NEUROLOGICAL PROGRESS
Frontotemporal Dementia and Related
Disorders: Deciphering the Enigma
Keith A. Josephs, MST, MD
In the past century, particularly the last decade, there has been enormous progress in our understanding of frontotemporal
dementia, a non-Alzheimer’s type dementia. Large clinicopathological series have been published that have clearly demonstrated
an overlap between the clinical syndromes subsumed under the term frontotemporal dementia and the progressive supranuclear
palsy syndrome, corticobasal syndrome, and motor neuron disease. There have also been significant advancements in brain
imaging, neuropathology, and molecular genetics that have led to different approaches to classification. Unfortunately, the field
is complicated by a barrage of overlapping clinical syndromes and histopathological diagnoses that does not allow one to easily
identify relations between individual clinical syndromic presentations and underlying neuropathology. This review deciphers this
web of terminology and highlights consistent, and hence important, associations between individual clinical syndromes and
neuropathology. These associations could ultimately allow the identification of appropriate patient phenotypes for future targeted
treatments.
Ann Neurol 2008;64:4 –14
The clinical diagnosis of frontotemporal dementia
(FTD) refers to a group of progressive overlapping
clinical syndromes characterized by the insidious onset
of behavioral changes, loss of word and object knowledge, and aphasia.1 Recent large clinicopathological
studies have demonstrated an overlap among the FTD
syndromes, some extrapyramidal syndromes, and motor neuron disease (MND).2–5 Furthermore, FTD and
these related disorders show overlapping histopathological and biochemical abnormalities that have led to the
recommendation by some researchers to lump FTD
and related disorders under one large umbrella term,
Pick’s complex.6 Parallel to the publications of clinicopathological series, neuroimaging and molecular genetic studies have published important findings that
have been shown to be useful in refining clinicopathological associations.
Unfortunately, the exponential number of publications of clinical, neuropathological, neuroimaging, and
molecular genetic research on FTD and related disorders has complicated the field with the reporting of a
barrage of overlapping diagnoses and interpretations of
histopathological classifications. This has led to a complex lattice of associations between clinical and neuropathological diagnoses, some of which are clearly minor associations whereas others are more significant.
Therefore, one cannot easily identify important rela-
tions between individual clinical syndromic presentations and underlying histopathologies. This review deciphers this web and highlights consistent, and hence
important, associations between the more common individual syndromes and neuropathology. Fine-tuning
these associations with better understanding of imaging
characteristics, environmental and genetic causes, and
biochemical alterations will ultimately allow the identification of appropriate patient phenotypes for targeted treatments currently in development.
In this review, the term FTD is applied as an umbrella term for the clinical syndromes of behavioral
variant FTD (bvFTD), semantic dementia (SD), and
progressive nonfluent aphasia (PNFA), whereas the
term frontotemporal lobar degeneration (FTLD) will be
used as an umbrella term for the spectrum of FTDrelated pathologies.7 Similarly, the term extrapyramidal
syndromes is used as an umbrella term for the clinical
syndromes of corticobasal syndrome (CBS) and the
progressive supranuclear palsy syndrome (PSP-S),
whereas the terms corticobasal degeneration and progressive supranuclear palsy (PSP) are used only in the context of pathological diagnosis.
From the Department of Neurology, Behavioral Neurology and
Movement Disorders, Mayo Clinic, Rochester, MN.
Address correspondence to Dr Josephs, Mayo Clinic, Department of
Neurology, 200 1st Street SW, Rochester, MN 55905.
E-mail: [email protected]
Received Jan 29, 2008, and in revised form Apr 22, 2008. Accepted
for publication Apr 25, 2008.
Clinical Syndromes
FTD is an umbrella term that includes a number of
different syndromic variants, all characterized by the
Published online in Wiley InterScience (www.interscience.wiley.com).
