Handbook of Clinical Neurology, Vol.
88 (3rd series)
Neuropsychology and behavioral neurology
G. Goldenberg, B.L. Miller, Editors
# 2008 Elsevier B.V. All rights reserved
Chapter 28
Neuropsychology of frontotemporal dementia
C.M. KIPPS, J.A. KNIBB, K. PATTERSON, AND J.R. HODGES*
MRC Cognition and Brain Sciences Unit, Cambridge, UK
28.1. Introduction
The current understanding of frontotemporal lobar
degeneration (FTLD) owes no small part to the original
observations and descriptions of Arnold Pick over a cen-
tury ago (Pick, 1892; 1901; 1904). Current classifications
recognize the heterogeneity within the disorder, and
three main variants are commonly described (Lund and
Manchester Groups, 1994; Neary et al., 1998; Hodges
et al., 1999; McKhann et al., 2001). Frontotemporal
dementia (FTD), also known as frontal variant (fv-FTD)
or behavioral variant (bv-FTD), typically presents with
disturbed behavior and is the most common of the three
syndromes. Two language variants are also described:
semantic dementia (SD), known also as temporal variant
FTD (tv-FTD) and a progressive nonfluent aphasic
syndrome (PNFA).
The clinical phenotype in FTLD has an inconsistent
association with the underlying pathology. Clinical pre-
sentations are seldom pure, and several symptoms are
shared across the different variants, with further overlap
on both a anatomical and pathological level. In this regard,
although FTD has been typically associated with frontal
lobe disturbance, it is frequently accompanied by tem-
poral lobe disease. The situation is mirrored in SD, and
to a lesser extent in PNFA. It is helpful to view these dis-
orders as individually reflecting the local extent of a wide-
spread pathological process affecting frontal and temporal
lobe networks. In clinical practice, diagnosis is based on
the predominant symptom, which is probably most useful
in categorizing the types of impairment that patients are
likely to manifest. Although bv-FTD is defined by its
behavioral presentation, patients with language variants
of FTD often also exhibit behavioral disturbance. Conver-
sely, a mild degree of language impairment frequently
accompanies the behavioral syndrome.
*
Correspondence to: John Hodges, MRC Cognition and Brain Sciences Unit, 15 Chaucer Rd, Cambridge CB2 2EF, UK. E-mail:
john.hodges@mrc-cbu.cam.ac.uk, Tel þ44-(0)1223-355294 Ext 690, Fax: þ44-(0)1223-359062.
28.2. Behavioral variant FTD
28.2.1. Clinical features
The disorder presented in Case Study 28.1 presents as a
behavioral syndrome with an insidious onset. There is
early decline in social conduct, both personal and inter-
personal, with emotional blunting and loss of insight
(Neary et al., 1998; Bozeat et al., 2000; McKhann
et al., 2001; Table 28.1). However, only a minority of
patients display all of these core features on initial pre-
sentation (Mendez and Perryman, 2002). As descriptive
criteria, many features remain difficult to quantify
although efforts are being made to operationalize them
(Rankin et al. 2005b).
Several further deficits may be observed, and comprise
the supportive clinical features for diagnosis: decline in
self-care, mental rigidity, distractibility, hyperorality, per-
severative and stereotyped behavior and several language
features such as altered speech output, echolalia, speech
stereotypies or mutism. Imaging abnormalities are not
essential for the diagnosis, but when present predomi-
nantly involve the frontal and temporal lobes. When
abnormal, neuropsychological testing should demon-
strate impairment on frontal lobe tests in the absence of
severe amnesia, aphasia or perceptuospatial disorder.
More recent clinically targeted criteria have broadened
the diagnostic scope, and simply require an early and
progressive alteration in personality, with abnormal
behavioral modulation resulting in responses or activities
which are inappropriate enough to disrupt social or
occupational functioning (McKhann et al. 2001).
Diagnosis is usually easy when many abnormal clini-
cal features are present, but can be particularly tricky in
the early stages of disease. It is important to establish that
symptom onset is indeed gradual, and that this represents
528 C.M. KIPPS ET AL.
Case Study 28.1
A 66-year-old man, married for 35 years, who at the
time of presentation ran a guest house, had developed
progressive and dramatic alteration in his personality
over 7 years. Previously gregarious, he became rather
withdrawn, and ceased conversation with his wife. He
lacked empathy, and was quite disinhibited with
friends and family, often making sexually suggestive
comments, despite a complete lack of libido. He was
profoundly unmotivated, and extremely repetitive.
He overate to a gross degree, and was quite suspicious
of those around him. His memory had also declined
somewhat, and there was a suggestion of mild diffi-
culty with naming objects. There was no insight into
any of these problems, yet he was able to give a fluent
and accurate account of his earlier life.
He had a pout and a grasp reflex, was slightly
unsteady on his feet, and had depressed ankle jerks,
but no other focal neurological signs. On cognitive
evaluation he was well oriented, and achieved 28
out of 30 on the Mini Mental State Examination
(MMSE). On the Addenbrooke’s Cognitive Examina-
tion (ACE), he scored 90 out a possible 100 points,
with marked impairment only on verbal fluency.
Table 28.1
Clinical features of bv-FTD (not all present in every case)
Clinical features
social–behavioral disinhibition
changes apathy
lack of empathy
mental rigidity or inflexibility
stereotypic behaviors
decline in personal care
eating behavior inability to regulate intake
changes preference for sweet foods
insight lost or markedly impaired
relatively episodic memory (usually)
unimpaired visuospatial function
language (variable)
imaging predominantly frontal and/or right
temporal atrophy
Formal neuropsychological assessment showed
intact story recall, with information retained after a
delay. There was very mild impairment of backwards
digit span consistent with some impairment of work-
ing memory. Language and visuospatial functions
were well preserved, but there were marked deficits
on tests of frontal function, particularly on the Wis-
consin Card Sorting and Trails tests. There was sym-
metrical frontal and temporopolar atrophy on an MRI
scan, and there was marked frontotemporal hypoper-
fusion on an 18FDG-PET scan.
There was a marked deterioration over the subse-
quent 12 months, and he became increasingly impul-
sive and unpredictable. His MMSE dropped to 6 over
this time.
At postmortem there was a moderate degree of
cerebral atrophy, particularly of the anterior frontal
and temporal lobes, with generalized enlargement of
the ventricles. Microscopic examination showed
frontotemporal lamina II vacuolation with the pre-
sence of ubiquinated inclusions in the inferior olivary
nucleus, consistent with a diagnosis of frontotem-
poral dementia.
a distinct change from premorbid functioning. Apathy,
manifesting as passivity, inertia, or social withdrawal is
perhaps the most common problem, and may result in sig-
nificant impairment in activities of daily living (ADL)
(Kertesz et al., 1997; Gregory, 1999; Mendez and Perry-
man, 2002; Pijnenburg et al., 2004). Lack of insight is
usual in bv-FTD, and stands in marked contrast to patients
with predominant language impairment, who commonly
recognize their deficits. Most FTD patients do not believe
they are unwell, and in fact up to a third have no com-
plaint at all when assessed (Pijnenburg et al., 2004). This
can make the consultational challenging, but often these
patients have minor somatic complaints or forgetfulness
which are less confrontational about discuss, and may
be a way of engaging their co-operation (Pijnenburg
et al., 2004). It is important to interview caregivers sepa-
rately, as there are often sensitive issues to consider which
are difficult to broach during a joint discussion. It is often
easier to mention specific behavioral issues to the patient
after the full extent of the problem has been ascertained
from the caregiver in private.
 NEUROPSYCHOLOGY OF FRONTOTEMPORAL DEMENTIA
Disinhibition is a common early symptom, and
seems particularly prevalent in those with predominant
frontal and right temporal lobe dysfunction (Edwards-
Lee et al., 1997; Lindau et al., 2000). Patients with
FTD may act impulsively without thought for the conse-
quences, or make tactless, inappropriate social remarks.
Crude or improper sexual commentary is quite com-
mon, but does not appear to be invariably associated
with hypersexuality. The use of pornography or sexual
chat lines is often mentioned, sometimes with signifi-
cant financial consequence, but in fact reduced libido
is reported in the majority (Miller et al., 1995).
Abnormal eating behavior can be profound, causing
marked weight gain. Patients with bv-FTD typically
become gluttonous with altered eating habits. Table
manners deteriorate; food is sometimes taken from
others, piled inappropriately high on the plate, or stuffed
into the mouth all at once. Often there is undue haste to
start eating. Changes in food preference such as refusing
to eat new foods, insisting on eating particular favorites
(e.g., fish and chips, or bananas and milk) for every meal,
or becoming a vegetarian or fruitarian are less common in
bv-FTD than in SD, although they may occur in either
condition. As progressive temporal lobe pathology dis-
rupts semantic knowledge about food, bizarre food
choices may emerge: orange juice used as gravy, or the
eating of partially thawed or moldy food.
