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doi:10.

1093/brain/aws011

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BRAIN
A JOURNAL OF NEUROLOGY

REVIEW ARTICLE

Episodic memory in frontotemporal dementia:


a critical review
Michael Hornberger1,2 and Olivier Piguet1,2
1 Neuroscience Research Australia, Sydney, NSW 2031, Australia
2 School of Medical Sciences, University of New South Wales, Sydney, NSW 2051, Australia

This review offers a critical appraisal of the literature on episodic memory performance in frontotemporal dementia. Historically,
description of patients diagnosed with what was then known as Picks disease included the presence of memory deficits and an
underlying amnestic syndrome was noted in some of these patients. Over the last 20 years, however, the clinical view has been
that episodic memory processing is relatively intact in the frontotemporal dementia syndrome. In particular, patients with the
subtypes of behavioural variant frontotemporal dementia and progressive non-fluent aphasia are reported to perform within
normal limits on standard memory tests. In the third clinical presentation of frontotemporal dementia, semantic dementia,
relatively intact episodic memory against a significantly impaired semantic memory was regarded as the hallmark. This position
was instrumental in the development of clinical diagnostic criteria for frontotemporal dementia in which amnesia was explicitly
listed as an exclusion criterion for the disease. The relative intactness of episodic memory, therefore, appeared to be a useful
diagnostic marker to distinguish early frontotemporal dementia from Alzheimers disease, in which early episodic memory
disturbance remains the most common clinical feature. We argue that recent evidence questions the validity of preserved
episodic memory in frontotemporal dementia, particularly in behavioural variant frontotemporal dementia. In semantic dementia,
a complex picture emerges with preservation of some components of episodic memory, notably recognition-based visual
memory and recall of recent autobiographical events. We propose a critical synthesis of recent neuropsychological evidence
on retrograde and anterograde memory in light of neuroimaging and neuropathological findings, demonstrating involvement of
medial temporal structures in frontotemporal dementia, structures known to be critical for episodic memory processing.
We further argue that the multifactorial nature of most memory tests commonly used clinically fail to capture the memory
deficits in frontotemporal dementia and that sensitive assessment tools of memory are needed. Together, recent clinical and
experimental findings and the historical evidence represent a strong case for a re-evaluation of the importance of memory
disturbance in the clinical diagnosis of frontotemporal dementia.

Keywords: anterograde memory; retrograde memory; semantic dementia


Abbreviations: FTD = frontotemporal dementia; PNFA = progressive non-fluent aphasia

Received June 29, 2011. Revised November 10, 2011. Accepted December 19, 2011
The Author (2012). Published by Oxford University Press on behalf of the Guarantors of Brain. All rights reserved.
For Permissions, please email: journals.permissions@oup.com

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Correspondence to: Olivier Piguet,


Neuroscience Research Australia,
Barker St,
Randwick NSW 2031,
Australia
E-mail: o.piguet@neura.edu.au

Episodic memory in FTD

Introduction

Historical evidence
Arnold Pick: original cases
Between 1892 and 1904, Arnold Pick, a neurologist in Prague,
meticulously described five patients with distinct language changes
(Pick, 1892, 1901, 1904). The clinical presentation was characterized by loss of word despite preserved knowledge of action and
usage and was labelled amnestic aphasia. Other language disturbances included impaired repetition, phonemic substitution and
neologisms. Significant focal brain atrophy was present in all
cases at post-mortem, being most pronounced in the left temporal
region with involvement of the frontal regions. Picks reports
demonstrated that specific language symptoms could result from
focal degeneration rather than diffuse and generalized atrophy as
previously believed. Despite an emphasis on language and behavioural changes, episodic memory disturbance was reported in three

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of these five patients. In particular, one patient, Josefa V., was


described to have a striking loss of memory with geographical
and time disorientation and disturbance of autobiographical information. In other words, although not a central feature of the
clinical phenomenology of this disease, evidence of anterograde
and retrograde episodic memory disturbance was present in one,
possibly three, of the five cases reported by Pick.

19201950: early case series of


Picks disease
The next 50 years saw the publication of small series of clinical
cases of Picks disease with or without pathological confirmation,
with a majority of clinical descriptions focusing on language disturbance. Two types of Picks disease were described: with or
without aphasia (Kahn and Thompson, 1934) and with the presence of behavioural changes (e.g. a loss of high-level social graces
and behaviours). The presentation of Picks disease was reported
to be uniform and predictable (monotonie de la presentation) in
contrast to Alzheimers disease (Caron, 1934).
In these case series, memory was generally reported to be
impaired due to faulty retrieval strategies resulting in inefficient
memory processes (i.e. loss of memory as a tool) (Kahn and
Thompson, 1934) or a lack of attention (Schneider, 1929).
Memory deficits could be present in later stages of the disease
due to developing dementia (Caron, 1934), although some disputed the presence of true amnesic deficits in Picks disease
(Nichols and Weigner, 1938). For these authors, the preserved
memory was one of the chief features distinguishing Picks disease
from other dementias, including Alzheimers disease.
Concurrently, evidence of anterograde memory deficit in
cases of Picks disease with pathological confirmation emerged
(Lowenberg, 1936; Urechia, 1940). Such anterograde memory
deficits took the form of impaired memory for recent events,
disorientation in time, with increased apathy and indifference
(Urechia, 1940), preserved long-term autobiographical memory
and absence of language disturbance at presentation
(Lowenberg, 1936). Post-mortem investigations revealed significant anterior frontal and temporal atrophy that was asymmetric.
Microscopic investigations revealed neuronal loss, spongiosis and
the presence of Pick bodies and argentophilic inclusions, involving
subregions of the hippocampus. Importantly, none of these cases
showed Alzheimer-related pathology (plaques or tangles).

