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Inherited frontotemporal dementia in nine British families associated with intronic mutations in the tau gene

S. M. Pickering‐Brown, A. M. T. Richardson, J. S. Snowden, A. M McDonagh, A. Burns, W. Braude, M. Baker, W.‐K. Liu, S.‐H. Yen, J. Hardy, M. Hutton, Y. Davies, D. Allsop, D. Craufurd, D. Neary, D. M. A. Mann
DOI: http://dx.doi.org/10.1093/brain/awf069 732-751 First published online: 1 April 2002

Summary

Genetic screening of 171 patients with frontotemporal lobar degeneration disclosed 14 patients, across nine pedigrees, with mutations in the intron to exon 10 in the tau gene, a region regulating the splicing of exon 10 via a stem loop mechanism. Thirteen of these patients had the +16 splice site mutation and one had the +13 splice site mutation. Affected members of all nine families presented with changes in behaviour and social conduct that were prototypical of frontotemporal dementia (FTD). In all patients with the +16 splice site mutation, the behavioural profile was characterized by disinhibition, restless overactivity, a fatuous affect, puerile behaviour and verbal and motor stereotypies. The single patient with the +13 mutation presented a contrasting picture of apathy and inertia. In addition, all patients had evidence of semantic loss. Pathologically, five of the six patients so far autopsied shared frontotemporal atrophy with involvement of the substantia nigra. The underlying histology was that of microvacuolar‐type cortical degeneration with a few swollen cells. Tau pathology was widespread throughout the brain and present in neurones and glial cells, mostly in the frontal and temporal cortical regions. This was in the form of neurofibrillary tangles and amorphous tau deposits (pre‐tangles); Pick bodies were not observed. Ultrastructurally, the tau filaments had a twisted, ribbon‐like morphology distinct from the paired helical filaments of Alzheimer’s disease. One patient died from an unrelated illness whilst in the early clinical stages of FTD. In this patient, cortical microvacuolar and astrocytic changes were absent, though there were scattered neurones and glial cells, immunoreactive to tau, throughout the cortical and subcortical regions. The disease process underlying the neurodegeneration within these inherited forms of FTD may therefore stem directly from early, primary alterations in the function of tau. All eight families with the +16 mutation seem to be part of a common extended pedigree, possibly originating from a founder member residing within the North Wales region of Great Britain.

  • Keywords: familial frontotemporal dementia; tau gene mutations; neuropsychology; tau pathology; tau biochemistry
  • Abbreviations: Aβ = amyloid β protein; APO E = apolipoprotein E; DDPAC = disinhibition, dementia, parkinsonism and amyotrophy complex; FTD = frontotemporal dementia; FTDP‐17 = frontotemporal dementia with parkinsonism linked to chromosome 17; GFAP = glial fibrillary acidic protein; MSTD = multisystem tauopathy dementia; PPND = pallidopontonigral degeneration; SPECT = single‐photon emission tomography; VOSP = Visual Object and Space Perception Battery

Introduction

Frontotemporal lobar degeneration refers to a group of non‐Alzheimer forms of dementia associated with circumscribed progressive degeneration of the frontal and temporal lobes. The associated clinical syndromes are dictated by the distribution of the pathology. Frontotemporal dementia (FTD), characterized clinically by personality and behavioural changes progressing to apathy and mutism, is the commonest clinical syndrome, in which there is prominent bilateral and usually symmetrical involvement of the frontal lobes. When atrophy affects chiefly the anterior temporal neocortex, usually bilaterally, the syndrome of semantic dementia occurs, in which there is a multimodal breakdown of meaning, characterized by impaired word comprehension and naming and impaired face and object recognition. Progressive aphasia, a disorder of expressive language, occurs when the atrophy affects chiefly the left frontotemporal lobe (Lund and Manchester Groups, 1994; Snowden et al., 1996; Neary et al., 1998).

A history of a similar disorder in one or more first‐degree relatives is seen in about half of all cases (Snowden et al., 1996). In most of these families, the pattern of inheritance is suggestive of autosomal dominant transmission. Many of these familial forms of FTD are associated with a genetic locus on chromosome 17 (17q 21‐22) [known as frontotemporal dementia with parkinsonism linked to chromosome 17 (FTDP‐17)] (Foster et al., 1997) and are caused by missense or intronic mutations within the tau gene (for a review, see Mann et al., 2000). Our initial sequencing of the tau gene in 22 patients with FTD (Hutton et al., 1998), supplemented by sequencing in 149 other patients (all 171 patients having been assessed between 1987 and 2000) has disclosed in nine families a total of 14 patients (8%) with mutations in the tau gene. All of these patients displayed mutations in the intron to exon 10, a region regulating the splicing of exon 10 via a stem loop mechanism (Hutton et al., 1998; Spillantini et al., 1998).

In the present study we present clinical, neuropathological and molecular biological details of these nine British families with prototypical FTD. Some family members were represented in our earliest clinical (Neary et al., 1988) and pathological (Mann and South, 1993) descriptions, upon which the clinicopathological criteria for FTD were based (Lund and Manchester Groups, 1994; Neary et al., 1998).

Material and methods

Patients

The 14 patients described here all have intronic mutations in the tau gene; 13 have the +16 splice site mutation and one has the +13 splice site mutation (Hutton et al., 1998). The patients represent nine pedigrees (Fig. 1 and Table 1). The +13 splice mutation was originally described in a family known as MAN19, whereas two of the families with the +16 splice site mutation were known as MAN6 and MAN23 (Hutton et al., 1998). The other six pedigrees were ascertained subsequently. For each of these families, only those patients seen by us at the Cerebral Function Unit at the Department of Neurology, Manchester Royal Infirmary are described in detail. Information regarding other previously affected members of such families was obtained through interview with patients’ relatives and relevant details are presented in the pedigrees for each family (Fig. 1). Subjects or next of kin gave informed consent for collection of blood samples or brain tissue, as appropriate. The study was approved by the Central Manchester Healthcare Trust.

Fig. 1 Pedigrees of eight families (Families 1–7 and 9) with splice site mutations in the tau gene. Families 1–7 all have the +16 splice mutation, whereas Family 9 has the +13 splice mutation. The question mark indicates uncertainty whether the individual was affected or not; filled symbols indicate that the individual was definitely affected; arrows indicate the pedigree position of the proband. Age at death (with duration of illness where known) is indicated.

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Table 1

Selected demographic and genetic data for 14 patients with mutations in tau gene

PatientFamily, pedigree positionGenderAge at onset (years)Age at death (years)Duration of illness (years)*Tau mutationAPO E genotype
11, III:7M506111+16ϵ3/ϵ4
21, III:4F465812+16ϵ3/ϵ3
31, III:9F526513+16ϵ2/ϵ3
42, III:1M50555+16ϵ3/ϵ4
53, III:1M5014*+16ϵ3/ϵ3
63, III:2M56571+16ϵ3/ϵ3
74, III:1M4717*+16ϵ2/ϵ3
85, III:4M486*+16ϵ3/ϵ4
96, II:1M542*+16ϵ3/ϵ3
107, IV:1F487*+16ϵ3/ϵ4
117, IV:3M527*+16ϵ3/ϵ4
127, IV:2M62664+16ϵ3/ϵ3
138F513*+16ϵ3/ϵ3
149, II:2M65705+13ϵ3/ϵ4

APO E = apolipoprotein E; M = male; F = female. *Current duration of illness.

Pathological methods

The brain was available at autopsy for examination in five of the 13 patients with the +16 splice site mutation (Patients 1, 2, 3, 4 and 6) and in the single patient with the +13 splice site mutation (Patient 14) in the tau gene. The brain was weighed fresh and the left cerebral hemisphere, brainstem and cerebellum were fixed in 10% neutral formalin for a minimum of 3 weeks before they were cut in the coronal plane. The right cerebral hemisphere was frozen for genetic and biochemical studies.

