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Frontotemporal Dementia

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© Springer Science+Business Media Singapore 2016
Nancy A. Pachana
Encyclopedia of Geropsychology
10.1007/978-981-287-080-3_311-1

Frontotemporal Dementia (FTD)

Maxime Bertoux1, 2 , Claire O’Callaghan3 , Emma Flanagan1 and Michael Hornberger1

(1)Norwich Medical School, University of East Anglia, Norfolk, UK

(2)Department of Clinical Neurosciences, University of Cambridge, Cambridge, UK
(3)Behavioral and Clinical Neurosciences Institute, University of Cambridge, Cambridge, UK

Maxime Bertoux (Corresponding author)

Email: maxime.bertoux@cantab.net

Claire O’Callaghan
Email: co365@cam.ac.uk

Emma Flanagan
Email: e.flanagan@uea.ac.uk

Michael Hornberger
Email: m.hornberger@uea.ac.uk

Synonyms
Behavioural variant frontotemporal dementia; Frontal dementia; Semantic Dementia; Progressive
non-fluent aphasia; Pick disease

Definition
Frontotemporal dementia is an insidious neurodegenerative disease characterised by progressive
deficits in behaviour and cognition. Three main clinical entities as well as overlaping syndromes
affecting the young subject (< 65 years old) are described here on a clinical, neuropsychological and
imaging point of view.
Introduction
Frontotemporal dementia (FTD) is an insidious neurodegenerative disease characterised by
progressive deficits in behaviour and cognition. FTD is a common type of dementia, particularly in
patients younger than 65 years. It is the second most common form of younger-onset dementia after
Alzheimer’s disease (AD) (Ratnavalli et al. 2002). Despite such prevalence, FTD has received far less
recognition compared to other dementias. This is surprising considering the overlap FTD shares
clinically and pathologically with many other dementias, making it a challenging condition in terms of
diagnosis and treatment. Currently, three different FTD subtypes are clinically recognized: behavioral
variant FTD (bvFTD) and two FTD subtypes with progressive aphasia (PPA) – semantic variant
primary progressive aphasia (sv-PPA) and nonfluent variant PPA (nfv-PPA) (Hodges 2011). All three
subtypes have specific but overlapping clinical, pathological, and neuroimaging features which will
be discussed in detail shortly. First, we will give a brief historical and general introduction to FTD
before discussing the main subtypes as well as the most prominent overlap syndromes.

FTD was first described by Arnold Pick in 1892 (Pick 1892). Pick published a series of patient cases
which all showed significant behavioral and language changes. Importantly, postmortem
examinations of the patients showed atrophy macroscopically in the temporal and frontal lobes and
microscopically ballooned cells, called Pick bodies. The disease has been historically known as Pick’s
disease, however was renamed frontotemporal dementia in the 1980s by researchers in Lund and
Manchester (Neary et al. 1986), according to the prominent macroscopic atrophy seen in these
patients. Diagnostic criteria for FTD were first published in the 1980s with revisions in the 1990s
(Neary et al. 1998). The most recent diagnostic criteria split the behavioral variant (Rascovsky et al.
2011) from the aphasic (Gorno-Tempini et al. 2011) subtypes to allow more detailed phenotyping of
the variants.

Over the years, FTD has moved from being considered a condition that only occurred occasionally to
a more prominent role. In particular, the genetic connection of amyotrophic lateral sclerosis (ALS)
and FTD has highlighted that FTD pathology and associated symptomology are more common than
previously assumed. The following book chapter will allow the reader to gain an insight into the FTD
spectrum which will hopefully trigger further clinical and research interest in the FTD field.

Behavioral Variant Frontotemporal Dementia (bvFTD)

Clinical Symptoms
bvFTD is the most frequent subtype of FTD. The median survival (from first assessment) is about
3.0–4.5 years (Piguet et al. 2011a), with a disease onset usually around 60 years old, although
younger and older cases have been frequently described. The clinical symptomatology of bvFTD is
dominated by progressive and dramatic changes in patients’ social behavior and personality that
become gradually evident to their relatives, often to great distress. Apathy, behavioral disinhibition,
inappropriate social conduct, lack of empathy, stereotyped and rigid behaviors, as well as changes in
eating behavior are the clinical hallmarks of bvFTD (Piguet et al. 2011a; Rascovsky et al. 2011).
Patients also exhibit a loss of insight that complicates their engagement and referral to the clinic
(Hornberger et al. 2014; Eslinger et al. 2005), as they do not recognize either their deficits or the
relevance of a medical consultation. These insight problems make a comprehensive interview with
informants crucial to establish symptoms. In that perspective, the use of carer questionnaires (such
as the Cambridge Behavioural Inventory – CBI, Bozeat et al. 2000) to identify and quantify
behavioral changes is particularly useful.