19501975: systematic investigations


The 1950s see a more systematic approach to Picks disease:
van Mansvelt (1954) published the first comprehensive and
systematic clinicopathological review of all known cases of
Picks disease. This exhaustive and painstaking work examined
the clinical features and pathological findings of 196 cases.
Disorientation was reported in 64 cases (33%) accompanied
by loss of memory in a majority of cases. For van Mansvelt, however, the disturbances of memory are not the result of a loss
in the function of memory (in the sense of imprinting, retention
and reproduction), but a result of an incapacity to order

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Frontotemporal dementia (FTD) is a progressive neurodegenerative brain disorder characterized by deterioration of behaviour,
personality and language abilities in association with prominent
frontal and temporal lobar atrophy. Three major clinical variants
are recognized: behavioural variant FTD, semantic dementia and
progressive non-fluent aphasia (PNFA) (Neary et al., 1998;
Hodges and Miller, 2001).
Neglected for over half of the 20th century following the original descriptions of the condition by Arnold Pick in the late 1890s
and early 1900s, FTD has received renewed interest in the past
30 years. This rediscovery was stimulated in part by the increased
awareness of patients presenting with focal neural degeneration
associated with circumscribed cognitive deficits and behavioural
changes, at least in the early disease stages of the disease.
Investigations of patients with FTD have therefore provided
invaluable insights into the nature of psychological processes
such as language, semantic knowledge, emotion processing and
social behaviour.
This review focuses on the cognitive processes related to episodic memory in FTD, which have been systematically investigated
only recently. One reason for this neglect is that impaired episodic
memory performance has been considered an exclusion criterion
for a clinical diagnosis of FTD, more particularly behavioural variant FTD. We will argue that the notion of absence of episodic
memory deficits in FTD is incorrect. Episodic memory deficits were
documented in the historical reports and recent findings on episodic memory function in FTD reinforce this position. As such, the
status of episodic memory in FTD deserves to be revisited. We will
also argue that appraisal of the current literature on episodic
memory in FTD has theoretical and clinical implications, in particular for distinguishing patients with early Alzheimers disease from
FTD, a distinction which is largely based on the difference in episodic memory performance. We will first review the historical evidence for episodic memory performance in FTD before discussing
contemporaneous findings.

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deficit was typically accompanied by severe atrophy of the frontal


convexity. The authors finally note that 5 of their 32 cases did not
show any memory disturbance, even in an advanced stage.
Taken together, the historical literature demonstrates that
disturbance of episodic memory is an early clinical feature in a
portion of patients with Picks disease. This memory deficit was
reported in the very first cases described by Pick. Undoubtedly,
memory deficits were less common than behavioural or language
changes and, as indicated by Tissot and colleagues (1975), could
be masked by other, more prominent, clinical features. In some
series, memory deficit was not reported, potentially not recognized, or, in some instances, possibly even ignored (e.g. Caron,
1934). Pathologically, the presence of neuropathological changes
(neuronal loss, intraneuronal deposition) in brain structures
known to play a critical role in episodic formation and retrieval
also provides strong support for the presence of episodic memory deficit in this disease. Importantly, the evidence reviewed suggests that the pathological evidence was not always taken into
account.
In the subsequent years, further systematic investigations got
under way, led by two research groups in Lund, Sweden and
Manchester, UK (Brun, 1987; Neary et al., 1988). This research
endeavoured to define the clinical characteristics of this
non-Alzheimer disease pathology. This research paved the way
for what is now known clinically as FTD and pathologically
referred to as frontotemporal lobar degeneration. One major outcome was the publication of clinical diagnostic criteria, which for
the first time proposed sets of guidelines that would help with the
diagnosis of the main subtypes of FTD: behavioural variant FTD or
simply FTD, semantic dementia and PNFA (Brun et al., 1994;
Neary et al., 1998). At that time, the prominence of Alzheimers
disease in dementia research, and the high prevalence of that
disease compared with that of FTD, probably played a role in
defining episodic memory deficit as an exclusion criterion for a
diagnosis of FTD; in other words, defining FTD as not
Alzheimers disease. These clinical diagnostic criteria guidelines
have been recently revisited in two separate publications, the
first focussing on behavioural variant FTD (Rascovsky et al.,
2011) and the second proposing a classification of the language
presentations of FTD within the umbrella of primary progressive
aphasias (Gorno-Tempini et al., 2011).
The neuropathological classification of FTD or frontotemporal
lobar degeneration has also evolved considerably since the
first description by Pick, but remains heterogeneous (Mackenzie
et al., 2010). About 40% of cases with FTD exhibit the
microtubule-binding protein tau inclusions. Most remaining cases
are tau-negative but show the 43 kDa TAR DNA-binding protein
(TDP-43) inclusions. Recently, a small proportion of cases that are
negative for both tau and TDP-43 have been found to show the
RNA-binding protein fused in sarcoma (FUS) inclusions (Neumann
et al., 2009). Within the current nosology, Picks disease is now
used to describe specifically cases with microtubule-binding protein tau inclusions exhibiting round argyrophilic intracytoplasmic
inclusions (Pick bodies) and ballooned achromatic neurons
(Pick cells).

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chronologically the material of memory which is related to their


own experiences (p. 66).
In 1957, the first systematic neuropathological classification of
Picks disease was published (Luers and Spatz, 1957), which followed on the work by Grunthal (1936). This classification reported
four main centres of atrophy: orbital, temporal-polar, frontal
convexity/frontal insula and Ammons horn. Detailed description
of the pathological changes (gliosis, inclusion, demyelination)
showed that some regions of the hippocampus (dentate, subiculum) were more affected than others (CA 14). Despite the pathological changes noted in the hippocampal region, these authors
did not specifically report on the presence of memory disturbance
during clinical examination.
Delay and colleagues (1957a, b) contrasted the clinical presentations in 12 cases with Picks disease (seven with pathological
confirmation) and 24 cases with Alzheimers disease (11 with
pathological confirmation). The clinical presentation of Picks disease was described as univocal, with a striking monotony.
Importantly, however, a disturbance of memory unrelated to
attentional deficits was reported in 9 of their 12 cases with
Picks disease, with five presenting with prominent memory deficits. Pathological investigations revealed bilateral frontotemporal
atrophy localized frontally in three cases. In three other cases,
neuronal loss was present in CA fields, accompanied by atrophy,
neuronal loss and gliosis of the amygdala, as well as neuronal
inclusions in the presubiculum in one case.
In the early 1970s, a group in Geneva, Switzerland, conducted
painstaking and important work that has received limited attention
but is highly germane to the issues under discussion here
(Constantinidis et al., 1974; Tissot et al., 1975). These authors
presented the clinicopathological correlations of 32 cases of
Picks disease, grouped according to the location and type of
underlying pathology. In 18 cases, behavioural changes (moria,
bipolar humour) were reported together with anterograde
memory disorder (amnesie de fixation), from early in the
course of the disease. The memory deficit was described to be
akin to that seen in Korsakoffs and Alzheimers disease, and characterized by temporal and spatial disorientation, confabulations
and poor recognition memory. In all these cases, atrophy was
present in the middle temporal region, involving the hippocampus
and other limbic structures, plus the anterior temporal lobe
extending into the orbitofrontal regions. In over half of these
cases, argentophilic neuronal inclusions (Pick bodies) and neuronal
swelling (Pick cells) were observed in the subiculum, Sommers
sector of the hippocampus, and dentate gyrus with gliosis and
demyelination of fornix. In addition, significant correlations were
reported between severity of pathology and memory performance. Importantly, the authors state that the failure to recognize
the memory deficit in Picks disease was often masked by language reduction and behavioural changes.
This presentation was contrasted with other cases where the
atrophy and pathology was found predominantly in the prefrontal
cortex and more particularly in the dorsolateral prefrontal region.
In this group, clinical signs included memory inefficiency characterized clinically by preserved spatial orientation but impaired temporal orientation and inability to order events in the correct order
(dyschronologic amnesia, frontal type). This type of memory

