C 2005)
Neuropsychology Review, Vol. 15, No. 3, September 2005 (
DOI: 10.1007/s11065-005-7093-4
Neuropsychological Differences Between Frontotemporal
Dementia and Alzheimer’s Disease: A Review
Michal Harciarek1,2 and Krzysztof Jodzio1
This paper surveys the similarities and differences between frontotemporal dementia (FTD) and
Alzheimer’s disease (AD). The review covers findings primarily from neuropsychological studies on
memory, language, attention/executive function, and visuospatial abilities. However, neuropsychiatric
and neuroimaging data are also briefly discussed. Distinguishing features of both FTD and AD are
described in order to present a comprehensive clinical picture of these dementing diseases, which
is essential for the process of differential diagnosis. The cause of specific cognitive deficits is also
considered. Our comprehensive review of the empirical literature reveals that AD is characterized by
early memory loss and visuospatial problems, while among the main features of FTD are behavioral
abnormalities and executive dysfunctions.
KEY WORDS: frontotemporal dementia; Alzheimer’s disease; neuropsychological tests; differential diagnosis.
including frontal lobe degeneration of non-Alzheimer’s
type (Brun, 1987; Gregory et al., 1997; Gustafson, 1987;
Risberg, 1987), frontal lobe degeneration (Miller et al.,
1991), and dementia of frontal type (Neary et al., 1988).
These diagnostic labels were initially coined mostly for
the behavioral presentation but later on were also used to
describe other components of the disease (Kertesz et al.,
2003b).
Recently, it has been shown that some cases of FTD
present initially with comprehension and naming problems accompanied by a general loss of the meaning of
words (Hodges, 2001). This constellation of symptoms
with disproportionate language impairment is now recognized as semantic dementia (SD) (Snowden et al., 1989).
Because neuroimaging typically shows atrophy involving
the anterior temporal lobes, SD is often defined as the
temporal variant of FTD (tv-FTD). Except severe multimodal naming and comprehension deficits, the cognitive
profile of SD is also characterized by unique memory
problems. SD patients have difficulty with recall of remote memories, while their day-to-day (episodic) memory is typically preserved (Hodges, 2001). Interestingly,
many other cognitive processes like phonological and syntactic aspects of language, working memory, non-verbal
problem solving, visuospatial and frontal executive functions are relatively preserved, at least during the early
stages of the disease (Thompson et al., 2004). Although
INTRODUCTION
Both frontotemporal dementia (FTD) and
Alzheimer’s disease (AD) have been recognized as
distinct clinical syndromes for a number of years. In
1892, Arnold Pick described a patient with a unique
dementing disease. The autopsy revealed frontotemporal
lobar degeneration (FTLD) and argentophilic intranuclear
inclusions (Pick bodies) (Mendez and Cummings, 2003).
During the following years, a number of cases with
similar pathological and clinical findings were reported
(Hodges, 1994; Tissot et al., 1985). It subsequently
turned out that only a small subset of cases of frontal
lobe degeneration were, in fact, associated with Pick
cells and Pick bodies (Brun, 1987; Gregory et al., 1997;
Neary et al., 1988). Rather, the postmortem examination
of the brains of these cases often revealed only neuronal
loss, gliosis, tangles, or a combination of these changes
(Kersaitis et al., 2004; Taniguchi et al., 2004). Moreover,
it has later been shown that Pick bodies may also be found
in other neurodegenerative conditions (Halliday et al.,
2005). As a result, many other terms were proposed,
1 Institute
of Psychology, University of Gdansk, Gdansk, Poland.
whom correspondence should be addressed at Institute of Psychology, University of Gdansk, ul. Pomorska 68, 80-343 Gdansk, Poland;
e-mail: mharciarek1@wp.pl.
2 To
131
C 2005 Springer Science+Business Media, Inc.
1040-7308/05/0900-0131/0 132
the pathological correlates of SD include bilateral atrophy of the anterior temporal neocortex (Hodges, 2001),
the clinical manifestations (loss of word meaning versus
object recognition difficulties) appear to correlate with
involvement of the left versus right temporal atrophy seen
on magnetic resonance imagining (MRI) (Rosen et al.,
2002a).
Subsequently, some cases with frontal pathology
accompanied by progressive nonfluent aphasia were reported and labeled as primary progressive aphasia (PPA)
(Kertesz and Munoz, 2003; Mesulam, 1982, 1987; Selnes
and Harciarek, in press). However, there is growing evidence that many of the clinical and pathological features
of PPA and FTD overlap with each other (Kertesz, 2004).
Moreover, the identification of mutations in the gene encoding the microtubule-associated protein tau in the inherited forms of FTD and Parkinsonism linked to chromosome 17 (FTDP-17) established an association between
tau mutations and neurodegenerative syndromes (Hutton,
2001). Some patients diagnosed with FTD have prominent
extrapyramidal features similar to what is typically seen in
patients with corticobasial degeneration (CBD) and progressive supranuclear palsy (PSP) (Kertesz, 1997). Interestingly, recent studies have shown that among patients
with CBD and PSP, many had either language deficits or
behavioral and personality changes associated with FTD
(Kertesz et al., 2000). The above suggests a significant
overlap among FTD, CBD, and PSP both clinically and
pathologically. There is also evidence that FTD and PPA
may be associated with motor neuron disease (MND), as
well as cases of MND like amylotrophic lateral sclerosis
(ALS) related to frontal type of dementia (Neary et al.,
1990).
Presently, FTD is the preferred term used to describe
a spectrum of non-Alzheimer’s degenerative conditions
associated with focal atrophy of the frontal lobes and/or
temporal lobes (Bozeat et al., 2000). However, unlike the
recently proposed term “Pick Complex” (which is a concept intended to unify the overlapping syndromes of FTD,
PPA, SD, CBD, PSP, and FTD-MND), the label FTD
does not encompass the extrapyramidal apractic disorders (Kertesz, 2003; Kertesz et al., 2003b). Based on neuroimaging studies, there are two principal variants of FTD:
frontal variant of FTD (fv-FTD) and tv-FTD. The former
is usually characterized by early behavioral disorders and
executive dysfunction, the latter by significant language
and semantic impairments (Gregory, 1999; Grossi et al.,
2002; Hodges, 2001; Hodges et al., 1992). However, not
only the clinical presentation but also the neuropathology
of frontotemporal degeneration is variable and the distinction between variant with Pick bodies, specific genetically linked disorders, and other tau-opathies should be
Harciarek and Jodzio
made (Grossman, 2002). Importantly, although the neuropathology of FTD seems to be relatively diverse, there
is no amyloid accumulation associated with this type of
dementia, which at the postmortem examination helps in
distinguishing FTD from AD (Gustafson et al., 2004).