Apathy is observed in many, if not all, bvFTD patients. A striking reduction of motivation and
interest in others, work, hobbies, and hygiene may be observed, resulting in social withdrawal and a
significant reduction of premorbid activities (Chow et al. 2009) that could be mistaken for depression
(Woolley et al. 2011). Importantly, although loss of libido may be commonly observed, patients
generally do not report the other key symptoms that characterize depression, such as feeling of
worthlessness or guilt, sleep disturbances, and recurrent sad thoughts. Behavioral disinhibition is
also an early symptom of bvFTD and usually coexists with apathy (Le Ber et al. 2006; Seelaar et al.
2011). Patients can act impulsively without taking into account the consequences of their actions and
thus make poor financial decisions and reckless purchases, or engage in pathological gambling
(Manes et al. 2010). Another key symptom of bvFTD is inappropriate social conduct, manifesting
as abnormal intimacy with strangers, loss of manners, and embarrassing or tactless personal remarks
(Lu et al. 2006). Such socially awkward behaviors are further aggravated by a lack of empathy and a
decreased ability to decode others’ thoughts and beliefs. This leads to decreased interest and concern
for others, including closest relatives, which is a major cause of carer and family distress (Baez et al.
2014; Lough et al. 2006). Stereotyped behaviors are commonly observed, with simple repetitive
movements such as grunting, humming, food tapping, or lip smacking being frequent as well as the
repetitive verbalization of words or phrases (Snowden et al. 1996, 2001). Mental rigidity is also
habitually observed, manifesting as a rigid adherence to everyday routine, a lack of creativity, and,
sometimes, compulsive ritualistic behaviors (Snowdmeen et al. 2001; de Souza et al. 2010). Change
in eating behavior is also an early symptom of bvFTD. Patients can be gluttonous, which can cause
significant weight gain. A deterioration of table manners, impulsivity to start eating before everyone
else, snatching food from others and stuffing it into the month all at once are frequently observed
symptoms (Ahmed et al. 2014; Piguet et al. 2011b; Woolley et al. 2007).

It should be noted that some patients differ in their progression, showing hardly any change over a
decade (Davies et al. 2006) while still exhibiting the behavioral symptoms of bvFTD. Comparative
investigations between these “phenocopy” patients and the patients who progress suggest that an
absence of brain atrophy, normal or sub-normal executive functioning, and preservation of everyday
living activities allow for accurate identification of these nonprogressors (Hornberger et al. 2009).

Neuropsychology
Apart from the neuropsychiatric symptoms, the neuropsychological profile of bvFTD is dominated by
deficits in all aspects of social cognition, including empathy, theory of mind, and emotion recognition
(Lavenu et al. 1999; Gregory et al. 2002; Bertoux et al. 2013). Carer questionnaires such as the
Interpersonal Reactivity Index (IRI – Davis 1983) can be useful to measure a decrease in empathic
concern. Faux pas and sarcasm detection are among the most sensitive assessments to capture theory
of mind impairments in bvFTD (Bora et al. 2015; Henry et al. 2014). Finally, emotion recognition
tests show difficulties in identifying negative emotions (Bertoux et al. 2015a).

Dysexecutive symptoms, such as impaired organization and planning, decreased verbal fluency,
difficulties in verbal and nonverbal conceptualization, inhibition dysfunctions, and working memory
deficits are commonly observed, although they can be absent or subtle in the earliest stages of the
disease (Lindau et al. 2000; Gregory and Hodges 1996; Rahman et al. 1999: Harciarek and Jodzio
2005; Perry and Hodges 2000; Hornberger et al. 2011). It should be noted that these symptoms have a
poor discriminative value between bvFTD and AD or depression (Libon et al. 2007; Stopford et al.
2012).

Impairments in decision- making and reward processing have also been documented in bvFTD
(Rahman et al. 1999). Patients exhibit a decreased sensitivity to reward (Fletcher et al. 2015), reduced
aversion to losses (Chiong et al. 2016), an increased discounting of future reward (Bertoux et al.
2015c), and striking difficulties in reversing the selection of a previously rewarding item that becomes
punishing (Bertoux et al. 2013).