DOI: 10.1002/ana.21426
4
© 2008 American Neurological Association
Published by Wiley-Liss, Inc., through Wiley Subscription Services
Table 1. Different Terminologies Associated with Progressive Aphasias
Terminology
Description of Terminology
Semantic dementia
Characterized by a loss of word meaning (single words) and comprehension
difficulties
Progressive nonfluent
aphasia
Nonfluent speech output with agrammatic and telegraphic speech (such as writing a
telegram)
Apraxia of speech
Characterized by slow speaking rate, abnormal prosody, and distorted sound
substitutions, sometimes accompanied by groping and trial-and-error articulatory
movements
Logopenic aphasia
Characterized by slow speech and impaired syntactic comprehension and naming
Aphasic dementia
Characterized by prominent speech and language deficits but accompanied by mild
behavioral or cognitive deficits such as loss of episodic memory or visuospatial/
perceptual deficits
PPA subtypes21
Agrammatic/
dysfluent PPA
Equivalent to progressive nonfluent aphasia and is characterized by poor syntax and
fluency but good comprehension
Semantic variant
PPA
Equivalent to the nonagnostic form of semantic dementia and is characterized by
poor comprehension but good syntax and fluency
Logopenic variant
PPA
Equivalent to logopenic aphasia and is characterized by good syntax and
comprehension but frequent word-finding pauses
PPA ⫽ primary progressive aphasia.
presence of behavioral and personality changes and
aphasia.1 The consensus criteria published in 1998
identifies three variants of FTD that are now referred
to as bvFTD, SD, and PNFA.1 These syndromes have
overlapping features but are each characterized by the
predominant feature. Hence, bvFTD is diagnosed
when the dominant presenting feature is a change in
personality or behavior associated with executive dysfunction. Language impairment can also occur in
bvFTD but is overwhelmingly overshadowed by the
change in personality. A small subset of patients with
bvFTD has been noted to have bizarre visual hallucinations and prominent Parkinsonism, although the pathology underlying these patients is unclear. It also appears that a small proportion of patients fulfilling
criteria for bvFTD show little progression in their
symptoms over time.8,9 These are referred to as slowly
progressive FTD. SD is characterized by loss of word
and object knowledge and comprehension deficits that
can be associated with varying degrees of prosopagnosia
(loss of facial recognition).1 Behavioral changes are also
noted in SD but tend to be somewhat distinct from
the behavioral changes seen in bvFTD.10,11 Some researchers have further divided SD into right and left
temporal variants based on which temporal lobe shows
the greater amount of atrophy. Behavioral changes
rather than prosopagnosia, as originally reported, are
the typical presenting feature of the right temporal
variant.12,13 The third syndrome, known as PNFA, is
characterized by a nonfluent speech output, agrammatism, and telegraphic speech. Unlike bvFTD and SD,
behavioral and personality changes are less common in
PNFA. More commonly seen in PNFA, particularly
later on in the disease course, is the development of
extrapyramidal features, sometimes leading to a change
in the diagnosis from PNFA to CBS.4,14
A parallel development to PNFA and SD was primary progressive aphasia (PPA),15 a term coined by
Mesulam,16 who first reported a series of six patients
with progressive aphasia. A diagnosis of PPA can be
made in any patient with a progressive neurodegenerative disease in which language impairment is the most
salient feature,15 and hence the term PPA subsumes
PNFA, and overlaps with SD. Other terminologies
have also been described in relation to progressive
aphasias,17–20 and a recent publication suggested dividing PPA into three clinical variants (Table 1).21 It remains controversial, however, whether a semantic variant of PPA exists in which a visual associative agnosia
(loss of the meaning of objects when viewed) is truly
absent, or whether semantic PPA is simply SD dominated by a verbal associative agnosia.22
Although bvFTD, SD, and PNFA are syndromes
dominated by behavioral and language changes, extrapyramidal features, especially in PNFA, can be prominent. Over the past decade, many case reports, as well
as large clinicopathological series, have recognized an
overlap among these three syndromes and PSP-S, CBS,
and MND.2–5 PSP-S is typically characterized by akinesia and rigidity, vertical supranuclear gaze palsy, and
early falls.23,24 Behavioral and personality changes and
executive dysfunction can occur in PSP-S but tend to
Josephs: Deciphering the FTD Enigma
5
be mild, whereas apathy can be a prominent feature,
hence the overlap with bvFTD. The CBS is also characterized by akinesia and rigidity, but this tends to be
asymmetric.25 A combination of limb apraxia and myoclonus, and alien limb phenomenon can be prominent. Behavioral and personality changes and nonfluent speech can also be prominent, hence the overlap
with the FTD syndromes. In some cases of FTD, features of MND are observed, suggesting that FTD and
MND may be on the same disease spectrum.26 Features of MND may include bulbar symptoms such as
difficulty speaking and swallowing, weakness, spasticity, fasciculations, hyperactive reflexes, clonus, and a
Babinski sign. The features of MND tend to be mixed
upper and predominantly lower but can be predominantly upper. MND is rare in SD, PNFA, PSP-S, and
CBS, but it has been described.17,27,28 MND is more
commonly associated with features of bvFTD, hence
the term FTD-MND, although many patients diagnosed with FTD-MND do not meet strict criteria for
bvFTD.1 In FTD-MND, disease progression is rapid,
with death occurring after an illness duration of approximately 2 years.29 Behavioral and cognitive deficits
usually precede clinical features of MND, although a
sizable proportion of patients with MND have, or can
later develop, features suggestive of FTD.30
Imaging
In clinical practice, routine imaging is performed primarily to rule out other nondegenerative processes that
can mimic the FTD syndromes and related disorders.