Stereotypic and ritualistic behaviors such as preoccu-
pation with counting or clockwatching, consistently
choosing the same leisure activity, repeatedly eating the
same food and rigid adherence to routine are all more
common in the FTD subgroups than in AD (Nyatsanza
et al., 2003). Simple motor stereotypes involving grunt-
ing, humming, lip smacking, hand rubbing, or foot tap-
ping are seen in up to 75% of patients with prominent
apathy (Snowden et al., 2001). Repeated wandering or
pacing a fixed route is quite common in bv-FTD. More
complex repetitive routines such as the use of a catch-
phrase (verbal stereotypy), or clapping the same rhythm,
are consistently seen in both bv-FTD and SD, but to a
greater extent in the latter. Many patients with SD develop
a particular, and obsessive, interest in puzzles and jigsaws.
Neglect of self-care and impairment of other activ-
ities of daily living is common, and reflects a combina-
tion of apathy, unconcern, and poor judgment. As a
consequence, these patients are far more functionally
disabled than AD patients matched for Mini Mental
State Examination (MMSE) scores (Rosen et al.,
2004a). In the absence of a carer, the inevitable result
is varying degrees of squalor which in turn may prompt
conflict with neighbors or local authorities. Inability
to handle financial affairs renders these patients
529
susceptible to deception by others, and liable to run up
significant debt without concern for the consequences.
Concern about poor memory may prompt patients or
their carers to seek medical advice, but it is oversha-
dowed by accounts of the behavioral disturbance. Often
the memory problems are actually the result of apathy,
inattention, or a degree of semantic impairment for
words and concepts. Although true amnesic symptoms
have good discriminatory value for AD, particularly in
the early stages, there are several reports highlighting
genuine episodic memory disturbance in FTD at presen-
tation (Binetti et al., 2000; Caine et al., 2001; Hodges
and Miller, 2001; Pasquier et al., 2001; Rosen et al.,
2002b; Hodges et al., 2004; Graham et al., 2005). In
practice, it is usually impaired registration and/or ineffi-
cient retrieval of information—both probably related to
reduced attention or effort—that are to blame for the
memory complaint (Pasquier et al., 2001).
There is a distinct lack of empathy for the emotional
concerns of others, which may manifest as selfishness or
an insensitivity to embarrassment (Perry et al., 2001).
Similarly, it appears that personal emotional expression
is affected, as is the recognition of emotion in others
(Lavenu et al., 1999; Snowden et al., 2001). Generalized
emotional blunting becomes particularly common as the
disease progresses (Mendez and Perryman, 2002). Fail-
ure to recognize and respond to anger expressed by
others may partly explain some of the socially inap-
propriate behavior of these patients. Depression is rare
in FTD, but this is not the case in SD. Irritability, aggres-
sive behavior, and ‘cold-heartedness’ are common
(Rankin et al., 2003).
Dysexecutive symptoms, such as impaired organiza-
tion, planning, and goal-setting are present in both FTD
and AD, and are related to disease severity. As such
they do not discriminate well between the two diseases
(Bozeat et al., 2000), and such symptoms may be as
much a consequence of apathy as poor judgment.
28.2.2. Behavioral rating scales
Behavior in FTD can be quantified using a variety of rat-
ing scales: the Frontal Behavioural Inventory (FBI) (Ker-
tesz et al., 1997; 2000b; 2003a), Frontal Behavioural
Score (FBS) (Lebert et al., 1998), Neuropsychiatric
Inventory (NPI) (Cummings et al., 1994), Cambridge
Behavioural Inventory (CBI) (Bozeat et al., 2000) and
an inventory used by the Manchester Group (Barber
et al. 1995). A rating scale of stereotypical behaviors
commonly found in FTD has also been reported (Shigen-
obu et al., 2002). Some are based on direct interview;
others, such as the CBI, which is the instrument used in
530 C.M. KIPPS ET AL.
the Cambridge memory clinics, can be filled out by the
carer prior to the clinical interview. Incorporating a num-
ber of memory items, as well as a functional assessment,
in the inventory is useful as it often allows one to distin-
guish the symptom complex from that of AD, and to
estimate the likely level of disability and carer burden.
The FBI, applied to a mixed group of neurodegen-
erative disorders, was useful in discriminating FTLD
from AD, PNFA and depression, but had less success
when FTLD was compared with vascular dementia,
as there was significant overlap. In that situation it
was indifference, perseveration, and utilization beha-
vior that helped distinguish the two disorders (Kertesz
et al., 2000b). Using the FBS—in which endorsement
of any item within one of four domains (self monitoring
dyscontrol, self neglect, self-centered behavior, affec-
tive disorder) is scored as positive for that feature—
a distinction could be made between FTD and either
vascular dementia or AD (Lebert et al., 1998). These
patients were defined clinically, although several had
pathological confirmation.
Behavioral features that are common in FTD and
SD may cluster: using the CBI, abnormal stereotypic
and eating behaviors, together with impaired social
awareness, were useful in contrasting the profile of
the FTLD variants with AD, but not each other. Other
researchers have reported separate behavioral profiles
for FTD and SD, and describe an apathetic (FTD-A)
and disinhibited (FTD-D) form of the classic beha-
vioral disorder. Emotional impairments and compul-
sive, repetitive behaviors were more common in FTD
than SD, as was gluttony, and separated the groups
using discriminant analysis. The FTD-D group shared
characteristics from each group, and no feature had a
unique association with this group. Using the NPI,
disinhibition and apathy were more commonly seen
in FTD than AD, with the reverse pattern seen for
depression (Levy et al., 1996).
The overall benefit of such rating scales undoubt-
edly lies more in providing a structured behavioral
symptom profile than in any summated behavioral
score. This profile may then be used to guide subse-
quent, more detailed enquiry. Interestingly, total beha-
vioral scores appear to remain relatively stable over
time in FTD (Kertesz et al., 1997; Gregory, 1999;
Marczinski et al., 2004), and high scores are often pre-
sent early in the disease. Relatively stable scores may
well reflect adaptation by carers to the changed circum-
stances, as well as the effect of interventions such as
psychotropic medication. High scores at presentation
may also reflect a bias whereby mild behaviors,
initially tolerated as being eccentric, escalate and reach
crisis point around the time of diagnosis.
It is difficult to be confident that behavioral rating
scales do not simply reflect biases in the predominantly
clinical diagnoses that are being predicted, particularly
when these scales are being used to discriminate FTD
from other neurodegenerative diseases. There is the
potential for a degree of circularity as the inclusion cri-
teria for FTD involve mainly behavioral characteristics
which are also incorporated into behavioral rating
scales. Prospective studies with consecutive recruit-
ment, with diagnoses defined additionally on imaging
or pathological grounds, would be very useful.
In a number of patients, it remains remarkably diffi-
cult to be certain about the clinical diagnosis. Such
patients display the behavioral phenotype of the disor-
der, but seem to have a particularly good prognosis,
and do not deteriorate at the same rate as other cases.
In some of them it is true to say that frank dementia
supervenes. A normal MRI scan at presentation, parti-
cularly if the disease onset has been relatively slow,
suggests that a degree of caution is warranted when
giving prognostic information, or indeed a confirmed
diagnosis (Davies et al., 2005b). It is not until these
patients are followed longitudinally without significant
neuroradiological or behavioral deterioration that
doubts about the diagnosis can be resolved. To our
knowledge, well documented patients of this nature
have yet to come to postmortem.
28.3. Neuropsychological tests in FTD
A wide range of neuropsychological tests have been
applied to patients with FTD in order to characterize
their deficits, and to distinguish them from patients
who have other neurodegenerative disorders.
28.3.1. Cognitive screening tests
In predominantly behavioral cases, both bedside cogni-
tive assessments and standard formal neuropsychology
may be normal (Gregory and Hodges, 1996; Gregory
et al., 1998). A high score on the mini-mental state
examination (MMSE) (Folstein et al., 1975) does not
exclude the diagnosis, as this scale focuses on memory,
orientation, and a small number of language items,
which can be preserved until late in the course of FTD.
In a recent epidemiological study across several sites
(Johnson et al., 2005), the mean initial MMSE score
was 22.4 out of a maximum possible 30. The variance
of this estimate was large, emphasizing that some
patients may score very well on this test at presentation.
The Addenbrooke’s Cognitive Examination (ACE) is a
more comprehensive instrument, with a maximum score
of 100, that incorporates all of the MMSE components
 NEUROPSYCHOLOGY OF FRONTOTEMPORAL DEMENTIA
but additionally provides more assessment of language
and semantic memory than the 30-item MMSE.
The frontal assessment battery (FAB) combines
tests of concept similarities, letter fluency, and motor
sequencing with assessment of inhibitory control and
frontal release signs such as the grasp reflex (Dubois
et al., 2000). Performance correlates with scores on
the Mattis Dementia Rating Scale (DRS) and with per-
formance (number of categories achieved and number
of perseverative errors) on the Wisconsin Card Sorting
Test (WCST), but does not distinguish well between
FTD and subcortical frontal syndromes such as PSP.
The FAB similarities test assesses concept knowledge
and the ability to express it via questions such as how
a table and a chair, or a banana and an orange, are alike.
This is easy to perform at the bedside and is the most
discriminating subtest of the battery. Scores in AD
are higher than in FTD, and the performance is inde-
pendent of age (Slachevsky et al., 2004). Although
the battery was also assessed on a small subgroup of
patients with relatively preserved MMSE, this may
not adequately match for degree of dementia severity,
and it remains unclear as to what happens in more
subtle situations when FTD patients score very well
on the MMSE.