Poor episodic memory has only recently been recognized as a possible cognitive symptom of bvFTD
(Hornberger et al. 2010) and can be observed in 50% of bvFTD patients (Bertoux et al. 2014)
although spatial orientation appears to remain relatively preserved (Tu et al. 2015).

The language profile of bvFTD is characterized by diminished spontaneous speech and deficits in
noun and verb naming as well as impaired single word comprehension, but to a lesser extent than
in sv-PPA (Snowden et al. 1996; Hardy et al. 2015).

Praxis disturbances can be observed after the earliest stages of the disease, particularly difficulties
imitating face postures (Johnen et al. 2015).

Neuroimaging
Structural imaging such as magnetic resonance imaging (MRI) scans show a typical pattern of atrophy
that is ideally seen in coronal orientation. It is characterized by predominant frontal, fronto-insular
and/or anterior temporal atrophy, which is sometimes asymmetrical (Agosta et al. 2012). Because
atrophy can be very subtle in the early stages of the disease, a normal MRI should not exclude the
diagnosis of bvFTD. Regions that are more likely to be atrophied in the earliest stages are the medial
prefrontal and orbitofrontal cortices, as well as the anterior insula (Perry et al. 2006; Seeley et al.
2008). In the temporal lobe, the amygdala and hippocampus are also affected (Seeley et al. 2008; de
Souza et al. 2013). Subcortical structures such as the striatum (Bertoux et al. 2015b), thalamus
(Hornberger et al. 2012), and hypothalamus (Piguet et al. 2011b) are also involved, as well as white
matter tracts such as the paracallosal cingulum bundle, corpus callosum, uncinate fasciculus, and
fornix (Hornberger et al. 2012; Mahoney et al. 2015).

Functional imaging such as single photon-emission computed tomography (SPECT) shows important
hypoperfusion in the fronto-insular and polar tempolar regions (Le Ber et al. 2006; Jeong et al.
2005). As amyloid deposition is not a neuropathological feature of FTD, amyloid tracer can
efficiently distinguish bvFTD from AD (Rabinovici et al. 2011).
Semantic Variant Primary Progressive Aphasia (sv-PPA)

Clinical Symptoms
Sv-PPA, also called semantic dementia (Snowden et al. 1989; Hodges et al. 1992), is a progressive
disorder of language. It is a presenile disease with onset commonly ranging between 66 and 70 years.
Anomia and single-word comprehension deficits are the core features of the disease. Although these
symptoms, particularly anomia, may be observed in other FTD variants or neurodegenerative
conditions such as AD, these disturbances are especially severe in sv-PPA. The disease involves a
gradual degradation of conceptual knowledge (thus affecting all modalities), which impairs object
knowledge and object use after the earliest stages. Behavioral changes similar to those observed in
bvFTD are also common symptoms of sv-PPA (Hodges and Patterson 2007; Bang et al. 2015; Gorno-
Tempini et al. 2011). Finally, prosopagnosia can be observed, most commonly in sv-PPA with right
predominant atrophy, which accounts for one third of sv-PPA cases and shares many behavioral
similarities with bvFTD (Thompson et al. 2003; Evans et al. 1995; Kamminga et al. 2015).

Anomia is a key symptom of sv-PPA, occurring in the spontaneous speech that, by contrast with
other PPA variants, is not marked by phonological or grammar difficulties. This symptom is obvious
during language assessment (e.g., picture naming test) but less noticeable in spontaneous speech, as
patients compensate for their difficulties with the use of circumlocutions (Hodges and Patterson
2007). A single- word comprehension deficit is also a hallmark of the disease. It is also less obvious
in conversation than during testing because of the critical importance that contextual cues have in a
discussion. Similarly to what is observed with anomia, factors such as familiarity and prototypicality
(e.g., “dog” for the category “animal”) influence performance (Rogers et al. 2015). The progressive
deterioration of conceptual knowledge leads to an impairment of object knowledge and use,
although patients should function normally with everyday objects at home (also reflecting an effect
of familiarity for objects). Surface dyslexia and dysgraphia are also observed, where irregular
words (e.g., “pint”) are pronounced or written as if they were regular (e.g., “mint”). Although
symptoms and complaints preferentially focus on language impairment with less emphasis on
behavior, behavioral symptoms are common and can mimic the changes observed in bvFTD
(Kamminga et al. 2015; Seeley et al. 2005), particularly for sv-PPA with predominant right-sided
atrophy. Therefore, apathy, behavioral disinhibition, changes in eating behavior (e.g., restriction of
food preferences and bizarre food choices), and emotional withdrawal are commonly observed.
Patients also often present with an abnormal egocentric behavior (Snowden et al. 2001; Belliard et al.
2007), extreme rigidity, and compulsions such as repetitive playing of puzzles (Hodges and Patterson
2007). Finally, newfound religiosity, collectionism, and eccentricity of dress are also reported
(Edwards-Lee et al. 1997; Snowden et al. 2001). Insight abilities in sv-PPA are mostly impaired for
behavioral changes but, by contrast, patients show only a mild anosognosia regarding language
deficits (Hornberger et al. 2014; Savage et al. 2015).