Tissue blocks were cut from standardized regions of the brain and processed routinely into paraffin wax. Sections were cut at a thickness of 5 µm and stained by routine neurohistological methods (Weigert’s haematoxylin–eosin, Luxol fast blue, methenamine silver, Palmgren silver) and by immunohistochemistry. Sections were immunostained using anti‐tau antibodies AT8 (1 : 200) (Innogenetics, Antwerp, Belgium), CP13 (1 : 2000) and PHF‐1 (1 : 200) (gifts from Dr P. Davies). These antibodies recognize tau phosphorylated at Ser202/Thr205 (AT8, CP13) and Ser396/404 (PHF‐1), and are extremely sensitive markers of neurofibrillary pathology. Other antibodies used were anti‐GFAP (glial fibrillary acidic protein) (1 : 1000) (Sigma, Poole, UK), anti‐ubiquitin (1 : 750), anti‐B‐crystallin (1:500) and anti‐amyloid β (Aβ) protein (1 : 250) (all from Dako, Ely, UK), anti‐α‐synuclein (1 : 500) (gift from Dr D. Hanger), and BC05 (1 : 500) and BA27 (1 : 500) antibodies to Aβ42(43) and Aβ40 (immunostaining courtesy of Professor T. Iwatsubo), respectively.

Samples of formalin‐fixed cerebral cortex grey and white matter from Patients 1, 2, 4, 6 and 14 were postfixed in 4% paraformaldehyde/0.2% glutaraldehyde and then embedded in LR Whiteresin. Ultrathin sections were immunolabelled for tau with AT8 (1 : 40) and 15 nm colloidal gold conjugated to goat anti‐mouse immunoglobulin G (British Biocell International, Cardiff, UK) at a dilution of 1 : 50, counterstained with uranyl acetate and osmium tetroxide vapour, then viewed in a Jeol 1010 electron microscope.

Biochemical and genetic methods

Tau gene analysis was performed as described previously (Hutton et al., 1998). Briefly, tau exons (1–4, 5, 7 and 9–13) were amplified from genomic DNA with primers designed for flanking intronic sequences (Hutton et al., 1998). Polymerase chain reaction (PCR) contained 0.8 pM of each primer and 1 unit of Taq Gold polymerase (Perkin‐Elmer, Warrington, UK). Amplification was performed using a 60° to 50°C touchdown protocol over 35 cycles with final extension at 72°C for 10 min. PCR products were purified using the Qiagen PCR kit and their concentrations estimated on an agarose gel. For each exon, 100 ng of clean PCR product was sequenced on both strands using the dRhodamine dye terminator cycle sequencing kit (Perkin‐Elmer, Warrington, UK) and relevant PCR primers. Sequencing was performed on an ABI377 automated sequencer. Heterozygote base calls were made using Factura software (Perkin‐Elmer, Warrington, UK). Sequence alignment was performed with Sequence Navigator (Perkin‐Elmer, Warrington, UK). The apolipoprotein E genotype (APO E) was determined as described previously (Wenham et al., 1991).

Sarcosyl‐insoluble tau was extracted from frontal lobe brain tissue from the case with the +13 mutation patient 14 and a patient with the +16 splice mutation patient 2. Dephosphorylation and western blot analysis was performed using a modified hydrofluoric acid method as described (Greenberg et al., 1992).

Results

Clinical findings

One patient from each of the nine pedigrees (six males and three females) was studied in detail. The age of the patients at the onset of their first symptoms ranged from 48 to 65 years (mean 51 years). The total duration of illness ranged from 5 to 12 years in the three patients who died during follow‐up and from 2 to 17 years in the patients still alive. The progression of the illness in eight patients was followed for a number of years, during which time detailed neurological and neuropsychological examinations were documented at intervals of 6–9 months. One patient has been seen only once thus far. Individual case histories are reported in Appendix I.

All patients presented with an alteration of personality and disorder of social conduct, with personal neglect and loss of insight [i.e. lack of awareness of mental symptoms (Neary et al., 1998)] (Table 2). Repetitive and ritualistic behaviours were seen in seven patients. All patients with the +16 splice site mutation exhibited restless, overactive and socially disinhibited behaviour, consistent with the disinhibited form of FTD (Snowden et al., 1996). The single patient with the +13 splice site mutation presented with a contrasting picture of apathy and loss of volition, consistent with the apathetic form of FTD (Snowden et al., 1996).

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Table 2

Clinical features and investigation at time of presentation in the nine patients studied personally

Patient
245789101314
History
 Personality change+++++++++
 Conduct disorder+++++++++
 Self‐neglect+++++++++
 Loss of insight+++++++++
 Disinhibition++++++++
 Apathy+
Neurology
 Limb rigidity+
 Reduced eye movements+
 Primitive reflexes+++++++
Neuropsychology
 Disorientation
 Phonological impairment
 Semantic impairment++++++++
 Spatial disorder
 Limbic amnesia
 Executive disorder++++++++
Investigation
 Normal EEG++n.d.+n.d.n.d.+++
 Temporal atrophy on MRIn.d.n.d.n.d.n.d.++n.d.++
 Anterior hypoperfusion on SPECT+++++++++

SPECT = single photon emission tomography; n.d. = not determined; + = change; – = no change.

When first seen, eight of the nine patients were free from neurological signs other than primitive reflexes, despite disease duration at that time of up to 14 years (Table 2). One patient (Patient 2) had limb rigidity and akinesia within a year of onset of symptoms.

With the exception of Patient 14, all patients were inattentive and distractible, with a perfunctory mode of responding. Most patients exhibited economy of speech and verbal stereotypies. No patient made phonological or grammatical errors. Nearly all patients performed poorly on naming tasks, and the presence of semantic errors, e.g. ‘dog’ for ‘tiger’, suggested an underlying semantic deficit (Table 2). Indeed, semantic loss was not limited to the verbal domain and impaired performance was seen on tests of recognition of famous faces, famous monuments and the Pyramids and Palm Trees test, a test of non‐verbal associative semantic knowledge (Howard and Patterson, 1992). All patients performed within normal limits on tests of primary visuospatial function and praxis. All patients were orientated and could give a good account of autobiographical information. Poor scores on formal tests of memory were attributed to inattention and strategic impairments secondary to frontal lobe dysfunction and not to primary limbic amnesia. All but one patient performed poorly on tests sensitive to frontal lobe dysfunction at their initial examination. Performance on tests of category and design fluency and the Wisconsin Card Sorting Test (Nelson, 1976) was characterized by impaired attention, abstraction, planning and mental set‐shifting.

EEG was normal (Table 2). MRI in four patients showed bilateral temporal lobe atrophy. CT in other patients was reported as normal or showing generalized atrophic change. Functional imaging, using single‐photon emission tomography (SPECT), showed a reduction in tracer uptake in the frontotemporal regions in all cases.

From initial presentation until the last time of examination or death, all patients became increasingly dependent on others for acts of daily living. All patients developed an increasingly bland affect and there was a gradual diminution of overtly disinhibited behaviour, giving way to increasing apathy (Table 3). The two behaviours were noted to coexist in some patients, who, whilst inert for most of the time, with poor self‐motivation, could be stimulated into overactivity and disinhibition in the presence of others. Two patients developed environmentally dependent behaviours, displaying hyperoral tendencies and utilization behaviour. Of the six living patients, five remain neurologically well and one has developed mild limb rigidity 7 years into her illness. Rigidity and akinesia developed in three patients who died. Some patients exhibited an impaired range of eye movements, most commonly limitation of voluntary upgaze and impaired convergence. No patient showed corticospinal weakness, ataxia or myoclonus. Seizures did not occur. Most patients displayed increasingly economical speech, and mutism supervened in the three patients who died. Phonological errors did not emerge. Most patients developed increasing semantic problems. There was no evidence of visuospatial impairment in any patient and no patient was reported to have become lost.