FTD is considered to be one of the most common
neurodegenerative dementia syndrome after AD and dementia with Lewy bodies (Kertesz, 2004). The mean age
of onset of FTD is about 52 years, and the syndrome
may be somewhat more common in men than women
(Ratnavalli et al., 2002). The specific cause of FTD is still
unknown, but some investigators suggest that a positive
family history of similar dementia might be one of the
significant risk factors (Mendez and Cummings, 2003).
Among other risk factors, thyroid disease and head trauma
accompanied by loss of consciousness have been proposed
(Rosso et al., 2003). The clinical course of FTD can be
divided into three stages and begins with significant personality and behavioral alternations, lack of awareness,
and poor judgment (Rossor, 1999). The second stage is
characterized by increasing cognitive problems with language deficits being the most prominent. Patients often
become aphasic and progress to complete muteness (third
stage). Although the usual survival after symptom onset
for FTD is about 10 years, in patients with FTDP-17 or
those with MND the duration of the disease may be a
bit shorter (Pasquier and Delacourte, 1998). The cause of
death among these patients is often sudden and unexpected
(Pasquier et al., 2004).
A few years after Arnold Pick had described his patient with FTLD, Alois Alzheimer observed a 51-year-old
woman who had impaired memory, topographical disorientation, persecutory delusions, and language abnormalities including dysnomia, paraphasias, and poor comprehension (Mendez and Cummings, 2003). After 4.5 years
of gradual deterioration, the patient died. Autopsy revealed marked atrophy of her entire brain. Microscopic
studies disclosed cortical cell loss, neurofibrillary degenerative changes in many neurons, and neuritic plaques
across the cortex (Mendez and Cummings, 2003). These
clinical and pathological findings remain to this day the
core basic features of AD.
Although the underlying cause of AD is unknown,
there are some putative risk factors that include family
history of AD, head trauma, low educational level, family
history of Down’s syndrome (Mendez and Cummings,
2003), and smoking (Ott et al., 1998; Rosso et al., 2003).
However, the highest and the most documented risk factor of AD seems to be the age. Many investigators show
that AD is the most prevalent form of dementia in the
elderly throughout the world with its onset usually after
age 65. Some data also suggest that AD affects women
Differential Diagnosis
more frequently than men, and there are higher rates for
AD among African-Americans compared to Caucasians
and Africans (Hendrie et al., 1995; Heyman et al., 1991;
Mendez and Cummings, 2003; Ogunniyi et al., 1992). Patients with an APOE e4 genotype, coded on chromosome
19, have a higher risk of AD and present with 3–7 years
earlier onset of the disease than patients who are homozygous for APOE e3 or APOE e2 (Dal Forno et al., 2002;
Goldstein et al., 2001; Heyman et al., 1996; Mendez and
Cummings, 2003).
Similarly to FTD, the clinical course of AD also can
be divided into three stages. In AD, memory difficulties
are among the first and the most striking cognitive manifestations of the disease. The preclinical stage of AD
is characterized by mild and isolated memory problems
recently labeled as “mild cognitive impairment” (MCI)
(Petersen, 2003). Importantly, although patients with MCI
do not meet criteria for dementia, many of them will meet
criteria for AD as additional cognitive deficits emerge
with time. As the disease progresses, other symptoms
like agnosia, aphasia, and apraxia may appear (second
stage); thus eventually progressing to a more severe dementia, with weight loss, motor impairment, and death
(third stage) (Bullock and Hammond, 2003). The median
duration of AD is approximately 10 years but the range can
be variable and patients may survive from 2 up to 20 years
since the first symptoms appear (Wolfson et al., 2001).
Currently, there are approximately 4.5 million people
affected by AD only in the United States (Hy and Keller,
2000). But despite its high prevalence, it is still difficult for
health care providers to differentiate possible or probable
AD from FTD at the very early stages of the disease.
The accurate diagnosis of dementia subtypes has not
only psychological consequences for the patients and their
caregivers but also a major influence on the choice of pharmacological treatment. Although acetylcholinesterase inhibitors may improve cognitive deficits in AD, they do not
appear to have similar benefits in FTD patients (Procter
et al., 1999). Moreover, in FTD behavioral symptoms like
aggressiveness, disinhibition, or verbal outbursts can be
well controlled by small doses of antipsychotics, while
similar pharmacological treatments may contribute to additional cognitive decline in AD (Mendez and Cummings,
2003).
The purpose of this review is to describe both similarities and differences in neurocognitive functioning, behavior, and neuroimaging in these two forms of dementia,
particularly during the early stages of the disease. A comprehensive clinical evaluation includes neuropsychiatric
assessment (i.e., interview with family members or caregivers), neuropsychological testing, and neuroimaging
(Hodges, 2001). A complete neurologic examination is
133
also important because cognitive symptoms can be associated with MND (ALS), producing one of the most
common subtypes of dementia of frontal type. It is especially important if the disease progresses rapidly and
if bulbar symptoms develop since the identification of
additional language impairment like aphasia or mutism is
very important for the appropriate management of such
patients (Bak and Hodges, 1999; Hodges, 2001; Rakowicz
and Hodges, 1998).
CLINICAL CHARACTERISTICS
Although there are no definitive laboratory tests for
either AD or FTD, specific clinical criteria for these
diseases have been proposed. For the diagnosis of AD,
there are at least two sets of clinical criteria. The first
and commonly used is described in the Diagnostic and
Statistical Manual-IV (DSM-IV) (American Psychiatric
Association, 2000). In order to meet the DSM-IV criteria,
the patient must have not only memory impairment but
also a deficit in at least one other cognitive domain, including praxis, visuospatial, language, or executive function. The symptoms of cognitive impairment should be
present for at least 6 months and must be severe enough
to have an impact on social, occupational, or other daily
functions.