28.3.2. Executive function measures
Poor performance on tests of executive function has
been demonstrated in many studies comparing FTD
with controls, but the ability of such tests to discriminate
between FTD and AD remains relatively poor because
the performance of both groups may be impaired (Miller
et al., 1991; Frisoni et al., 1995; Pachana et al., 1996;
Hodges et al., 1999; Pasquier et al., 2001). Nevertheless,
they remain useful for documenting one aspect of the
overall profile of the disorder, both behavioral and
cognitive.
28.3.3. Trails, card sorting, Brixton, Hayling, and
Tower of London tests
Patients with FTD do badly on the Trails test, especially
the alternating letter–number task in Part B of this test.
Their performance is below that of controls (Rosen
et al., 2002b), but is similar to that of many patients with
AD (Kramer et al., 2003). They take longer to reach the
first category on the Wisconsin Card Sorting Test
(WCST), achieve fewer categories overall, and make a
greater number of perseverative errors relative to con-
trols (Miller et al., 1991; Neary et al., 1998; Snowden
et al., 2003; Diehl et al., 2005; Thompson et al., 2005).
A similar failure to shift attentional set has been shown
531
on the Brixton spatial anticipation task (Lough et al.,
2005). Ability to inhibit prepotent responses to a sen-
tence completion task such as the Hayling test may also
be quite abnormal, even in mild FTD (Lough et al.,
2005). In contrast, ability to correctly plan the minimum
number of moves needed on the Tower of London task
was not significantly impaired in mild FTD relative to
controls, although patients were slower at it (Rahman
et al., 1999b).
28.3.4. Verbal fluency
A reduction in verbal output is a common finding in
FTD. Many studies report verbal fluency measures
(Elfgren et al., 1993; Gregory et al., 1997; Mathuranath
et al., 2000; Rosen et al., 2002b; Perri et al., 2005), prob-
ably because these are so simple to administer. Letter
fluency involves the timed generation of as many words
as possible beginning with a particular letter (e.g., F, A,
S), while category fluency tests the ability to provide
words that are semantically related (e.g., animals).
In FTD there is usually a marked deterioration in letter
fluency, accompanied to a lesser extent by category flu-
ency, whereas in SD, scores are usually much lower for
categories than letters.
28.3.5. Digit span
Digit span, a measure of working memory which is
dependent on executive and phonological processes, is
inconsistently impaired in FTD, thus limiting its useful-
ness as a measure of impaired attention (Gregory et al.,
1997; Boone et al., 1999; Rahman et al., 1999b; Pasqu-
ier et al., 2001; Gregory et al., 2002; Rosen et al., 2002b;
Graham et al., 2005). This is likely to reflect poor
disease severity matching across studies. In our own
experience, it is a relatively insensitive measure,
particularly in early disease.
28.3.6. Visuospatial function
Visuospatial function remains intact in FTD until the
late stages (Brun et al., 1994; Barber et al., 1995; Varma
et al., 1999) although poor organizational strategies may
impair scores on some tasks such as copying of the Rey
Figure. Inconsistencies can often be resolved by normal
performance on visuospatial tasks such as those con-
tained in the Visual Object and Space Perception Bat-
tery (VOSP) (Warrington and James, 1991). In tests of
spatial span and spatial working memory, patients with
mild FTD perform similarly to controls (Rahman
et al., 1999a). Their performance on spatial and pattern
recognition is normal, but they are slower than controls.
532 C.M. KIPPS ET AL.
28.3.7. Language
In addition to a commonly observed degree of abnorm-
ality on the verbal fluency measures mentioned above,
severe reduction in fluency without phonological, syn-
tactic, or semantic deficits (‘dynamic aphasia’) has
occasionally been documented in FTD (Snowden
et al., 1996). Otherwise, language skills appear to be
relatively unaffected in FTD (Thompson et al., 2005),
with good comprehension and largely intact perfor-
mance on tests of picture naming, word–picture match-
ing, generation of word definitions and other
semantically based tasks such as the Pyramids and
Palm Trees Test (Hodges et al. 1999; Perry and
Hodges, 2000; Howard and Patterson, 1992). There
are, however, several reports of disproportionate
impairment in comprehension of verbs (actions) rela-
tive to nouns (objects) in this patient group (Cappa
et al., 1998; Rhee et al., 2001; Snowden et al., 2003).
On a word–picture matching task, verb processing abil-
ity correlated with executive function performance,
namely the Stroop, letter fluency, and Trails B tasks,
suggesting that this skill is sensitive to executive
resource demands. Similar findings have been seen in
FTD associated with motor neuron disease (FTD-
MND). Syntactic deficits can be shown using the Test
of Reception of Grammar (TROG) (Bishop, 1983;
Bak et al., 2001).
28.3.8. Episodic memory
Memory complaints in FTD are relatively common, but
usually not specific. About 8% of pathologically con-
firmed cases have reported memory symptoms in the
initial stages of disease (Hodges et al., 2004), and
showed documented impairments on verbal memory
tasks relative to controls (Rosen et al., 2002b). The pre-
dictive value of such amnesic symptoms may not be
very high, given both the nonspecific way in which
carers and patients describe memory complaints, and
the heterogeneous manner in which they manifest.
Although most patients with primary memory com-
plaints are likely to have AD, the diagnostic criteria
for this disease have poor specificity with respect to
FTD (Varma et al., 1999), and impairments in memory
are poorly discriminatory. Thus, absence of severe
amnesia (giving a high negative predictive value) mark-
edly increases the odds ratio for FTLD to be confirmed
pathologically, but the converse is not true (Rosen
et al., 2002b).
In contrast to AD, patients with FTD perform better
on both recognition and recall tasks (Glosser et al.,
2002), and do not have the accelerated forgetting typical
of AD in delayed free recall conditions. Verbal priming
improves performance on a word completion task in
FTD, prompting suggestions that memory dysfunction
results from inefficient retrieval strategies, rather than
true amnesia (Pasquier et al., 2001). On the other hand,
a study comparing forced-choice recognition and free
recall for verbal and nonverbal material showed no dif-
ference in performance between AD and FTD variants,
leading the authors to propose that it was encoding
rather than retrieval that accounted for differences
between groups (Glosser et al., 2002). They commented
on the rather inefficient, serial order, stimulus-bound
means of this encoding in FTD. While item detection
(discriminating previously seen from novel items) is at
control levels, temporal source memory (remembering
that an item came from list A vs. list B) is at chance
(Simons et al., 2002). Spatial source memory (memory
for an item’s spatial location), by contrast, seems to be
normal in FTD (A Graham, unpublished data). In AD,
patients are typically impaired at both item detection
and source memory, temporal or spatial. There remain,
however, a number of FTD patients with true amnesic
symptoms, who remain indistinguishable from AD
during life notwithstanding the presence of behavioral
disturbance (Caine et al., 2001).
Assessing accuracy at task performance is the most
commonly used means of neuropsychological evalua-
tion, but such an approach lacks specificity; patients
with either AD or FTD may perform poorly, but the rea-
sons for this may be quite different. Analysis of the dif-
ferent kinds of errors typical of the two disorders has
produced interesting results (Thompson et al., 2005).
Concrete thought and interpretation, perseveration, con-
fabulation, and poor organization were responsible for
the profile of performance of FTD subjects across a
range of neuropsychological tasks, and seem to echo
their behavioral dysfunction.
28.3.9. Newer tests
The relative lack of success in delineating a typical pat-
tern of neuropsychological dysfunction in FTD has
prompted investigators to explore a range of novel
tasks in an attempt to quantify the social cognitive def-
icit in these patients. Executive function measures are
believed to be sensitive to abnormalities in dorsolateral
prefrontal cortex (Duncan and Owen, 2000) but the
initial locus of pathology in FTD often seems to
involve the orbitofrontal and superior medial frontal
cortices (Broe et al., 2003; Kril and Halliday, 2004).
Lesions in these regions have been associated with
abnormalities of social conduct and emotion (Hornak
et al., 2003).
 NEUROPSYCHOLOGY OF FRONTOTEMPORAL DEMENTIA
28.3.10. Decision-making
In view of the prominent impairments shown by
patients with FTD in the areas of appetite and reward
processing, there is surprisingly little data on learning
for reward in this condition. Rahman et al. (1999a)
tested decision-making using a reversal paradigm
called the ID-ED shift task. Patients were specifically
impaired at the reversal aspects of the task. They could
not change their behavior when a previously rewarded
stimulus was no longer rewarded, but had no difficulty
in transferring a rule learnt on one set of exemplars to a
different, but related set of stimuli. In the same study,
the authors used the Cambridge Gamble task to assess
risk-taking behavior. In this task, bets are placed on
the likely position of yellow tokens hidden under one
of two boxes on the screen. Patients with FTD showed
true risk taking behavior in that they bet a larger pro-
portion of their accumulated winnings on the outcome.
They did not, however, perform less accurately than
controls in this task, even though their deliberation
times were significantly longer, a feature seen in other
patients with orbitofrontal lesions (Rogers et al., 1999).
