- Prevalence and age characteristics
- Clinical features
- Disordered behaviour
- Affective symptoms
- Other symptoms
- Dissolution of language
- Physical signs
- Comparison between FLD and Pick's disease
- Dementia in motor neurone disease
- Brain imaging
- Assessment of cognitive impairment
- Differential diagnosis
- Aetiology and pathogenesis
- Treatment and care
The medical classification of organic dementia is based on current knowledge and theories of aetiology, clinical picture, the pathological substrate, and the predominant location of brain damage. This article is concerned with dementia caused by a degenerative disease primarily affecting the frontal and temporal lobes called frontal-lobe dementia (1) or frontotemporal dementia (FTD). (2) The terminology should be viewed from a historical perspective. The relationship between localized cortical atrophy within the frontal and temporal lobes in dementia and symptoms of aphasia was first reported by Pick in a series of publications, starting in 1892. (3) The pathological account of this lobar degeneration by Alzheimer in 1911 described inflated, ‘ballooned' neurones (Pick cells) and argentophilic globes (Pick bodies), (4) and in the 1920s this clinicopathological entity was named Pick's disease. (5)
However, ‘pure' Pick's disease is rare, and in recent decades attention has been drawn to a much larger group of frontal-lobe dementias clinically similar to Pick's disease but lacking the pathological characteristics of Pick's disease and Alzheimer's disease. (6,7 and 8) The disease was named frontal-lobe degeneration of non-Alzheimer type (FLD)(6) to mark its dissimilarity to Alzheimer's disease. Alternative designations are ‘dementia lacking distinctive histology' (9) and ‘primary degenerative dementia without Alzheimer pathology'. (10) In 1994 the Lund–Manchester consensus delineated the clinical and neuropathological criteria for FTD, with Pick's disease, frontal lobe dementia, and motor neurone disease with dementia as the main constituents. (2) Other diseases, such as progressive non-fluent aphasia, (11) and FTD with parkinsonism linked to chromosome 17 (FTDP-17) are considered as belonging to the same clinicopathological spectrum. (12)
The cortical atrophy in Pick's disease is severe, circumscribed with knife-blade appearance, often asymmetrical, and involves the striatum and hippocampus. The degeneration involves all cortical laminae, with inflated neurones and Pick bodies, which are tau and ubiquitin positive. (13) The white-matter degeneration and atrophy are quite pronounced. Fronal lobe dementia (FLD) is characterized by mild to moderate atrophy which is most marked in the frontal convexity cortex, the anterior cingulate gyrus, and in about a third of the cases also in the anterior temporal cortex. Degenerative changes are restricted to the cortical layers 1, 2, and 3, and the histopathological changes are non-specific with neuronal loss and atrophy, microvacuolation, and astrocytic gliosis.
The posterior cingulate gyrus, hippocampus, and striatum are unremarkable but the substantia nigra sometimes shows moderate degeneration, although never as severe as in Parkinson's disease. (14) The frontal white matter often shows mild loss of myelin.(15) The parietal cortex and the posterior cingulate gyrus are comparatively spared in contrast with the pattern of degeneration in Alzheimer's disease with similar age at onset.(6) There are no neuronal inclusions or prions, plaques, tangles, or Lewy bodies and no amyloid in FLD. The brain pathology in motor neurone disease with dementia is similar to that described in FLD, but in addition there are ubiquitin-positive neuronal inclusions in the superficial laminae, for example in the frontotemporal cortex, in addition to anterior horn cell loss. (13,16)
Prevalence and age characteristics
Pick's disease as defined above is rare, with a prevalence of 1 to 2 per cent in post-mortem studies of dementia, (17) compared to a prevalence of 7.5 per cent of FLD and 40 to 50 per cent of Alzheimer's disease. (18) Little is known about the true prevalence and incidence of frontotemporal dementia (FTD). It might be responsible for as much as 20 per cent of all early onset dementia. (19) Most demographic data concern the grouping of FTD, not separating FLD and Pick's disease. The overall frequency of Pick's disease in a wider sense has been estimated at 24 to 60 per 100 000 in Minnesota and 30 to 60 in Switzerland. (20)