Neuropsychology
Alterations of language are the main causes of complaint and functional impairment in sv-PPA, as well
as being the core features for its diagnosis. Anomia is especially salient during picture-naming tests,
where specific terms tend to be replaced by more prototypical words or by the superordinate
category name (e.g., “dog” or “animal” instead of “wolf”) or, in latest stages, by no answer (Hodges
and Patterson 2007; Belliard et al. 2007; Savage et al. 2013). Phonological cues such as pronouncing
the first letter or the first phoneme of the word to help its production have little or no effect (Jefferies
et al. 2008). Semantic fluency is dramatically impaired, reflecting a severe difficulty to generate
words in a particular category, while phonemic/letter fluency is relatively preserved during the early
stages (Hodges and Patterson 1996; 2007). After the earliest stages, identification of objects in any
modality is also impaired and reflects a central semantic deficit (Golden et al. 2015; Luzzi et al. 2015;
Hodges and Patterson 2007; Savage et al. 2013). Consequently, object use may also be altered
(Hodges and Patterson 2007). Similarly to anomia, patients with sv-PPA invariably have an impaired
comprehension of single words, which is strongly modulated by word familiarity (Hodges and
Patterson 1996, 2007; Savage et al. 2013). Therefore, while patients may be able to repeat words
without errors, difficulties arise when they have to provide definitions: definitions lack in detail at
first and, in the most severe stages, can be impossible. When the patient is asked to read or write,
“typicalization” errors are observed: irregular words are pronounced or written as if they were regular,
including verbs (e.g., “drinked” instead of “drank”), which is typical of surface dyslexia and
dysgraphia (Hodges and Patterson 2007; Savage et al. 2013).

Executive functions in sv-PPA are overall relatively preserved in left-sided presentations of sv-PPA
and impaired in right-sided sv-PPA. Digit or visuospatial spans are well preserved, and semantic
deficits may explain day-to-day working memory impairment as well as verbal fluency deficits
(Laisney et al. 2009; Jefferies et al. 2008; Desgranges et al. 2007; Hodges et al. 1999). While
alteration of cognitive flexibility may be observed in left-sided sv-PPA, it is more often seen in right-
sided sv-PPA as part of a more general dysexecutive syndrome (Desgranges et al. 2007; Kamminga et
al. 2015).

Although many patients complain of memory problems, this does not reflect a true amnesia. Memory
deficits in sv-PPA are modality-specific, occurring mostly on verbal tasks, with a relative preservation
of day-to-day memory (Irish et al. 2016; Hodges and Patterson 2007) and autobiographical memory
(Irish et al. 2011) as well as spatial navigation (Pengas et al. 2010).

Visuospatial abilities are well preserved (Desgranges et al. 2007; Perry and Hodges 2000) with
normal copy of complex figures (Hodges and Patterson 2007). Prosopagnosia appears predominantly
in right-sided sv-PPA and can be its principal symptom at presentation, helping to differentiate these
cases from bvFTD. By contrast, it is rarely observed in cases with left-side predominant atrophy
(Thompson et al. 2003; Kamminga et al. 2015).

Social cognition deficits can be seen in both left- and right-sided sv-PPA. Facial and musical emotion
recognition is altered (Hsieh et al. 2012) as well as empathy and theory of mind. In particular,
nonverbal sarcasm detection has been shown to be impaired (Rankin et al. 2009) as well as false-
belief, mental-state inference, and attribution of intention (Irish et al. 2014; Duval et al. 2012).

Neuroimaging
Structural imaging examinations show characteristic focal and bilateral, though asymmetric, atrophy
of the temporal lobe, involving the polar, lateral, and inferior surface (including fusiform gyrus) with
relative preservation of the superior temporal gyrus (Chan et al. 2001; Galton et al. 2001). This
atrophy is typically left-sided (the right-sided atrophy is observed in one third of cases) and ideally
appreciated in coronal orientation. Medial temporal structures are also involved, with the amygdala
and hippocampus being severely atrophied as well, particularly anteriorly (Galton et al. 2001; La
Joie et al. 2013). Involvement of the ventromedial frontal cortex and insula is also frequently
observed (Agosta et al. 2012; Gorno-Tempini et al. 2004; Rosen et al. 2002).