Their risk-taking was not just a reflection of impulsive
behavior, as bets had to be placed in a manner that
minimized this possibility. More recent work by our
group has shown that patients with FTD are significantly
impaired on a task requiring concurrent visual discrimi-
nations and that, unlike controls, their performance is
not enhanced by the addition of a genuine, and otherwise
motivating, monetary reward (A Graham, unpublished
data).
28.3.11. Theory of mind
Demonstration of abnormalities in the ventromedial
aspect of the frontal lobes in FTD prompted interest
in the possibility that aspects of social cognition such
as the Theory of Mind (ToM) might be impaired in
these patients. In a comparison with normal controls,
and MMSE-matched AD patients, Gregory et al.
(2002), showed that in FTD both first and second order
ToM was significantly worse than in controls, and that
an even greater proportion of FTD patients were
impaired on the faux pas task. On the faux pas task,
patients made a number of errors, with false positive
and false negative endorsements, as well as inappropri-
ately inferring that a faux pas had been caused inten-
tionally. In contrast, performance by patients with AD
was compromised by memory impairment as indicated
by their scores on control questions.
In an interesting study, Snowden et al. (2003)
showed that FTD patients were more likely than con-
trols or Huntington’s disease patients to make errors
533
of omission, and to provide inappropriately concrete
responses in a cartoon interpretation task. They also
used relatively fewer verbs depicting mental states
(e.g., thinking, believing) when asked to describe a
mental state cartoon. This was not just an effect of poor
verbal fluency, as mental state verbs were affected
more than physical state verbs. When tested on a story
comprehension task which involved representation of
first and second order Theory of Mind, the FTD
patients performed poorly, although this was for both
physical and mental state stories. Verb production
overall was impaired relative to controls, and is reso-
nant with findings from studies mentioned earlier that
suggest a disproportionate impairment of verbs relative
to nouns in FTD (Bak et al., 2001; Cappa et al., 1998;
Rhee et al., 2001). On a test of eye gaze preference,
several of the patients persisted in selecting their own
personal favorites as the target. In a similar vein, we
have observed patients who use idiosyncratic patterns
in their use of rating scales (e.g., 10, 9, 8, 7, etc. for
successive items). Such eccentricity highlights one of
the potential confounds in testing this particular group.
The role of executive function in performing some of
these tasks is controversial. In a recent study (Lough
et al., 2005), performance on both the Hayling and Brix-
ton tasks was unrelated to the performance of FTD
patients on a mental state cartoon interpretation task.
In fact, it appeared that executive function played a sup-
portive role in processing of cartoons and story vignettes
rather than being directly involved in mental state repre-
sentation. Executive impairments, however, have the
potential to mask more specific deficits in the theory
of mind (Snowden et al., 2003), particularly if they are
severe. Furthermore, it seems that the ability to process
social rule violations is related to executive function
measures; despite this, knowledge of social rules them-
selves is unaffected (Lough et al., 2005). The ability to
judge the severity of rule violations (moral versus
conventional) is compromised in FTD, with patients
tending to judge all social violations equally severely.
28.3.12. Personality measures
Poor recognition of emotional responses in others, and a
lack of empathy, are frequently seen in FTD, and yet
there are relatively few studies which attempt to quan-
tify these aspects of impaired social functioning in this
disease. On the interpersonal adjectives scale (IAS), a
caregiver-based rating of interpersonal functioning,
FTD patients show increased submissiveness, possibly
as a function of increased apathy. Patients with semantic
dementia, by contrast, were rated as more cold-hearted
instead, with only a marginal decrease in social domi-
nance (Rankin et al., 2003). Both groups maintained
534 C.M. KIPPS ET AL.
their dysfunctional personality styles more rigidly than
comparable patients with Alzheimer’s disease. A subse-
quent study reported a correlation between the volume
of right orbitofrontal cortex with ‘agreeableness’
(Rankin et al., 2004).
Disintegration of the sense of self, as reflected in
changes in behavior, dress, or religious ideas, was
reported in six patients with right-sided frontotemporal
hypoperfusion on SPECT imaging. This occurred
despite the patients’ retained knowledge of their own
premorbid personality traits (Miller et al., 2001). Many
other socially inappropriate behaviors have been linked
to right-predominant frontotemporal dysfunction in
FTD patients (Mychack et al., 2001). It is worth bear-
ing in mind, however, that whilst the disease process
in FTD is often asymmetric, it is virtually never unilat-
eral (Chan et al., 2001; Thompson et al., 2003; Seeley
et al., 2005).
Other research groups have attempted to use person-
ality indices to quantify aspects of the behavioral
changes in FTD such as impaired insight. On the same
interpersonal adjectives questionnaire (IAS) as above,
self reports of current personality in FTD actually match
relatives’ accounts of premorbid personality most clo-
sely (Rankin et al., 2005a). Patients tend to exaggerate
their positive qualities, whilst minimizing any negative
ones, and have worst insight for areas of their personal-
ity that have undergone the most significant change.
28.3.13. Empathy
Two studies have assessed the characteristic indiffer-
ence to the emotional concerns of others using the
interpersonal reactivity index (IRI), a four factor struc-
ture reflecting cognitive (perspective-taking and fan-
tasy) and emotional (empathic concern and personal
distress) aspects of empathy (Davis, 1980; Lough
et al., 2005; Rankin et al., 2005b). In frontal or beha-
vioral variant patients, perspective-taking (Lough
et al., 2005; Rankin et al., 2005b) and empathic con-
cern (Lough et al., 2005) were impaired relative to
age-matched controls. Semantic dementia patients
were impaired across all four factors, reflecting a more
profound cognitive and emotional indifference to
others. Interestingly, patients with AD were not
impaired on these measures, suggesting a defined
neural substrate for empathy, and not just brain degen-
eration per se as the source of its deterioration.
28.3.14. Emotional recognition and regulation
The ability of patients with FTD to recognize facial
emotional expressions in others is particularly impaired
for anger, sadness, and disgust (Lavenu et al., 1999;
Keane et al., 2002; Lough et al., 2005). There are, how-
ever, inconsistent results when this type of test is applied
longitudinally, with AD, but not FTD, patients showing
deteriorating performance (Lavenu and Pasquier, 2005).
In two cross-sectional studies, fear recognition was also
impaired (Rosen et al., 2004b; Lough et al., 2005). A test
of identifying vocal emotion yielded similar results:
angry and sad voices were poorly identified, but there
were additional deficits in recognizing the sounds of
happiness or surprise (Keane et al., 2002).
28.4. Progressive nonfluent aphasia
28.4.1. Clinical features
Traditionally, the first level of classification of aphasic
syndromes has been based on whether or not a patient’s
speech remains fluent, as this is one of the most salient
differences between the classical fixed-lesion aphasias
of Broca and Wernicke types. More recently, fluency
has been used as a marker of the heterogeneity within
progressive aphasia (Snowden et al., 1989; Hodges
and Patterson, 1996; Mesulam, 2001), and indeed this
observation is useful in distinguishing between SD and
PNFA in the clinic. The distinction is not, however, as
straightforward as it might seem. One problem, as we
shall see, is that SD patients sometimes show dysfluency
related to their word-finding impairment, and conver-
sely that PNFA patients may at times produce at least
some stretches of fluent speech. Another is that different
observers use different—and not always explicit—
criteria to define the terms. The description ‘non-fluent’
may refer to any or all of abnormally slow speech in
terms of words per minute, an excessive length of
time between utterances, disordered speech rhythm or
melody, effortful articulation, hesitation due to word-
finding difficulty, or other speech abnormalities.
Though each of these features is useful in describing
an individual patient’s speech, none is reliably present
in PNFA, and not all are reliably absent in SD. In other
words, a description based on fluency alone is neither
precise nor powerful enough to discriminate between
the two syndromes.
The most frequent initial symptom in PNFA is of
word-finding difficulty, though a substantial minority
of cases do not report this at the first consultation. Other
possible presenting complaints include hesitant speech,
difficulty constructing a sentence, or difficulty with
writing (Table 28.3). Behavioral features similar to
those of bv-FTD may occur (Kertesz et al., 2003b;
Hodges et al., 2004), sometimes reported as a change
in personality, but these typically appear later (if at all)
and almost never dominate the clinical picture. The
onset is gradual, and usually precedes presentation to
 NEUROPSYCHOLOGY OF FRONTOTEMPORAL DEMENTIA 535

Case Study 28.2

A 75-year-old retired clerk presented to the Memory in spontaneous speech as well as on formal tests of
Clinic with an 18-month history of speech problems. naming, and often resorted to stereotyped phrases such
He complained of hesitancy, word-finding difficulty, as ‘it’s all right.’ His ability to understand complex
and distorted speech. There were no complaints sug- syntax had also deteriorated. He continued to make
gestive of autobiographical or day-to-day memory use of nonverbal means of communication, even
impairment, and he continued to pursue hobbies such learning new gestures, and his semantic and visuospa-
as gardening without difficulty. No personality change tial abilities were still intact. He died seven years after
was reported, and he had insight into his problems. His the onset of his symptoms.
spontaneous speech was poorly articulated, with short A sample of his speech is given in Table 28.2, pre-
phrases and many phonological errors. Word-finding sumed target words are italicized; line breaks indicate
difficulty was obvious and led to frequent pauses; pauses in speech.