The second broadly used criteria for the diagnosis of
“probable AD” was developed by the National Institute of
Neurologic and Communicative Disorders and Stroke and
the AD and Related Disorders Association Work Group
(NINCDS-ADRDA) (McKhann et al., 1984). The diagnosis requires documentation of dementia with at least two
areas of cognition being impaired: a progressive deterioration in these cognitive deficits, onset between age 40 and
90, the absence of delirium, and the completion of a negative work-up for other dementing diseases. The same set of
criteria also describes “possible AD” if there is a comorbid
systemic or brain disorder not thought to be the cause of
the dementia, or a progressive deficit in only one cognitive
domain (McKhann et al., 1984; Mendez and Cummings,
2003). However, even if these formal clinical criteria are
met, the neuropathological examination may not always
be consistent with AD. Some studies have found that the
accuracy of clinical diagnosis was between 50% and 60%
(Mendez et al., 1992). The same studies also found that
using DSM-IV criteria together with NINCDS-ADRDA
set can improve the accuracy of the clinical diagnosis to
85–95%, but postmortem examination of the brain is still
necessary to confirm a diagnosis of definite AD.
Similar difficulties with diagnostic criteria and
accuracy of clinical diagnosis can be seen in FTD. In
134
this syndrome, personality changes may play a very
important role, sometimes overshadowing the cognitive
deficits (Mendez and Cummings, 2003; Pasquier and
Delacourte, 1998). The diagnose of FTD is often based on
the Lund and Manchester clinical criteria (The Lund and
Manchester Groups, 1994) and frontotemporal atrophy
as seen on neuroimaging (Boccardi et al., 2002, 2003;
Varma et al., 2002). The core of the Lund and Manchester
diagnostic features for FTD consists of insidious onset
with slow progression; early loss of insight; early signs
of disinhibition; loss of mental flexibility; stereotyped,
perseverative and utilization behavior; hyperorality;
distractibility, and impulsivity. Although these features
were based on a group of over 60 patients and were
proposed by clinicians highly experienced with FTD,
clinicians may still fail to recognize FTD or may
misdiagnose it as AD (Halliday et al., 2002; Litvan et al.,
1997; McKahnn et al., 2001; Mendez and Cummings,
2003; Mendez et al., 1993). This is mostly because the
features listed above may have high sensitivity but are
often associated with poor specificity (Grossman, 2002).
For instance, Miller et al. (1997) showed that criteria like
loss of personal awareness, hyperorality, stereotyped and
perseverative behavior, progressive reduction of speech
were particularly useful in differentiating FTD from AD.
Conversely, items relating to affect and physical findings
failed to discriminate between these two dementing
disorders. Moreover, the same investigators suggested
that Lund and Manchester criteria should be modified to
take into account the time course of the symptoms.
A study of differentiation of AD and FTD using NINCDS-ADRDA criteria found that these criteria
did not accurately distinguish the two disorders (Varma
et al., 1999). Most patients with FTD fulfilled NINCDSADRDA criteria for AD, suggesting that the specificity
of these diagnostic set of criteria could be improved. The
mini mental state examination (MMSE) (Folstein et al.,
1975) does not appear to be a useful tool for screening
patients with FTD, since even severely impaired FTD patients can have a relatively normal MMSE (Gregory and
Hodges, 1996a,b; Grossman, 2002; Miller et al., 1991).
In a series of prospective studies by Gregory and Hodges
(1996b), the majority of FTD patients scored above the
classic cut-off of 24, while approximately one third of
all FTD subjects obtained a maximum of 30/30. Even
with impaired MMSE performance, it may still be difficult to differentiate between FTD and AD. For example,
MMSE relies heavily on language. Therefore, the low
scores obtained by some of FTD patients may be caused
by language impairment as well as executive dysfunction.
Conversely, in AD, MMSE scores are usually low because
of early memory impairment as well as problems with
Harciarek and Jodzio
executive function (Kertesz et al., 2003a; Lezak, 1995).
Although Clock Drawing Test (CDT) is another widely
used example of a sensitive instrument to detect early
cognitive decline in neurodegenerative diseases, this tool
also seems to have a relatively poor specificity for distinguishing between FTD and AD. This might be due to the
fact that CDT engages not only visuospatial and constructional abilities but also conceptual and executive functions
(Mendez and Cummings, 2003). However, in a study by
Cahn-Weiner et al. (1999), CDT showed significant associations with tests of semantic knowledge, executive
function, visuoconstruction, and receptive language in AD
subjects. Moreover, Rascovsky et al. (2002) revealed that
AD patients perform poorly on CDT, while FTD subjects
are typically less impaired on this particular measure. Interestingly, Kertesz et al. (2003a) have suggested that the
behavioral quantitation may be more sensitive than neuropsychological testing in detecting FTD. This suggests
that screening tests such as the MMSE or CDT may not be
particularly helpful in the differential diagnoses and that
use of other more specialized neuropsychological methods in combination with behavioral inventories and neuroimaging may be needed. Nevertheless, both FTD and
AD can potentially be clinically distinguishable based on
some specific deficits described below.
MEMORY IMPAIRMENT
AD is characterized by an insidious onset and gradual
progression of memory loss and other cognitive changes
(Katzman, 1986; Lange et al., 2002). AD patients have
difficulty with memory of recent events, presumably due
to their inability to encode and store information for later
recall (Knopman and Selnes, 2003).The loss of newly
learned verbal information is one of the defining aspects
of the memory disturbance in AD (Kaltreider et al., 2000;
Welsh et al., 1992). Among the most frequently used
measures aimed at specific evaluation of these deficits are
Auditory-Verbal Learning Test (AVLT), California Verbal
Learning Test (CVLT), and Hopkins Verbal Learning TestRevised (HVLT-R) (Lezak, 1995). The early occurrence
of episodic memory impairment in AD is consistent with
neuropathologic and neuroimaging evidences, suggesting
that the entorhinal cortex and hippocampus are affected in
the earliest stage of the disease (Braak and Braak, 1991;
Hyman et al., 1984; Jack et al., 1992; Killiany et al., 1993;
Lange et al., 2002). In validation studies of the well-known
neuropsychological battery used in The Consortium to
Establish a Registry for Alzheimer’s Disease (CERAD),
delayed recall of a word list was the best discriminator
between subjects with AD and normal control subjects,
Differential Diagnosis
and one of the few CERAD variables which consistently
identified those in the early stages of AD (Kaltreider et al.,
2000; Welsh et al., 1992). Many other studies have also
suggested that list learning and recall seem to be impaired
relatively early in AD (Fox et al., 1998).