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Table 3

Clinical features at last assessment (eight patients)

Patient
245*7*8*9*10*14
Disease duration (years)12514176275
History
 Disinhibition+++++
 Apathy+++++
Neurology
 Reduced eye movements+++++
 Limb rigidity++++
 Primitive reflexes++++++++
Neuropsychology
 Reduced speech/mute+++++
 Phonological error
 Semantic impairment+++++/–+++
 Spatial disorder
 Executive disorder++++++++

*Patient still alive; + = change; – = no change. Patient 13 has so far only been seen at initial presentation and therefore does not appear in this table.

Neuropathological changes

The gross and histopathological changes in the brains of six patients with a tau gene mutation are described below and comparative details for each of the patients are given in Table 4.

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Table 4

Pathological characteristics of six patients with mutations in the tau gene

Patient (mutation)Duration (years)Cortical atrophyBallooned neuronesCortical NFTBrainstem NFTGlial tanglesNigral damageHippocampal (h) amygdalar (a) atrophyStriatal atrophy
Patient 1 (+16)11+++ (k)++++++++0/+ (h)++
+ (a)
Patient 2 (+16)12++++++++++++++0 (h)+
0 (a)
Patient 3 (+16)13++++++++++++++ (h)++
+ (a)
Patient 4 (+16)5+++ (k)++++++++++++ (h)++
++ (a)
Patient 6 (+16)100+0/++00 (h)0
0 (a)
Patient14 (+13)5+++ (k)+++++++++++++ (h)+
+/++ (a)

k = ‘knife‐edge’ atrophy present within frontal and temporal lobes; 0/+ = rare; + = mild or occasional; ++ = moderate; +++ = frequent or severe.

The macroscopic and microscopic changes were broadly similar for five of the six brains (the exception being that of Patient 6), and these five brains will therefore be described collectively. The major cerebral arteries and those of the circle of Willis were normal or showed only minimal atherosclerosis (Patient 14). The leptomeninges were without abnormality. In all cases except Patient 6, the brain showed severe and bilateral atrophy of the frontal and temporal lobes (Fig. 2 and Table 4), in some patients producing ‘knife‐edge’ atrophy of the frontal and temporal poles. The anterior two‐thirds of the temporal lobe was more affected than the posterior third, with preferential involvement of the inferior and middle temporal gyri and relative preservation of the superior temporal gyrus. Usually, all frontal gyri were severely and equally atrophic, though in Patient 2 the inferior and middle frontal gyri were more atrophic than the superior frontal gyri. The posterior parietal and occipital lobes were only mildly atrophied or without involvement (Fig. 2). The brainstem and cerebellum were normal externally.

Fig. 2 Coronal sections of the brain of Patient 1 showing atrophy of the frontal and temporal lobes, with relative sparing of the superior temporal gyrus and the posterior parietal and occipital lobes.

On coronal section (Fig. 2), the lateral ventricles were moderately or grossly dilated, especially at their anterior extent. The caudate nucleus, putamen and globus pallidus were variably atrophied, as were the hippocampus and amygdala (Table 4). The corpus callosum was always thinned, especially the anterior part. The substantia nigra and locus coeruleus were markedly underpigmented in all except Patient 2 (Table 4). The cerebellum and brainstem were otherwise normal on sectioning. There were no cerebrovascular changes of note in any patient, nor were any tissue infarctions seen. In Patient 6, there were no gross morphological changes present in the brain; the substantia nigra and locus coeruleus were well pigmented (Table 4).

All patients except Patient 6 showed a similar histological profile. The frontal, anterior temporal, anterior parietal, cingulate and anterior insular cortices showed severe microvacuolation of the superficial laminae, especially layer II and upper layer III (Fig. 3A). There was extensive loss of small and large pyramidal nerve cells from layers II and III, with some loss, but mostly shrinkage, of pyramidal cells of layers V and VI. Mild to moderate subpial gliosis (Fig. 3B) extended into layer II and gliosis was also present at the boundary of the grey and white matter of the frontal and parietal cortices (mostly) and within the white matter itself. There was much loss of myelin from these white matter regions, though axonal loss was less severe. In many areas the residual cortex had collapsed, obscuring the microvacuolation and resulting in loss of distinction between laminar boundaries. The inferior and middle temporal gyri were affected equally, especially at the anterior levels, though the superior temporal gyrus was spared, as were the occipital and posterior parietal cortices. No Pick‐type inclusion bodies were seen in surviving neocortical neurones and swollen B‐crystallin‐positive neurones were rare, usually being found in the deeper layers of the frontal cortex. The hippocampus and amygdala were histologically normal, except for mild loss of nerve cells from areas CA1 and the subiculum and astrocytosis within the end‐folium of the former and within the basolateral nucleus of the latter. Although atrophied, the caudate nucleus and putamen showed mild to moderate reactive astrocytosis. In all patients, the substantia nigra and locus coeruleus showed almost complete loss of nerve cells, there being residual pigment within macrophages (microglia) (Fig. 3C). Mild astrocytosis was present and some ubiquitinated grumose bodies were seen (Fig. 3D).

Fig. 3 Microvacuolar degeneration of the frontal cortex in Patient 2. There is spongiosis of the outer cortical laminae (arrowed in A) with mild subpial and laminar gliosis, chiefly at the junction between grey and white matter (arrowed in B). There is also severe loss of nerve cells from the substantia nigra of this patient (C), with ubiquitinated grumose bodies (D) present in some surviving cells (arrowed in C and D). Stains are haematoxylin–eosin in A and C, GFAP immunoperoxidase–haematoxylin in B and ubiquitin immunoperoxidase–haematoxylin in D.

In all cases, with the AT8, CP13 and PHF‐1 antibodies tau‐immunopositive pyramidal cells were widely seen throughout the frontal, temporal and anterior parietal cortices, more often in the deeper than in the superficial, layers (Fig. 4A and Table 4). Sometimes these cells had a definite filamentous appearance, resembling the neurofibrillary tangles typical of Alzheimer’s disease, and were also stained by Palmgren silver impregnation. More often, however, the tau deposits were present as amorphous, granular deposits within the soma and proximal dendrites (‘pre‐tangles’ (Fig. 4A). Some of the tangle‐like structures were stainable with anti‐ubiquitin antibodies. Occasionally, large, swollen neurones, strongly immunoreactive to tau and B‐crystallin but weakly ubiquitin‐immunoreactive, were seen (Table 4). No inclusions resembling Pick bodies were present in either pyramidal cells or dentate granule cells. Neuropil threads were seen widely within the deeper layers of the affected cortex.

Fig. 4 Tau immunoreactivity in the brains of Patients 14 (AF) and 7 (G and H). In Patient 14, there are numerous neurofibrillary tangles and amorphous tau deposits within the nerve cells of the grey matter (A) and glial cells of the white matter (B) of the frontal cortex. In the CA1 region of the hippocampus, there are numerous dot‐ and thread‐like profiles intermingling with the pyramidal neurones (C). Neurofibrillary tangles are widespread throughout subcortical structures, such as the nucleus basalis (D), dorsal raphe (E) and substantia nigra (F). In G and H, arrows indicate occasional tau‐positive neurones (G) and glial cells (H) in the frontal cortex of Patient 7. Tau immunoperoxidase–haematoxylin stain.

Tau‐ and (sometimes) ubiquitin‐positive glial cells were prominently present within the deep white matter of the frontal, temporal and parietal cortex (Fig. 4B and Table 4) and were also present in the globus pallidus, interfascicular bundles of the caudate nucleus and putamen, and the internal capsule. In double‐immunolabelling, such tau‐immunopositive glial cells were not stained with GFAP antibody and had the morphological appearance of oligodendrocytes. Tufted astrocytes and astrocytic plaques were not seen.