speech melody and rhythm were abnormal even on
occasions when there was no particularly marked Table 28.2
word-finding difficulty. He was frustrated by his
Sample of speech in PNFA patient
inability to communicate, and used gesture to supple-
ment speech where possible. er nides (nine days) [holding up nine fingers]
He performed poorly on simple tests of naming, And [points to the window]
phonological processing, and syntactic comprehen- an air oh nd (aeroplane)
sion. His digit span was reduced, as was his fluency have flow and er mornd
in word production from an initial letter cue (P) as well bandelenz (?) and er the
as from a semantic category (animals). He processed when we came out a coach [pointing down]
and took ed us all round
written words accurately in tasks requiring nonverbal
er hohdel (hotel)
output, but he made errors in reading aloud. He
three days and er [holds up three fingers]
showed good recall of both verbal and nonverbal we er coach er two days [holds up two fingers]
material, performed well on a nonverbal semantic and aspleep (asleep) and [holds up five fingers]
task, and his visuospatial abilities were preserved. oat five days
Two years later, his speech had deteriorated uz er uz like [laughs, mimes sleeping]
further, and was now only partially intelligible, with it’s alright [gives ‘thumbs up’ sign]
very frequent phonetic errors occurring in short,
telegraphic utterances. He was profoundly anomic

clinic by two or three years. Most PNFA patients present
in their sixties; the diagnosis is unusual outside the ages
of 50 to 75. No sex bias has been demonstrated (West-
bury and Bub, 1997; Kertesz et al., 2003b; Gorno-
Tempini et al., 2004; Knibb et al., 2005), and there are
no known risk factors other than age. There is some-
times a family history of early-onset dementia, but only
rarely is there a clear-cut Mendelian inheritance pattern.
The number of words uttered per minute is not always
low in PNFA, although the length of individual sentences
or utterances is almost universally reduced. Some
patients fill in the gaps in their online speech using stereo-
typed, overlearned phrases. In others, initiating speech
becomes more difficult; they prefer to listen rather than
to speak, and give mostly monosyllabic answers when
asked a direct question. Such a patient may appear
laconic rather than dysphasic, a pattern known as
‘dynamic aphasia’ (Costello and Warrington, 1989;
Esmonde et al., 1996). Other patients are closer to classi-
cal nonfluent aphasia, and show effortful, labored speech
with distorted rhythm and melody. Still others show
largely normal runs of speech in between prolonged
word-finding pauses.
Phonetic paraphasias are a characteristic, though not
ubiquitous, feature of PNFA. Many patients make spon-
taneous speech errors which are clearly phonetically
related to the target, for example ‘spoot’ for ‘spoon.’ In
others, these occur more frequently in naming or repeti-
tion tasks. Patients are usually aware of their errors, and
may attempt to self-correct, sometimes producing suc-
cessively better approximations (conduit d’approche):
‘elective, elecrit, electry’ for ‘electricity.’ Patients only
536 C.M. KIPPS ET AL.
Table 28.3 whose speech is distorted and nonfluent, should be
assessed for other possible diagnoses, such as bulbar
Clinical features of PNFA (not all present in every case)
motor neuron disease (MND). Handwriting may also
Clinical features be affected nonlinguistically by the co-occurrence of
upper-limb apraxia with PNFA, as in the syndrome of
word-finding difficulty in spontaneous speech corticobasal degeneration (CBD) (see below).
in picture naming tests
speech production difficulty initiating speech
difficulty disordered articulation 28.5. Semantic dementia
phoneme substitution in spontaneous speech
errors on repetition, especially of 28.5.1. Clinical features
nonwords
disordered grammar in spontaneous speech The first complaint in SD is almost always of isolated
in syntactic comprehension word-finding difficulty. However, this is so insidious in
tests onset, and speech is otherwise so well preserved, that
on repetition of complex other symptoms have usually evolved by the time the
sentences patient presents to clinic. Among these are difficulty
nonlinguistic deficits executive impairment understanding spoken words, deterioration in spelling,
upper-limb and/or orofacial and difficulty recognizing faces (Table 28.4). Behavioral
apraxia
features are commoner and occur earlier in SD than in
relatively unimpaired word comprehension
PNFA, and include irritability, stereotyped behaviors,
knowledge of items they cannot
name
imaging left perisylvian atrophy
Table 28.4
Clinical features of SD (most present in most cases)
rarely complain of difficulty understanding speech, but
Clinical features
testing very often uncovers problems in sentence com-
prehension. The deficit is in the understanding of syntax, word-finding difficulty in spontaneous speech
rather than of individual words. For example, the passive in picture naming tests
construction in the sentence ‘A lion was attacked by a unable to give information
tiger’ may be misinterpreted as active voice, causing about the items
the patient to assign the roles of attacker and victim the word comprehension alienation du mot (‘what’s a
wrong way round. Closed-class words such as preposi- hobby?’)
tions may also be misunderstood. By contrast, frank in word-picture matching tests
speech errors overuse of generic words
grammatical errors in speech are a less common feature,
circumlocution
and are less common in PNFA than in nonfluent aphasia
coordinate semantic errors
due to fixed lesions (Graham et al., 2004). They do occur difficulty with uncommon in reading and writing
in some patients, however, and consist of omission or irregular words in verb inflection
misuse of inflections or grammatical words, or abnormal other semantic on picture–picture matching
word order: ‘She’s in the washing, er, doing the wash- impairments tests
ing;’ ‘Well, woman cleaning;’ ‘Cupboard. Plate.’ on sound–picture matching tests
Impairments of reading and writing also occur as part face recognition
of the PNFA syndrome. Surface dyslexia has been behavioral changes bizarre food combinations or
reported (Watt et al., 1997), and may be commoner than food fads
previously thought (Knibb and Hodges, 2005), although stereotyped behaviors
inflexibility, irritability
it is unusual for a PNFA patient to complain of difficulty
loss of empathy
with reading. In fact, reading a passage of text aloud
relatively unimpaired syntactic comprehension
usually elicits speech which is more fluent and less para- speech articulation, phonology,
phasic than when the patient speaks spontaneously, and grammar
although reading text aloud is more difficult and error- imaging striking anterior temporal lobe
prone than reading the same component words as single atrophy
items (Patterson et al., 2005). Grammatical deficits are usually asymmetric, most often
sometimes more apparent in writing than in speech. A left worse than right
patient who can write fluently and grammatically, but
 NEUROPSYCHOLOGY OF FRONTOTEMPORAL DEMENTIA
Case Study 28.3
A 54-year-old care assistant in a nursing home pre-
sented to the Memory Clinic with a 12-month history
of ‘loss of memory for words,’ gradual in onset and
progressive. She first noticed a problem when she
had difficulty naming the contents of the food trolley
at work. She had also noticed difficulty in remember-
ing the names of friends and family members. There
was no problem with day-to-day or autobiographical
memory. Her family reported no behavioral changes,
and she was functioning normally in terms of practical
skills and daily living. Physical neurological examina-
tion was normal. She was fully orientated, and rapidly
learned her way around the ward where she had been
admitted for investigation. Her conversation was flu-
ent and superficially normal, with intact speech
rhythm and melody, accurate articulation, and correct
pronunciation and grammar. However, her complaint
of word-finding difficulty was borne out in her
speech, which was characterized by extensive circum-
locution and a tendency to use generic words such as
‘thing.’
She was severely impaired in naming tasks, and her
errors were semantically related to the target (‘horse’
for ‘elephant’). When asked to generate the names of
and changes in eating behavior (Snowden et al., 2001;
Thompson et al., 2003). SD and PNFA share a similar
profile in terms of age, sex, and family history (see
comments above.)
Spontaneous speech may appear normal to the casual
listener, even at quite advanced stages of the disease.
Early on, however, the trained ear should notice a shift
towards the use of general, high-level category terms
when the context requires a specific word, for example
‘place’ instead of ‘hospital’ or ‘creature’ instead of
‘goat’; frank within-category semantic errors (‘dog’
for ‘goat’) may also be seen. Circumlocution is another
common strategy—‘play music with it’ for ‘violin,’ or
‘you see them outside, it goes around’ for ‘goat.’ All
of these naming errors become more noticeable on for-
mal naming tests. Hesitation while searching for a word
is less prominent in SD than in PNFA, although the
anomia is much more profound, and semantic errors
are typical.
Impairment of single-word comprehension is often
equally striking. Occasionally a patient loses familiarity
537
as many animals as possible, she could think of only
five in a minute, but she was better at generating words
from an initial letter. Her conversational comprehen-
sion was good, and she could follow complex com-
mands easily provided that they were composed of
common nouns and verbs; but her understanding of
less common individual words was impaired. She
could read aloud fluently, but regularized the pronun-
ciation of words with an irregular spelling-to-sound
correspondence (e.g., pint pronounced to rhyme with
‘mint,’ gauge pronounced ‘gorge,’ etc.). Her nonver-
bal memory was normal, but word-list learning and
other measures of verbal memory were impaired.