The neuropsychological features of FTD overlap to
some extent with those of AD, since both FTD and AD
patients may have problems in encoding and retention of
newly learned verbal information in the earliest stages of
disease (Broe et al., 2003). Nevertheless, FTD patients
tend to be less impaired than AD patients on some tests of
memory (Rascovsky et al., 2002). However, verbal and visual memory deficits appear to be present in FTD patients
as well (Strong et al., 2003). The differences between FTD
and AD may not relate only to the severity of forgetting
symptoms but also to the different types of memory impairment. For instance, FTD patients performing significantly better than AD patients on word-list learning, and
delayed verbal recall (Diehl and Kurz, 2002). In addition,
there is some evidence to suggest that AD patients may
have impaired access to semantic representation even in
the earliest stages (Chan et al., 1995; Martin and Fedio,
1983; Nebes, 1989). This finding might explain why AD
subjects are often able to recall only the last presented
words on tasks of verbal learning (the recency effect)
(Lezak, 1995). Semantic deficits seen in AD seem to influence the performance on recognition trial as well. On
the HVLT-R, patients with AD often tend to make falsepositive identifications, particularly of nontarget words
that are semantically related to the targets (Brandt and
Benedict, 1998). These differences in access to semantic representation may be useful in distinguishing FTD
patients from AD patients, early in the course of the dementia. The memory changes seen in FTD may be in
part due to frontal-executive impairments such as lack of
active strategies for learning and retrieval (Mendez and
Cummings, 2003). The same authors suggest that in FTD
there is a relative preservation of recognition compared to
free recall. Unlike patients with AD, FTD patients are also
able to use cues or production priming to improve memory
and appear to have lower rates of forgetting (Mendez and
Cummings, 2003).
There are some data to suggest that in the first stage of
AD, patients often do not have problems with retrieval of
old remote memories, and perceptual memory also seems
to be preserved (Jodzio and Lenart, 2003). However, some
investigators claim that it is not unusual even for patients
early in the course of AD to show impaired performance
on tests of autobiographical memory, although the degree
of this impairment is certainly less than that seen on test
of anterograde memory (Gregory and Hodges, 1996b).
Tallberg (2001) has argued that the retrieval problems in
135
AD are the consequence of poor encoding and storage
of recent episode memories, while in FTD (particularly
the right hemisphere variant) this can be due to problems with disinhibition. However, Gregory and Hodges
(1996b) have provided alternate explanations of the progressive amnestic disorder seen in AD, showing that it
can be followed by breakdown in attentional, perceptual,
and visuospatial abilities. These investigators have argued
that the deficits found on tests of semantic memory are
due to a breakdown in the structure of semantic memory.
According to Gregory and Hodges (1996b), this hypothesis is supported by previous research using a battery of
tests of semantic memory which tests knowledge about
the same consistent set of items via differing modalities
of sensory input and/or output. Based on that, the authors
have established that the majority of patients presenting
with even minimal AD (MMSE > 24) show impairment
on tests of semantic memory. This is particularly true as
the disease progresses into the moderate stage (MMSE <
18) and becomes a ubiquitous finding which is reflected in
the increasing anomia, emptiness of language, and failure
on general knowledge tests. The above explanation is also
consistent with the major locus of pathology seen in AD,
namely the medial temporal lobe.
In conclusion, the qualitative analyses of the memory
impairment seem to be helpful in distinguishing FTD from
AD. In the early stages of the disease, FTD patients tend
to have better performance on word-list learning and the
delayed verbal recall than AD patients who may be more
likely to have impaired access to semantic representations.
Well-preserved recognition memory among FTD patients
can also be a helpful feature for the differential diagnosis.
LANGUAGE ABNORMALITIES
Both AD and FTD typically present with language
disturbances but the profile of linguistic abnormalities
may be somewhat different in these syndromes. Although
in the first stage of AD, memory deficits may overshadow
the language problems, there is evidence of an early
anomia as well (Galton et al., 2000). At the beginning of
AD, patients are often unable to retrieve words and show
poor word-list generation, especially for a given semantic
category (Cerhan et al., 2002). Early in the course of the
illness, conversational speech is usually well preserved
(Jodzio, 1999), but in the mid-stage AD, naming difficulty
typically becomes more pronounced (usually measured
with the Boston Naming Test), and spontaneous speech
becomes increasingly empty (Mendez and Cummings,
2003). However, in this kind of dementia object naming
seems to be impaired to a significantly greater extent than
136
action naming (Williamson et al., 1998). With further
progression of AD, impaired comprehension of speech
and writing with relatively preserved verbal repetition
and reading aloud is often seen. This suggests a clinical
picture similar to that of transcortical sensory aphasia
(Gates et al., 2002; Mendez and Cummings, 2003).
Progressive deterioration involves semantic aspects,
grammatical complexity, and prepositional content but
basic syntactic and phonologic aspects of language seem
to be less vulnerable in AD (Backman and Small, 1998;
Harasty et al., 2001; Kemper et al., 2001). In the more
severe stage of AD, additional speech disturbances can
also appear. Among the most common are echolalia,
logoclonia, and in some cases even complete mutism
may occur (Mendez and Cummings, 2003).