M. Hornberger and O. Piguet

Episodic memory in FTD

Recent evidence
This section reviews the current evidence on episodic memory in
FTD. Unlike the historical studies reviewed above, most recent
investigations have been group studies. We start by reviewing
the evidence on retrograde memory (i.e. personal memories
from the past) before examining studies investigating anterograde
memory (i.e. acquisition of novel episodic memories). The distinction between retrograde and anterograde memory is deliberate as
different patterns of performance for both types of memory have
been reported in FTD subtypes.

Retrograde memory

Semantic dementia
Early studies in semantic dementia reported significantly better
recall for events from the recent than from the more distant
past (Snowden et al., 1996; Graham and Hodges, 1997; Hodges
and Graham, 1998; Graham et al., 1999; Nestor et al., 2002; Hou
et al., 2005). This profile of preserved recent episodic memories is
the reverse of the temporal gradient seen in amnesia and
Alzheimers disease (Ribot, 1882; Greene et al., 1995) where
memory for recent events is most vulnerable arguably because
of the pathological changes in medial temporal lobe structures,
notably the hippocampi and surrounding structures (Scoville and
Milner, 1957). Detailed investigations have suggested that autobiographical memory in semantic dementia is characterized by a
temporal step-function whereby recall of memories for
18 months to 2 years prior to testing is maintained, but memories
beyond this recent period show a flat, impaired retrieval function,
most likely due to the progressive semanticization of the memory
traces (Graham and Hodges, 1997; Hodges and Graham, 1998).
The finding of a step-function is, however, not universal with
some reports of a relative intact episodic memory across all life
periods in semantic dementia (Westmacott et al., 2001; Moss
et al., 2003; McKinnon et al., 2006; Maguire et al., 2010). One
potential reason for these discrepant findings is that the integrity
of remote memory in semantic dementia may have been underestimated in some studies because of these patients pervasive
comprehension and language production difficulties. This position
implies that such language problems will be overcome when
patients are provided with specific cueing or probing of event

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information compared with free recall. Evidence of autobiographical memory performance in semantic dementia matching that
of healthy controls following the provision of additional cueing
or probing corroborates this view (Moss et al., 2003; McKinnon
et al., 2006).
A recent study that used the same methodology as McKinnon
and colleagues (2006), however, again found evidence for a
step-function and no additional benefit from cueing in a large
group of patients with semantic dementia (n = 25) (Irish et al.,
2011). It remains unclear whether these conflicting results may
be due to different sample sizes [case studies (Moss et al.,
2003; McKinnon et al., 2006) versus group study (Irish et al.,
2011)] and associated statistical power, or reflect other variables,
such as disease severity effects (Matuszewski et al., 2009;
Maguire et al., 2010) (Fig. 1).
The finding of preserved recent autobiographical memory certainly accords with clinical experience in that patients with semantic dementia appear much more aware of recent events in their life
than those with Alzheimers disease (Hodges, 2001; Rosen et al.,
2004). In contrast, when questioned about more distant life
events, responses appear reasonable but are stereotyped and
lack specific content. At a theoretical level, the temporal
step-function reported by some studies has implications for the
debate between competing theories of the neural mechanisms
underlying long-term memory storage. Hodges and Graham
(2001) argue that the reverse temporal step-function seen in
semantic dementia lends support to the hypothesis that the hippocampus and related structures may play a time-limited role in
encoding and storage of episodic memories. The greater impairment to recall distant, as opposed to recent, memories suggests
that neocortical areas of the temporal lobes may be the critical
location for our enduring stores of autobiographical and semantic
memory, independent of the hippocampal complex (Graham and
Hodges, 1997; Hodges and Graham, 1998; Graham, 1999).
Proponents of the multiple-trace theory of memory storage
(Nadel and Moscovitch, 1997; Moscovitch and Nadel, 1998;
Winocur et al., 2010), which advocate that the hippocampal complex is involved in the storage of a memory for the whole of its
lifetime, dispute Grahams (1999) interpretation of the evidence
arising from studies on semantic dementia. They argue that the
impairment to distant memories may be attributable to dysfunctional strategic retrieval processes due to frontal cortical damage,
which would affect distant memories more so than those from the
recent past (Nadel and Moscovitch, 1997). It is not clear, however, how defective strategic retrieval processes would result in the
reverse temporal step-function documented in semantic dementia (Graham, 1999). This debate remains unresolved (Moscovitch
and Nadel, 1999), although recent functional imaging findings
(Maguire et al., 2010), which are discussed below, shed some
new light on this issue.
Both theories of episodic long-term memory agree that
the hippocampus and related structures are heavily involved in
the acquisition and, at least temporary, storage of novel episodic
memories. Patients with semantic dementia typically show severe
temporal lobe atrophy including the perirhinal cortex and temporal
pole (Chan et al., 2001; Galton et al., 2001; Rosen et al., 2002a;
Davies et al., 2004; Du et al., 2007; Mion et al., 2010).