With progression of the illness, her speech became
almost empty of meaningful words, dominated by
‘thing,’ ‘do,’ ‘go’ and similar words. Later still, she
was only able to speak in stereotyped expressions—
‘special place,’ ‘those bits.’ She developed impair-
ment on nonverbal tests of semantic knowledge, and
became unable to demonstrate the use of household
objects, although her level of function at home
remained good for a long time. She died 14 years after
the onset of her symptoms and had MND-type Ubiqui-
tin pathology.
with a word to the extent of saying, ‘Hobby, hobby. . . I
should know what a hobby is, but I can’t remember.’
This has been called alienation du mot (Poeck and Luz-
zatti, 1988), and is a very specific sign of SD. Usually,
however, comprehension impairment must be specifi-
cally elicited, by saying a word to the patient and asking
them to point to a picture, or to define the word in as
much detail as possible. The definitions produced may
be frankly inaccurate, but more typically they are vague
as in ‘a big one, I’ve got one of those,’ or simply
overgeneralized and lacking in specific details.
The progressive loss of vocabulary leads to parallel
deficits on tests of word production and word compre-
hension, and errors occur on corresponding items in
each test (Lambon Ralph and Howard, 2000). This also
applies to surface dyslexia, another core feature of the
SD syndrome. The pronunciation of many English
words is predictable from their spelling (e.g., ‘cord,’
‘loot,’ or ‘mint’), while for others it is not (e.g., ‘word,’
‘foot,’ or ‘pint’). In surface dyslexia, irregular words
are pronounced as if they had a typical spelling–sound
538 C.M. KIPPS ET AL.
relationship. Similarly, although the grammatical struc-
ture of speech is preserved, over-regularization errors
frequently occur when SD patients are asked to trans-
form a sentence in present tense into the past: e.g.,
‘Today I fall on the stairs’ ! ‘Yesterday I falled on
the stairs.’
28.5.2. Behavioral features
The behavioral and personality changes associated
with bv-FTD are common in SD, at presentation as
well as later in the illness, but the emphasis is different.
Impaired social functioning results from a combination
of emotional withdrawal, depression, disinhibition,
apathy, and irritability. Changes in eating behavior,
such as the development of a sweet tooth, are common,
but usually there is a restriction of food preferences, or
bizarre food choices, rather than the overeating often
seen in bv-FTD. Loss of physiological drives is com-
mon and includes poor appetite, weight loss, and
decreased libido. New religiosity and eccentricity of
dress is also reported (Edwards-Lee et al., 1997). The
right temporal variant, which has only one-third the
prevalence of left sided cases, seems to be more con-
vincingly associated with behavioral disturbance than
the left (Edwards-Lee et al., 1997; Perry et al., 2001;
Thompson et al., 2003; Seeley et al., 2005), but cases
are seldom, if ever, purely unilateral. In a recent study,
after an average of three years, the symptoms that were
not present initially have generally emerged, whether
they be behavioral or semantic (Seeley et al., 2005).
Compulsions are a prominent, but delayed feature,
and reflect the predominant temporal lobe involved.
This study suggested that with left-predominant SD,
visual objects such as coins or buttons are likely to
become the target stimulus, while in the right-sided
variant, the focus is on letters, words, and symbols
(e.g., word puzzles, and writing notes to doctors),
although we have observed exceptions to these general
rules. Clockwatching and an intense interest in jigsaws
are very common (Thompson et al., 2002). Compul-
sions evolve approximately 5 to 7 years after the initial
symptoms, and are often accompanied by disinhibition,
prosopagnosia, and altered food preference. Strong
visual compulsions may result in accusations of sho-
plifting and theft. Lack of empathy is a feature that
appears to be more common as a later feature in dis-
ease, although it may be seen at presentation if this is
delayed. Mental inflexibility can be extreme and pro-
voke marked behavioral fluctuations in response to
changes in the immediate environment.
Deficits in person recognition frequently occur at
some stage in the disease (Thompson et al., 2003).
Inability to retrieve a person’s name is extremely
common, and it is important in the clinical history to
distinguish this from a failure to recognize a familiar
person. There seems to be a specific problem with face
processing in many SD patients, a progressive proso-
pagnosia, and this is more common in the right-predo-
minant variant. We have observed a right-dominant SD
patient emerge from the clinic testing room out into the
waiting room where (as she knew) her husband awaited
her; but she went up to a stranger in the waiting room to
tell him that she was ready to go home.
A recent study found a number of clinical features
which were associated with either left- or right-
predominant cases at the time of first presentation to
the clinic (Thompson et al., 2003). The features which
were significantly more common in left-predominant
SD were both language-related, namely word-finding
difficulty and impaired comprehension. By contrast,
right-predominant cases showed a higher prevalence
of person recognition problems, social awkwardness,
and poor insight into their condition. Perhaps because
of this, right-predominant patients were more likely
to have lost their jobs before presenting to clinic.
28.6. Neuropsychological tests in SD and PNFA
28.6.1. Language
28.6.1.1. Naming
Most aphasic patients, whatever the nature of their syn-
drome or lesion, show some impairment on tests of pic-
ture or object naming. This includes both PNFA and
SD patients, but these groups differ in their error pat-
terns. PNFA patients obtain mid-range scores, and their
errors are more often phonetic approximations than
failures of retrieval (Mendez et al., 2003; Weintraub
et al., 1990). They can usually demonstrate knowledge
of the items they cannot name (Gorno-Tempini et al.,
2004), either by giving definitions or properties of the
item, by miming its shape or use, or by pointing cor-
rectly to the item given a particular property (‘which
one of these has a nautical connection?’). On the other
hand, all but the very earliest SD patients score very
poorly on simple naming tests. Their errors are often
‘don’t know’ responses; they may also make semanti-
cally related errors, either at an inappropriately generic
level (‘animal’ for ‘horse’), or from within the same
category (‘piano’ for ‘harp’) (Snowden et al., 1992;
Hodges et al., 1995). They have much more limited
knowledge about the items that they fail to name.
28.6.1.2. Noun generation
Again, both PNFA and SD affect the ability to generate
words, either from a specified initial letter or from a par-
ticular category. Normal subjects can produce an
 NEUROPSYCHOLOGY OF FRONTOTEMPORAL DEMENTIA
average of 18 animal names or 15 words beginning with
‘F’ in a minute, with 10 as a lower limit. In SD, category
fluency drops dramatically, often to just a handful of
words, while letter fluency (at least early in the disease)
is relatively spared—this dissociation is characteristic
of SD, and reflects the underlying impairment of seman-
tic knowledge. PNFA tends to affect both varieties
of fluency to a similar extent, and the words produced
often continue to show a reasonably wide variation as
in normal speakers; in SD, by contrast, the instances pro-
duced are restricted to the most common, high-frequency
words (e.g., ‘cat,’ ‘dog,’ and ‘horse’ for animals).
28.6.1.3. Repetition
Impairment at repeating spoken words back to the
examiner is a reliable feature of PNFA, and errors may
be observed here before they become obvious in sponta-
neous speech. Long words with complex or repeated
sequences of consonants are particularly difficult (‘epis-
copal,’ ‘hippopotamus’). The phonological structure of
the word is distorted by phoneme omissions, transposi-
tions or insertions. Often the patient will make multiple
false starts, coming to a halt in midword each time.
Repetition of long nonwords is even more difficult, as
it relies more specifically on phonological working
memory, which is typically impaired in PNFA. The
Children’s Test of Nonword Repetition (Gathercole
and Baddeley, 1996) is useful in eliciting subtle deficits.
These problems are also reflected in a low digit span,
and in difficulty with repeating sentences or following
a three-part command. On the other hand, SD patients
mostly find word repetition easy, and show a striking
dissociation between production of a word and
knowledge of its meaning.
28.6.1.4. Comprehension tasks
Impairments of comprehension of single words and of
syntax are characteristic of SD and PNFA respectively,
and each may occur in the absence of the other. Word
comprehension deficits are tested by word–picture
matching, or by asking the patient to define a word, as
described above. Because the underlying problem in
SD is a breakdown of conceptual knowledge, item con-
sistency is seen between tests of word production (or
retrieval) and comprehension. For the same reason, SD
patients also show impairment on nonverbal tests of
semantic association, such as the Pyramids and Palm
Trees Test (Howard and Patterson, 1992); a low score
here is quite specific for SD. Simple syntactic compre-
hension tests are also described above, but for formal
testing the TROG is particularly suitable, as it uses very
common words which both PNFA and SD patients are
likely to understand in isolation.
539
28.6.1.5. Reading and writing
The surface dyslexia of SD is elicited using reading
tests with irregular words, such as the NART (National
Adult Reading Test; Nelson and Willison, 1991) or the
‘Surface List’ (Patterson and Hodges, 1992). Other-
wise, tests of reading and writing are of little specific
diagnostic value in these conditions.
28.6.2. Memory in PNFA and SD
From a clinical perspective, there is often a striking dis-
sociation between language and everyday memory
functions in both PNFA and SD. Indeed, diagnostic cri-
teria for progressive aphasic syndromes have generally
demanded relatively preserved everyday (episodic)
memory (Neary et al., 1998). However, demonstrating
this preservation using standard tests is fraught with dif-
ficulty. Understanding test instructions can sometimes
be a problem in PNFA as well as in SD, owing to im-
pairments of sentence and single-word comprehension
respectively. More dramatically, tests requiring spoken
output are likely to be affected by anomia and other pro-
duction impairments. For this reason, patients may score
better (relative to control ranges) on tests of recognition
than recall.