The language abnormalities associated with FTD appear more variable, in part because of the distinct frontal or
temporal variants that can occur, as well as the asymmetric
cortical atrophies. In general, FTD patients tend to have
decreased verbal output that may progress to complete
mutism (Snowden et al., 1992). One of the most sensitive early measures of language impairment in FTD is
verbal fluency measure, particularly the word generation
beginning with the same letter (Kertesz, 2003). The speech
output is usually characterized by aspontaneity, decreased
conversation with impoverished utterance (single word
or short phrase) as well as decreased verb comprehension (Mendez and Cummings, 2003; Rhee and Grossman,
2001). Dysexecutive problems seen in FTD can also have
an impact on tasks like action naming on which FTD
patients are particularly impaired (Cappa et al., 1998).
Ostberg et al. (2001) suggest that pressure of speech can
also occur on rare occasions. Patients often interrupt,
monopolizing a conversational interchange, or manifest
a jargonaphasia. Many FTD patients present reiterative
speech disorders such as logoclonic, festinant speech,
palilalia, echolalia, and verbal stereotypy, or prominent
automatic speech (Mendez and Cummings, 2003) what
often can make them similar to AD patients. Among the
early symptoms of FTD can be empty speech, semantic anomia, better written naming than oral naming, and
difficulty with sentence comprehension that can be due
to impaired processing of grammatical structure (Cappa
et al., 1998; Grossman et al., 1996; Tainturier et al., 2001).
Some patients with FTD and AD present with a
progressive aphasia (Grossman, 2002; Jodzio, 1999). Although these patients do not present with deficits restricted
to a single domain of impaired functioning, more detailed
characterization of the language dysfunction can play an
important role in finding clues to the underlying nature
of the patient’s decline. Also cases of anomic aphasia
or SD are initially very similar to the language impair-
Harciarek and Jodzio
ment of AD, only multimodal loss of semantic knowledge
can help to classify these patients independently (Kertesz,
2004; Snowden, 1999). Moreover, language abnormalities
seen in SD also often overlap with FTD, emphasizing that
their description deserves special attention and should be
discussed separately.
In summary, language problems are often seen in AD
and FTD. Both dementing diseases can lead to aphasia
with preserved repetition abilities. Although the occurrence of transcortical aphasia and word-finding problems
seems to be equally common for both conditions, FTD
patients are more likely to present with impoverished
spontaneous speech. In contrast, AD subjects have more
severe comprehension difficulties and their discourse is
usually disturbed. The different pattern of language abnormalities seen in AD and FTD can therefore be a helpful
feature distinguishing between these two kinds of dementing diseases and should be taken into account during the
neuropsychological evaluation.
ATTENTION/EXECUTIVE IMPAIRMENT
Although both AD and FTD patients appear to have
impaired executive functions, these deficits appear to be
much more subtle in patients with AD. Lindau et al.
(2000), for instance, examined AD and FTD patients
with a battery of neuropsychological tests. The results
showed that FTD group exhibited significantly greater
impairment on executive tasks compared to AD subjects.
However, Gregory and Hodges (1996b) assumed that although the performance of FTD patients on executive
tasks such as Wisconsin Card Sorting Test, Trail Making
Test, Stroop Test, Shallice’s Cognitive Estimates Test, and
Verbal Fluency (FAS) is often markedly impaired, there
are many FTD subjects with severe neurobehavioral abnormalities but relatively normal neuropsychological profile. Also some recently conducted studies did not find a
difference on executive measures when these groups of patients were directly compared (Grossman, 2002; Kertesz
et al., 2003a). Pachana et al. (1996) performed withingroup comparisons and found that FTD patients were
more impaired in the executive functioning (FAS, Stroop
Test) than their memory performance (Rey–Osterrieth
Complex Figure delayed recall), while AD subjects exhibited the reverse pattern. The profile of performance on
verbal fluency task can be another distinguishing feature
in early differential diagnosis. FTD patients (especially
with fv-FTD) tend to generate less words beginning with
the letter “f,” “a,” and “s” in comparison to the total
number of words generated with a given semantic category (animals, supermarket), while the opposite pattern
Differential Diagnosis
is usually observed in AD (Gregory and Hodges, 1996b;
Lezak 1995; Mendez and Cummings, 2003). These findings are particularly valuable because they underline the
importance of within-subject comparisons instead of analyzing the performance on executive tasks alone. Although both AD and FTD patients generally present with
impaired insight, planning, goal-oriented behavior, abstraction, and judgment (Mendez and Cummings, 2003),
there is some evidence to suggest that even subjects with
fv-FTD may sometimes perform at the relatively normal
level on goal-oriented tasks requiring planning such as
Tower of London (Rahman et al., 1999). Patients with
FTD are usually concrete when tested on proverb interpretation and tests assessing comprehension of differences
and similarities. Loss of awareness of their disabilities or
the consequences of their behavior is also often seen in
FTD and AD (Mendez and Cummings, 2003).
There is some evidence to suggest that FTD patients
have deficits in the area of attention that can range from
mild to severe (Neary et al., 1986) but not all investigators
have confirmed this (Miller et al., 1991). AD patients often
display impairments in sustained or divided attention, disengagement of attention, impaired working memory, set
changing, response inhibition, and motor programming
(Baddeley et al., 2001; Cherry et al., 2002; Mendez and
Cummings, 2003). AD patients are also less motivated
than normal, which results in decreased initiation of activity (Friedland et al., 2001; Mendez and Cummings,
2003). However, the last finding seems to be equally true
for FTD patients as well. Changes in attention may be
one of the earliest cognitive manifestations of AD, with
impaired performance on tasks like Digit Span, Symbol
Digit, and Stroop Test (Lezak, 1995). Foldi et al. (2002) as
well as Jodzio and Lenart (2003) showed that the severity
of AD is strongly correlated with decline in performance
of measures of attention. These investigators attribute a
disruption of attentional functions due to increased load of
a task. Moreover, Jodzio (1999) and others have suggested
that attentional deficits may have a marked influence on
performance in other cognitive domains such as memory,
visuospatial functions, and language.