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A large proportion of studies investigating episodic memory in FTD


have focused on memory for past events and experiences. In
clinical practice, enquiries about personal events in the patients
life are often unsystematic. To address this issue, a number of
investigators have devised autobiographical memory tests (e.g.
Kopelman et al., 1989; Levine et al., 2002). These tests typically
comprise a free recall procedure, which allows participants to
generate events across different life periods, followed, in some
instances, by a cued recall procedure to probe further for
contextual-rich event information. Despite these systematic
approaches, conflicting findings have emerged in FTD subtypes,
particularly in semantic dementia where most of the studies have
been conducted. Findings from each FTD subtype are reviewed in
the following sections.

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performance across time periods according to the type of tasks.


The step-function with better performance for recent events
is present under free recall condition only (A) but not under
probed recall (B) or high retrieval support condition (C). In C, the
triangles denote performance of semantic dementia Patient A.A.
tested on two separate occasions, 12 months apart; the squares
denoted the performance of semantic dementia Patient B.B.;
and the open circles the performance of healthy controls. A
and B are from Irish et al. (2011), C is from McKinnon et al.
(2006). Reprinted with permission from Elsevier.
AD = Alzheimers disease; bvFTD = behavioural variant FTD;
SD = semantic dementia.

Although earlier studies (e.g. Galton et al., 2001) suggested a


selective sparing of the hippocampus, more recent objective measures have shown that the hippocampus and the entorhinal cortex
are substantially involved in the pathological process (Chan et al.,
2001; Davies et al., 2004, 2005; Williams et al., 2005).
Surprisingly, despite such pervasive hippocampal involvement,
patients with semantic dementia show partial or complete

autobiographical memories in comparison to patients with


Alzheimers disease presenting with a comparable degree of hippocampal atrophy. One plausible explanation for this finding is the
differential atrophy severity within the hippocampus between the
two patient groups: patients with semantic dementia show a rostralcaudal atrophy gradient in the hippocampus, with anterior
parts most affected, while patients with Alzheimers disease
show equivalent atrophy across all hippocampal parts (Chan
et al., 2001; Davies et al., 2005). Another possible explanation
is that patients with Alzheimers disease exhibit dysfunction in
additional brain areas relevant for supporting autobiographical
memory processing, such as posterior cingulate and precuneus
cortices (Nestor et al., 2003). Importantly, these brain regions
have been implicated in episodic memory disturbance in neurodegenerative diseases (Nestor et al., 2006) and shown to be consistently activated in autobiographical memory functional MRI studies
in healthy volunteers (e.g. Maguire et al., 2001; Svoboda et al.,
2006). A critical study by Nestor et al. (2006) compared structural
and metabolic changes in key limbic structures across semantic
dementia and Alzheimers disease groups. Although the degree
of hippocampal atrophy on quantitative MRI and hypometabolism
on FDG-PET was equivalent in the two groups, patients with
semantic dementia showed sparing of the precuneus, which was
severely hypometabolic in patients with Alzheimers disease.
A recent case study further explored the neural correlates of
autobiographical memory retrieval in semantic dementia using
functional MRI (Maguire et al., 2010). In this patient, autobiographical memories were relatively intact initially but deteriorated
over time with no evidence of a temporal gradient. The overall
autobiographical performance remained relatively robust with
increasing disease severity, which was corroborated by residual
hippocampal and temporal lobe activation during recollection of
autobiographical information. Interestingly, Maguire and colleagues (2010) also reported activation in the precuneus, which
appears upregulated after the hippocampal activation was compromised by atrophy. Involvement of the precuneus confirms the
importance of extra-hippocampal regions in autobiographical
memory recall (Fig. 2). It is therefore not surprising that patients
with Alzheimers disease, who show atrophy and dysfunction in
both regions, will exhibit the greatest deficits in autobiographical
memory from an early disease stage.

Progressive non-fluent aphasia


To our knowledge, only one study systematically investigated
autobiographical memory in PNFA (McKinnon et al., 2008),
which may be due to the inherent language production deficits
impacting on any verbal recall performance in these patients. A
mild autobiographical memory impairment was reported, which
was abolished by providing additional probing of event information. The authors concluded that the autobiographical memory
deficits were secondary to pervasive expressive language difficulties in these patients. The relatively intact performance after probing further suggested that the memory retrieval processes and
medial temporal lobe functions were not impaired in PNFA. This
conclusion is corroborated by voxel-based morphometry studies
which have demonstrated absence of medial temporal lobe

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Figure 1 Variability in the pattern of autobiographical memory

M. Hornberger and O. Piguet

Episodic memory in FTD

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Figure 2 Longitudinal changes in the pattern of brain activation during autobiographical memory retrieval in a patient with semantic

atrophy in this group (e.g. Gorno-Tempini et al., 2004; Rohrer


et al., 2009).

Behavioural variant frontotemporal dementia


Systematic investigations of episodic memory in behavioural variant FTD are sparse because the presence of amnesia remains a
diagnostic exclusion criterion for the disease (Neary et al., 1998;
Rascovsky et al., 2011). From a clinical perspective, however,
growing evidence has shown that many patients with behavioural
variant FTD present with complaints (either self- or carer-report)
of memory problems. Around 10% of pathologically confirmed
cases with behavioural variant FTD have marked episodic
memory deficits in the initial stages of disease (Hodges et al.,
2004), and occasional cases have severe amnesia (Caine et al.,
2001; Graham et al., 2005). A clinicopathological study (Rosen
et al., 2002b) confirmed that although the absence of severe amnesia markedly increased the odds for FTD, the converse was not
true. Although patients with dementia with primary memory complaints are likely to have Alzheimers disease, the specificity of this
complaint is low (Rascovsky et al., 2007, 2011).
Investigations of retrograde autobiographical memory in behavioural variant FTD have also yielded inconsistent results. An early
investigation using the Autobiographical Memory Interview failed
to find impairment (Nestor et al., 2002) but recent studies that
distinguished specific from generic information found uniform impairment across all time periods with a loss of specific details but
no temporal gradient (Thomas-Anterion et al., 2000; Piolino et al.,
2003, 2007; Matuszewski et al., 2006). Similarly, Irish and colleagues (2011) showed impaired recall of specific and contextualrich autobiographical memory across all time periods, regardless of
how much cueing was provided. This pattern was interpreted as
reflecting a disorder of strategic retrieval processes. Indeed, several
studies have shown that autobiographical memory deficits in behavioural variant FTD are strongly correlated to executive dysfunction, which is a common neuropsychological feature of this group