However, imaging can also be useful to aid in the clinical diagnosis based on the identification of specific
patterns of atrophy that are best observed on head
magnetic resonance imaging scans. It is important to
note that many of the findings reported on magnetic
resonance imaging do not have pathological confirmation and, therefore, represent the clinical syndrome and
not the pathology. The three main FTD syndromes,
bvFTD, SD and PNFA, have somewhat distinct patterns of atrophy. The bvFTD is associated with atrophy affecting bilateral frontal lobes, particularly the
medial frontal lobes, and anterior temporal lobes,
whereas SD is associated with bilateral, although usually asymmetric, middle, inferior, and medial anterior
temporal lobe atrophy. In contrast, PNFA shows left
perisylvian atrophy. In the related disorders, atrophy of
the midbrain tegmentum and superior cerebellar peduncle is characteristic of the PSP-S, whereas frontoparietal atrophy is associated with the CBS. Functional
imaging studies such as single-photon computed tomography and positron emission tomography have
found similar patterns of neocortical hypoperfusion
and hypometabolism in these clinical syndromes. In
addition, some patients may also show changes in basal
ganglia and thalamus. A recent study showed that on
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first presentation, bvFTD disproportionately had right
frontal hypoperfusion on single-photon computed tomography, although the temporal lobes were also involved and were associated with specific clinical features.31
A number of group studies using an automated technique called voxel-based morphometry have assessed the
patterns of atrophy in the different clinical variants of
FTD. This technique performs statistical comparisons
across groups of subjects to identify regions that show
significant atrophy. Studies have largely confirmed the
patterns observed in observational case studies, although they have also provided further insight into the
extent of brain loss in these disorders. For example,
voxel-based morphometry studies that examine
bvFTD, SD, PNFA, PSP-S, and CBS have been published.18,19,32–34 Interestingly, one group of researchers
demonstrated that a distinct pattern of atrophy affecting posterior temporal and parietal regions was associated with logopenic aphasia.18 This same pattern of atrophy was also reported to be associated with aphasic
dementia20 and with PPA patients with impaired word
finding but intact comprehension on conversational
speech.35 Atrophy of the supplemental motor cortex
and superior premotor cortex extending into the motor
cortex has been shown to be associated with apraxia of
speech,19 and posterior frontal lobe atrophy has been
observed in FTD-MND.36
Histopathology
With the advent of immunohistochemistry it became
clear that many different pathologies underlie the FTD
syndromes, and that these same pathologies were associated with the FTD-related disorders, such as PSP-S,
CBS, and MND. It is now well established in the field
that more than 15 different pathologies can underlie
FTD and related disorders.7,37
The most common pathology associated with FTD
was thought to be dementia lacking distinctive histology (DLDH),38 a diagnosis made when there was gross
evidence of frontal and temporal lobe atrophy and histological findings of neuronal loss and gliosis affecting
superficial cortical lamina of these same cortical regions
and absence of the typical pathological findings of Alzheimer’s disease. It was also recognized that many cases
