two studies15,43 have reported that free picture recall is
aected in patients with ALS. Immediate recall, as
judged by the registration component of the mini
mental state examination (MMSE), might not be
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aected,47 although this examination is not a very

sensitive test of memory.

Visuoperceptual function
Visuoperceptual functions are a heterogeneous set of
processes that include attention, object identication,
and object recognition. Visuoperceptual processes are
largely preserved in many patients with ALS,15,60,61 but
Strong and colleagues62 have noted some visuoperceptual
decits. Patients with ALS with frontotemporal dementia
often have little diculty in navigation around their own
home environment, in location of objects, in copying of
non-representational hand postures, and in identication
of their home town on a map.63

Language
Language networks seem to be impaired in MRI and PET
studies of ALS patients,54 which lends support to the
aforementioned ndings that ALS aects extramotor
pathways. Language decits noted in studies of ALS have
included reduced verbal output,62,64 decits in naming of
objects,45,46,60 perseverations, echolalia (repetition of words
said by other people), stereotypic expressions,47 and
semantic paraphasias (substitution of words that relate
closely to one another, eg, sock for glove, or rabbit for
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squirrel).47,62 Patients with ALS can have features of

progressive non-uent aphasia, semantic dementia that is
often atypical, or both.6567
Rakowicz and Hodges47 reported signicant language
decits in patients with ALS and dementia, particularly on
tests of naming and syntactic comprehension. Patients
with ALS who did not have dementia had a language
output disorder characterised by diculties with word
nding and naming, with a tendency to make categorycoordinate semantic errors or circumlocutions. Both
groups performed well on tests of non-verbal semantic
knowledge and grammar.
Naming decits have been reported in other studies of
ALS,45,47,49 which suggests that a language dysfunction
underlies basic word-nding processes. However, in
some patients, confrontation naming ability is intact.15,68
Processing of verbs has been reported to be greater than
that of nouns in patients who have primary progressive
aphasia69 or ALS with dementia.64 Hillis and colleagues69
suggest that such dierences in the patterns of language
deterioration might relate to degeneration of dierent
brain areas, which implicates the posterior inferior
frontal cortex and insula in motor speech and naming
actions. Results from other studies have suggested that
language decits such as progressive slowing of word
retrieval form a continuum with aphasia in ALS.49,67,70 The
possibility that decits in executive functions, such as
verbal uency, are related to language decits needs to be
explored further.
Whether aphasia in patients with ALS is an early stage of
an aphasic type of dementia is unclear. Another possibility
is that language decits occur independently of cognitive
impairment, and that patients with such decits have a
distinct subtype of ALS-related dementia. However,
consistent with the idea that some subtypes of ALS and
frontotemporal dementia form a continuum, mutations in
GRN have been associated with ALS, typical frontotemporal
dementia, and a non-uent progressive aphasia within a
single family.31
Language dysfunction in frontotemporal dementia
might also form clinical subtypes. For example, the
language decits of patients with frontotemporal dementia
who have mutations in GRN might dier from those in
patients with mutations in the microtubule-associated
protein tau gene (MAPT). People with mutations in GRN
have been reported to show phonological decits, whereas
patients with mutations in MAPT showed language
abnormalities in the form of semantic disturbance.31 These
ndings further support the link between frontotemporal
dementia and non-uent progressive aphasia, and suggest
that patients with FTLD who have mutations in MAPT are
clinically dierent to those who have mutations in GRN.

Social cognition and emotional processing

Social cognition, which is crucial for human interaction,
has been reported as impaired in various studies of
frontotemporal dementia. Lough and colleagues71 showed
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that patients with fvFTD had impaired recognition of all

emotions, and particularly anger and disgust, which
might partly explain the diculty these patients have
with identication of social violations. Empathy, as rated
by carers, was also abnormal in these patients. Thus,
social reasoning seems to be disrupted in various ways in
fvFTD. This possibility has also been examined in
patients with ALS. Lule and colleagues72 presented
52 emotive picture slides to 12 patients with sporadic
ALS. The researchers recorded subjective reports of
pleasantness and arousal, and brain responses to the
aective pictures were measured with functional MRI.
Patients with ALS showed lower responses in the anterior
insula and extrastriate visual areas than did other
participants. This suggests that arousal is reduced at the
neural and behavioural levels during the course of ALS.
Lule and colleagues72 also noted a greater response in the
right supramarginal area in patients with ALS than in
control patients. This might represent an altered
sensitivity to social and emotional cues.