(Piolino et al., 2003, 2007; Matuszewski et al., 2006). This relation is further corroborated by findings of dorsolateral and ventromedial atrophy on structural MRI (Seeley, 2008), which would
explain the dysexecutive deficits in these patients. Additional evidence of dysfunction in these regions and their importance for
autobiographical memory processing comes from metabolic neuroimaging. Recall of specific autobiographical memories was associated with resting-state FDG-PET activation in the orbitofrontal
cortex in a group of patients with behavioural variant FTD (Piolino
et al., 2007). In contrast, generic or semantic event information
was related to anterior temporal lobe activation. These findings
further substantiate the contribution of prefrontal cortex regions,
and in particular orbitofrontal cortex, to autobiographical memory
performance. Disturbance in these regions leads to a retrieval
access deficit for all autobiographical memories regardless of
their time of acquisition.
In summary, retrograde memory performance differs across FTD
subtypes. It is in semantic dementia that evidence is most variable
and complex. While some studies have reported impairment for
most recent retrograde memories with more remote memories
being relatively intact, others show relative intact performance
across all time periods tested in the early disease stages and an
overall impairment later on in the disease. It is currently not clear
which factors cause these discrepant findings. One potential explanation is that most of the studies used only single cases with
semantic dementia or small samples, while the only large semantic
dementia group study (Irish et al., 2011) shows a temporal gradient. The limited data suggest that patients with PNFA are mostly
intact for this type of episodic memory. In contrast, patients with
behavioural variant FTD show an overall impairment of retrograde
memories regardless of the time of acquisition. Recent findings
suggest that the retrograde memory deficits in patients with behavioural variant FTD are strongly related to their executive deficits. In turn, this finding supports the view that retrograde
memory deficits in this group are due to a failure in strategic

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dementia 43 years. Top: Loss of activation in the hippocampal region over time. Bottom: Increased activation in posterior brain regions
with disease progression. Autobiographical memory was relatively intact in this patient until late in the disease with no evidence of
temporal gradient. Adapted from Maguire et al. (2010) with permission from Elsevier.

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retrieval processes, which are mainly mediated by prefrontal


cortex, brain regions showing the most severe atrophy in behavioural variant FTD.

Anterograde memory
Semantic dementia

atrophy. Such a pattern was indeed observed, whereby patients


with semantic dementia with predominant left-sided atrophy performed normally on non-verbal memory tasks, whereas those with
predominant right-sided atrophy performed poorly on unfamiliar
face memory tasks, such as the Warrington Recognition Memory
Test. Thus, examination of anterograde memory in semantic dementia needs to take into account the laterality of greatest brain
atrophy, given its influence on test performance.
As Warrington (1975) suggested, patients with semantic dementia appear to rely on perceptual information from the studied
stimuli to assist their recognition memory. To follow-up on this
observation, Graham and colleagues (2000) investigated recognition memory in patients with semantic dementia using colour pictures. Crucially, while some target items were perceptually
identical at study and test (e.g. the same telephone), others
were perceptually different (e.g. telephones of different colours
or shapes). Despite their profound semantic memory problems,
the patients with semantic dementia showed relatively preserved
episodic memory for perceptually identical pictures. In contrast,
recognition performance was much poorer for the items that
were perceptually different at study and test, some patients performing at chance level. These findings demonstrate that patients
with semantic dementia rely, therefore, heavily on perceptual
inputs whereas in healthy people both semantic and perceptual
features can be used to encode new information. Not surprisingly,
patients with semantic dementia show high rates of false recognition when perceptually similar objects are used for episodic
memory testing (Simons et al., 2005). Further experimentation
demonstrated that most perceptual aspects (colour, viewpoint, exemplar types) are important for object recognition memory performance in semantic dementia, with the exception of size (Ikeda
et al., 2006). Patients with semantic dementia made false recognitions in all conditions, except the size change condition. These
findings also explain the impaired recognition memory for words
found in semantic dementia, given the little distinctive perceptual
features written words have in comparison to pictures.
The perirhinal cortex, which is consistently affected in semantic
dementia (Davies et al., 2004), emerges as the critical neuroanatomical region supporting episodic memory under perceptually difficult conditions. The role of perirhinal cortex in memory has been
known for quite some time, with experimentally induced lesions of
this region leading to severe recognition memory deficits in monkeys (e.g. Buckley and Gaffan, 1997). Recent evidence, however,
suggests that such perirhinal cortex damage may cause a higher
perceptual deficit, rather than a memory deficit per se (Bussey and
Saksida, 2007). The perirhinal cortex appears critically involved in
analysing and representing complex conjunctions of the features
that comprise an individual object, which in turn affects the recognition of an object in a memory test. This position could explain
the change in memory performance following perceptual manipulations (Graham et al., 2000; Simons et al., 2001). Indeed, perceptual tasks with virtually no memory load that use concurrent
visual discrimination or object oddity judgements have been
shown to be severely impaired in semantic dementia (Barense
et al., 2005; Lee et al., 2005a, b, but see Levy et al., 2005;
Shrager et al., 2006). These findings provide further evidence
that visual memory problems in semantic dementia may be related

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The first systematic neuropsychological assessment of anterograde


episodic memory in FTD involved three patients with semantic
dementia who demonstrated impaired recall of the Wechsler
Memory Scale short story and a virtually complete failure in free
recall of 10-word lists (Warrington, 1975). In addition, these patients with semantic dementia performed as poorly as four amnesic patients on word and face stimuli on forced-choice
recognition memory tests. When recognition memory for paintings
was tested, however, all patients with semantic dementia scored in
the normal range, in contrast to the amnesic patients. Warrington
speculated that the patients with semantic dementia might have
utilized perceptual features, such as colours, to remember the
paintings, whereas memory for words relies essentially on semantic information. As Warrington indicated: the patients reported
here are by no means as amnesic as a patient with a severe
amnesic syndrome, although their verbal memory is far from
normal (Warrington, 1975, p. 653).
This classic description still best summarizes the distinction between verbal and visual anterograde memory performance in semantic dementia, in particular for recall-based tests. Verbal recall
tests have the inherent confound of requiring spoken output from
the participant that is affected by the semantic knowledge loss
and pervasive anomia in semantic dementia. Not surprisingly, performance on word-list learning, such as the Rey Auditory Verbal
Learning Test, or recall of a story (e.g. Wechsler short story passages) can be particularly impaired in semantic dementia and can
make a distinction from Alzheimers disease difficult (e.g. Perry
and Hodges, 2000). Patients perform in general better on tests
using non-verbal material, such as the Rey complex figure test,
and show overall better performance on recognition tests.
From the late 1990s, a series of studies investigated systematically aspects of anterograde memory in semantic dementia. One
of the first studies used black and white line drawings of real and
fictitious animals (Graham et al., 1997). While no significant difference between a group of patients with semantic dementia and
healthy controls was found on a test of recognition memory for
these drawings, patients with semantic dementia were significantly
impaired when asked to indicate during the study task whether
the animals were real or not. This observation was confirmed using
colour pictures of objects (Graham et al., 2000) and photographs
of people (Simons et al., 2001). Scahill and colleagues (2005)
went on to address the issue of laterality of atrophy and episodic
memory processing in semantic dementia. Anatomical distinctions
in semantic dementia are important in that predominant leftversus right-sided patients with semantic dementia can present
with varying degrees of anomia. Patients with predominant
left-sided atrophy are assumed to perform worse on verbal tasks
than non-verbal tasks, whereas the opposite should be true for
patients with semantic dementia with predominant right-sided