with DLDH had evidence of neuronal loss and gliosis
affecting the CA1 and subicular regions of the hippocampus, that is, hippocampal sclerosis.39 With the
advent of ubiquitin immunohistochemistry, many cases
of DLDH were observed to have ubiquitinated inclusions and dystrophic neurites in lamina II of the frontal and temporal cortices, as well as in the dentate
granule cells of the hippocampus.39 – 42 Hence, the majority of DLDH cases were renamed frontotemporal lobar degeneration with ubiquitin-only–immunoreactive
changes (FTLD-U), although rare cases of FTLD-U
Fig 1. Classification scheme demonstrating the subdivision of the spectrum of frontotemporal lobar degeneration (FTLD) pathologies
into tauopathies versus TAR DNA-binding protein 43 (TDP-43) proteinopathies. Some cases, however, are neither a tauopathy nor
a TDP-43 proteinopathy and are therefore classified as “Others.” AGD ⫽ argyrophilic grain disease; ALS-PDC ⫽ amyotrophic
lateral sclerosis-parkinsonism complex of Guam; BIBD ⫽ basophilic inclusion body disease; CBD ⫽ corticobasal degeneration;
DLDH ⫽ dementia lacking distinctive histology; DNTC ⫽ diffuse neurofibrillary tangle dementia with calcifications; FTLD-U ⫽
frontotemporal lobar degeneration with ubiquitin-only–immunoreactive changes; MST ⫽ sporadic multisystem tauopathy; MBD ⫽
neurofilament inclusion body disease; PiD ⫽ Pick’s disease; PSP ⫽ progressive supranuclear palsy; TDD ⫽ tangle dominate
dementia.
without lobar atrophy have also been described.8 It was
also observed that, in addition to the ubiquitinated
neocortical lesions and those in the dentate granule
cells of the hippocampus, some cases of DLDH also
had evidence of motor neuron degeneration or descending corticospinal tract degeneration. Those cases
have been separated from FTLD-U and were called
FTLD-MND.40 Further subclassification of FTLDMND has been recently suggested, based on the findings of isolated upper MND in some cases for which
the term FTLD with primary lateral sclerosis was proposed.43 The separation of FTLD-U from FTLDMND is supported by the fact that hippocampal sclerosis is common in FTLD-U but uncommon in
FTLD-MND.43,44 The diagnosis of true DLDH is
now extremely rare and is reserved only for cases in
which there is evidence of frontal and temporal lobar
atrophy but absent lesions on hematoxylin and eosin,
silver, and all immunohistochemistry.
Molecular Pathology
In 2006, researchers from the University of Pennsylvania and from Japan identified one of the major ubiquitinated proteins in FTLD-U, FTLD-MND, as well as
amyotrophic lateral sclerosis (ALS) as the TAR DNAbinding protein 43 (TDP-43).45,46 These diseases
therefore became known as TDP-43 proteinopathies
(Fig 1). TDP-43 is a highly conserved nuclear protein
that functions in the regulation of transcription and
alternative splicing. Consensus criteria were published
using TDP-43, and data generated from two previous
studies,47,48 suggesting that FTLD-U be further subclassified into three variants based on the morphology,
distribution, and ratio of TDP-43–positive neuronal
cytoplasmic inclusions to dystrophic neurites: FTLD-U
types 1, 2, and 337 (Fig 1: Table 2). FTLD-MND essentially was subsumed under FTLD-U type 2. It has
also been suggested that these three variants show an
association with the FTD syndromes: type 1 was associated with SD, type 2 with FTD-MND and bvFTD,
and type 3 with bvFTD and PNFA.48 –50 Further studies, however, are needed to confirm this observation.
