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The Genetic and Pathological Classification of Familial Frontotemporal Dementia
Huw R. Morris, MRCP;
M. Nadeem Khan, MSc;
John C. Janssen, MRCP;
Jeremy M. Brown, MD;
Jordi Perez-Tur, PhD;
Matthew Baker, BSc;
Mehmet Ozansoy, MSc;
John Hardy, PhD;
Michael Hutton, PhD;
Nicholas W. Wood, PhD;
Andrew J. Lees, MD;
Tamas Revesz, MD;
Peter Lantos, MD;
Martin N. Rossor, MD
Arch Neurol. 2001;58:1813-1816.
ABSTRACT
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Background Frontotemporal dementia (FTD) is an important
cause of neurodegenerative dementia, particularly in younger patients.
TAU has been identified as the gene responsible for FTD linked
to chromosome 17, but it is likely that there is pathological and
genetic heterogeneity among families with FTD.
Objective To explore the genetic and pathological basis of
familial FTD.
Design Clinical case series with genetic analysis of each
family, and pathological confirmation of diagnosis where possible.
Setting Specialist dementia research group, particularly
recruiting patients with young-onset dementia.
Patients Twenty-two families with an index member with FTD,
meeting Lund-Manchester criteria, and a family history of other
affected members with dementia were ascertained.
Results Half of the families had mutations in the TAU
gene (TAU exon 10 +14, +16, and P301S), and pathological
diagnoses were available in 17 of 22 families. Three main pathological
diagnoses were made: FTD with neuronal and glial tau deposition, FTD
with ubiquitin inclusions, and FTD with neuronal loss and spongiosis
but without intracellular inclusions. No cases of familial Pick disease
were identified. With the use of the pathological diagnoses, each
family with FTD with neuronal and glial tau deposition had a
TAU mutation, whereas TAU mutations were not
identified in families in the other 2 diagnostic groups.
Conclusions This study illustrates the value of
TAU sequencing in FTD and suggests that around one half of
individuals with familial FTD have TAU mutations and dementia
with tau pathological findings. Furthermore, these data suggest that
there are at least 2 additional genes to be identified among families
with autosomal dominant FTD.
INTRODUCTION
FRONTOTEMPORAL dementia (FTD) is a clinical diagnosis based on progressive personality change
and language impairment related to frontotemporal lobar atrophy. It is
a frequent cause of dementia, particularly in the younger age group,
accounting for between 12% and 20% of all dementia
cases.1 Pick disease is the archetypal pathological form of
FTD. It is characterized pathologically by the presence of swollen
 -B-crystallin–positive neurons (Pick cells), and argyrophilic,
tau-positive round inclusions (Pick bodies) that are particularly
numerous in the granule cells of the hippocampal dentate fascia and the
superficial layers of the frontotemporal neocortex. Pick
disease is sometimes also used as a clinical term for patients
presenting with a progressive frontal syndrome or language
disorder, and as a diagnosis for neurological conditions with
radiologic frontotemporal lobar atrophy; strictly, however, Pick
disease should be reserved for pathologically diagnosed disease.
Although Pick disease is one pathological form of clinically diagnosed
FTD, FTD may be caused by a number of other pathological
substrates.1 These include (1) dementia with ubiquitinated
inclusions, first associated with motor neuron disease; (2) dementia
lacking distinctive histopathologic features; (3) corticobasal
degeneration; (4) Alzheimer disease; and (5) familial frontotemporal
dementia linked to chromosome 17 (FTDP-17).1, 2, 3, 4
Immunocytochemistry has greatly facilitated the diagnosis of these
conditions, in particular with the identification of ubiquitin and/or
tau-positive inclusions.
Analysis of the genetic basis of familial diseases has proved to
be a powerful and successful approach to the study of
neurodegeneration. The identification of pathogenic gene mutations in
familial Alzheimer disease has helped our understanding of the
pathogenesis of the more common sporadic forms of this
disease.5 This approach is likely to be more difficult in
FTD because of the underlying pathological heterogeneity. Although
analysis of a
pathological classification of FTD has been
previously described, it is worthwhile focusing on the classification
of the familial forms of this disease, since each of these families is
likely to have an identifiable pathogenic gene mutation.6
The description of kindreds with FTDP-17 and the identification of
pathogenic mutations in TAU has wider implications for
neurodegenerative disease, but it is also the first step toward the
genetic classification of the different FTD subtypes.7, 8, 9 In
this study, we reviewed the pathological and genetic findings in a
series of autosomal dominant families with FTD, in an attempt to define
the pathological subtypes and to predict the minimum number of genes
that remain to be identified in this condition.