M. Hornberger and O. Piguet

Episodic memory in FTD

Progressive non-fluent aphasia


To our knowledge, only one study has examined performance of
patients with PNFA on neuropsychological memory tests (Libon
et al., 2007). This study showed that patients with PNFA performed significantly better than patients with Alzheimers disease
on the Verbal Serial List Learning Test. In contrast, patients with
PNFA experienced working memory deficits, which are dependent
on prefrontal cortex integrity. Clearly, future investigations of
PNFA memory performance are needed, in particular in light of
recent findings indicating that a subset of patients with PNFA have
underlying Alzheimer pathology (Hu et al., 2010).

Behavioural variant frontotemporal dementia


Anterograde episodic memory function in behavioural variant FTD
has been investigated systematically only recently. As mentioned
before, the scarcity of such studies arises from the fact that amnesia is an exclusion criterion for behavioural variant FTD (Neary
et al., 1998). While patients with behavioural variant FTD are
often impaired on memory tasks compared with healthy controls
(e.g. Pachana et al. 1996; Giovagnoli et al. 2008), these deficits
are variable and tend to be overshadowed by the predominant
behavioural changes. Compared with Alzheimers disease, patients
with behavioural variant FTD are generally reported to perform
better on verbal and visuospatial anterograde memory tasks
(Elfgren et al., 1994; Frisoni et al., 1995; Pachana et al., 1996;

| 685

Lindau et al., 1998; Thomas-Anterion et al., 2000; Rascovsky


et al., 2002; Kramer et al., 2003; Lee et al., 2003; Rosen et al.,
2004; Perri et al., 2005; Heidler-Gary et al., 2007; Libon et al.,
2007; Giovagnoli et al., 2008) and do not normally show the
accelerated forgetting under delayed free recall conditions typically
found in Alzheimers disease (Hodges et al., 1999; Perry and
Hodges, 2000; Glosser et al., 2002; Wicklund et al., 2006;
Hutchinson and Mathias, 2007). Importantly, however, exceptions
exist and patients with behavioural variant FTD with neuropathological confirmation at post-mortem have presented with severe
amnesia in some cases (Caine et al., 2001; Graham et al., 2005).
Relatively intact memory performance, at least in the early
stages of behavioural variant FTD, has also been reported on complex associative memory tasks, such as the computerized Paired
Associate Learning Test from the CANTAB (Cambridge
Neuropsychological Testing Automated Battery). This task, in
which subjects are required to learn the association between coloured patterns and spatial locations, is very sensitive to early
Alzheimers disease (Swainson et al., 2001; Blackwell et al.,
2004), whereas patients with early behavioural variant FTD tend
to perform within the normal range (Lee et al., 2003). A similar
dissociation between Alzheimers disease and behavioural variant
FTD has been reported on a face-location association task (Clague
et al., 2005). In contrast, no reliable difference between
Alzheimers disease and behavioural variant FTD has been found
on forced-choice recognition and free recall for verbal and
non-verbal material (Glosser et al., 2002). A selective retrieval
disorder, potentially caused by the known attention problems,
was postulated for the impaired memory in behavioural variant
FTD (Glosser et al., 2002). In addition, a dissociation has been
reported in patients with behavioural variant FTD with a relatively
preserved recognition memory but impaired temporal source
memory (remembering whether an item was shown in list A or
list B) (Simons et al., 2002), in contrast to patients with
Alzheimers disease who are typically impaired on both recognition
and source memory tasks (Multhaup and Balota, 1997).
Source memory performance is generally attributed to prefrontal
cortex function (e.g. Duarte et al., 2011). Whether the variable
memory performance observed in behavioural variant FTD is due
to the prefrontal cortex atrophy or, like Alzheimers disease, due
to hippocampal atrophy is unknown. Evidence regarding the severity of hippocampal atrophy in behavioural variant FTD is mixed.
At post-mortem, significant hippocampal atrophy has been reported in patients with FTD, even early in the course of the disease (van Mansvelt, 1954; Broe et al., 2003; Kril and Halliday,
2004) (Fig. 3). Medial temporal atrophy has also been found on
neuroimaging (Seeley, 2008; Seeley et al., 2008; Whitwell et al.,
2009), although no hypoperfusion has been reported in this region
in behavioural variant FTD (Kanda et al., 2008). Involvement of
medial temporal regions in behavioural variant FTD remains somewhat contentious but a consensus exists on the early involvement
of mesial and orbital prefrontal cortical regions (Rosen et al.,
2002a; Seeley, 2008). Questions, however, remain regarding the
variability in the pattern of change in behavioural variant FTD and
whether the anterior temporal and/or parietal atrophy, which is
found in addition to the frontal atrophy, is dependent on the
underlying pathology (Whitwell et al., 2009, 2011). Whether