In a study by Perry and Hodges (2000), the assessment of attention/executive function was found to aid the
early differentiation of FTD and AD. Lindau et al. (2000)
also suggested that loss of executive function can be a distinguishing feature and is more common in FTD than AD
even in the very early disease stage. However, AD patients
are often impaired on executive tasks like Trail Making
Test B (Chen et al., 2000) but not to the same extent as
FTD patients. Attention/executive function testing is also
very useful in differentiating tv-FTD from fv-FTD. The
above study by Perry and Hodges showed well-preserved
137
attention and executive function in group with tv-FTD,
while patients with fv-FTD were very impaired in this
domain. Lately, quantifiable tasks that involve processes
like decision making and risk taking have been developed
(Hodges, 2001; Rahman et al., 1999). These tests are sensitive for detecting orbitobasial frontal function and are
based on the ability to make inferences about the mental
state of others, which can be especially useful for the
differential diagnosis.
In conclusion, although changes in attention are believed to be one of the earliest cognitive manifestations
of AD, FTD subjects are relatively more impaired on executive functions tasks requiring planning. Patients with
fv-FTD have particularly severe difficulties on tests of
attention and executive function, especially when compared with other cognitive tests scores. Therefore, the
assessment of deficits in these domains facilitate not only
the early differentiation of FTD and AD, but can also
distinguish fv-FTD from tv-FTD as well.
VISUOSPATIAL IMPAIRMENT
Perhaps one of the most striking neuropsychological
features is how well FTD subjects perform on visuospatial
tests. Studies using the CERAD-NP have shown that FTD
patients perform consistently better than AD subjects on
measures of visuospatial construction (Diehl and Kurz,
2002) thus confirming that patients with FTD tend to be
less impaired than AD patients on some tests of visuospatial abilities (Rascovsky et al., 2002). However, a study
conducted by Pachana et al. (1996) showed that FTD subjects had mild impairments in constructional skills that
could be attributed to poor planning or lack of strategy.
Visuospatial deficits are among the earliest manifestations of AD. Patients have particular problems with
drawing, constructions, and orientation in their own surrounding (Mendez and Cummings, 2003; Mendez et al.,
1990b; Smith et al., 2001). Although the previously described CDT is one of the most widely used instruments
sensitive to visuospatial impairment, it is often applied as
a general measure of cognitive decline since it engages
more than visuospatial functions. Copying tasks also do
not appear to reliably distinguish between FTD, especially
its frontal variant, and AD. Grossi et al. (2002) reported
a study in which fv-FTD and AD at mild and moderate
stage of the disease had similar scores on copying tasks,
presented similar drawing procedure in copying Rey Complex Figure, and made nearly the same quantitative and
qualitative pattern of errors in copying simple geometric
drawings. They also did not find a significant difference on
a specific battery for visuospatial abilities. These results
138
suggest that basic visuospatial and constructional skills
may not be a differentiating sign in diagnosis of AD or
FTD. Moreover, authors suggest that the clinical belief
of preserved spatial abilities in fv-FTD is due to the lack
of topographic disorientation in comparison to AD. However, Hodges (2001) and Warrington and James (1991)
explain that the poor performance on copying Rey Figure
by FTD patients is caused by the impulsiveness and a
poor strategy formation. Furthermore, these subjects can
perform perfectly on subtests of the Visual Object and
Space Perception Battery even at an advanced stage of the
illness (Hodges, 2001).
In summary, in contrast to AD patients, FTD subjects usually perform relatively well on measures of visuospatial abilities. Visuospatial deficits are among the
first manifestations of AD, thus making AD patients significantly impaired on tests like CDT and Rey Complex
Figure. Hence, the differential diagnosis should be based
not only on the results of memory, language, and attentional/executive function tasks, but should also take into
account the assessment of visuospatial abilities as a reliable measurement distinguishing AD from FTD.
BEHAVIOR AND PERSONALITY CHANGES
Another distinguishing features are the behavioral
and personality changes. These symptoms are different
in FTD and AD, particularly during the early stages of
the disease. In the early stages of AD, usually neither
personality nor social behavior are significantly altered,
whereas there is a considerable range of such changes
seen in FTD patients (Bozeat et al., 2000). The slow development of mood abnormalities in AD can often cause
the underestimation of the cognitive disabilities.
Another distinguishing feature is the affective profile. As the disease progresses, most AD patients become indifferent and increasingly apathetic (Mendez and
Cummings, 2003), while patients with FTD are more
likely to be impulsive and disinhibited, with a decline
of social and interpersonal skills (Bozeat et al., 2000;
Mendez and Cummings, 2003). Mychack et al. (2001)
suggest that the early appearance of socially inappropriate behavior in FTD might help differentiate patients
with predominantly right-sided from left-sided degeneration. Their results emphasize the importance of right
frontotemporal regions in the mediation of social behavior. Nonetheless, as the disease progresses, there may be
considerable overlap in personality and behavior changes
seen in FTD and AD patients. Although many AD patients
develop apathy, others are prone to euphoria and loss of
anxiety. The lack of awareness of their impairment can
also be apparent in many cases (Mendez and Cummings,
Harciarek and Jodzio
2003). However, the same authors suggest that patients
with AD might be also aggressive, irritated, anxious, and
present a limited impulsive control. The more the disease progresses, the more apparent these personality and
behavioral changes become. In advanced stages of AD,
aggression can not only be verbal but also sometimes be
physical (Mendez and Cummings, 2003; Mendez et al.,
1990a). A study using the Columbia University Scale for
Psychopathology in Alzheimer’s Disease found that the
symptoms of psychopathology in AD change somewhat
over time (Devanand, 1999), with agitation being the most
frequent and persistent symptom. Consistent with previous findings, agitation, aggression, and disinhibited behaviors may appear during the later stages of the illness.
No association was found between depressive features and
either cognitive or functional impairment among patients
with AD (Devanand, 1999).
Other emotional disturbances, such as depression,
can be also seen among both AD and FTD patients
(Mendez and Cummings, 2003). Although the frequency
of depression in AD has been reported to occur in up to
87% of patients (Wragg and Jeste, 1989), most of these
patients have mild dysthymia rather than major depression
(Mendez and Cummings, 2003). Patients with FTD have
lower prevalence of depression in comparison with AD
patients (Levy et al., 1996) but disturbances like mania,
anger, and irritability appear to be very common in this
type of dementia (Mendez and Cummings, 2003; Miller
et al., 1991). It is still unclear how often cognitive decline
may mask depression and to what extent depression itself
can impair cognitive performance on neuropsychological
testing.