Behaviour
Behavioural impairment is now recognised as a feature
of ALS. Rating scales such as the Neuropsychiatry
Inventory, Frontal Behaviour Inventory, and Frontal
Systems Behaviour Scale have shown that up to 63% of
patients with ALS are apathetic, irritable, inexible,
restless, and disinhibited.5,73,74 Apathy and diculties with
social judgment seem to be more frequent in patients
whose ALS has bulbar onset than in those whose ALS is
non-bulbar.73,75 Apathy, one of the most common ndings,
should be dierentiated from depression, fatigue, and
respiratory dysfunction by careful examination of medical
history and use of validated scales. For example, by
contrast with apathy, depression can be linked to
particular stressors, and is characteristically associated
with pervasive anhedonia, sadness, tearfulness,
hopelessness, suicidal ideation, and guilt.
Although there is no consensus for behavioural
impairment in ALS, the clinical presentation is thought
to represent abnormalities that do not meet the Neary
criteria for frontotemporal dementia.76 Behavioural
impairment in ALS can be classied on the basis of
presentation of frontal-lobe-type behavioural impairment
in two or more areas, as measured from a standardised
caregiver interview.77 However, the debate of whether to
classify patients with ALS who have cognitive impairment
together with or separate from those who have
behavioural impairment continues. Although cognitively
normal patients with ALS can have profound behavioural
abnormalities,5 cognitive and behavioural impairments
can coexist in 25% or more of ALS patients.78 Maintenance
of a division between cognitive and behavioural
impairment in research studies might be useful in
identication of dierent pathogenic mechanisms and
clinical courses, but there is currently insucient
evidence to make this distinction.
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Incidence and prevalence of cognitive decline

The exact phenotype and natural history of impaired
cognition in ALS are unclear. The confusion lies partly in
the source of patients: those who attend a behavioural
clinic and later have evidence of motor system
degeneration might dier from those who attend a
neuromuscular clinic and later develop impaired
cognition. Thus, reports of the frequency, severity, and
type of cognitive impairment in ALS patients vary
substantially. Methods used to assess cognitive
impairment have also diered, and much of the analysis
has been based on non-standard neuropsychological
assessments; few studies have combined neuropsychology, neuroimaging, and post-mortem verication.
Some studies have not accounted for motor and speech
impairment in ALS. Moreover, all studies so far have
recruited patients from tertiary referral clinics, and this
approach can lead to bias in denition of a common
phenotype.
One of the largest studies of ALS so far50 detected
cognitive impairment in 132 (47%) of 279 consecutive
patients who attended an ALS clinic. Most notable of
these impairments was executive dysfunction alongside
mild memory decline. About 15% of patients had severe
cognitive impairment with features that were consistent
with frontotemporal dementia. However, there have been
no large population-based clinical studies of the
prevalence of cognitive decline in ALS. Current estimates,
which suggest that more than half of patients with ALS
have cognitive impairment, are likely to be aected by
the selection bias caused by use of tertiary-clinic-based
referral from prevalent rather than incident populations.
Less is known about the natural history of cognitive
decline in ALS than about the incidence and prevalence.
Few longitudinal studies have characterised the progress
of the cognitive decline, but some small clinic-based
studies suggest that cognitive impairment evolves in
patients with ALS over the course of their illness. A
longitudinal study of eight patients with ALS62 noted
progressive impairment of working memory, problem
solving, cognitive exibility, visual perception, and
recognition memory for words and faces in patients with
bulbar-onset ALS over a 6-month period. Subsequent
neuropathological analysis of these patients showed
neuronal loss in the anterior cingulate gyrus. In a
separate study,60 seven of 19 patients with ALS developed
cognitive decits over a similar period, although the
between-group and within-group comparisons did not
show signicant dierences in cognitive function over
time. These ndings were not replicated by a third
longitudinal study,49 in which all cognitive functions were
stable over a 6-month period in patients who had ALS
but no dementia.
Because there have been no large population-based
studies of cognitive function in ALS, there has been little
detailed analysis of the clinical implications of cognitive
impairment in disease management. There are several
http://neurology.thelancet.com Vol 6 November 2007

suggested risk factors for dementia in ALS, such as old

age, male sex, poor education, family history of dementia,
low forced vital capacity, pseudobulbar palsy, and bulbar
site of onset,5,45,46,79 but these associations have not been
reported consistently.