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to perception rather than to memory per se. This finding could


further explain the difficulty patients with semantic dementia experience with face recognition, as a more thorough feature conjunction analysis is necessary to discriminate among similar faces
successfully.
Importantly, however, anterograde memory deficits in semantic
dementia are unlikely to be due solely to higher perceptual deficits
caused by perirhinal damage but rather to a combined perirhinal
and hippocampal atrophy. Performance on memory tests that are
highly sensitive to hippocampal damage, such as associative
memory or source memory, is impaired in semantic dementia
(Simons et al., 2002; Clague et al., 2005). Tests of high perceptual/perirhinal functioning may potentially be helpful in discriminating semantic dementia from Alzheimers disease, as this
function is relatively intact in Alzheimers disease, while both patient groups are impaired on hippocampal-dependent tests.
Another promising avenue to discriminate patients with semantic
dementia and Alzheimers disease is the use of naturalistic episodic memory tasks with incidental encoding of information. An
elegant study demonstrated that patients with semantic dementia
remembered most spatial (e.g. Did I sit in this chair?), temporal
(e.g. How long did I stay?) and event (e.g. Did I wear a brooch
yesterday?) details from the examiners visit to their home, even
after a 24-h delay in contrast to patients with Alzheimers disease
(Adlam et al., 2009). Similarly, topographical memory was found
to be relatively intact in semantic dementia but very impaired in
Alzheimers disease using a virtual reality task (Pengas et al.,
2010). Importantly, in this study, performance on a virtual route
learning task in combination with naming performance resulted in
a complete discrimination of patients with semantic dementia and
Alzheimers disease.

Brain 2012: 135; 678692

686

| Brain 2012: 135; 678692

logical confirmation of frontotemporal lobar degeneration


pathology. Significant atrophy is present involving the hippocampus and the middle temporal region on coronal MRI (A).
At post-mortem, significant neuronal loss was found in the CA1
field of the hippocampus (B) and ubiquitin-positive staining (C).
Adapted from Graham et al. (2005) with permission from
Oxford University Press.

this pathological heterogeneity is also reflected in the memory


performance of these patients remains unclear. Existing evidence
would suggest that cases with severe memory disturbance at presentation appear to have pathological changes associated with

TDP-43 protein deposition (Graham et al., 2005) (Fig. 3). A critical


issue in the next few years will be the development of reliable
biomarkers capable of detecting those with underlying tau versus
TDP-43 or FUS pathology, recent studies showing promising results (Piguet et al., 2011; Schofield et al., 2011). It may then be
possible to relate the clinical phenotype, including the degree and
nature of episodic memory impairment to the pathological type
in vivo.
The reported dissociation between intact implicit but impaired
explicit anterograde memory in behavioural variant FTD (Pasquier
et al., 2001) provides further support for a disturbance of prefrontal mediated memory function in these patients. Critically, this
study demonstrated that retrieval cues provided greater benefit in
the explicit memory condition for patients with behavioural variant
FTD than for Alzheimers disease. This finding prompted the suggestion that memory dysfunction in behavioural variant FTD resulted from frontally dependent, defective cognitive (retrieval)
control processes rather than true amnesia (e.g. Collette et al.,
2010). Further support arises from neuroimaging investigations
showing that disturbance in the strategic aspects of episodic
memory recall and retrieval processes are associated with prefrontal cortex atrophy, in particular the orbitofrontal cortex
(Kramer et al., 2005; Pennington et al., 2011) as well as reduced
metabolism in prefrontal, parietal and posterior cingulate cortices
in patients with behavioural variant FTD (Bastin et al., 2011). The
failure of these prefrontally mediated retrieval control mechanisms
also explains the increased false recognition rates (de Boysson
et al., 2011) and confabulations found in behavioural variant
FTD (Nedjam et al., 2004).
The inconsistent findings across studies regarding episodic
memory in behavioural variant FTD are also likely to be due to
the inclusion of patients who do not have a progressive neurodegenerative disease. Recent studies have identified a subset of
patients who meet current clinical criteria for behavioural variant
FTD, yet show little or no progression over a decade or more
(Davies et al., 2006; Kipps et al., 2007b, 2010; Piguet et al.,
2009). These patients with non-progressor or phenocopy behavioural variant FTD mimic the clinical features of behavioural variant FTD but lack the typical brain atrophy found on MRI and
demonstrate preserved glucose metabolism on PET (Davies et al.,
2006; Kipps et al., 2007a, 2009) and the pathology of these
cases remains unclear. The prevalence of these phenocopy
cases in existing studies is unknown but their inclusion is likely
to underplay the magnitude of the deficits in progressive, or patients with real, behavioural variant FTD. This position was confirmed in a recent study in which patients with behavioural
variant FTD, who had been followed over many years, were
grouped according to their disease progression status (real
versus phenocopy behavioural variant FTD) and their anterograde
episodic memory performance at presentation compared with
Alzheimers disease (Hornberger et al., 2010a). Patients with progressive behavioural variant FTD were nearly as impaired as patients with Alzheimers disease on most verbal and visual
neuropsychological memory measures, in contrast to the phenocopy cases who showed only mild deficits compared with control
participants (Fig. 4). The same study also showed that patients
with Alzheimers disease scored worse on delayed recall tests and

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Figure 3 Patient presenting with severe amnesia and patho-

M. Hornberger and O. Piguet

Episodic memory in FTD

Brain 2012: 135; 678692

| 687

on orientation scores of the Addenbrookes Cognitive


Examination-Revised compared with the patients with behavioural
variant FTD. Importantly, these findings were replicated in an
independent prospective sample (Pennington et al., 2011) (Fig.
4), which further showed that prefrontal atrophy ratings in patients with real behavioural variant FTD correlated with the
memory performance. Interestingly, patients with behavioural
variant FTD and Alzheimers disease showed hippocampal atrophy of similar severity. The pattern of atrophy, however, differed
between the two groups with behavioural variant FTD showing
more pronounced anterior than posterior hippocampal atrophy
compared with Alzheimers disease (see also Laakso et al.
2000). Disturbance in both prefrontal and medial temporal lobe
regions are therefore likely to contribute to the memory impairments seen in patients with behavioural variant FTD, with the
relative contribution varying across patients, possibly related to
the site of underlying pathology or to the disease severity.