Some pyramidal cells in the CA1 region of the hippocampus contained amorphous deposits of tau, and thread‐like structures and dots of tau‐immunoreactive material were widespread in this region (Fig. 4C). Tau‐ (and ubiquitin‐) positive, strongly argyrophilic, globose neurofibrillary tangles were seen widely in the basal forebrain nuclei [nucleus basalis of Meynert (Fig. 4D), septal nuclei and diagonal band of Broca] and dorsal raphe (nucleus supratrochlearis) (Fig. 4E) of all patients except Patient 6 (Table 4). There was severe loss of the magnocellular neurones of the nucleus basalis, especially in Patient 1. Occasional pre‐tangle cells, and others with argyrophilic, neurofibrillary tangles and neuropil threads were present in the caudate nucleus, putamen, globus pallidus, thalamus, amygdala, pontine nuclei and, exceptionally, in the dentate nucleus of the cerebellum. The cerebellar cortex was normal. Scattered tangles and pre‐tangles were widespread throughout the reticular substance of the pons and medulla, but tangles were common in the remaining cells of the locus coeruleus (Fig. 4F) and substantia nigra. No tau‐immunoreactive glial cells were seen within the corticospinal tracts or within the cerebellar white matter. Extracellular neurofibrillary tangles were exceptional in any part of the brain. In Patient 6, occasional tau‐immunopositive neurones were scattered through the frontal (Fig. 4G) and temporal cortex and in some subcortical regions (Table 4). In these cells, the tau was always amorphous and no distinct neurofibrillary tangles were seen in either tau or ubiquitin immunostaining or with silver impregnation. There were also a few tau‐ (but not ubiquitin‐) immunopositive glial cells within the deep white matter of the cerebral cortex (Fig. 4H) and in the internal capsule (Table 4).

No senile plaques or deposits of Aβ protein were present in the brains of Patients 1, 2, 3, 4 and 6. However, in Patient 14 silver staining showed a moderate number of amyloid deposits scattered throughout the cerebral cortex (Fig. 5A). These were mostly present as diffuse Aβ42(43)‐containing plaques (Fig. 5B); cored Aβ40‐containing neuritic plaques were rare and when present were usually located at the depths of the cortical sulci (not shown). Patient 14 also showed a few deposits of Aβ in the hippocampus, amygdala, caudate nucleus and putamen, but none within the cerebellum.

Fig. 5 Amyloid β (Aβ) protein deposition in the frontal cortex of Patient 14. There is a moderate number of silver‐stained plaques scattered through all layers (A), the Aβ being present mostly as diffuse deposits (B). Stains are methenamine silver (A) and Aβ immunoperoxidase–haematoxylin (B).

In Patients 1, 2, 4 and 14, electron microscopy showed strong immunogold labelling of filaments with antibody AT8 within both grey and white matter. These filaments had a flat, twisted appearance with diameter ∼15 nm and periodicity 300 nm (Fig. 6). Other AT8‐labelled filaments were seen, with a diameter of 7–10 nm, but it was not possible to measure their periodicity. In Patient 6 there were similar AT8‐labelled filaments within the few immunoreactive nerve and glial cells present.

Fig. 6 Electron micrographs of (A) grey and (B) white matter from the frontal cortex of (A) Patient 14, with the +13 splice mutation, and (B) Patient 1, with the +16 splice mutation. In both instances, flat, twisted filaments with a periodicity of 200 nm (arrowheads) are seen. Scale bar = 200 nm.

Genetic and biochemical analysis

Sequencing revealed a G→A transition 16 base pairs from the 5′ splice site of exon 10 of the tau gene in Patients 1–13 and a G→A transition 13 base pairs from the 5′ splice site of exon 10 in Patient 14. The genetic changes in Patients 1, 2, 4 and 14 have been reported previously (Hutton et al., 1998).

Western blot analysis of hyperphosphorylated sarcosyl‐insoluble tau from the +13 and +16 splice mutations cases revealed two prominent bands of 68 and 64 kDa. Dephosphorylation analysis demonstrated that the major component of this insoluble tau was tau with four microtubule‐binding domains, mostly 4R2N, though minor quantities of 3R2N were observed. A representative example of this analysis with tau from the patient with the +13 splice mutation is shown in Fig. 7 and similar observations were seen in the +16 cases (data not shown). These observations are consistent with previous findings reported for missense mutations of exon 10 and other mutations that affect the alternative splicing of this exon, including +16, and they show that mutations of this type lead to the deposition of insoluble tau mainly with four microtubule‐binding domains (Hutton et al., 1998; Spillantini et al., 1998; D’Souza et al., 1999; Goedert et al., 1999; Hasegawa et al., 1999; Yasuda et al., 2000).

Fig. 7 (A) Left: western blot comparing insoluble tau extracted from brain tissue from a case of FTDP‐17 with the +13 exon 10 splice mutation (patient 14) (two bands at 68 and 64 kDa) with that from a case of Alzheimer’s disease (AD) (three bands at 68, 64 and 60 kDa) and a patient with the P301L tau missense mutation (two bands at 68 and 64kDa). Right: equivalent blot of insoluble tau after dephosphorylation, demonstrating the predominance of four‐repeat tau in the +13 and P301L cases. (B) Analysis of insoluble tau from the brain of a patient with the +16 splice mutation (patient 2). Lane 1, insoluble tau; lane 2, insoluble tau after dephosphorylation; lane 3, recombinant tau. 4R2N, 4R1N, 4R0N is tau with microtubule binding domains with 2, 1, or no N‐terminal inserts, respectively. 3R2N, 3R1N, 3R0N is tau with microtubule binding domains with 2, 1 or no N‐terminal inserts, respectively.

APO E genotyping

Of the 14 patients, two bore the APO E ϵ2/ϵ3 genotype, six the ϵ3/ϵ3 genotype and six the ϵ3/ϵ4 genotype (ϵ4 allele frequency = 0.21) (Table 1). There was no difference in mean age at onset of disease between bearers (mean age 52.3 ± 5.1 years) and non‐bearers (mean age 52.3 ± 8.8 years) of the ϵ4 allele.

Genealogical studies

Although we were not able to link families with the +16 mutation into a common extended pedigree using genealogy, family tracing showed that all (except Family 8, in which the proband had been adopted as a child and no other family members were known) families originated from a cluster of small towns and villages in North Wales (Fig. 8). Genetic analysis of the region of chromosome 17 that contains the tau gene demonstrated that all these carriers of the +16 splice site mutation share a common extended haplotype of this region, suggesting that they are all part of a single pedigree (S. M. Pickering‐Brown, unpublished data). It is likely that earlier members of these families migrated from this geographically isolated, rural region of Great Britain to the manufacturing regions of the North‐West of England (the Manchester and Liverpool conurbations) during the Industrial Revolution of the 19th century, establishing the disorder in this region over subsequent generations.

Fig. 8 Map of North‐West England and North Wales indicating the geographical location of each family with the +16 splice site mutation. Families 2, 7 and 8 originated from this sparsely populated region of Great Britain and many present members still reside within this locality. Families 1, 4, 5 and 6 reside within Greater Manchester and Family 3 within North Cheshire.

Discussion

In this study, we have presented the clinical and pathological features of eight British families with the +16 splice site mutation in the tau gene and one with the +13 mutation.

Clinically, affected members of all nine families exhibited change in behaviour and social conduct that was prototypical of FTD (Gustafson, 1987; Neary et al., 1988). In all patients with the +16 mutation, the behavioural profile was characterized by disinhibition, restless overactivity, a fatuous affect, puerile behaviour and verbal and motor stereotypies. The single patient (Patient 14) with the +13 mutation presented a contrasting picture of apathy and inertia. The disinhibited, overactive behavioural profile of FTD has been attributed to preferential involvement of orbitofrontal and anterior temporal regions, whereas the apathetic profile has been associated with more widespread frontal lobe dysfunction encompassing dorsolateral frontal cortex (Snowden et al., 1996).