On a more fundamental level, a specific impairment of
verbal memory is common, particularly in SD. This def-
icit affects performance on tests of word-list learning
such as the RAVLT (Rey Auditory–Verbal Learning
Test), as well as recall of a narrative. As the phonological
and semantic representations of words are disordered in
PNFA and SD respectively, such a deficit is not surpris-
ing, and does not necessarily imply an impairment of
anterograde memory systems. Tests which use exclu-
sively nonverbal material, such as recall of the Rey com-
plex figure, are more useful in this regard, provided that
the patient does not have an impairment of visuospatial
processing, which sometimes accompanies PNFA as part
of its overlap with the corticobasal syndrome (Graham
et al., 2003a; Kertesz and Munoz, 2003).
It is difficult to find a single ‘memory’ test which is
reliably normal in all cases, and so clinical judgment is
crucial: a patient who complains mainly of symptoms
of anterograde episodic memory deficits is more likely
to be suffering from Alzheimer’s disease, but a degree
of impairment on language-dependent tests without
such symptoms does not rule out a diagnosis of PNFA
or SD.
28.6.3. Executive function in PNFA and SD
Impaired executive function has rarely been discussed
in the context of progressive aphasia, although it is
540 C.M. KIPPS ET AL.
frequently cited as a defining impairment of the bv-FTD
group (Neary et al., 1998). By implication, then, it might
be taken as a relative exclusion criterion for PNFA or
SD, but little published work has addressed this issue.
One study (Nestor et al., 2003) found that a group of
10 PNFA patients (selected on the basis of reduced
and distorted speech and impaired syntactic comprehen-
sion) showed impairment on the WCST compared with
controls, although a group of AD patients were almost as
impaired. Our own experience is that executive impair-
ments are commoner in PNFA than in SD, but further
investigation is needed.
28.7. Interpretation of neuropsychological test
performance
The interpretation of neuropsychological test scores,
either routine or experimental, warrants a degree of
caution. Significant heterogeneity exists in the perfor-
mance of FTD patients; group effects may not be repre-
sentative of individual cases. There is also frequent
overlap in performance with either controls or patients
with other neurodegenerative disorders, particularly
Alzheimer’s disease. Conflicting results are often
obtained across different studies, and can be ascribed
to a number of methodological issues.
Matching of patients across disease categories is one
significant issue. The most common method of matching
uses performance on the Mini-Mental State Examination
(MMSE) to control for differences in disease severity.
This is not particularly satisfactory as the MMSE does
not weight different cognitive domains equally. Other
studies (Kramer et al., 2003; Diehl et al., 2005) have used
Clinical Dementia Rating (CDR) scores to match
patients, but as illustrated in one study (Rosen et al.,
2004a), this measure emphasizes functional disability,
which can be inflated by marked behavioral disturbance,
and may not truly reflect an equivalent pathological
burden across disease groups. Failure to distinguish
FTD from the language variants (PNFA and SD) has
Fig. 28.1. Imaging findings associated with frontotemporal dementia syndromes (A) behavioral variant FTD with marked fron-
tal atrophy and ventricular enlargement; (B) progressive nonfluent aphasia showing left perisylvian atrophy; and (C) semantic
dementia with anterior temporal lobe pathology, worse on the left. The images are shown in radiological convention with the
left side of the patient on the right side of the image.
blurred the distinct cognitive profiles of these disorders,
and presumably contributed in some part to the conflict-
ing results. Furthermore, FTLD often exhibits hemi-
spheric asymmetry, and at least one study has
demonstrated differential performance in left and right
predominant FTD (Boone et al., 1999).
Studies with prospective assessment of consecu-
tively enrolled subjects are rare, but should be encour-
aged. As this is a field that is still dynamic, it is difficult
to standardize test batteries across studies, and group
sizes are likely to remain small. Pathological confirma-
tion should be obtained wherever possible to reduce
any bias resulting from clinical diagnosis, and postmor-
tem series should aim to recruit widely, and not just
patients with classical clinical features (Fig. 28.1). Care
should be taken to avoid circularity whereby inclusion
criteria are used to discriminate the disease from
others. Lastly, even the pathologists, as final arbiters,
have something to learn in this evolving field (Halliday
et al., 2002).
Patients with FTD are often impaired on standard neu-
ropsychological test batteries relative to controls (Binetti
et al., 2000). Whilst these tests are sensitive, however,
they are often not specific in discriminating between
FTD and other neurodegenerative diseases. We now
discuss what is known about such discrimination.
28.8. Differential diagnosis
See Table 28.5 for a summary.
28.8.1. Alzheimer’s disease
Since most studies in FTD compare patients to normal
controls or to those who have Alzheimer’s disease,
many of the issues relevant to this section have already
been discussed. Age of onset in the FTD syndromes is
typically a decade earlier than in AD (Hodges et al.,
2003) although this may reflect an ascertainment bias
with many studies using a cutoff of 65 or 70 years.
 NEUROPSYCHOLOGY OF FRONTOTEMPORAL DEMENTIA
Table 28.5
Other diagnoses to consider in suspected FTD
Category Diseases
Neurodegenerative Alzheimer’s disease
Corticobasal degeneration
Progressive supranuclear palsy
FTD with motor neuron disease
Vascular dementia
Dementia with Lewy bodies
Creutzfeldt–Jakob disease
Huntington’s disease
Psychiatric Adult Asperger’s syndrome
Affective disorders
Schizophrenia
Miscellaneous Frontal tumor
Hypothyroidism
Vasculitis
Vitamin deficiencies
The very high prevalence of Alzheimer’s disease over
the age of 75 is likely to obscure the detection of
FTD in patients presenting in this age group. Because
AD pathology is very common in the elderly popula-
tion, atypical clinical presentations are seen relatively
frequently, especially in specialist clinics.
Personality change, unconcern, and socially inap-
propriate behavior typically distinguish FTD from the
anterograde memory disturbance and topographical
disorientation characteristic of Alzheimer’s disease.
Stereotypic behavior, changes in eating preference or
hyperorality and emotional blunting also reliably separate
the groups (Bozeat et al., 2000; Rosen et al., 2002a).
Failure to assess behavioral characteristics results in the
incorrect classification of many FTLD subjects as AD.
When the presence of social conduct disorder, hyperoral-
ity and akinesia are combined with absence of amnesia
and perceptual disturbance, up to 93% of the FTLD and
97% of the AD patients are correctly classified (Rosen
et al., 2002b). Although apathy is more frequent in
FTD, it is not a particularly helpful discriminating feature.
Abnormal perception and praxis are more discrimi-
natory for AD than amnesic symptoms. Impaired spatial
perception with spatial disorientation, inability to loca-
lize objects, or failure on spatial tasks such as tracking,
copying line drawings or counting dots, dramatically
increases the probability of AD in an individual patient
(Varma et al., 1999). Although there is substantial over-
lap in the performance of FTD and AD patients, assess-
ment of the type of errors made (i.e., perseveration,
or concrete interpretation of sentences) may help
distinguish the two groups (Thompson et al., 2005).
541
Focal variants of AD with marked dysexecutive fea-
tures have been described (Johnson et al., 1999), but
these patients have a coexisting typical AD profile, with
memory and visuospatial impairment. In our Cambridge
experience, non-AD patients with this pattern typically
evolve into other dementia syndromes such as progres-
sive supranuclear palsy (PSP), or have vascular demen-
tia. Similarly, patients with proven FTD pathology have
occasionally been shown to have the anterograde mem-
ory disturbance usually associated with Alzheimer’s
(Caine et al., 2001; Hodges et al., 2004; Graham et al.,
2005). In practice, diagnostic confusion is less common
than might be imagined, as in bv-FTD it is the beha-
vioral disturbance that dominates the clinical picture.
An inventory such as the CBI readily distinguishes the
symptom complexes that are typical of these disorders,
and highlights the memory disturbance in cases that
might otherwise be diagnosed as bv-FTD.
AD pathology occasionally causes PNFA. This may
be indistinguishable from the syndrome caused by
FTD-spectrum pathologies (Pogacar and Williams,
1984; Green et al., 1990; Kempler et al., 1990; Benson
and Zaias, 1991; Karbe et al., 1993; Galton et al.,
2000; Li et al., 2000; Clark et al., 2003; Godbolt et al.,
2004), at least on strictly linguistic criteria. A more fre-
quent presentation, however, is of prominent phonologi-
cal impairments and/or dysfluency in the context of
episodic memory impairment or other cognitive defi-
cits, and AD may be diagnosed confidently in this situa-
tion. Care must be exercised in interpreting the results of
tests of verbal memory, tests with complicated instruc-
tions, or tests which rely on spoken or written answers,
as language impairment may cause falsely low scores
and suggest global impairment in a purely aphasic
patient. Even when the language syndrome is relatively
pure, AD pathology is very likely when the onset occurs
at over 70 years of age.