The estimated prevalence of FTD in the Netherlands is 10.7 per million between 50 and 60 years of age, and 28 between 60 and 70 years. (21) Pasquier et al.(22) diagnosed FTD in 4.8 per cent, and probable or possible Alzheimer's disease in 71.4 per cent of 1015 consecutive cases examined at the Memory Clinic in Lille, France. The marked geographic variation of the prevalence of FTD might be due to genetic and environmental factors, but it might also be influenced by differences in the diagnostic process. The prevalence of dementia with a mainly presenile clinical onset in motor neurone disease has been estimated at 2 to 6 per cent. (23)
The first clinical manifestations of frontotemporal dementia usually appear in the presenium, in some cases as early as 35 and seldom after 70 years of age. The mean age at onset in postmortem-verified frontal lobe dementia (FLD) cases is 56 ± 7.6 years with a mean duration of 8 ± 3.4 years (range 3–17 years). (18) The mean age of onset in Pick's disease is similar, 62 years, with a range of 45 to 80 years, and a mean survival of 9.8 years with a range of 4.8 to 21.2 years. (20) This large variation of the duration of FLD and Pick's disease is similar to that of early-onset Alzheimer's disease, which is 10.6 ± 3 years, with a range of 5 to 16 years. (18) The clinical onset of dementia in motor neurone disease is usually in the sixth decade and the mean duration is about 30 months. (24)
The Lund–Manchester consensus on clinical criteria for FTD is summarized in Table 1 (below).The early stage of FLD and Pick's disease is characterized by changes of personality and behaviour, affective symptoms, and a progressive reduction of expressive speech, revealing the dysfunction of frontotemporal brain structures. The clinical onset is insidious with slow progression without ictal events. Therefore the duration of the disease may easily be underestimated. The changes of personality and behaviour are mainly non-specific and easily misinterpreted as expressions of non-organic mental disease such as mood disorder, hypochondriasis, schizophrenia, or other psychotic reaction.
Other explanations of the patient's behaviour such as a reaction to problems in the family may also be suggested, especially by people lacking previous knowledge of the patient. Loss of insight concerning the mental changes and their consequences is an early and alarming manifestation of the disease. Although most patients deny any awareness of mental change or illness, several patients ask for medical xamination referring to symptoms such as anxiety, tiredness, and strange somatic complaints combined with bizarre hypochondriacal ideas. The hypochondriasis may sometimes be secondary to hallucinations or sensory distortion.
- insidious onset and gradual progression
- early decline in social interpersonal conduct
- early impairment in regulation of personal conduct
- early emotional blunting
- early loss of insight
- decline in personal hygiene and grooming mental rigidity and inflexibility
- distractibility and impersistence
- hyperorality and dietary change
- utilization behavior
- neuropsychology: impaired frontal lobe tests; no amnesia or perceptual deficits
- EEG: normal on conventional EEG despite clinically-evident dementia
- brain imaging: predominant frontal and/or anterior temporal abnormality
The early loss of personal and social awareness is seen as neglect of personal hygiene and grooming, and tactlessness and antisocial behaviour. The impaired control and modulation of emotions are seen as increased sentimentality, inadequate smiling, inappropriate joking, irritability, and acts of aggressiveness, leading to conflicts at home and at work. Craving for affection and sexual contact may be easily provoked, but usually expressions of sexual disinhibition are rather childish and innocent, and possible to divert. Impulse buying, shoplifting, indecency, and other disinhibited behaviour may, however, lead to rejection by the family and society. Such unpredictable and pseudopsychopathic behaviour imposes severe strain on the patient's family, leading in some cases to economic problems, divorce, and even suicide in the family. Complications of this type are uncommon in families with an Alzheimer patient.
Traffic accidents may also result from the patient's impaired regulation of conduct. Frontotemporal dementia patients tend to become inattentive and careless; although using the correct traffic lane they may neglect traffic lights, speed limits, and other regulations. The typical Alzheimer patient is more self-critical and anxiously aware of the difficulties in driving. Changes in drinking behaviour are sometimes reported. Patients with previous restricted alcohol consumption start to drink more frequently and in larger quantities than before. The alcohol is probably sometimes used to reduce anxiety and depressed mood. The pathological drinking behaviour, which may lead to misdiagnosis of alcohol-induced dementia, can often be controlled by a firm attitude from relatives.