Although behavioural change and frontal executive deficits were prominent features, in addition all patients had language impairment, the qualitative nature of which was relatively consistent across patients. Output was fluent, effortless, grammatically correct and free from phonological errors but was punctuated by stereotyped phrases and inappropriate word usage. Patients made semantic errors, suggesting a primary semantic impairment. Interpretation of these observations as indicating the presence of a primary semantic deficit needs to be made with caution. Inattentiveness, a perfunctory mode of responding and lack of concern for accuracy in disinhibited FTD patients would be expected to lead to secondarily reduced performance accuracy. Moreover, the unrelated nature of some errors (e.g. ‘periscope’ for ‘tie’) is not characteristic of patients with a circumscribed semantic disorder (semantic dementia). Nevertheless, frontal executive deficits are unlikely to account fully for the patients’ semantic errors. First, semantic errors are not an inevitable feature of FTD per se, and indeed are usually absent in most cases of sporadic and familial disease associated with histopathological changes other than those described here. Secondly, semantic errors related to the target word are unlikely to be attributable to random, perfunctory responding. Thirdly, such errors occur in the context of preserved performance on other tests, for example spatial and praxis tests. A general reduction in accuracy of performance due to attention ought to affect a range of tasks. Additionally, semantic impairment was not confined to the verbal domain: patients performed poorly on tasks of face and object recognition in the presence of preserved primary perceptual skills. The semantic deficits in these patients are consistent with a mild semantic dementia (Snowden et al., 1989, 1996; Hodges et al., 1992). Patients thus show the prototypical behavioural disorder of FTD combined with features of semantic dementia. Typically, patients with semantic dementia present with cognitive impairment and it is only late in the course of the disease that behavioural features emerge. Conversely, patients with the behavioural disorder of FTD may exhibit features suggestive of semantic deficit, but typically not until several years into their illness, often at a stage when it is difficult to define accurately. Other patients and families with the +16 mutation have been described clinically (Lanska et al., 1994; Petersen et al., 1995; Yamaoka et al., 1996; Dark, 1997; Goedert et al., 1999; Hulette et al., 1999; Morris et al., 1999). All cases presented with personality change and behavioural disturbance and one patient is reported as having semantic loss (Morris et al., 1999). The earlier clinical descriptions do not mention semantic impairment specifically, and it is difficult to judge its presence from published neuropsychological data. However, one patient is said to have shown impaired naming and visuoperception (Yamaoka et al., 1996). No further details are available, but it is tempting to think that the deficits occurred on the basis of semantic loss.

Thus, all patients exhibited the behavioural disorder of FTD combined with semantic loss. It is interesting that all patients with the +16 mutation presented with the disinhibited form of FTD, whereas the single patient with the +13 mutation was apathetic from the start of his illness. This patient is the only reported case of the +13 mutation, and it remains to be seen whether other individuals with this particular mutation display a similar phenotype.

Parkinsonism is an important, but not inevitable, feature of these patients. Some individuals show no neurological signs for many years, whereas in others akinesia and rigidity are early and prominent features. No patient exhibited amyotrophy or pyramidal signs.

The onset of symptoms in the patients with the +16 splice site mutation occurred in the presenium, which is characteristic of FTD, the average age at onset being around 51 years of age. This seems to be typical of families with FTDP‐17 (for a review, see Reed et al., 2001), though a younger age at onset (around 43 years of age) is seen in pallidopontonigral degeneration (PPND) associated with the N279K tau gene mutation (Reed et al., 1998). Disease duration may, again typically, be lengthy—it was up to 17 years in our series. Interestingly, the patient who died from his illness within 5 years of onset (Patient 2) manifested parkinsonian features at an early stage. This is consistent with the clinical impression that the duration of illness is indeed inversely correlated with the severity of extrapyramidal signs. The only patient with the +13 mutation (Patient 14) had a later age at onset (65 years) and a short disease duration (5 years). A similar pattern was reported in his father and sister.

Possession of the APO E ϵ4 allele has been often associated with an earlier age at onset of illness in Alzheimer’s disease. However, in our group of patients with FTDP‐17, the APO E ϵ4 allele frequency was not elevated, nor did the mean age at onset differ in bearers of the ϵ4 allele from that in non‐bearers. Similar findings have been reported in other FTDP‐17 families (Houlden et al., 1999) and in sporadic and non‐FTDP‐17 familial FTD (Minthon et al., 1997; Pickering‐Brown et al., 2000a; Mann et al., 2001) and emphasize the lack of impact of this genetic variation in this form of dementia. Nonetheless, a recent clinic‐based study (Fabre et al., 2001) has reported an increased frequency (0.31) of the APO E ϵ4 allele in a Swedish FTD population, not including patients with tau gene mutations, but the age at onset effect of the ϵ4 allele was not observed.

Pathologically, all of the six patients who have so far come to autopsy with end‐stage illness share a picture of frontotemporal atrophy with involvement of the substantia nigra (Table 4). The underlying histology is that of cortical degeneration with microvacuolation of the outer laminae. Tau pathology is widespread in both neurones and glial cells throughout the brain, but mostly within cerebral cortical structures (Table 4). Ultrastructurally, the tau filaments have a twisted, ribbon‐like morphology (Spillantini et al., 1998) that is quite distinct from the paired helical filaments of Alzheimer’s disease. The +16 splice mutation has also been reported in an Australian family (AUS1) (Dark, 1997), an American pedigree [Duke 1684 (Yamaoka et al., 1996; Hulette et al., 1999)] and in several other British families (Morris et al., 1999). The same +16 mutation has been reported in a family with an illness known as progressive subcortical gliosis (Lanska et al., 1994; Petersen et al., 1995; Goedert et al., 1999). Pathological details of patients with the +16 mutation presented in these other studies are consistent with the findings reported here.

Nonetheless, there are other mutations in the tau gene that occur within and around the exon 10 splice site region. These are the +3 (Spillantini et al., 1998; Tolnay et al., 2000) [in patients with multiple system tauopathy dementia (MSTD)] (Spillantini et al., 1996, 1997, 1998), the +12 (Yasuda et al., 2000) and the +14 [in patients with disinhibition, dementia, parkinsonism and amyotrophy complex (DDPAC)] (Lynch et al., 1994; Wilhelmsen et al., 1994; Hutton et al., 1998) splice mutations, and the –1 (S305N) (Iijima et al., 1999) mutation. Certain other coding mutations in the vicinity of the exon 10 splice site are the missense mutation N279K (Clark et al., 1998; Delisle et al., 1999; Yasuda et al., 1999) and the silent mutations L284L (D’Souza et al., 1999) and S305S (Stanford et al., 2000). As with the +13 and +16 splice site mutations (Hutton et al., 1998), all these other mutations have the same physiological effect on tau transcription, inducing increased inclusion of exon 10 via alternative splicing. This increased splicing results in excess production of tau isoforms containing four microtubule‐binding domains (four‐repeat tau) (Hutton et al., 1998; Spillantini et al., 1998; D’Souza et al., 1999; Hasegawa et al., 1999; Yasuda et al., 2000). These tau isoforms accumulate and assemble into twisted, ribbon‐like structures (Spillantini et al., 1998; Yasuda et al., 2000) composed principally, but not necessarily exclusively, of four‐repeat tau species.

The clinical and pathological features of patients bearing these other tau mutations are generally similar to those shown by members of the +13 and +16 mutation families. However, variants such as DDPAC, PPND and MSTD show a more pronounced extrapyramidal and pyramidal symptomatology, dementia being less prominent (Wszolek et al., 1992; Lynch et al., 1994; Spillantini et al., 1997). In these instances, the tau pathology is more severe, often widely affecting subcortical structures (Wszolek et al., 1992; Sima et al., 1996; Spillantini et al., 1997; Reed et al., 1998). The silent S305S mutation produces a clinical and pathological phenotype strongly reminiscent of progressive supranuclear palsy (Stanford et al., 2000). Such clinical similarity has also been noted in some cases with the missense mutation N279K (Delisle et al., 1999) and others with a homozygous deletion mutation at codon 296 (Pastor et al., 2001). As noted above, extrapyramidal signs were frequently seen in our patients with the +13 and +16 mutations. However, when present, these were characteristically parkinsonian, and no abnormalities of vertical gaze, suggestive of a progressive supranuclear palsy phenotype, were seen. Nevertheless, variations like these suggest that the range of clinical phenotypes associated with this tau mutation (and perhaps other tau mutations) might be broader than is currently appreciated, and that certain patients with parkinsonism that is unresponsive to l‐dopa might also be bearers of mutations in the tau gene.