Functional imaging shows hypoperfusion/hypometabolism in anterior temporal regions as well as in

the hippocampus and orbitofrontal cortex, which is more marked on the left side (Rabinovici et al.
2008; Agosta et al. 2012).

Nonfluent/Agrammatic Variant Primary Progressive

Aphasia (nfv-PPA)

Clinical Profile
Consistent with other syndromes on the FTD spectrum, nfv-PPA is a younger-onset condition with an
average age of 60 years and equal prevalence in male and female patients (Johnson et al. 2005).
Survival is approximately 7 years after symptom onset (Hodges et al. 2003; Kertesz et al. 2005).
According to current diagnostic criteria, hallmark features of nfv-PPA are agrammatism and slow,
effortful speech, typically with accompanying deficits in syntax comprehension in the context of
spared single-word comprehension and object knowledge (Gorno-Tempini et al. 2011). Speech
production in nfv-PPA contrasts with the fluid, syntactically correct, but meaningless speech
production seen in sv-PPA, and patients are usually aware of their speech output deficits (Hodges and
Patterson 1996). Speech becomes increasingly effortful over the disease course and typically ends in
mutism. Communication via writing has been anecdotally reported as better preserved compared to
speech output; however, formal assessment can reveal equivalent impairments in both domains
(Graham et al. 2004). Prominent behavioral disturbance is uncommon early in the course of nfv-PPA;
however, apathy, agitation, and depression have been documented (Rohrer and Warren 2010) and
more profound personality changes and deficits in social functioning can emerge with disease
progression (Grossman 2012). Neurological examination in nfv-PPA patients is often unremarkable,
although the presence of extrapyramidal features is suggestive of an FTD overlap syndrome such as
ALS or corticobasal degeneration (CBD).

Neuropsychology
Slow, effortful speech in nfv-PPA is marked by errors, with abnormal prosody and a slowed rate of
speech (Gorno-Tempini et al. 2004, 2011; Ogar et al. 2007). Errors can include distortions (lack of
accurate articulation), deletions, substitutions, insertions, or transpositions of speech sounds. Changes
in prosody can reflect the incorrect placement of stress or intonation on syllables or words within a
sentence (Leyton et al. 2011). Trial and error processes often accompany this speech output where the
patient “gropes” for the correct sound or mouth formation. Apraxia of speech (AOS), which refers to
disordered articulatory planning and speech sound coordination, is a prominent mechanism
underlying the labored speech in nfv-PPA (Josephs et al. 2006). Slowed rate and effortful speech are
apparent in spontaneous speech output. On more standardized assessment, when nfv-PPA patients are
asked to provide a description of a series of pictures or a visual scene, their rate of speech is less than
one-third the speech rate of healthy control subjects and slower than other FTD variants (Ash et al.
2009; Wilson et al. 2010b; Grossman 2012). Formal assessment tools for this include describing the
“Picnic Scene” from the Western Aphasia Battery (Kertesz 1982) or the “Cookie Theft” picture from
the Boston Diagnostic Aphasia Examination (Goodglass and Kaplan 1983). These tools can also be
used to quantify the frequency of agrammatic errors. Severely reduced fluency in nfv-PPA is also
evident on classical tests of phonemic and semantic fluency (Nestor et al. 2003; Wilson et al. 2010b).
Agrammatism in nfv-PPA is reflected in the reliance on short, simplified phrases; omissions of
grammatical morphemes such as function words or inflections; and errors in word arrangement (i.e.,
syntax) (Gorno-Tempini et al. 2011; Leyton et al. 2011). Frequency of grammatical errors also
contributes to the reduced rate of speech production (Gunawardena et al. 2010). Related to this are
deficits in syntax comprehension, where patients have difficulty understanding the syntactic aspects
of speech (Hodges and Patterson 1996; Thompson et al. 1997). Agrammatism can be observed in
spontaneous speech or tested informally by asking the patient to follow sequential commands that
increase in their syntactic complexity (e.g., “put the pen on the watch before giving me the scissors”).
Standardized assessment of complex sequential commands reveals impairments relative to healthy
controls (Gorno-Tempini et al. 2004). Tasks that assess syntactic comprehension, such as responding
to questions about a complex sentence (e.g., “The friendly boy that the girl chased was nice.” versus
a simple sentence, “The nice, tall girl chased the friendly boy.”) show pronounced deficits relative to
controls, sv-PPA, and bvFTD (Peelle et al. 2008). Matching syntactically complex sentences with the
correct line drawing using the Test for Reception of Grammar (Bishop 2003) also reveals significant
impairment in nfv-PPA patients (Nestor et al. 2003).