The frontotemporal dementia patient becomes emotionally shallow and blunt, showing less concern about family and friends. The patient is described as egocentric, rigid, and lacking empathy. The early emotional changes may be difficult to differentiate from non-organic personality disorders and affective disorder. Mood changes towards euphoria, especially when associated with increased talkativeness and restlessness, may at first be mistaken for a hypomanic or manic state. Slowly developing apathy, in combination with sparse mimical movements and verbal aspontaneity, may be misdiagnosed as depression. During the depressive reactions, which are mostly of short duration, the patient may become agitated or dysphoric, and may dwell on suicidal thoughts. FTD patients are often diagnosed as depressed and treated with antidepressant medication during the early stage of the disease.
Early symptoms of dementia must be judged against information about the patient's premorbid personality, education, and social background. The vast majority of cases show normal premorbid personality although a few have previously manifested anxiety and restlessness. The emotional features in FTD do not seem primarily related to premorbid personality traits but rather to the distribution of brain pathology as shown at autopsy and brain imaging. (25)
A striking feature of frontotemporal dementia is the stereotyped and perseverative behaviour seen as wandering, clapping, humming, dancing, and hoarding of objects, as well as complex rituals involving washing and dressing. The intensity of such behaviour sometimes reaches psychotic intensity. Imitative behaviour seen as repetition of other people's gestures and utterances is frequent in FTD and occurs more often than in Alzheimer's disease.
Hallucinations and delusions are reported in about 20 per cent of FTD and early-onset Alzheimer's disease cases and even more frequently when the patients are followed closely from the easily stage of the disease. The psychotic symptoms in FTD are often bizarre and the combination with loss of insight, emotional blunting, restlessness, and stereotypy of speech and behaviour gives the impression of functional psychosis with schizophrenia as an early tentative diagnosis. (7,8 and 9) The psychotic symptoms in early-onset Alzheimer's disease seem more strongly related to the cognitive failure with memory failure, impaired recognition, and disorientation, and the degeneration of the temporoparietal association cortex.
The human counterpart of the Klüver–Bucy syndrome with elements such as blunted affect, hyperorality, and unrestrained sexuality has been reported in FLD and in Pick's disease. The hyperorality and changes of oral/dietary behaviour are seen as overeating, food fads, excessive smoking and alcohol consumption, and oral exploration of inanimate objects. Utilization behaviour, defined as an irresistible impulse to explore and use objects in the visual environmental, shows important similarity to the hypermetamorphosis and distractibility of the Klüver–Bucy syndrome especially when oral exploration is present. (26) The Klüver–Bucy syndrome in Alzheimer's disease is usually less complete than in FTD with less hypersexuality and utilization behaviour, supporting the suggestion that frontal as well as temporal lobe involvement is needed to produce the syndrome in humans.
Dissolution of language
A core feature of frontotemporal dementia is progressive impairment of expressive speech described as dissolution du langage or Sprachverödung. (27) Speech becomes aspontaneous with word-finding difficulties and frequent use of stereotyped comments and set phrases. During the early stage there may be a period of increased pressure of speech. The FTD patient may also loose his or her normal pitch of voice and speaks in an unmodulated inappropriately high tone. The language dysfunction is dominated by dynamic expressive failure rather than by a semantic receptive one, which is in agreement with damage in the frontal cortex especially premotor areas.
Echolalia is observed in about 50 per cent of FTD and Pick cases. (18) Finally the patients become mute which in combination with the amimia makes communication extremely difficult. The ability to understand information and instructions usually remains until comparatively late in the course of the disease, as does the ability to write. The handwriting may, however, change in magnitude, spelling, and speed of writing. These disturbances are unlike the temporoparietal type of dysgraphia and global dysphasia observed in Alzheimer's disease. The symptom constellation of palilalia (stereotypy of speech), echolalia, mutism, and amimia (PEMA syndrome of Guiraud) is typical of FTD and seldom found in Alzheimer's disease.