It is possible that certain tau gene mutations may not always be completely penetrant or might display delayed penetrance in certain individuals. For example, one bearer of the +16 mutation in family AUS1 has lived well beyond the average age at onset of disease for this family without showing clinical symptoms (Dark, 1997). Similarly, in one of our families there is an individual who bears the +16 splice mutation and is currently aged 57 years (i.e. beyond the usual age at onset of disease for this family) but is so far alive and well. However, in our Family 7, we noted that one patient (Patient 11) had a late onset of illness (66 years) compared with siblings (Patients 10 and 12; 45 and 52 years, respectively). It remains to be seen whether these currently and apparently unaffected individuals become ill later in life, presenting with different symptoms. No such issues of penetrance have yet been raised in respect of the other exon 10 mutations.

Only one of the six autopsied patients showed any deposition of Aβ within the brain, mostly in the form of diffuse plaques containing Aβ42(43). This patient (Patient 14) bore the APO E ϵ4 allele, though another patient, also a bearer of the ϵ4 allele (Patient 1), did not show deposition of Aβ. Some previous studies have commented upon Aβ deposition in cases of FTDP‐17 (Dark, 1997; Reed et al., 1998; D’Souza et al., 1999; van Swieten et al., 1999; Morris et al., 2000), especially in certain patients with splice site mutations (Dark, 1997; D’Souza et al., 1999; Morris et al., 2000). However, we have shown (Mann et al., 2001) that, among 53 autopsy cases of frontotemporal lobe degeneration (including the five cases reported here), Aβ deposition occurred in only 14 cases (26%), and then usually when the ϵ4 allele was present or when there was a late onset (i.e. after 60 years of age) or long duration of illness. Indeed, the patient with the L284L mutation (D’Souza et al., 1999) was 61 years old at death and bore the APO E ϵ3/ϵ4 genotype (the APO E genotype was not given in the studies of Dark, 1997, Reed et al., 1998, van Swieten et al., 1999 and Morris et al., 2000). It is therefore unlikely that Aβ deposition plays any significant role in the pathogenesis of FTD and associated conditions, and its presence in the brains of such patients is entirely incidental dependent upon age at onset of illness and APO E genotype.

Because Patient 6 died of myocardial infarction with only minimal clinical signs of FTD, we had the opportunity to seek the site and nature of the early pathological lesions. Cortical microvacuolar and astrocytic changes were absent. The only histopathological features of note were the presence of scattered neurones and glial cells immunoreactive to tau throughout the cortical and subcortical regions. Although these tau‐positive cells did not, in light microscope immunohistochemistry, have the appearance of classic neurofibrillary structures, tau filaments similar to those seen in the other four patients with established pathology were observed by electron microscopy, though they were sparse. Such findings imply that the disease process underlying the neurodegeneration within these inherited forms of FTD, associated with mutations in the tau gene, does indeed stem directly from primary alterations in the structure/function of tau. However, it is remarkable that, even at end‐stage illness, the amount of tau pathology, as evidenced by the tissue accumulation of pathological tau, is much lower in FTDP‐17 than in Alzheimer’s disease. This calls into question the role of pathological tau per se in the neurodegenerative process of FTD. It is possible that the metabolic derangement of neuronal function that leads to clinical symptoms may be related to alterations in soluble tau that interfere with microtubule structure and function rather than to the potential (neurotoxic) effects of intracellular accumulation of pathological fibrils per se.

In British persons, mutations associated with FTD include the +13 and +16 splice site mutations (see also Morris et al., 1999), the +3 splice site mutation (Tolnay et al., 2000) and the mutations N296N (Spillantini et al., 2000), K257T (Pickering‐Brown et al., 2000b; Rizzini et al., 2000), G389R (Pickering‐Brown et al., 2000b) and A239T (S. M. Pickering‐Brown, unpublished data). At autopsy, patients with K257T and G389R mutations presented with Pick‐like histology and the A239T patient with a tau‐negative, microvacuolar‐type histology. It therefore appears that, in British populations, the most common, and therefore most likely, form of FTDP‐17 is that which is associated with inheritance of the +16 splice site mutation in the tau gene.

The likelihood that all eight of these families with the +16 mutation are related to a common extended pedigree has now been confirmed by haplotyping (S. M. Pickering‐Brown, unpublished data). Many family members still reside within, or originate from, a common geographical region of Great Britain (North Wales), and it is from this region that a founder member may have arisen. Other British families with the same mutation (Morris et al., 1999) may also be related to our present eight families, and the family with the +16 mutation in Australia (Dark, 1997) may have descended from immigrants from Britain. Such patterns of migration may explain the (relatively common) occurrence of certain mutations associated with FTD, such as P301L, within North American populations of French and Dutch ancestry (Clark et al., 1998; Hutton et al., 1998; Nasreddine et al., 1999); P301L is the most common mutation associated with FTD in natives of France and The Netherlands (Heutink et al., 1997; Dumanchin et al., 1998; Rizzu et al., 1999).

Appendix I

Family 1 (also known as MAN23)

Patient 2 (III:4)

At 46 years, this woman began to neglect self‐care and domestic responsibilities, to pace restlessly and to wander about the neighbourhood. She was insightless and unconcerned. Neurological examination 3 years after onset of symptoms was normal. On neuropsychological examination she was impulsive and distractible. A standard IQ test (Wechsler Adult Intelligence Scale) revealed a full IQ of 90. Speech output was economical, with idiosyncratic word usage but without grammatical or phonemic paraphasic errors. There were no primary deficits in the realms of visual perception, spatial skills and praxis, and she was not clinically amnesic. She was fully oriented in time and place and could give a good account of day‐to‐day events. Poor performance on formal memory tests was attributed to inattentiveness and lack of application and use of strategy. In contrast to the relative preservation of instrumental functions, performance on tests sensitive to frontal lobe dysfunction indicated impaired attention, abstraction, planning and mental set‐shifting, with marked response perseveration. EEG was normal and functional brain imaging using SPECT showed reduced tracer uptake in the frontal lobe bilaterally. The clinical picture was considered typical of FTD.

She was re‐examined at intervals until her death 12 years after the onset of symptoms. She had an increasingly bland affect. Her restlessness and purposeless overactivity was superseded by apathy and inertia. Gluttony and indiscriminate eating gave way to lost interest in food. She was incontinent without concern. Four years after symptom onset, neurological examination revealed suck and grasp reflexes and mild limb rigidity, which increased over the ensuing years. After 8 years, she was wheelchair‐bound, had a flexed posture, poverty of facial expression with reduction in eye movements, and profound bradykinesia. There was gradual diminution in her speech output, with increasingly economical and stereotyped responses, echolalia, perseveration, hypophonia and dysprosody. After 8 years she was mute. Her ability spontaneously to locate, reach for and align objects suggested preservation of visuospatial skills even at a time when she was mute and formally untestable.

She died of bronchopneumonia aged 58 years after an illness totalling 12 years. The brain was available at autopsy.

In the family history, her brother, her mother, her mother’s four sibs and four maternal cousins suffered from a dementing illness with similar characteristics. The diagnosis of FTD has been confirmed at autopsy in two of these family members (Patients 1 and 3 of this study).

Family 2 (also known as MAN6)

Patient 4 (III:1)

At the age of 50 years, this man underwent a radical alteration in his personality. He became fatuous, puerile, sexually disinhibited and lewd. He neglected self‐care and was incontinent without concern. He was inattentive and distractible. He paced restlessly and walked an identical route each day in a ritualistic fashion. He developed a preference for sweet foods and showed hoarding behaviour. Neurological examination 1 year after onset of symptoms revealed marked akinesia and rigidity and bilateral grasp reflexes. On neuropsychological testing he showed poor application and responses were perfunctory. Speech output was reduced, with stereotyped use of words and phrases and semantic errors in naming. Primary visual perceptual and spatial skills were well preserved and he had no difficulty reproducing line drawings. However, he recognized no high‐profile famous faces and on the Pyramids and Palm Trees test (Howard and Patterson, 1992), which requires retrieval of semantic associations between pictures, his performance was significantly impaired, suggesting the presence of semantic impairment.