Repetition of multisyllabic words (e.g., stethoscope) is particularly sensitive to nfv-PPA, and

impaired repetition seen in the context of spared naming and comprehension supports a breakdown in
grammatical processing or articulatory planning (Leyton et al. 2014). Testing of repetition can be
done informally or using standardized repetition tests contained in language assessment batteries such
as the Sydney Language Battery (SYDBAT) (Savage et al. 2013) and the Western Aphasia Battery. In
contrast to the striking language deficits, performance is better preserved in other cognitive domains,
such as episodic memory, visuospatial skills, and nonverbal reasoning (Graham et al. 2004).
However, measures of working memory (e.g., digit span) are reliably impaired in nfv-PPA (Nestor et
al. 2003; Wilson et al. 2010b) consistent with a deficit in phonological rehearsal abilities (Leyton et
al. 2014). Impairments in attentional set-shifting are also observed on the trail making test (Savage et
al. 2013; Brambati et al. 2015).

Neuroimaging
Structural MRI in nfv-PPA reveals gray matter atrophy in the inferior frontal region of the left
hemisphere, which can extend to the anterior insula, frontal operculum, dorsal prefrontal cortex, and
superior left anterior temporal lobe (Gorno-Tempini et al. 2004; Peelle et al. 2008; Rogalski et al.
2011; Grossman 2012). Progression of gray matter loss in the left frontal regions is evident in
longitudinal studies, accompanied by involvement of subcortical regions (Brambati et al. 2015).
Metabolic abnormalities in left hemispheric regions are also documented by PET imaging (Grossman
et al. 1996; Nestor et al. 2003). Local white matter abnormalities in the dorsal language network
(e.g., superior longitudinal fasciculus) are documented, as well as more diffuse white matter changes
outside the language network (Galantucci et al. 2011; Schwindt et al. 2013). Fluency impairment has
been directly related to gray matter volume in the left inferior frontal regions, insula, and superior
temporal area (Ash et al. 2009), whereas apraxia of speech is associated with changes in the premotor
and supplemental motor cortices (Josephs et al. 2006). Posterior regions of the inferior frontal cortex
show functional abnormalities related to processing of syntactically complex sentences during fMRI
(Wilson et al. 2010a).

Neuropathology of FTD Variants

Neuronal loss, gliosis, and microvacuolar changes characterize frontotemporal lobar degeneration
(FTLD). Specific patterns of abnormal protein deposition are observed in FTLD, such as microtubule-
associated protein tau (MAPT), TAR DNA-binding protein with molecular weight 43 kDa (TDP-43),
and fused-in-sarcoma protein (FUS). Ubiquitin-only, p62-only positive inclusions, or no inclusions
are sometimes observed, but in many fewer cases (Mackenzie et al. 2010; Bang et al. 2015). FTLD-
MAPT or tau accounts for 36–50% of all FTLD cases, almost equally distributed between Pick’s
disease, CBD, and PSP cases (Josephs et al. 2011; Sieben et al. 2012; Dickson et al. 2011). FTLD-
TDP accounts for about 50% of all FTLD cases, with three major subtypes (A, B, and C) accounting
for about half of the nfv-PPA cases (FTLD-TDP-A), two-thirds of FTD-MND cases (FTLD-TDP-B),
and the majority of sv-PPA cases (FTLD-TDP-C) (Josephs et al. 2011; Sieben et al. 2012; Mackenzie
et al. 2011; Le Ber 2013). Deposition of TDP-43 pathology in the hypoglossal nucleus and in the
anterior cingulate cortex has been found to have high value to respectively identify MND and bvFTD
patients (Tan et al. 2015). FTLD-FUS accounts for about 10% of all FTLD cases and is characterized
by early-onset FTD with severe behavioral and psychiatric abnormalities without linguistic and motor
impairments (Mackenzie et al. 2011).
Finally, AD pathology is observed at autopsy in 15–30% of patients with a diagnosis of FTD (Hodges
et al. 2004; Grossman et al. 2007; Alladi et al. 2007), mostly in bvFTD and nfv-PPA.