Recent studies have demonstrated that abnormal
TDP-43 immunoreactivity also occurs in Alzheimer’s
disease,51 Pick’s disease (PiD),46,52 pure hippocampal
sclerosis (no evidence of lobar atrophy),51 Lewy body
disease,53 and the ALS-parkinsonism complex of
Guam,54,55 and one study demonstrated alterations in
the Alzheimer’s disease phenotype when TDP-43 was
copresent.56 Rare cases of FTLD-U without abnormal
TDP-43 immunoreactivity have also been published.57
Although the majority of FTLD cases are TDP-43
proteinopathies,40 – 42 a significant number of FTLD
and related disorders are characterized by the accumu-
Josephs: Deciphering the FTD Enigma
7
Table 2. Histological Features and Genetic Associations of the Different Frontotemporal Lobar Degeneration with
Ubiquitin-Only–Immunoreactive Changes Subtypes
FTLD-U Subtype
Description of Histological Features
Genetic
Associations
Type 1
Frontotemporal neuronal loss and gliosis with a predominance of
TDP-43/ubiquitin/P62-positive elongated dystrophic neurites
with few neuronal cytoplasmic inclusions
No associations yet
identified
Type 2
Frontotemporal neuronal loss and gliosis with a predominance of
TDP-43/ubiquitin/P62-positive neuronal cytoplasmic inclusions
with few short dystrophic neurites
Intraflagellar
transport 74
(IFT74)
mutation
Type 3
Frontotemporal neuronal loss and gliosis with TDP-43/
ubiquitin/P62-immunoreactive neuronal cytoplasmic inclusions,
short dystrophic neurites, and intranuclear inclusions
Progranulin
(PGRN)
mutations
Type 4
Frontotemporal neuronal loss and gliosis with TDP-43/
ubiquitin/P62 neuronal intranuclear inclusions and dystrophic
neurites with scant neuronal cytoplasmic inclusions
Valosin-containing
protein (VCP)
mutations
Type 5
Frontotemporal neuronal loss and gliosis with ubiquitin/P62 but
without TDP-43–positive neuronal cytoplasmic inclusions and
dystrophic neurites
Charged
multivesicular
body protein 2B
(CHMP2B)
mutations
FTLD-U ⫽ frontotemporal lobar degeneration with ubiquitin-only–immunoreactive changes; TDP-43 ⫽ TAR DNA-binding protein
43.
lation of another abnormal protein, the microtubuleassociated protein tau (MAPT).58,59 This group of diseases became known as the tauopathies (see Fig 1). Tau
is a microtubule-associated protein that functions to
stabilize microtubule and promote microtubule assembly by binding to tubulin.60 Tau has six different isoforms that are generated by alternative splicing of exons 2, 3, and 10. Alternative splicing of exons 2 and 3
results in tau isoforms that differ by the presence of
one or two amino-terminal inserts, whereas alternative
splicing of exon 10 affects the number of carboxylterminal repeats.61,62 Inclusion of exon 10 results in
four-repeat (4R) tau, whereas exclusion of exon 10 results in three-repeat (3R) tau. Each tauopathy has distinct morphological characteristics of neuronal and
glial lesions, differ in the anatomic distribution of the
lesions, and may differ by the molecular pathology
(Table 3). Some tauopathies, such as progressive supranuclear palsy and corticobasal degeneration, are
much more common than others, such as PiD, whereas
some tauopathies are extremely rare, such as diffuse
neurofibrillary tangle dementia with calcifications63
and diffuse argyrophilic grain disease.64
Although more than 90% of cases of FTD and related disorders can be classified as a TDP-43 proteinopathy or a tauopathy (see Fig 1), a small proportion of FTD cases is associated with additional rare
pathologies that are not characterized by either abnormal TDP-43 or tau (see Fig 1). One such pathology is
known as neurofilament inclusion body disease65 or
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neuronal intermediate filament inclusion dementia,66
which is characterized by the accumulation of intraneuronal inclusions that are immunoreactive to neurofilament and ␣-internexin.65,67 Another rare pathology
is characterized by the identification of basophilic
round neuronal inclusions that show variable immunoreactivity to ubiquitin but are negative to all other routine stains, silver stains, and immunostains.68 This disease now known as basophilic inclusion body disease
tends to be associated with MND,69 although initial
descriptions of this pathology were associated with
bvFTD where the pathology was called generalized
variant of PiD.70 Inclusions in neurofilament inclusion
body disease and basophilic inclusion body disease are
not immunoreactive to either TDP-43 or tau.