Does cognitive impairment form a continuum?

Clinical evidence that cognitive dysfunction in ALS forms
a continuum, from mild impairment to frontotemporal
lobar dementia,80 remains weak. Most patients with ALS
do not have overt clinical features of dementia; there is
evidence that such patients have a subtle impairment of
frontal executive functions that include verbal uency
and attention, but visuospatial abilities and psychomotor
speed are usually preserved. Whether some of these
neuropsychological changes are a consequence of
declining motor function is unclear, but an association
between increasing ALS severity and decreasing verbal
uency has been noted.81
Ascertainment and evaluation of cognitive impairment
in patients with ALS is further complicated by the existing
classication system. Cognitive impairment cannot be
characterised formally or uniformly with the El Escorial
criteria because these criteria by denition exclude
evidence of impaired cognition. Patients with ALS and
cognitive impairment are currently classied within the
ALS-plus category, without any further denition of the
degree or extent of upper and lower motor neuron
symptoms.

Optimum methods for examination

There is currently no consensus among researchers on
the denition and measurement of cognitive impairment
in ALS,50 on the psychometric methods used to assess
patients, or on the nature of the cognitive decits
associated with frontotemporal dementia. However,
working guidelines for optimum cognitive assessment in
patients with ALS have been suggested by Strong and
colleagues,82 and more conclusive consensus documents
are due to be published as a result of discussions at the
Second International Frontotemporal Dementia in ALS
Research Conference (London, Ontario, June 2007).
Despite the absence of consensus, identication of
cognitive impairment has been improved by the use
of untimed neuropsychological tests, experimental
adjustments to control for slower motor speed, and use
of recognition rather than free recall. However, before
these modications are used to diagnose patients with
ALS, they should undergo extensive validation and be
tested to ensure that they have sucient sensitivity and
statistical power to identify eects.
In patients who have features of frontotemporal
dementia, neuropsychological testing might be more
useful when combined with carer-based instruments for
measurement of behaviour, such as the Neuropsychiatric
Inventory or Frontal Systems Behavioural Scale.82,83 Such
questionnaires allow caregivers to convey how the patient
999

Review

functions on a day-to-day basis compared with his or her

premorbid status, although cognitive impairment can be
underestimated.49 Carer-based questionnaires also avoid
the issue of decreased patient insight.
Depression can mimic impaired cognition, but this
similarity does not seem to be a factor in ALS because
few studies have detected signicant mood disorders in
patients with this disease.84 Scales such as the Hospital
Anxiety and Depression Scale85 have been used to ensure
that abnormal cognitive proles are not related to an
underlying mood disorder.

Does cognitive impairment matter?

The potential clinical implications of cognitive
impairment in patients with classic ALS have major
importance. Problems with judgment, attention,
inhibition, and generation of responses should be taken
into account when patient care is planned. For example,
deteriorating cognitive or executive function can
compromise capacity to make decisions about health
care or nancial circumstances, and the ability to engage
competently in end-of-life decisions. Cognitive
impairment can also reduce initiative and compliance
with interventions such as occupational and physical
therapy: patients with ALS who also have FTLD are half
as likely as are those who do not have FTLD to comply
with non-invasive ventilation.86 Awareness of safety
issues, such as how to avoid or cope with falls or choking
episodes, might also be compromised by cognitive
impairment. The increasing use of braincomputer
interfaces in patients with long-term assisted ventilation
means that the evaluation of cognitive impairment and
decision-making capacity by such interfaces will become
highly relevant, both scientically and ethically.
ALS with dementia has not been shown consistently to
aect carer burden or quality of life of patients. However,
carer burden is consistently higher for patients with
dementia than for patients with other disorders,87 and
this might also be the case when patients with ALS and
dementia are compared with patients with ALS but no
dementia. In many neurodegenerative diseases, carer
burden is directly related to the need for residential or
respite care. Furthermore, survival times seem to be
signicantly shorter for patients who have ALS and
frontotemporal dementia than for patients with classic
ALS.86 In particular, patients with bulbar-onset ALS with
FTLD were more than twice as likely to die at any interval
after ALS onset than were patients who had bulbar-onset
classic ALS, which suggests that these disease variants
have dierent clinical trajectories.