Overlap Syndromes (ALS, AD, Logopenic, PSP, CBD)

A number of syndromes overlap with the classical FTD spectrum, with shared clinical, pathological,
and genetic characteristics. Overlap syndromes include ALS, progressive supranuclear palsy (PSP),
CBD, AD, and logopenic aphasia.

Amyotrophic Lateral Sclerosis (ALS)

ALS is dominated by motor symptoms caused by lower and upper motor neuron dysfunction. These
symptoms include weakness, spasticity, muscle wasting, dysarthria, and swallowing difficulties
(Mitchell and Borasio 2007; Kiernan et al. 2011). Cognitive and psychiatric changes are increasingly
recognized in ALS and 20–50% of patients meet diagnostic criteria for FTD (Ringholz et al. 2005). A
proportion of FTD patients also go on to develop ALS motor features (Lomen-Hoerth et al. 2002).
Cognitive dysfunction in ALS is characterized by executive impairment, personality changes, poor
insight, and behavioral changes that include disinhibition and apathy (Flaherty-Craig et al. 2006;
Phukan et al. 2007). Clinically, this presentation overlaps considerably with bvFTD (Lillo et al.
2012b). Neuroimaging in ALS patients with cognitive and behavioral dysfunction reveals
frontotemporal atrophy (Lillo et al. 2012a; Mioshi et al. 2013). Consistent with the clinical overlap,
FTD and ALS also share overlapping pathology and genetic susceptibility. TDP-43-positive
inclusions are present in half of the patients with FTD and in the majority of ALS patients (Neumann
et al. 2006) and expansions in the C9 or f72 gene are a common cause of both familial FTD and ALS
(DeJesus-Hernandez et al. 2011; Renton et al. 2011).

Progressive Supranuclear Palsy (PSP)

PSP is characterized by vertical gaze palsy, postural instability, and cognitive decline (Litvan et al.
1996a). Cognitive impairment occurs in the majority of patients and is characteristically “fronto-
subcortical,” with mental slowing and executive dysfunction (especially attention and verbal fluency)
and inefficient memory recall (Brown et al. 2010). PSP patients also exhibit significant levels of
apathy and disinhibition (Litvan et al. 1996b; Aarsland et al. 2001). The combination of executive
dysfunction and neuropsychiatric features supports a clinical overlap with FTD, and one case series
identified over 30% of pathologically confirmed PSP cases met clinical criteria for possible bvFTD
(Kobylecki et al. 2015). Pathologically, PSP is characterized by accumulation of tau protein and
neuropil threads primarily in the basal ganglia and brainstem (Hauw et al. 1994; Williams and Lees
2009). Tau pathology represents a common substrate underlying PSP, which is also present in nearly
half of FTD cases (Josephs et al. 2011). A PSP-FTD subtype has been proposed to identify those
patients with a prominent FTD cognitive/behavioral syndrome. Those patients show more extensive
cortical pathology compared to PSP without prominent cognitive/behavioral changes (Dickson et al.
2010).

Corticobasal Degeneration (CBD)

CBD is characterized by tau pathology and a combination of motor and cognitive/behavioral features
related to frontoparietal neuronal loss and basal ganglia degeneration. Numerous diagnostic criteria
and terminologies have been proposed (Riley et al. 1990; Boeve et al. 2003; Bak and Hodges 2008;
Armstrong et al. 2013). The clinical motor syndrome commonly associated with CBD is
parkinsonism, asymmetric rigidity, and corticobasal dysfunction evidenced by limb or oculomotor
apraxia, cortical sensory deficits, and alien limb or dystonic limb posturing (Kouri et al. 2011). The
cognitive/behavioral syndrome is characterized by language and visuospatial dysfunction and changes
in behavior and personality (Burrell et al. 2014). Visuospatial dysfunction is typically striking and
may include Balint’s syndrome (simultanagnosia, oculomotor apraxia, and optic ataxia) (Graham et al.
2003). Language features overlap with nfv-PPA (Kertesz et al. 2000; McMonagle et al. 2006) and
behavioral symptoms mirror those seen in bvFTD, particularly apathy and disinhibition (Kertesz and
McMonagle 2010; Bruns and Josephs 2013).