The prominent feature, however, was profound executive deficits, with impairments in attention, abstraction, planning and sequencing skills, and verbal and motor perseverations. The pattern of memory loss strongly suggested ‘frontal’ rather than ‘limbic’ amnesia. Responses were confabulatory and there was interference across tasks. EEG was normal and a SPECT scan revealed bilateral frontal lobe dysfunction that was more marked on the left. The clinical diagnosis was of FTD.

He was assessed regularly over the next 4 years until his death. There was a dramatic deterioration both physically and mentally. He was unsteady and had a fixed posture. There was marked right‐sided tremor. He was hyperoral and would place inedible objects in his mouth. He showed utilization behaviour. Speech was hypophonic, repetitive and stereotyped. He continued to pace, negotiating the environment with ease, suggesting preservation of spatial skills. He died aged 55 years, 5 years after the onset of symptoms.

The patient’s mother (II:5) was admitted to a psychiatric hospital at the age of 50 years because of progressive change in her behaviour and self‐neglect. She was disinhibited, puerile and fatuous and made childish jokes, she hoarded objects and she paced and wandered. A diagnosis was made of schizophrenia and Parkinson’s disease. Latterly, she was mute, rigid and totally dependent in activities of daily living. She died at the age of 68 years.

Family 3

Patient 5

At the age of 50 years, this man began to show obsessional and ritualistic traits. He clock‐watched and adhered to a fixed routine. He hoarded magazines and birthday cards, and rifled through dustbins in search of them. He had a number of mannerisms and verbal stereotypies, and he affected a French accent or ecclesiastical tone. He was overfamiliar and disinhibited, often acting the clown or mimicking others. He was restless and wandered the country without purpose. He neglected personal hygiene. He acquired a preference for sweet foods. He became more parsimonious and dressed inappropriately. There was no history of visuospatial disorder and he could find his way without becoming lost. He was not clinically amnesic.

At 64 years, 14 years after the recorded onset of symptoms, he remained overactive, restless, disinhibited and without insight. Neurological examination was normal, apart from powerful grasp reflexes and motor mannerisms. Cognitive evaluation with the Wechsler Adult Intelligence Scale—Revised revealed a verbal IQ of 109, a performance IQ of 100 and a full scale IQ of 105. He performed well on a range of tests of language, elementary perception, spatial functioning, praxis and memory. Performance was also intact on two frontal executive tasks: the Wisconsin Card Sorting Test and the FAS verbal fluency test. By contrast, he had difficulty recognizing line drawings, which was attributed to an associative (semantic) form of agnosia, and his knowledge of famous names was profoundly impaired.

The clinical picture suggested a disinhibited form of FTD with semantic impairment, particularly in the non‐verbal domain, suggesting orbitofrontal and temporal lobe dysfunction on the right side. SPECT scans confirmed impaired function in the right frontotemporal lobes, particularly the right temporal pole.

His brother (Patient 6) came under psychiatric care at the age of 49 years with a depressive illness unresponsive to treatment. No cognitive deficits were detected at that time. Seven years later he re‐presented with increasingly obsessional features and stereotyped behaviours. Cycling was one such obsession and he would undertake lengthy journeys, invariably without becoming lost. Neuropsychological examination revealed mild word‐finding difficulty and verbal stereotypies. MRI and EEG were normal. It was concluded that he had a mild language impairment together with behavioural features suggestive of a frontal lobe syndrome. He died suddenly of myocardial infarction at the age of 57 years and a post‐mortem examination was carried out.

Family 4

Patient 7 (III:1)

At the age of 47 years, this man began to show increasing behavioural change and lack of emotional warmth, culminating in estrangement from his family. At the age of 52 years, he was found to be living in a state of neglect and dining entirely on Pot Noodles. He was disinhibited and overfamiliar and he would grimace and make sexually suggestive gestures. He wandered naked without embarrassment, and gave his money to strangers. He came under psychiatric care.

Ten years later, when he was 62, he was referred for neurological investigation. Neurological examination was entirely normal, with the exception of a right grasp reflex. His manner was fatuous and puerile and he giggled inappropriately. Several stereotyped behaviours were prominent: grimacing, protruding and wiggling his tongue, blowing into his sleeve and making animal noises. He was restless, distractible and difficult to engage. He responded rapidly and impulsively, with no concern for accuracy. Speech was limited to short, generally irrelevant, phrases of a perseverative or stereotyped nature, such as ‘Daffy duck’, ‘kerbstone edge’, ‘I’ve got no cigarettes’ and ‘quack quack’. There was no articulatory or phonological disorder. Naming and word‐picture matching performance were profoundly impaired. Although attributed partly to his inattention and perfunctory mode of responding, the presence of numerous semantic errors in naming suggested the presence of semantic impairment. Semantic impairment was not confined to the verbal domain. He recognized no famous faces or famous buildings and, despite his extensive repertoire of animal noises, he failed to produce the appropriate noise in response to an animal name or picture. There was no suggestion of a primary visuospatial disorder and scores on sections of the Visual Object and Space Perception (VOSP) battery (Warrington and James, 1991) were within normal limits. Interpretation of memory test performance was complicated by his inattention and lack of application. Performance on frontal executive tests was at floor level. He achieved no sorting categories in the Weigl’s block test (De Renzi et al., 1966) and his ordering of pictures in a picture‐sequencing test was random. In verbal fluency tasks he produced two animal names and no words beginning with the letter F in 1 min. The neuropsychological profile was interpreted as indicative of orbitofrontal and anterior temporal lobe dysfunction.

EEG was normal. Structural imaging could not be undertaken because of his lack of compliance. Functional imaging using SPECT showed reduced uptake in the frontal and temporal lobes, which was more severe on the left and most marked in the orbital parts of the frontal lobes.

He is now 66 years of age and dependent on others for all activities of daily living. He does not recognize family members. He shows environmentally dependent behaviours: hyperorality, involving mouthing of inanimate objects, and utilization behaviour. He wanders, but does not become lost. He is physically well, but is doubly incontinent. Neurological examination remains unremarkable, aside from powerful grasping and groping reflexes. Power and tone are normal. He is increasingly distractible and inattentive and is difficult to engage. He shows stereotyped grimacing and makes rude noises and animal sounds. His utterances continue to be stereotyped and perseverative, although his repertoire of stereotyped phrases has diminished and he speaks less. He has more difficulty in word comprehension and object recognition, suggesting increasing semantic impairment.

His mother (II:2) died at age 63 years, having developed similar symptoms in her fifties. She spent the last years of her life in psychiatric care. Two maternal aunts (II:4 and II:5) were reported as displaying the same features, but further details are not available.

Family 5

Patient 8 (III:4)

At the age of 48 years, this man underwent a striking change in personality. He would embarrass his family by commenting aloud on strangers’ smoking habits and body habitus. In general he was lacking in motivation and had become socially reclusive. He required prompting in self‐care. He began to overeat, especially sweet items, and would hoard food in large quantities. He developed a fixed daily routine, especially regarding meal times and television programmes, becoming irritable if disrupted. He whistled the same tune repeatedly. Mild forgetfulness was reported. He was assessed 4 years after the onset of symptoms. Neurological examination was normal, apart from weak bilateral grasp reflexes. In contrast to the striking behavioural change, the only abnormality on cognitive testing was a mild memory retrieval deficit. He scored 30 out of 30 on the Mini‐Mental State Examination. Qualitatively, he responded rapidly and was somewhat facetious during testing. The clinical diagnosis was FTD. MRI revealed bilateral temporal lobe atrophy. A SPECT scan disclosed marked hypoperfusion in both frontal lobes.

Six years after onset, the clinical picture remains very similar. He has become increasingly inflexible in his behaviour and has developed a number of stereotyped behaviours. His family reports a striking lack of empathy and increasing egocentricity. The neurological examination remains unchanged. On serial cognitive testing, the only abnormalities to date are mild impairment in frontal lobe executive tests and the suggestion of an emerging semantic deficit.

