Over a century ago, Arnold Pick described focal syndromes associated with degeneration of the frontal and temporal lobes. For many years these focal disorders were unrecognised, were subsumed within the broad rubric of dementia, and typically assumed to be Alzheimer's disease. Their rediscovery (Reference GustafsonGustafson, 1987; Reference Neary, Snowden and NorthenNeary et al, 1988) led to the development of clinical and neuropathological diagnostic criteria (Reference AnonymousAnonymous, 1994), the clinical criteria having undergone recent revision (Reference Neary, Snowden and GustafsonNeary et al, 1998). Frontotemporal dementia denotes a clinical syndrome, characterised by behavioural change. Only a minority of patients exhibit Pick-type histological changes, hence the term ‘frontotemporal dementia’ is preferred to ‘Pick's disease’, which forms part of the ICD-10 and DSM-IV classifications of dementia (World Health Organization, 1992; American Psychiatric Association, 1994).

OVERVIEW OF FRONTOTEMPORAL DEMENTIA

SUBTYPES OF FRONTOTEMPORAL DEMENTIA

There is evidence of heterogeneity of clinical presentation. Some patients are disinhibited, fatuous, purposelessly overactive, easily distracted, socially inappropriate and lacking in concern. At the other extreme, patients are bland, apathetic, inert, lacking volition and mental effort, mentally rigid and perseverative. In a proportion of patients the salient presenting characteristic is stereotyped, ritualistic behaviour. The disinhibited form of frontotemporal dementia is associated with pathological changes confined to orbitomedial frontal and anterior temporal regions, whereas the apathetic form occurs when pathological change is extensive throughout the frontal lobes and extending into the dorsolateral frontal cortex. The stereotypic form of frontotemporal dementia occurs in association with marked striatal changes and variable cortical involvement, often with the emphasis on temporal rather than frontal lobe pathology.

These broad behavioural subtypes reflect regional but not hemispheric differences between patients. There is, however, some evidence that hemispheric asymmetries too may influence the behavioural presentation. Social behaviour has been shown to be more disrupted in patients with predominantly right-hemisphere pathological changes (Reference Edwards-Lee, Miller and BensonEdwards-Lee et al, 1997), suggesting a particular role of the right hemisphere in social behaviour.

RELATED CLINICAL SYNDROMES

Patients with the behavioural disorder of frontotemporal dementia account for the largest proportion (at least 70%) of patients with non-Alzheimer frontotemporal lobar degeneration. However, other clinical syndromes share the same histopathological characteristics (Reference Snowden, Neary and MannSnowden et al, 1996; Reference Neary, Snowden and GustafsonNeary et al, 1998). One is semantic dementia, in which there is progressive loss of concepts, affecting the ability to understand the meaning of words, objects, faces, non-verbal environmental sounds, smells, tastes and tactile stimuli. Pathological change is pronounced in the temporal neocortices, particularly the inferior and middle temporal gyri. Another syndrome is progressive non-fluent aphasia, in which a highly circumscribed disorder of language is associated with markedly asymmetric atrophy affecting the left hemisphere extensively. Occasionally patients may present with a circumscribed apraxia, in association with atrophy of the frontoparietal regions. These syndromes are less common than the behavioural disorder of frontotemporal dementia. Semantic dementia accounts for about 15%, progressive aphasia 10% and progressive apraxia 2% of cases of frontotemporal lobar degeneration.

BEHAVIOUR AND DIFFERENTIAL DIAGNOSIS

The overriding feature of frontotemporal dementia is the profound character and behavioural changes and it is the historical account of these changes that plays the most critical part in diagnosis. In a study of the original consensus statement (Reference AnonymousAnonymous, 1994), Miller et al (Reference Miller, Ikonte and Ponton1997a ) made a comparison of 30 patients with frontotemporal dementia and 30 with Alzheimer's disease, classified clinically on the basis of SPECT findings; 8 of the patients with frontotemporal dementia had subsequent confirmation of diagnosis at autopsy. The behavioural features of loss of social awareness, hyperorality, stereotyped and perseverative behaviour, reduced speech output and preserved spatial orientation best discriminated the two groups, with sensitivity for frontotemporal dementia ranging between 63% and 73% and specificity between 97% and 100%. A discriminant function analysis correctly classified 100% of patients with frontotemporal dementia or Alzheimer's disease on the basis of these behavioural features.

Our own more recent studies provide further evidence of the importance of dietary changes and repetitive and stereotyped behaviours in differential diagnosis. We have found too that the loss of affective response (generalised blunting of emotions) is a key factor in distinguishing frontotemporal dementia from both Alzheimer's disease and cerebrovascular dementia. It is known that emotional unconcern may be heralded in the prodromal and early stage of frontotemporal dementia by symptoms of anxiety, depression and hypochondriacal rumination (Reference AnonymousAnonymous, 1994). However, these symptoms are typically transient, and provide a less reliable diagnostic marker than the blunting of affect. Similarly, although irritability may be reported in some patients with frontotemporal dementia, it is not more frequent than in other forms of dementia, and is therefore a relatively poor diagnostic marker. In line with the loss of social emotions, social behaviour is highly disordered in frontotemporal dementia, and is a valuable factor in differential diagnosis (Reference Miller, Darby and BensonMiller et al, 1997b ; Reference Sjögren, Wallin and EdmanSjögrenet al, 1997).