Alzheimer’s Disease (AD)

AD is pathologically distinct from FTD; however, shared clinical features can make these diseases
difficult to distinguish. AD is characterized by impaired ability to retain newly learnt information
(anterograde episodic memory) (Kopelman 1985; Butters et al. 1987; Perry et al. 2000). Progression sees
decline in other aspects of memory (i.e., semantic knowledge and remote memory), accompanied by
attentional, executive, and visuospatial deficits (Hodges 2006). Cognitive decline in AD is associated with
early hippocampal and medial temporal pathological changes and later frontal and parietal changes, which
are apparent on structural, functional, and metabolic imaging (Jack 2012).
Episodic memory impairment was previously considered a distinguishing feature to separate AD from
FTD as it was presumed to be intact in FTD (Neary et al. 1998). However, memory impairment in
FTD, in particularly bvFTD, can be equally severe as seen in AD (Hornberger et al. 2010; Bertoux et
al. 2014). Atypically presenting AD may also manifest a “frontal” behavioral syndrome characterized
by behavioral abnormalities and executive dysfunction (Warren et al. 2012). The potential overlap
between memory impairment and behavioral change means in certain cases AD and bvFTD might
only be distinguished postmortem. AD pathology involves the accumulation of beta-amyloid plaques
and neurofibrillary tangles beginning in the transentorhinal cortex and hippocampus, before
progressing to adjacent medial temporal regions and later neocortical association regions (Braak and
Braak 1991).

Logopenic Aphasia
Sv-PPA and nfv-PPA were the prototypical primary progressive aphasias prior to identification of a
third variant known as logopenic aphasia (Gorno-Tempini et al. 2004). Word retrieval and sentence
repetition deficits, accompanied by slowed speech with frequent word-finding pauses, are hallmark
features of logopenic aphasia and linked to a core phonologic short-term memory deficit (Gorno-
Tempini et al. 2008, 2011). Although the slowed speech overlaps with the nfv-PPA presentation,
logopenic aphasics do not exhibit the same degree of motor speech errors or agrammatism
(Grossman et al. 1996). The confrontation naming impairment is typically less severe than in sv-PPA
and characterized by phonological errors as opposed to semantic errors (Gorno-Tempini et al. 2004).
Compared with the two other progressive aphasias, logopenic aphasia is associated with a more rapid
progression toward a global dementia that encompasses nonverbal domains (Leyton et al. 2013).
Imaging abnormalities in the left temporoparietal junction and dorsal language network are found in
logopenic aphasia (Rohrer et al. 2010; Leyton et al. 2012). Amyloid imaging and neuropathological
studies confirm that Alzheimer pathology is the most common underlying cause of logopenic aphasia
(Mesulam et al. 2008; Rabinovici et al. 2008; Rohrer et al. 2012).

Conclusion and Outlook

The current chapter gave an overview of the FTD spectrums as well as the most prominent overlap
syndromes. As evident from the chapter, FTD is a complex and multifaceted disease, which covers
different cognitive, neuroimaging, and pathological domains. More specifically, FTD patients can not
only present with behavioral and language problems but can also show social cognition and memory
deficits as well as motor symptoms. Similarly, brain regions affected by structural and functional
changes can be widely distributed or focal. Finally, the admixture of tau and TDP-43 pathology adds
the last level of complexity for this disease spectrum.
Such multifaceted complexity might at first seem daunting for any clinician or researcher. However,
FTD is therefore emerging often as a critical disease to determine pathological specificity. More
specifically, comparisons between FTD and other dementias allow to delineate cognitive,
neuropsychiatric, and neuroimaging biomarkers specific to each conditions. This is particularly
relevant for phenotypological variability across dementias, i.e., where patients can show
overlapping cognitive symptoms.
Taken together, our overview shows the importance of FTD as a syndrome within the dementias,
especially for early-onset cases. Despite its lower prevalence than AD, FTD emerges as important
syndrome to delineate different dementia pathologies on a cognitive and neuropsychiatric level.
Clearly future investigations are needed to explore this further via novel cognitive biomarkers that
can be then also used as outcome measures in disease modifying trials. Finally, the longitudinal
trajectories of cognitive and neuropsychiatric changes are still virtually unknown in FTD, which are
important to explore as to allow better symptom management in patients in the future.

Cross-References
Behavior Modification
Behavioral and Psychological Symptoms of Dementia
Challenging Behavior
Dementia and Neurocognitive Disorders
Language: Comprehension
Language: Naming
Semantic Dementia
Social Cognition & Aging
Younger Onset Dementia: Diagnosis, Course and Interventions

Acknowledgments
Dr. M. Bertoux is supported by the European Commission and Dr. C. O’Callaghan by the National
Health and Medical Research Council (MRC-Australia).

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