PATIENTS AND METHODS
Twenty-two families with autosomal dominant FTD were studied as part of
an ongoing London, England–based study of early-onset dementia. Blood
for DNA analysis and agreement for autopsy examination were obtained
after patients gave informed consent. Exons 9 to 13 of TAU
were sequenced after standard polymerase chain reaction and sequencing
reactions were performed (Big-Dye terminator sequencing kits; ABI,
Foster City, Calif), as previously described. Mutations in TAU
were confirmed by both sequence analysis and restriction enzyme
digestion.7 Sequence products were analyzed on a sequencer
(ABI 377) and the results were visualized with software (Sequence
Analysis and Auto Assembler; ABI). Autopsy examination was
available in 17 of 22 families. From each brain, a comprehensive and
standardized set of tissue blocks was taken, processed, sectioned, and
stained with a variety of histologic and immunohistochemical stains,
including antibodies to tau (AT8, monoclonal mouse, 1:200; Innogenetics
N.V., Gent, Belgium) and ubiquitin (ubiquitin, polyclonal rabbit,
1:500; Dako Ltd, Ely, England).
RESULTS
Half (11/22) of the families identified had TAU mutations
(Table 1). Nine families had the
TAU exon 10 +16 mutation, 1 family had the TAU exon
10 +14 mutation, and 1 family with the exon 10 codon 301
proline-to-serine mutation (P301S) was identified. Two of these cases
have been previously reported.10 The average age at onset
for the family with the P301S mutation was 34 years, as compared with
an average age at onset for the families with the +16 mutation of 49
years. Three main pathological subtypes were identified
(Figure 1, Table 1). The FTD with
tau deposition (FTD-tau) involved extensive neuronal and glial tau
deposition with coiled oligodendroglial inclusions and tufted
astrocytes. The FTD with ubiquitin inclusions (FTD-Ub) involved the
occurrence of ubiquitin-positive, tau-negative small tanglelike or dot
inclusions and neuropil threads in the frontal and temporal
cortices, most prominently in the superficial cortical layers.
Ubiquitin inclusions were also consistently seen in the dentate fascia
of the hippocampus (Figure 1). The third pathological subtype
showed neither tau nor ubiquitin-positive inclusions and was described
as FTD with neuronal loss and spongiosis (FTD-NLS) (Figure 1).
In family 1, immunocytochemical findings were not available, but in
families 2 and 8, immunocytochemical analysis (including examination of
the dentate fascia) confirmed the absence of both ubiquitin and tau
inclusions. Other pathological findings were similar in all 3 groups.
All 3 pathological subtypes generally involved superficial vacuolation
and astrocytosis of the frontal and temporal cortex, and
flattening and atrophy of the caudate nucleus. Clinically, some
affected individuals in each pathological subtype showed evidence of
parkinsonism. Only 1 family in this series was identified to have
clinical motor neuron involvement (family 21), and this family did not
have typical neuronal ubiquitin inclusions, although some granular
neuronal ubiquitin immunoreactivity was identified.
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Clinical Features of Families With FTD Studied*
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High-power view of dentate gyrus showing lack of ubiquitin
immunoreactivity in frontotemporal dementia with neuronal loss and
spongiosis but without intracellular inclusions (A), dense ubiquitin
inclusions in frontotemporal dementia with ubiquitin inclusions (B),
and dense and granular tau immunoreactivity in frontotemporal dementia
with neuronal and glial tau deposition (C). Bar indicates 50
µm.
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Despite the frequent clinical diagnosis of familial Pick disease, no
familial pathological Pick disease was identified. Although Pick
disease was pathologically diagnosed in 1 autopsy examination, another
member of that family had pathologically verified Alzheimer disease,
suggesting that this is not a pathologically homogeneous FTD family.
All FTD-tau families were identified as having a TAU mutation
(Table 1), and the TAU sequence was normal in each of the FTD-Ub
and FTD-NLS families.
COMMENT
This study indicates the genetic and pathological heterogeneity of
familial FTD; in this series, 11 (50%) of 22 familial FTD cases had
TAU mutations. Three other groups have studied the prevalence
of TAU mutations in familial FTD.11, 12, 13 Rizzu and
colleagues12 report that 47% of patients with FTD and a
positive family history had mutations in TAU, whereas Houlden
and colleagues11 suggested that only 11% (6/54) of FTD
families had identifiable TAU mutations. However, neither of
these studies provided a pathological analysis of the families studied.
More recently, Poorkaj and colleagues13 studied a large
series of familial FTD cases and identified TAU mutations in
10.5% of the familial cases and only 33% of the familial cases with
tau pathological findings.13
In contrast, our study suggests that the presence of tau
pathological findings in a familial FTD case strongly predicts the
presence of a TAU mutation, whereas the presence of FTD-NLS or
FTD-Ub pathological findings effectively excludes a mutation in
TAU. Possible reasons for the discrepancies between these
studies include the age at onset of families studied and the strength
of evidence of a concordant family history. Our results
correlate well with analysis of pathological findings in the families
with unequivocally chromosome 17q21–linked FTD, in which practically
all affected members had significant tau deposition and concomitant
mutations in TAU.2 Although neurodegeneration in
familial tau deposition without TAU mutations can occur in
families with clinically diagnosed progressive supranuclear
palsy,14 this has not been commonly described in families
with pathologically diagnosed tau-deposition FTD with multiple affected
members. One exception may be the family with hereditary dysphasic
disinhibition
(HDD2), linked to the TAU region with a
maximum lod score of 3.68. Tau immunocytochemical analysis has
identified variable tau deposition in this family, although a recent
report described depletion of tau on Western blot
analysis.15, 16 A mutation in TAU has not been
reported in the family with HDD2.