REPETITIVE AND COMPULSIVE BEHAVIOURS

Repetitive behaviours in frontotemporal dementia take a variety of forms. They include simple motor mannerisms as well as complex behavioural routines. They occur in the verbal domain in the form of stereotyped use of words or phrases, and in the motor domain as wandering and pacing. Some repetitive behaviours have a distinctly compulsive quality. Compulsive-type behaviours may take the form of clock-watching and adherence to a fixed routine, superstitious rituals such as avoiding standing on cracks in the pavement, or may involve a complex sequence of actions, such as tapping each wall twice upon entering a room.

At first sight the presence of compulsive behaviours seem at odds with the prevailing lack of emotional concern. However, ritualistic and compulsive behaviours are not present in all patients with frontotemporal dementia. Our own experience (Reference Snowden, Neary and MannSnowden et al, 1996) suggests that they occur in patients with predominantly striatal rather than neocortical pathological changes and in patients with the disinhibited form of frontotemporal dementia, in whom there are orbitofrontal and anterior temporal lobe changes, rather than in those with apathetic frontotemporal dementia who have widespread frontal changes extending into dorsolateral frontal cortices. That the temporal lobes, in addition to the striatum, may have an important role in compulsive behaviours is suggested, moreover, by the high frequency of these behaviours in patients with semantic dementia, in whom the predominant pathology is temporal rather than frontal (Reference Snowden, Bathgate and VarmaSnowden et al, 2001). In these patients clock-watching and adherence to a fixed routine are prominent features. Although the compulsive behaviours in frontotemporal dementia and related syndromes have affinities with those of obsessive—compulsive disorder, patients with frontotemporal dementia do not typically experience the feelings of anxiety and release from anxiety characteristic of obsessive—compulsive disorder.

TREATMENT

Rational treatments for frontotemporal dementia are currently limited. Neurochemical studies indicate no abnormality of the cholinergic system, so that pharmacological agents designed for Alzheimer's disease are unlikely to benefit patients with frontotemporal dementia. Nevertheless, there is some evidence that behavioural symptoms, such as disinhibition, overeating and compulsions, may benefit from treatment with selective serotonin reuptake inhibitors (Reference Swartz, Miller and LesserSwartz et al, 1997), suggesting that a modicum of symptomatic improvement can be achieved at least in some cases.

NOSOLOGICAL ISSUES

Uncertainties regarding the nosological status of frontotemporal dementia have arisen for a number of reasons. The clinical syndromes arising from frontotemporal lobar degeneration are not uniform. The disorder itself can be separated into disinhibited, apathetic and stereotypic forms. In a minority of patients with frontotemporal dementia, extrapyramidal signs occur early and are marked, leading to distinct designations of dementia with parkinsonism. Clinically distinct syndromes such as progressive non-fluent aphasia and semantic dementia share the same pathological findings. Moreover, the pattern of histological change also is not uniform, being characterised by microvacuolation (frontal lobe dementia (FLD) type), sometimes combined with histological changes of motor neuron disease (MND type), or severe gliosis with or without inclusions and ballooned cells (Pick type). The clinical syndrome does not predict histological type, so that clinical distinctiveness itself does not imply aetiological difference. Nevertheless, the presence of distinct histological characteristics raises the question whether frontotemporal dementia reflects a single or multiple entities. Advances in molecular genetics are beginning to unravel this issue.

Genetic linkage studies have established the presence of a causative gene on the long arm of chromosome 17 (17q21-22) in some families with autosomal dominant inheritance, and mutations in the tau gene have been identified in some cases (Reference Hutton, Lendon and RizzuHutton et al, 1998). The identification of mutations in tau associated with Pick type as well as microvascuolar histological changes links the two histological patterns into the same disease entity. Nevertheless, tau pathology, as shown by immunohistochemistry and mutations in tau, accounts for only a proportion of patients with frontotemporal dementia (Reference Mann, McDonagh and SnowdenMann et al, 2000). Moreover, a frontotemporal dementia clinical phenotype has shown linkage to chromosome 3 (Reference Brown, Ashworth and GydesenBrown et al, 1995) and frontotemporal dementia occurring in association with motor neuron disease has shown linkage to chromosome 9 (Reference Hosier, Siddique and SappHosler et al, 2000). There is thus a need for caution in assuming that all cases of frontotemporal dementia represent tauopathies and have a common aetiology. The clinical and pathological variants of frontotemporal lobar degeneration may reflect different phenotypic expressions of particular genetic changes, some of which involve the tau gene while others relate to as yet undefined genetic variations at this or other chromosomal loci.

CLINICAL AND THEORETICAL IMPORTANCE

Until recently patients presenting with primary degenerative dementia in the presenium were invariably believed to have Alzheimer's disease. It is now recognised that approximately 20% of those patients have frontotemporal dementia. These patients' relative youth, physical well-being and bizarre, socially disruptive behaviour represent a unique challenge for medical, social and therapeutic management.

The nature of frontotemporal dementia forces re-evaluation of the traditional assumption of dementia as an undifferentiated impairment of intellect. Dementia syndromes have highly distinct characteristics, reflecting the regional distribution of atrophy, allowing accurate differentiation between dementing conditions on clinical grounds. Frontotemporal dementia gives rise to characterstic behavioural changes, which include altered emotions, changes in social functioning, altered eating habits, and a spectrum of repetitive and compulsive behaviours. Characterisation of behavioural changes may increase understanding not only of frontotemporal dementia but also of other neuropsychiatric disorders in which parallel changes occur. Future clinical research is likely to shed further light on the functions of the frontotemporal lobes, while basic scientific research may lead to identification of additional genetic loci and to effective treatment strategies.

Clinical Implications and Limitations

APPENDIX