Molecular Genetics
Parallel to the discoveries in molecular pathology, and
refinement of clinical and histopathological features of
FTLD and related disorders, there have been major
discoveries in the molecular genetics of FTLD. Four
major genes and one confirmed genetic locus for
FTLD have been reported.
The first major discovery was the identification of
mutations in the MAPT gene,71 which was identified
in 9 of 13 families with varying degrees of behavioral
and personality changes and extrapyramidal features
that had been linked to chromosome 17.72 By the end
of 2007, 41 different potential pathogenic MAPT mutations had been reported.73 These include 27 missense
Table 3. Tauopathies Associated with Frontotemporal Dementia and the Related Disorders
Diseases
Brief Description of the Key Histological Features
Dominant
Tau-Isoform
Pick’s disease
Tau- and silver-positive rounded inclusions visible on hematoxylin and
eosin and balloon neurons (Pick cells)
3R
Progressive supranuclear
palsy
Tau-positive neuronal and glial lesions especially globose
neurofibrillary tangles and tufted astrocytes in cardinal nuclei
4R
Progressive supranuclear
palsy with
corticospinal tract
degeneration
Prominent tau-positive globular cytoplasmic inclusions in
oligodendrocytes in motor cortex, subjacent white matter, and
corticospinal tract
4R
Corticobasal
degeneration
Tau-positive neuronal and glial lesions, especially astrocytic plaques
and threadlike lesions in cardinal regions
4R
ALS-parkinsonismdementia complex of
Guam
Widespread tau-positive neurofibrillary tangles in neocortex, absentsparse senile plaques, and substantia nigra degeneration
3R ⫹ 4R
Tangle dominant
dementia
Tau-positive neurofibrillary tangles, frequent ghost tangles, and threads
almost limited to limbic areas, and absent neuritic plaques
3R ⫹ 4R
Neurofibrillary tangle
dementia with
calcifications
Tau-positive neurofibrillary tangles, absent neuritic plaques, and
prominent basal ganglia and cerebellar calcification
3R ⫹ 4R
Argyrophilic grain
disease
Tau-positive spindle- or comma-shaped argyrophilic grains and coiled
bodies limited to limbic regions
4R
Diffuse argyrophilic
grain disease
Tau-positive spindle- or comma-shaped argyrophilic grains and coiled
bodies in neocortical, subcortical, and brainstem regions
4R
Sporadic multiple
system tauopathy
Tau-positive globular neuronal and glial tau-positive inclusions in both
gray and white matter of the neocortex
4R
3R ⫽ three repeat; 4R ⫽ four repeat; ALS ⫽ amyotrophic lateral sclerosis.
mutations, 4 silent mutations, 2 in-frame single codon
deletions, and 8 intronic mutations. MAPT mutation
frequencies in FTLD populations have been shown to
vary from 0 to 50% depending on the study design.74
The pathology identified in patients with mutations in
the MAPT gene is invariable tau, although the tau isoform deposition is heterogeneous.75 Patients with mutations in exon or intron 10 most commonly show 4R
tau deposition, whereas missense mutations outside of
exon 10 usually produce 3R ⫹ 4R tauopathy. There
has been no reproducible association between clinical
phenotypes and the position of a mutation within the
MAPT gene. The majority of patients with an identified mutation in the MAPT gene have behavioral and
personality changes; however, the clinical features
widely vary and at times even mimic Alzheimer’s disease. Clinical features can even vary widely in the same
family.74
Of the remaining four families who had been linked
to chromosome 17,72 no mutations in the MAPT gene
could be identified. In 2006, however, two groups of
researchers reported the identification of mutations in
the progranulin (PGRN) gene that were associated with
FTD and more specifically FTLD-U pathology.76,77
All but one of the remaining four families has been
proved to have PGRN mutations. By the end of 2007,
44 different pathogenetic PGRN mutations have been
reported.73 The mutations have been found scattered
over the gene, most commonly being small insertions
and deletions. All PGRN mutations identified so far
result in functional null alleles or haploinsufficiency by
producing a premature termination codon that leads to
degradation of mutant RNA by nonsense-mediated decay.77,78 Progranulin mutation frequencies in FTLD
populations have ranged from 5 to 10%, although a