What to do in the clinic

Currently, the frequency of impaired cognitive function
in patients with typical ALS cannot be established
denitively, and formal mechanisms to evaluate the
signicance of clinical ndings are not in place. Clinicians
should be aware that patients with ALS might have
1000

cognitive impairment, and that patients who attend

behavioural neurology clinics might well have anterior
horn cell dysfunction. Clinicians who work with patients
who have ALS should be alert to changes in character or
behaviour as reported by a spouse or relative, which might
provide a useful clue to a diagnosis of ALS with
frontotemporal dementia.
Short batteries of tests, such as the MMSE, cannot be
used to screen for frontotemporal dementia, although
such testing can reveal behavioural abnormalities such as
perseveration, inattention, and disinhibition. In other
simple cognitive tests, patients with frontotemporal
dementia might have diculty with interpretation of
proverbs and with cognitive estimates (eg, estimation of
the height of a well known building). However, because
many brief indices of general function have poor
sensitivity, a negative result does not mean that cognitive
function is intact.
A simple 2-min word-generation test is a highly
sensitive way to identify patients in whom more detailed
neuropsychological evaluation is needed. Patients with
decits in verbal uency are likely to show further frontal
decits, executive decits, or both, on more detailed
testing.5 However, results from these tests are often highly
correlated with intellectual ability, and care should be
taken to use educationally adjusted normative data rather
than simple cut-o scores.
Suspicion of impaired cognition should prompt referral
for formal neuropsychological examination, although the
Addenbrookes Cognitive Examination might also be
helpful. This preliminary examination incorporates the
MMSE with tests to evaluate the separate cognitive
domains of orientation, attention, memory, verbal uency,
language, and visuospatial ability, and can be given in a
clinic in 1520 min. The Addenbrookes Cognitive
Examination might be more sensitive and specic than
the MMSE in the dierentiation of Alzheimers disease
and frontotemporal dementia,88,89 but it cannot be used as
a substitute for formal neuropsychological testing.
Consensus guidelines from the Second International
Frontotemporal Dementia in ALS Research Conference
(London, Ontario, June 2007) are expected to clarify the
role of neuroimaging in patients with ALS and cognitive
impairment. In addition to excluding other pathology,
structural neuroimaging might reveal selective atrophy of
frontal and anterior temporal areas, although such
atrophy might not be apparent in early frontotemporal
dysfunction.56
Reversible causes of impaired cognition should not be
forgotten. Newsom-Davis and colleagues90 reported that
nocturnal hypoventilation and sleep disturbance can
cause cognitive dysfunction in ALS, and that this
dysfunction can be partly improved by non-invasive
positive-pressure ventilation for 6 weeks. Scores on
two of the seven cognitive tests in this study were
signicantly improved after non-invasive positivepressure ventilation.
http://neurology.thelancet.com Vol 6 November 2007

Review

Depression and other psychosocial causes might also

account for impaired cognition in patients with ALS.
Thorough review of medical history and the use of scales
such as the Hospital Anxiety and Depression Scale85 can
help to exclude the possibility that abnormal cognition is
related to these factors. Sleep disturbance and some
drugs can also have a confounding eect on
neuropsychological test performance. Sleep can be
disturbed by immobility, pain, anxiety, or nocturnal
hypoxia, and patients with subclinical or incipient
respiratory failure can have non-specic symptoms that
include frequent nocturnal awakening, early morning
headache, and daytime sleepiness.91 Respiratory function
should be assessed and failure of ventilation treated
before neuropsychological assessment if possible.
Similarly, use of agents such as amitriptyline and
dextromethorphan should be accounted for during
patient assessment. These drugs are used for
symptomatic relief in ALS, but can induce drowsiness
that might aect the outcome of neuropsychological
assessment.