Delusions appear in almost half of the AD patients
(Wragg and Jeste, 1989) and occur more frequently in the
middle stage of AD, accompanied by progressive cognitive decline (Mendez and Cummings, 2003). Patients
with AD often develop paranoia and suspiciousness which
may be related to right medial temporal lobe dysfunction
(Geroldi et al., 2000). They sometimes misinterpret the
behavior of their family members or caregivers, and this
may be less common among patients with FTD. Nevertheless, there have been FTD patients with an initial
schizophrenia-like psychosis or psychotic affective disorder (Mendez and Cummings, 2003). Rankin et al. (2003)
tried to differentiate FTD from AD on the basis of both
degree and type of personality changes using the Interpersonal Adjectives Scales. Interestingly, they found distinctly different patterns of change in social functioning
in two subtypes of FTD: patients with temporal variant
shifted toward severe interpersonal coldness with mild
loss of dominance, whereas patients with frontal variant
showed the opposite pattern.
Differential Diagnosis
Compulsive-like behavior are often seen in patients
with FTD (Mendez and Cummings, 2003). In a study by
Miller et al. (1997), stereotypical and preservative behaviors were among the five features that best discriminated
AD from FTD. Unfortunately they did not distinguish between fv-FTP and tv-FTP. In a more recent study, Bozeat
et al. (2000) found stereotypic and altered eating behaviors but also loss of social awareness to be distinguishing
between AD and FTD patients regardless of disease severity. The results showed increased rigidity and depression
in patients with tv-FTD (SD) compared to those with
fv-FTD. Conversely, the fv-FTD group revealed greater
disinhibition. Mendez and Cummings (2003) describe the
most common preservative and stereotyped behaviors in
FTD. They consist of simple repetitive acts and verbal or
motor stereotypies, such as lip smacking, hand rubbing
or clapping, counting aloud, humming, wandering a fixed
route, and collecting and hoarding objects.
Both AD and FTD patients can have problems with
demonstrating and identifying basic emotions. Lavenu
et al. (1999) had AD patients, FTD patients, and control
group recognize and point out the name of one of seven basic emotions (anger, disgust, happiness, fear, sadness, surprise, and contempt) for a set of 28 faces. The three groups
were equally able to distinguish a face displaying effect
from one not displaying effect. The investigators found
that naming of emotion was worse in patients with FTD
than in patients with AD who did not differ significantly
from control subjects. Anger, sadness, and disgust were
less often recognized in FTD than in AD patients who did
not differ from normal participants, whereas fear and contempt were poorly recognized by both groups of patients
compared with control subjects. They also showed that
patients with FTD are frequently unable to demonstrate
these basic emotions and that the perception of facial and
vocal emotions is also often impaired in FTD (Mendez
and Cummings, 2003). This seems to be consistent with
Lavenu et al. (1999) who go so far as to the behavioral
disturbance in FTD may be due partly to an impaired
interpretation of the emotional environment.
In summary, there are some behavioral features that
can help to differentiate AD from FTD especially in the
early stages of these diseases. Although most FTD patients present with impulsiveness and disinhibition, some
of them seem to be indifferent and apathetic as well. Nevertheless, indifference and apathy are mainly observed
in AD. However, in contrast to FTD, AD subjects are
usually very anxious and suspicious often developing
paranoia. Moreover, AD patients present with other psychopathological syndromes like hallucinations and delusions, which can be the useful features in distinguishing
between AD and FTD. AD patients are also less likely
139
to develop stereotypical and preservative behaviors which
are more often seen in FTD.
NEUROIMAGING FEATURES
Although there is no specific laboratory test either for
AD or for FTD, some neuroimaging methods such as MRI,
computerized tomography (CT), single photon emission
computed tomography (SPECT), and positron emission
tomography (PET) may help clinicians to distinguish AD
from FTD. MRI is more sensitive than CT in evaluating
patients with brain pathology and often can be helpful in
the diagnosis of suspected AD or FTD (Knopman et al.,
1989). However, both AD and FTD patients may have normal results on these scans or show nonspecific generalized
cerebral atrophy with sulcal and ventricular enlargement
or focal atrophy in mesiotemporal regions and hippocampal structures (Mendez and Cummings, 2003). Therefore,
structural neuroimaging may not always be helpful in the
earliest clinical stages (Kirshner, 1999).
In AD, the degree of hippocampal atrophy and/or
volume loss seen on MRI corresponds with the rate and
degree of cognitive decline and amount of hippocampal
pathology on autopsy (Mendez and Cummings, 2003;
Petersen et al., 2000; Wolf et al., 2001).The reduction
of size of the entorhinal cortex and limbic structures can
be also visible on MRI, but these alternations do not seem
to be as evident as the degree of hippocampal volume
loss (Csernansky et al., 2000; Killiany et al., 2000). By
comparison, in patients with FTD, MRI usually reveals
frontal or anterior temporal atrophy, enlargement of the
Sylvian fissures, anterior callosal atrophy, and sometimes
hippocampal and entorhinal volume loss (Friedland et al.,
1993; Frisoni et al., 1999; Kaufer et al., 1997; Kitagaki
et al., 1998; Mendez and Cummings, 2003; Miller et al.,
2000, 1991; Rosen et al., 2002b; Yamauchi et al., 2000).
Degree of entorhinal cortex atrophy does not appear to
be a sufficiently reliable feature to differentiate FTD from
AD, while hippocampal atrophy, which appears to be more
prominent in AD, can be a distinguishing feature (Frisoni
et al., 1999; Laakso et al., 2000). Boccardi et al. (2003)
also tried to identify specific MRI features that could differentiate FTD and AD. They found that FTD patients had
mild atrophy in the hippocampus, severe in the frontal, and
very severe in the temporal lobes. AD patients appeared
to have moderate atrophy in hippocampus and temporal
lobe and very mild in frontal regions. More asymmetrical
atrophy was seen in FTD than AD patients, especially in
the temporal lobes.