frequency of 13 to 25% has been reported in the subset of FTLD population in which a positive family history is identified.76,78,79 The pathology associated with
PGRN mutations has been FTLD-U, specifically
FTLD-U type 3.80,81 There have been no reported
cases of FTLD-MND. Similar to MAPT mutations,
the majority of patients with an identified mutation in
the PGRN gene have behavioral and personality
changes; however, the clinical features vary widely and
also may mimic Alzheimer’s disease.82 Aphasia, best
characterized as PPA because it does not always fit
nicely into the PNFA or SD criteria,1 has been described, and parkinsonism is a common feature.36,80,82
Rare presentations of Parkinson’s disease and PSP-S
Josephs: Deciphering the FTD Enigma
9
Fig 2. Schematic plot illustrating the most prominent associations between clinical syndromes, patterns of atrophy, pathological diagnoses, and protein biochemistry for sporadic frontotemporal dementia (FTD). TDP-43 ⫽ TAR DNA-binding protein 43. Clinical
syndromes: ⫹AOS ⫽ apraxia of speech present; ⫺AOS ⫽ apraxia of speech absent; bvFTD ⫽ behavioral variant FTD; CBS ⫽
corticobasal syndrome; EP ⫽ extrapyramidal; FTD-MND ⫽ FTD with motor neuron disease; PNFA ⫽ progressive nonfluent
aphasia; PSP-S ⫽ progressive supranuclear palsy syndrome; SD ⫽ semantic dementia. Pathological diagnoses: CBD ⫽ corticobasal
degeneration; FTLD-U ⫽ frontotemporal lobar degeneration with ubiquitin-only–immunoreactive changes; FTLD-MND ⫽ frontotemporal lobar degeneration with motor neuron disease; PiD ⫽ Pick’s disease; PSP ⫽ progressive supranuclear palsy.
have been reported,80 and CBS has been emphasized.82– 85
Unlike MAPT and PGRN, the other two major
genes account for a small subset of FTD cases. Mutations in the charged multivesicular body protein 2B
(CHMP2B) were identified in a large Danish family
originating for the Jutlan region of Denmark.86 Subsequently, other mutations have been identified, although some are of uncertain pathogenicity. Clinical
features are most typical of the bvFTD in CHMP2B
mutations. Initial pathological studies were consistent
with DLDH; however, recent reanalysis has demonstrated the presence of ubiquitinated inclusions that are
not immunoreactive to TDP-43.87 It has been proposed that FTLD with CHMP2B mutations (see Fig
1; see Table 1) be designated as FTLD-U type 5.87 An
association between FTD, inclusion body myopathy,
and Paget’s disease of the bone with an autosomal
dominant pattern of inheritance has been described.88
Mutations in the valosin-containing protein (VCP)
were subsequently identified.89 Histological analyses in
patients with VCP mutations show widespread
ubiquitin- and TDP-43–positive intranuclear inclusions90; hence, FTLD with VCP mutation (see Fig 1;
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see Table 1) has been designated FTLD-U type 4.37
Several families in which FTD and ALS cooccur have
now been linked to chromosome 9p.91–93 In addition,
a group of researchers reported a nonsense mutation in
the intraflagellar transport 74 (IFT74) gene in one family94; however, no causal mutations were conclusively
identified in other FTD-ALS families. Mutations in
the gene encoding for TDP-43 have now been identified in familial ALS95,96 but not in FTD-MND families.
Clinical, Pathological, and Genetic Correlations
It is clear that there are many different clinical, pathological, and genetic variants of FTD and related disorders. It is important to attempt to link these different
aspects of FTD. Over the last few years four large clinicopathological studies representative of different regions of the United States, as well as Europe and Canada, have been published.2–5 In three of these studies,
early clinical syndromic diagnoses were matched with
the associated pathological diagnoses.2– 4 What became
clear from these three studies is that there appears to be
trends for certain early clinical syndromes to be associated with certain pathologies and biochemistry (Fig 2),
even though clinical syndromes may change over
time.4 In addition, voxel-based morphometry studies in
autopsy-confirmed cohorts have identified regional patterns of atrophy that further link these clinical syndromes and the underlying biochemistries19,20,36,97,98
(see Fig 2).