Future research
Although evidence suggests that ALS and FTLDU are
dierent clinical manifestations of the same
neurodegenerative disorder, the nature of cognitive
impairment in ALS is still not fully understood. Major
diculties are that the degree and progression of
cognitive impairment have not been well characterised
within a population-based cohort, and that the clinical
boundary between patients with ALS who have dementia
and those who do not (ie, the distinction between
progressive dementia and subclinical cognitive
impairment) remains blurred.6 Dierent cognitive
performance across groups of patients might be related
to the severity or stage of ALS progression,50 but
conrmation of this suggestion would need large
population-based studies that use uniform and
reproducible methods. Prospective longitudinal,
population-based clinicopathological correlative studies
are needed to determine whether patients with ALS who
have no or mild impairment show progressive
impairment over time, and whether patients with mild
cognitive impairment but without dementia form a
separate subtype of patients with ALS, distinct from
patients with normal cognition and those with
dementia.
Population-based studies in ALS present a challenge.
Assessment of cognition in a longitudinal populationbased study poses particular diculties because the
rapid disease progression causes high attrition. Ideally,
such a study would use a population-based national
register and include patients with ALS as categorised by
the El Escorial criteria. In countries with high population
densities, home visits could overcome the issue of
inability to attend clinics during the later stages of the
illness.
http://neurology.thelancet.com Vol 6 November 2007

Search strategy and selection criteria

Only articles published in English were reviewed. Data were
searched during a 4 month period between March, 2007, and
June, 2007, on PubMed with the following keywords:
amyotrophic lateral sclerosis, motor neuron disease,
frontotemporal dementia, cognitive impairment,
behaviour, pathology, and genetics. Articles were also
identied through searches of the references of these articles.
Additionally, many articles were chosen from the les of the
authors. Abstracts and reports from meetings were used only
if they presented new relevant information. The nal
reference list was generated on the basis of originality and
relevance to the topics covered in the Review.

Systematic, standardised, and periodic data collection

would avoid medical surveillance bias. To segregate
patients with ALS into those at risk of impaired cognition
and those who will remain cognitively intact, prospective
longitudinal population-based studies would probably
need surveillance over at least 18 months, because
cognition is often impaired only late in ALS.
Revision of classication systems on the basis of
pathogenic mechanisms will improve diagnostic
accuracy. New developments in genomics, proteomics,
and bioinformatics, and advances in classic
neuropathology, might also clarify whether pure ALS,
ALS with cognitive impairment, ALS with frontotemporal
dementia, and pure FTLDU form a continuum of
ubiquitin-associated neurodegenerative disease.92
In the meantime, a formal validated and reproducible
battery of neuropsychological tests for ALS with
frontotemporal dementia is urgently needed. Standard
testing can underestimate or exaggerate the presence of
cognitive impairment in ALS. Future batteries will need
to account for limb and bulbar dysfunction and
incorporate tests that make minimal demands of speech
production, ne motor control, speed of cognitive
processing, and peripheral motor reaction time (ie, the
most sensitive measures of cognitive dysfunction).
Prospective studies would facilitate correlation of
neuropsychological evaluation with dynamic imaging
and pathological ndings.
With new discoveries about the clinical, pathological,
and molecular aspects of frontotemporal dementia in
patients with ALS, new questions and challenges have
arisen. Understanding of this condition will lead to better
care for patients with ALS and their families, and provide
further valuable insights into the pathogenesis of
neurodegeneration.
Contributors
JP designed and wrote the Review and collected the data. NPP revised
the Review, particularly from a neuropsychological perspective. OH
developed the initial idea, contributed to the design and content of the
paper at all stages, and provided expertise in the overall context of the
existing knowledge in the eld.

1001

Review

Conicts of interest
We have no conicts of interest.
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