Because of its sensitivity, functional MRI (fMRI)
can be also very useful, especially in cases with early
140
onset. Rombouts et al. (2003) reported results of a study
in which patients with FTD and AD had mild cerebral
atrophy on structural MRI with no difference between
these groups. Using a task that requires working memory abilities, the investigators activated a network that,
in both FTD and AD, included frontal, parietal lobe, and
thalamus. In FTD patients, brain activity was significantly
decreased in frontal and parietal cortex. Also, the FTD
group showed less linear activation in frontal regions that
increased with working memory load than in AD group.
There was a stronger response observed in the cerebellum
of FTD patients, which was attributed to a possible compensation mechanism. This study showed that even when
the results of structural MRI are not diagnostic, fMRI can
help differentiate FTD from AD in the early stage of the
disease.
Anatomical (MRI) and functional (SPECT) imaging
of early onset patients with AD and FTD was performed
by Varma et al. (2002). They found that severe frontal
atrophy (unilateral or bilateral) and/or asymmetrical atrophy on MRI, turned out to be highly diagnostic of
FTD. Mild or more severe parietal atrophy with signficant reduction in parietal regional cerebral blood flow on
SPECT was diagnostic of AD. The authors suggest that
the different information provided from MRI and SPECT
and the combination of these modalities can significantly
improve the diagnostic specificity. There are several research studies using SPECT and PET showing decreased
cerebral blood flow and hypometabolism in the frontal
cortex and anterior temporal lobes among FTD patients
(Alexander et al., 1995; Friedland et al., 1993; Mendez and
Cummings, 2003; Miller and Gearhart, 1998). In comparison to FTD, AD patients present decreased metabolism in
parietotemporal regions bilaterally, followed later by reduction in frontal association fields, on PET scan, and decreased cerebral perfusion especially in the posterior parietal cortex presented on SPECT (Masterman et al., 1997;
Mendez and Cummings, 2003; Merello et al., 1994; Wolfe
et al., 1995). Also other findings suggest that SPECT
might be very useful in differentiating FTD from AD
(Charpentier et al., 2000; Lojkowska et al., 2002). Nevertheless, Mendez and Cummings (2003) argue that although PET and SPECT can distinguish AD from normal
or even from some other dementing diseases, the imaging
findings are not specific to AD and may be seen in other
dementing illnesses.
Recently, PET studies with F-fluorodeoxyglucose
(FDG-PET) have been published, showing particular
promise in differential diagnosis (Foster, 2003; Grimmer
et al., 2004; Higdon et al., 2004; Jeong et al., 2005).
Several investigators have demonstrated that although dementing diseases may have overlapping clinical features,
Harciarek and Jodzio
they often have significantly different patterns of regional
glucose metabolism. Moreover, Foster (2003) has claimed
that FDG-PET can be a diagnostic biomarker in clinical identification of FTD, rather than AD, since the high
pretest probability of AD in elderly patients with dementia decreases the possibility of a high likelihood ratio (a
key indicator of the value of a diagnostic test). In studies conducted by Jeong et al. (2005), hypometabolism
in patients with FTD, similar to hypoperfusion seen in
SPECT studies described above, was found mainly in
frontal and anterior temporal regions. These investigators also showed that hypometabolism in FTD subjects
was frequently asymmetrical and lateralized to the left
hemisphere. This pattern was common (90%) and intense
in FTD, even after patients with PPA and SD were excluded from the study. However, although these results
can help to decrease diagnostic errors and hasten accurate diagnosis, imaging will never be substituted for a
careful clinical history and examination. Therefore, the
real diagnostic power of FDG-PET is realized when other
clues like clinical information and structural imaging are
available. Foster (2003) suggests that in some cases use
of FDG-PET may not be crucial to an accurate diagnosis
but can be of significant help when there is an atypical or
incompletely developed presentation.
In summary, several lines of data suggest that temporal atrophy is often seen in both dementing diseases.
However, there is a specific pattern of brain cell degeneration that helps in distinguishing between AD and FTD.
In AD especially medial parts of the posterior cortex
as well as hippocampal structures are initially affected,
while in FTD the severe frontal atrophy, hypoperfusion,
and hypometabolism (mostly in the left hemisphere) in
the frontal regions are mainly observed on neuroimaging.
These findings show that new neuroimaging techniques
are useful tools in the process of differential diagnosis
and should be included in the clinical evaluation.
CONCLUSIONS
Although both AD and FTD are common forms of
dementia, there are no specific tests that can accurately
distinguish these two degenerative diseases. This review
of the literature has aimed to show both similarities and
discrepancies between AD and FTD, especially in the very
early stages of these disorders. Table 1 shows some of the
specific features of AD and FTD that should be taken
into account when formulating the differential diagnosis.
However, caution must be exercised in interpreting separately only behavioral changes, neuroimaging, memory
impairment, or other neuropsychological findings in order
to find a single sign distinguishing AD from FTD. It is
Differential Diagnosis
141
Table 1. Features that Distinguish Dementia of Frontal Type and Dementia of Alzheimer’s Type in the Early Stage of the Disease
Feature
Memory
Frontotemporal dementia
Initially relatively spared
DAT (dementia of Alzheimer’s type)
Impaired encoding and storage of new information
with preserved retrieval of remote memories
Poor recognition
Well-preserved recognition
Language
Verbal fluency
Speech
Comprehension
Repetition
Naming
Attention/executive function
Visuospatial abilities
Behavioral
Neuroimaging findings
Very poor
Better for categories than letters
Decreased spontaneous conversation, stereotyped
speech with shortened phrase length, and
articulation problems
Relatively preserved; noun comprehension > verb
comprehension
Spared
Poor
Severely impaired; loss of planning
Preserved
Early personality changes; more behavioral than
psychotic features
Frequent compulsive—like behaviors
Frontal hemispheric atrophy
highly recommended that all of the features described
above should be taken into consideration. Only a comprehensive clinical evaluation is capable of providing the
differential diagnosis of possible or probable AD or FTD,
with its positive confirmation in autopsy.
ACKNOWLEDGMENTS
Authors are grateful to Dr. Jason Brandt and Dr. Ola
A. Selnes from Johns Hopkins Hospital and School of
Medicine for their help and comments.
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