In the family history, his father (II:4) had developed similar behavioural change in the few years before his death from ischaemic heart disease at 55 years of age. A paternal uncle (II:2) died with dementia in his 60s; he was reported to have displayed similar symptoms. The patient’s sister (III:3), 6 years older, was resident in a care home because of neuropsychiatric problems attributed to a stroke.

Family 6

Patient 9 (II:1)

At 54 years, this man became increasingly quiet, withdrawn and lacking in motivation. He showed obsessive traits, which were out of character, particularly the emptying of ashtrays. He would overeat. On examination 9 months after onset of symptoms, he had a bland, fatuous affect and he laughed inappropriately. He showed no insight or concern. General physical examination was normal. Neurological examination revealed an expressionless face with limited eye movements and bilateral grasp reflexes. Cognitive evaluation revealed him to be fully oriented in time and place. He showed economy of speech, which consisted chiefly of stereotyped phrases, but there were no articulatory, phonological or grammatical errors. Naming was profoundly impaired. Although some errors were semantically related (e.g. ‘spoon’ for ‘chopsticks’) the majority were unrelated (e.g. ‘a home and away’ for ‘thimble’) and there were frequent perseverations. Comprehension was impaired at both the single word and the sentence level. He showed normal perception at the presemantic level, as judged by his accurate copies of line drawings. However, there was evidence of associative agnosia and his performance was at floor level in the Silhouettes and Object Decision subtests of the VOSP battery (Warrington and James, 1991). By contrast, spatial skills were well preserved. His memory performance was poor on formal tests. He had good memory for personal autobiographical events but his general knowledge was poor. He was unable to accomplish simple tests of frontal executive function. On the Weigl block test, he showed perseveration along one sorting rule. In picture‐sequencing tests he was totally unable to order pictures.

The cognitive profile suggested semantic breakdown combined with frontal executive deficits. MRI showed atrophy, which was particularly marked in the temporal lobes. SPECT imaging showed reduced uptake in the temporal lobes, which was more marked on the left side.

During the last year, until the present time, he has shown increasing repetitive behaviours. On examination, he has bilateral grasp reflexes but no sign of rigidity. Cognitive evaluation elicits marked perseveration, echolalia and verbal stereotypies. Comprehension and naming are impaired profoundly, although repetition skills remain intact. Spatial skills are normal and he is oriented in time and place.

His father (I:1) died at 62 years with Parkinson’s disease and memory impairment. No other details of his illness are available.

Family 7

Patient 10 (IV:1)

Behavioural change was the first symptom in this 48‐year‐old housewife. She became rude, interrupted conversations, jumped queues and swore frequently. She required prompting in self‐care. She developed a fondness for sweet food. She developed a fixed routine in all her activities and became a clock‐watcher. Word‐finding difficulty and inappropriate word usage were also reported by her family. Nevertheless, she was not heard to make phonological errors. She was unable to recognize objects within the home or individuals. She had no difficulty negotiating her environment. Five years after onset of symptoms, general and neurological examinations were normal. Restlessness and inattentiveness dominated cognitive testing. Nevertheless, it was possible to engage her attention for short periods. She was fully orientated. Her speech was economical, with stereotyped phrases but without linguistic error. She performed poorly on an easy picture‐naming task. She could name no animals, invariably offering the superordinate category. In addition she made many semantic category errors. She scored zero on a test of recognition of famous monuments. On the VOSP battery (Warrington and James, 1991) she passed all the spatial subtests, performing at ceiling level. By contrast, she exhibited poor performance in perceptual tasks, which was interpreted as indicative of her underlying semantic disorder. Formal testing of memory revealed marked impairment. However, she was fully orientated and provided detailed autobiographical information. In the Weigl block test, she displayed perseveration for one sorting rule. The neuropsychological profile was interpreted as showing the features of semantic dementia accompanied by disinhibition. A CT scan elsewhere was reported as showing cerebral atrophy. SPECT scanning revealed anterior hypoperfusion.

A year later, the clinical picture remains similar. Interestingly, on naming tasks she now makes many unrelated errors, presumably reflecting the combination of semantic loss and unconcern.

In the family history, her paternal grandfather (II:2) had undergone a behavioural disturbance. Her father (III:2) was demented before his death. A brother (IV:2, Patient 11), 11 years older, died with Parkinson’s disease and dementia. Another brother (IV:3, Patient 12), 4 years older, had developed symptoms suggestive of obsessive–compulsive disorder.

Family 8

Patient 13

This woman underwent a behavioural change at the age of 50 years. She became disinhibited, and overfamiliar with strangers. She began to swear and crack jokes. Previously meticulous with regard to housework, she neglected her domestic chores and spent the day listening to the radio. She required prompting to bathe and change. She adopted a rigid routine, especially in her eating habits: she developed a preference for sweet food and gained weight.

Her family reported memory loss, especially for people’s names. She failed to recognize friends and no longer recognized common vegetables.

Three years after onset of symptoms, neurological examination was normal. On neuropsychological examination she was inappropriate and often replied with rhyming puns. Her replies were economical and there were several stereotyped phrases. Her speech was without phonological error. She scored zero out of 30 on the Graded Naming Test and zero out of 20 on a test of recognition of famous monuments. She scored 21 out of 40 on an easy picture‐naming task; the majority of her errors were semantically based. On the VOSP battery, she performed at ceiling level on spatial tasks but failed on the test of object identification, reflecting her semantic deficit. She was orientated and gave excellent detail of autobiographical information. On formal tests of memory she performed poorly, in part because of her failure to monitor her responses. Her performance was impaired on tasks sensitive to frontal lobe dysfunction: she produced just three animals in 1 min in a test of category fluency and failed to see an alternative sorting dimension in Weigl’s blocks test. She was unable to order the cards in a test of picture sequencing.

MRI revealed atrophy, involving particularly the temporal lobes. SPECT scanning showed a reduction in tracer uptake in the frontal and temporal lobes bilaterally. EEG was normal.

The diagnosis was FTD with severe semantic deficits.

The patient had been adopted as a baby and there was no information regarding her natural parents.

Family 9 (also known as MAN19)

Patient 14 (II:2)

At the age of 65 years, this man became profoundly apathetic, neglectful of personal care, hypersomnolent and uncommunicative. He was incontinent without concern. He acquired a preference for sweet foods and hoarded sweets and biscuits. He clock‐watched and adhered to a daily routine. Neurological examination 1 year after onset of symptoms was normal apart from bilateral grasp reflexes. Performance on cognitive tests was perfunctory, compromising test scores. However, there was no evidence of primary impairments in spatial functioning and praxis. By contrast, there was profound executive impairment. He showed concreteness of thought, poor organizational and sequencing skills and poor generation of information. In addition, naming and word comprehension were impaired and he made semantic errors. The neuropsychological picture suggested impaired frontal and temporal lobe dysfunction with relative preservation of function of the posterior cerebral hemispheres.

EEG was normal, MRI showed cerebral atrophy that was most marked in the temporal lobes and SPECT showed frontal and temporal dysfunction, particularly on the left side. The clinical diagnosis was of FTD.

He was reviewed regularly over 3 years until his death. During this period he was increasingly apathetic and amotivational. He exhibited repetitive rhythmical grunting and humming. He had a parkinsonian appearance and showed motor slowing. He was hypophonic and rigid. On mental testing, the salient features of his performance were inertia, lack of spontaneous generation of response and marked response perseveration. In addition, there was a language disorder with significant semantic involvement but no phonological impairment. Four years after the onset of symptoms he was mute apart from indecipherable mumblings. He died at the age of 70 years after an illness of 5 years and his brain was available for examination.

His father (I:1) developed a dementing illness at the age of 65 years and died 3 years later. His sister (II:1) also developed a dementing illness at the age of 67 years and died 3 years later. The pattern of dementia is not known.

References

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