Memory tests that are capable of differentiating between these


anatomical contributions are required.
In summary, studies investigating anterograde memory in behavioural variant FTD report inconsistent results. Possible reasons
for the discrepant findings are (i) the use of memory tests which
place different demands on prefrontal versus medial temporal lobe
functioning, such as recall versus recognition; and (ii) the potential
admixture of real patients with behavioural variant FTD with
phenocopy cases, resulting in some studies to an underrepresentation of anterograde memory deficits in this patient
group. Taking all the evidence reviewed into account indicates
that patients with true behavioural variant FTD can have
memory deficits of the same magnitude as seen in Alzheimers
disease. This finding poses a challenge to the widely used diagnostic criteria for behavioural variant FTD (Neary et al., 1998),
which states severe memory deficits as an exclusion criterion, as
well as for the recently revised criteria (Rascovsky et al., 2011)

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Figure 4 Pattern of performance on different tests of episodic memory in patients with behavioural variant FTD (bvFTD) compared with
Alzheimers disease (AD), phenocopy cases and controls. Patients with real behavioural variant FTD are impaired to a similar degree
to patients with Alzheimers disease. In contrast, performance of phenocopy cases is similar to that of controls. (A) Overall memory
performance, (B) performance across groups on various memory tasks. A is reprinted from Hornberger et al. (2010a) with permission from
Wolters Kluwer Health. B is reprinted from Pennington et al. (2011) with permission from IOS Press. AD = patients with Alzheimers
disease; PR = patients with real behavioural variant FTD; PH = phenocopy cases; Cntrl = healthy controls.

688

| Brain 2012: 135; 678692

which advocate a relative sparing of episodic memory on neuropsychological testing.

Conclusions and future


directions

and Alzheimers disease diagnosis (Hornberger et al., 2010a). In


contrast, recognition memory scores appear the least predictive
markers of episodic memory differences between the groups.
Improved clinical diagnostic accuracy may also be achieved using
executive function tests, such as the Hayling test of inhibition,
which discriminate behavioural variant FTD from Alzheimers disease and from phenocopy cases to a high degree even in the early
stages of the disease (Hornberger et al., 2008, 2010b).
As indicated above, accurate assessment of memory performance has crucial implications for the clinical diagnosis of patients
with FTD. The importance of evaluating memory performance
within the context of other cognitive abilities, however, cannot
be overemphasized, as presence/absence of deficits in other cognitive domains will inform as to the relative severity of the
memory impairment and help reach a clinical diagnosis. For example, comparing episodic memory and temporal orientation integrity appear useful, as disorientation is commonly observed in
Alzheimers disease but rarely so in behavioural variant FTD.
Complementing clinical tests with imaging investigations, imaging
neural correlates, in particular of prefrontal cortex regions, such
as in Pennington and colleagues (2011) appear very promising in
dissociating patients with behavioural variant FTD and Alzheimers
disease memory deficits.
Investigations of memory in FTD have improved our theoretical
understanding of episodic memory processes. In particular, the
retrograde memory findings in semantic dementia have informed
and challenged memory consolidation theories. Further, results of
anterograde memory investigations have addressed the interactions between memory (episodic and semantic) and high-level
perceptual processes. The disentangling of these processes continues to advance our understanding of medial temporal lobe
memory systems, which are critical to episodic memory functions.
Similarly, studies examining anterograde memory in behavioural
variant FTD have uncovered prefrontal cortex and/or medial temporal lobe contributions to memory deficits in this group. These
contributions, however, remain difficult to tease apart with standard neuropsychological tests. Memory tests, such as within- and
between-domain associative memory tasks, which are based on
current experimental findings and can be easily applied in the
clinics are needed. Such tests are capable of delineating between
prefrontal cortex and medial temporal lobe, as well as among regions within the medial temporal lobe, specific memory processes.
These new theoretical developments will inform clinical practice
which will lead to improved diagnosis and improved patient
management.

Acknowledgements
We thank Prof. J. Hodges for helpful comments on earlier versions
of the article.

Funding
The Australian Research Council (ARC) Centre of Excellence in
Cognition and its Disorders. ARC Research Fellowship

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The evidence reviewed in this article demonstrates the relevance


of episodic memory investigations in FTD with each subtype
showing specific changes in retrograde and anterograde
memory. In semantic dementia, the profile is one of significant
retrograde memory deficits (with or without step-gradient) modulated by disease severity and of anterograde memory deficits that
are affected by visuoperceptual aspects and the modality of the
information to be remembered. In contrast, both retrograde and
anterograde memory functions are mostly intact in PNFA, with the
exception of a mild autobiographical memory deficit, which is
abolished following the provision of retrieval cues. Finally, retrograde and anterograde memory performance is affected in behavioural variant FTD, and appears to be particularly sensitive to the
co-occurrence of executive dysfunction.
Importantly, aspects of this review are relevant for clinical practice. Patients with semantic dementia and behavioural variant FTD
experience episodic memory problems that have been under
recognized so far, likely due to their pervasive language and behavioural deficits. The historical and current evidence shows that
some patients with FTD can have episodic memory problems similar to Alzheimers disease, which can make a diagnostic distinction
difficult, particularly early in the disease course. More specifically,
patients with semantic dementia exhibit retrograde and anterograde memory deficits, the severity of which varies according to
the tests used. For clinicians, impaired performance on verbal but
not visuospatial memory tests combined with a loss of semantic
knowledge should raise the strong possibility of semantic dementia. Other features supportive of this diagnosis include preservation
of visual memory particularly under forced-choice recognition
format and preserved memory for temporal information and for
recent autobiographical events.
With regards to behavioural variant FTD, retrograde memory
data demonstrate that behavioural variant FTD and Alzheimers
disease show different autobiographical memory profiles, although
such evidence remains difficult to gather in the clinic. More concerning, however, is the evidence that patients with behavioural
variant FTD and Alzheimers disease can present with similar anterograde memory deficits on neuropsychological testing. This
overlap becomes particularly relevant for the patients with
Alzheimers disease who show additional executive dysfunction
(e.g. Gleichgerrcht et al., 2010). In addition, the likely inclusion
of phenocopy cases in previous studies will have underestimated
the severity of the episodic memory impairment in this patient
group, and cast further doubt on the validity of amnesia as a
diagnostic exclusion criterion for the disease (although this point
has been rectified somewhat in the recent revision of the clinical
diagnostic criteria for behavioural variant FTD). Nevertheless,
delayed recall memory tests, in particular of verbal material (e.g.
word lists), emerge as a good predictor of behavioural variant FTD

M. Hornberger and O. Piguet

Episodic memory in FTD


(DP110104202 to M.H.); National Health and Medical Research
Council of Australia Clinical Career Development Award
Fellowship (#510184 to O.P.).

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