One of the observed trends is that a clinical syndrome dominated by extrapyramidal features (akinesia,
rigidity, postural instability, less likely tremor) more
likely predicts an underlying tauopathy.2– 4 For example, of 69 patients with a diagnosis of PSP-S or CBS in
the three clinicopathological studies, 97% had a
tauopathy.2– 4 It has also been shown that the presence
of apraxia of speech accompanying PNFA is suggestive
of a tauopathy.19 Another observation is that SD is
more likely to be a TDP-43 proteinopathy.99 A strong
association occurs when MND coexists with bvFTD,
that is, FTD-MND,2,3 where 100% of cases have a
TDP-43 proteinopathy.2– 4 Although bvFTD may be
more commonly associated with a TDP-43 proteinopathy, it may also be associated with PiD, a tauopathy.3
Of 74 bvFTD patients reported in the United States
and Canadian pathological series, 55% were associated
with a TDP-43 proteinopathy, with only 16% having
PiD.2,4 However, the proportion of patients with PiD
appears significantly greater in the European series of
bvFTD patients (42%).3 Finally, aphasic dementia is
associated with underlying Alzheimer’s disease, and
logopenic aphasia has been suggested to also be associated with Alzheimer’s disease, although clinicopathological series have not yet been reported. Unlike in the
sporadic variants of FTD, no clear trends have been
demonstrated for familial FTD. One study suggested
subtle clinical differences between patients with MAPT
and PGRN mutations,100 whereas another found differences in atrophy patterns.101 Hence, in situations of
familial FTD, it would be advisable to begin by screening for mutations in both PGRN and MAPT.
Voxel-based morphometry studies have also identified patterns of atrophy in the different pathological
diagnoses. Patterns of atrophy vary across the different
tau variants, with the anterior frontal lobe particularly
involved in PiD,98 whereas the posterior frontal and
parietal lobes are involved more in PSP and corticobasal degeneration97 (Fig 3). Atrophy of the superior
cerebellar peduncle is associated with PSP.97 In contrast, the TDP-43 proteinopathies show atrophy of the
frontal and temporal lobes, with FTLD-MND restricted primarily to the midposterior frontal lobe36,98
(see Fig 3). Prominent medial frontal lobe atrophy also
occurs in the TDP-43 proteinopathies and the tauopathies.
Although not shown, an interesting subset of patients with slowly progressive FTD has been reported
Fig 3. Three-dimensional surface (top) and midsagittal renders
(bottom) of the brain showing the most prominent regions of
cortical and brainstem atrophy associated with tauopathy and
TAR DNA-binding protein 43 (TDP-43) proteinopathy, as
well as their specific pathologies, identified from voxel-based
morphometry (VBM) group studies. These figures are strictly
schematic, designed to highlight the main regions of atrophy in
these groups, and do not attempt to exactly duplicate actual
VBM output. Yellow sections indicate corticobasal degeneration/progressive supranuclear palsy; checkered yellow sections
indicate Pick’s disease; partial green sections and checkered
green sections indicate frontotemporal lobar degeneration with
ubiquitin-only–immunoreactive changes; checkered green sections indicate frontotemporal lobar degeneration with motor
neuron degeneration.
by two different groups.8,9 A common theme across
both series is that the majority of patients have features
characteristic of bvFTD; however, unlike in typical
bvFTD, there appears to be absent-minimal lobar atrophy on serial imaging and even at autopsy. One suggestion is that these patients may not have a neurodegenerative process9; however, FTLD-U pathology has
been reported.8
In summary, although many different syndromes
and pathologies underlie FTD and related disorders,
there are many trends between presenting and progressive clinical syndromes and underlying biochemistry.
Some of these trends appear particularly strong, such as
a sporadic syndrome dominated by extrapyramidal features suggesting an underlying tauopathy and the presence of MND suggesting a TDP-43 proteinopathy.
Other trends appear less strong but nevertheless are important to recognize if future treatments aim to target
specific proteins, such as tau.
Josephs: Deciphering the FTD Enigma
11
I acknowledge Dr J. L. Whitwell for her assistance with intellectual
content and manuscript preparation. I also acknowledge Dr R.
Rademakers for her critical review of the molecular genetics section.
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