Similar comments apply to SD, except that it is
unusual for AD pathology to mimic SD precisely. Occa-
sionally it may produce a forme fruste of SD (a fluent
aphasia without the usual attendant features). Semantic
memory impairment is a common component of a glo-
bal AD syndrome, but this is usually easily distinguished
from pure SD by the predominance of episodic memory
impairment and other deficits. In a recent pathologi-
cally confirmed series of 18 patients, only 2 patients
who were clinically diagnosed with SD were eventually
shown to have AD (Davies et al., 2005a).
28.8.2. Corticobasal degeneration
Corticobasal degeneration (CBD) was originally
described as an atypical Parkinsonian syndrome, with
limb apraxia, myoclonus, cortical sensory loss, and
542 C.M. KIPPS ET AL.
the alien limb phenomenon (Rebeiz et al., 1968). More
recently, language impairment has been recognized as
part of the syndrome, and impairments in phonological
processing have been demonstrated in patients with the
clinical features of CBD but no symptomatic aphasia
(Graham et al., 2003b). The term ‘CBD’ refers to a
set of pathological findings as well as a clinical pattern;
this association has largely stood the test of time, but a
number of patients who were diagnosed with unequivo-
cal PNFA in life have had CBD pathology at postmor-
tem (Kertesz and Munoz, 2002; Ferrer et al., 2003).
Kertesz et al. (2000a) highlighted the frequency of
reports of behavioral disturbance in the case reports of
CBD. This consists primarily of apathy, disinhibition,
perseveration, and inattention, although as usual these
deficits are not present in every subject. On the Neuro-
psychiatric Inventory (NPI), depression was the only
feature that was endorsed more frequently in CBD than
in FTD (Cummings and Litvan, 2000), although apathy
(40%), irritability (20%), anxiety (15%), and disinhibi-
tion (15%) were not uncommon. How these features
relate to underlying depression is unclear, but it is likely
to be a significant factor in their presence. Depression is
fairly uncommon in bv-FTD, as mentioned earlier. A
further study suggests that behavioral features are
marked in FTD from the start of the illness, and their fre-
quency does not alter significantly, whereas in CBD,
they accumulate gradually (Marczinski et al., 2004).
A patient with CBD may show the classical motor
features, language features, behavioral disturbance, or
all three (Graham et al., 2003a). Deficits may also
develop sequentially. A diagnosis of CBD should there-
fore be considered in a case of suspected PNFA or bv-
FTD, especially in the presence of visuospatial impair-
ments or apraxia (in copying either a geometric design
or a meaningless hand position). The aphasia is likely
to affect phonology predominantly, and naming may
be relatively spared.
28.8.3. Progressive supranuclear palsy
The classical features of progressive supranuclear palsy
(PSP) are disruptions of motor function, including axial
rigidity, postural instability with a tendency to fall back-
wards, bradykinesia, and a supranuclear vertical gaze
palsy (Richardson et al., 1963). However, language
may also be affected. Full-blown PNFA with paraphasia
and dysgrammatism has been reported (Mochizuki
et al., 2003), and speech apraxia may also occur (Sakai
et al., 2002), but the most frequent language impairment
is difficulty in initiating output. This manifests as
‘dynamic aphasia’ (Esmonde et al., 1996), with a
marked and progressive reduction in speech output and
shortened phrases, but otherwise normal speech and
comprehension. Bulbar features, including dysarthria,
are also common, and may hamper assessment of lin-
guistic function. These deficits may precede the onset
of the motor features, but it is usual for the PSP syn-
drome to appear later in the illness. The possibility of
PSP should be considered in a patient presenting with
a progressive dynamic aphasia, and the physical signs
should be sought both at presentation and at follow-up.
Apathy and disinhibition are prominent in PSP
(Aarsland et al., 2001), which is in keeping with the
medial and dorsolateral prefrontal cortex neuronal loss
seen in this disease. However, the picture is not the
florid disruption in social functioning that is seen more
typically in FTD. In a recent analysis (Bak, unpub-
lished data), there was no difference in the summed
behavioral scores on the Cambridge Behavioural
Inventory (CBI) across different stages of disease in
PSP. This implies that it is not simply the motor dys-
function that leads to a lower reporting of behavioral
disruption in PSP. Conversely, a recent report demon-
strated FTD pathology with ubiquitin inclusions in
three cases with a distinct PSP phenotype (Paviour
et al., 2004). Extrapyramidal features dominated the
clinical picture, but one patient had significant disinhi-
bition, another presented in his mid-seventies, and a
third developed fasciculations suggestive of motor
neuron disease.
28.8.4. Frontotemporal dementia with motor
neuron disease (FTD-MND)
Frontotemporal dementia with motor neuron disease
(FTD-MND) usually presents in the sixth decade, and
is more common in men. Behavioral and cognitive
changes invariably precede motor symptoms by 6 to
12 months. Bulbar features including dysphagia and
dysarthria are particularly common. The FTD-MND
syndrome is unusual for the fact that delusions and
indeed hallucinations have been described (Bak and
Hodges, 2001). These phenomena are not part of the
usual FTD spectrum, but the remainder of the beha-
vioral and cognitive features are indistinguishable from
classical FTD, with disinhibition being particularly
common (Neary et al., 2000).
Progressive aphasia is a common feature of this
syndrome (Bak et al., 2001). The aphasia may appear
before the onset of motor features, and is usually a typical
PNFA. Semantic deficits appear to be less frequent (Bak
and Hodges, 2001; 2004). Progression is rapid (Bak and
Hodges, 2004), and prognosis is poor—the median
survival of FTD-MND patients in a recent series was just
2 years from symptom onset (Hodges et al., 2003). If
physical signs of MND are not present at the first presen-
tation to clinic, they usually appear within a year.
 NEUROPSYCHOLOGY OF FRONTOTEMPORAL DEMENTIA
28.8.5. Vascular dementia
Although one might expect vascular dementia affecting
subcortical regions to affect the frontal lobes in a simi-
lar manner to frontotemporal dementia, this does not
appear to be the case. In fact, the behavioral symptoms
that distinguish FTD from vascular dementia are fairly
similar to those that distinguish the disorder from AD
(Snowden et al., 2001). Vascular risk factors, stepwise
decline and the presence of ischemic lesions are char-
acteristic of vascular dementia (Roman et al., 1993).
It has never been reported to cause progressive aphasia.
28.8.6. Dementia with Lewy bodies
The presence of delusions, hallucinations, and extra-
pyramidal features are uncommon in bv-FTD unless it
is associated with motor neuron disease. Thus, it is sel-
dom that DLB provokes diagnostic confusion. Simi-
larly, the presence of visuospatial impairment in FTD
would make one reconsider the diagnosis. There is a
single case report of progressive aphasia with cortical
Lewy body disease, but this case also had dysarthria
and developed rapidly into an MND syndrome. Even
as part of a broader syndrome, it is unusual for
language to be impaired in these disorders.
28.9. Psychiatric diagnoses
Patients with bv-FTD frequently arrive via the psychia-
trist’s office, but when they do not, the effects of mood
disturbance, either mania or depression, should be con-
sidered. The older patient who presents with a new mood
disorder in the absence of something similar in earlier
years should arouse more suspicion than someone who
has been chronically depressed for years. Similarly, schi-
zophrenic presentations tend to be in a younger age-group
than the 50–60 year olds most commonly affected by
FTD syndromes. In taking the history, it is vital to make
every attempt to verify that there is a change in function-
ing with regards to behavior. Imaging may be of use,
although in bv-FTD there may be little or no abnormality
of structural scans many years into the disease (Davies
et al., 2005b). This is not the case with SD or PNFA
however. One should also consider the possibility of adult
Asperger’s syndrome and be aware of the potential for
dysfunctional marital relationships to paint a colorful
picture of behavioral disruption.
28.10. Other differential diagnoses
Hypothyroidism, vasculitis, and vitamin deficiencies,
though unlikely, should be considered. Structural
lesions such as a frontal lobe tumor could in principle
present as a progressive Broca’s aphasia, and
543
particularly rapid deterioration should prompt concern
about prion disease. A few cases of Creutzfeldt–Jakob
disease presenting with progressive aphasia have been
reported (Shuttleworth et al., 1985; Yamanouchi et al.,
1986; Mandell et al., 1989), though the association is
controversial (Turner et al., 1996). Other cognitive and
physical features developed within weeks or months of
onset in these cases, and the progression of the aphasia
was also very rapid. Huntington’s disease is occasion-
ally suggested by an appropriate family history. Irrit-
ability is common in the early stages, and early
cognitive changes include impaired attention and
impaired executive dysfunction (Ho et al., 2003).
28.11. Conclusion
Symptoms in frontotemporal lobar dementia are related
to the underlying structures involved in the pathological
process, and not the nature of the pathology itself. There
are reliable symptom clusters which define syndromes,
but there are several language and behavioral features
that show significant overlap between the different var-
iants of FTLD. Future work needs to continue to deline-
ate the relevant neural substrates of the disturbed
cognition in these patients. As the nature of the disease
becomes clearer, it is likely that the disease will be
recognized in more patients, particularly those over the
age of 65 who have previously been given a diagnosis
of Alzheimer’s disease. Despite substantial progress in
delineating the features of this disease, there remains
no effective treatment, either symptomatic or curative.
Acknowledgements
Dr. C. Kipps is supported by the Wellcome Trust
(Grant No. 073580) and Prof. J. Hodges by the UK
Medical Research Council.
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