Our series suggests that there are no clinical features that can
reliably distinguish these 3 familial FTD subtypes, and clinical
features of motor neuron disease with FTD were uncommon. We identified
FTD-Ub pathological features in 3 (18%) of 17 families with
pathologically diagnosed FTD. These are similar to the family with
ubiquitin inclusion described by Kertesz and colleagues,4
the sporadic cases with semantic dementia identified by Rossor and
colleagues,17 and the sporadic and familial cases
identified by Jackson and colleagues18 and described as
motor neuron disease inclusion dementia. These pathological reports
confirm that superficial neocortical cell loss with vacuolation and
ubiquitin inclusions in the dentate gyrus are core features of this
disease.
We have also identified 4 (24%) of 17 families with FTD-NLS. The
relationship between the FTD-NLS reported herein and other reported FTD
subtypes is harder to establish given the overall pathological
similarities between all of these diseases and the absence of tau
and/or ubiquitin immunohistochemical analysis in some reports. The
diseases described as "dementia lacking distinctive
histopathology," "dementia lacking distinctive histological
features," "familial dementia of adult onset with pathological
features of a nonspecific nature," and "dementia with microvacuolar
pathology and laminar spongiosis" may all correspond to either FTD-Ub
or FTD-NLS, depending on the results of ubiquitin immunohistochemical
analysis.3, 6, 19, 20 Genetic linkage to chromosome 3 has been
reported in a Danish kindred originating in Jutland, apparently without
distinctive pathological features (OMIM No.
600795).21 A recent study using ubiquitin
immunohistochemical analysis did not show intraneuronal ubiquitinated
inclusions in the chromosome 3–linked kindred, and, conversely,
analysis of a large family with ubiquitin inclusion dementia excluded
linkage to chromosome 3.4, 22 This suggests that chromosome
3–linked dementia may correspond to FTD-NLS described in this series.
Assuming continuing pathological-genetic correlation across FTD, this
series suggests that there are at least 2 additional genes to be
identified that may be responsible for familial FTD.
In conclusion, we have demonstrated 3 pathological subtypes of familial
FTD and a close correlation between the presence of a TAU
mutation and the presence of tau pathological findings. Despite earlier
reports suggesting that Pick disease was a common familial dementia,
this was not supported by this study. There is genetic and pathological
heterogeneity in familial FTD and, undoubtedly, additional genes will
be identified that are responsible for these disorders.
AUTHOR INFORMATION
Accepted for publication July 23, 2001.
Dr Morris is a Medical Research Council clinical training fellow.
The Dementia Research Group and MRC Brain Bank are supported by the
Medical Research Council (London). This work was also
supported by the Progressive Supranuclear Palsy (Europe) Association
(Wappenham, England) (Dr Morris), the Guarantors of Brain (London) (Dr
Morris), the Bogue Research Fellowship, University College London (Dr
Morris), the National Institutes of Health/National Institute on Aging
(Bethesda, Md) program grant on tau (Drs Hardy and Hutton), the Mayo
Clinic (Jacksonville, Fla) (Drs Hardy and Hutton), and the Smith
Fellowship, Mayo Clinic (Dr Hutton). Dr Morris is now with
the Department of Neurology, St Thomas' Hospital, London.
We are grateful to J. V. Clark, FRCPath, and S. Huson, MD,
for allowing us to study their patients. We acknowledge the skillful
technical assistance of Heidi Barnes of the MRC Brain Bank.
From the Neurogenetics Section (Drs Morris and Wood), Dementia Research
Group (Drs Janssen and Rossor), and Department of
Neuropathology (Dr Revesz), Institute of Neurology, and Reta Lila
Weston Institute of Neurological Studies (Drs Morris and Lees and Mr
Ozansoy), University College London, London, England; MRC
Brain Bank, Department of Neuropathology, Institute of Psychiatry,
London (Mr Khan and Dr Lantos); Department of Neurology, Addenbrooke's
Hospital, Cambridge, England (Dr Brown); Unitat de Genetica Molecular,
Institut de Biomedicina de Valencia-CSIC, Valencia, Spain (Dr
Perez-Tur); and Neurogenetics Laboratory, Mayo Clinic Jacksonville,
Jacksonville, Fla (Mr Baker and Drs Hardy and Hutton)
Corresponding author and reprints: Martin N. Rossor, MD,
Dementia Research Group, Institute of Neurology, Queen Square, London
WC1N 3BG, England (e-mail: m.rossor{at}dementia.ion.ucl.ac.uk).
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