There are important similarities between the speech disorder of early frontotemporal dementia and the clinical spectrum of progressive non-fluent aphasia, (11) characterized by effortful speech production and relative preservation of memory and practical abilities. Dementia often develops later in the course, and the underlying degenerative process may be similar to that of FLD, with a predominant and early involvement of the speech-dominant hemisphere.
Few pathological somatic findings including neurological symptom are reported in FTD. Primitive reflexes such as grasp, snout, and sucking reflexes may appear comparatively early, while akinesia, rigidity, and tremor are late phenomena. Increased muscular tension is significantly more common in Alzheimer's disease, although it also occurs in FTD. (7) Recently the spectrum of dementing frontotemporal disorder has expanded to include the syndrome of the disinhibition–dementia –parkinsonism–amyotrophy complex, (28) also named FTDP-17. (29)
Generalized epileptic seizures may appear in FTD although less prevalent than in Alzheimer's disease, and myoclonic twitchings which are present in 50 per cent of early-onset Alzheimer's cases are uncommon in FTD. Urinary incontinence, which is reported early in about 50 per cent of FTD cases, is a comparatively late feature in uncomplicated early-onset Alzheimer's disease. This feature is also common in vascular dementia and late-onset Alzheimer's disease and seems related to frontobasal and anterior cingulate gyral damage.
FTD patients in general have low and labile blood pressure with a high prevalence (50 per cent) of orthostatic blood pressure drops and syncopal attacks. These symptoms are, however, also reported in early-onset Alzheimer's disease (40 per cent) and late in the course of vascular dementia (50 per cent). (30) The relationship between blood pressure changes and brain damage especially the white-matter changes in frontotemporal dementia are still unclear. (14)
Comparison between Frontal lobe dementia and Pick's disease
The clinical similarities between FLD and Pick's disease are important, in spite of differences in histopathology and distribution of brain pathology. Deterioration of personality and behaviour, expressive speech disorder, and gradual loss of mimical expression are found in both diseases as are an early normal EEG, incontinence, and low and labile blood pressure. Severe memory failure and confabulation are probably more prevalent in Pick's disease, while affective symptoms, especially depression, are more often reported in FLD. The analysis of larger patient materials and the use of functional brain imaging, and genetic and other biological markers will further elucidate the relationship between FLD and Pick's disease.
Dementia in motor neurone disease
The clinical picture of the dementia in motor neurone disease is similar to that in FLD with early changes of personality and behaviour, lack of insight, and signs of disinhibition such as restlessness, irritability, unrestrained sexuality, and hyperorality. (16,31) Speech becomes stereotyped and perseverative, later developing into mutism. Receptive speech function, orientation and practicable abilities remain relatively untouched by the degenerative process. Emotional changes such as euphoria and apathy may appear and the face becomes expressionless. The mental changes may appear early in motor neurone disease and even precede development of typical neurological features.
The EEG may be normal or only slightly pathological in FTD at a stage when dementia is strongly suspected or clinically evident, but it is usually pathological late in the course. This has been shown in FLD, Pick's disease, and motor neurone disease with dementia. (32) By contrast, EEG is almost always pathological in Alzheimer's disease even at an early stage. Quantitative EEG mapping and repeated recordings may strongly improve the differential diagnosis between FTD and Alzheimer's disease. (32)
Structural and functional brain imaging has strongly improved the recognition of frontal and frontotemporal degeneration in FTD. Cortical atrophy with more or less frontal focal accentuation is shown with CT and magnetic resonance imaging ( MRI). (9,33) MRI may show significantly more prevalent and severe periventricular hyperintense deep white-matter lesions in FTD patients than in matched normal controls. (34) The differential diagnosis from vascular dementia with frontal subcortical lesions, but lacking large cortical infarctions, may be difficult.
Brain imaging of metabolism and regional cerebral blood flow has radically improved recognition and differential diagnosis of dementing diseases. The frontotemporal regional cerebral blood flow abnormalities in FTD shown with xenon clearance technique, single-photon emission CT ( SPECT), and positron emission tomography (PET) contrast with the temporoparietal pathology in Alzheimer's disease. (35,36 and 37) The findings are not disease specific, but are also found in vascular brain damage, in Alzheimer's disease with marked frontal-lobe involvement, (38) and in progressive supranuclear palsy. The regional cerebral blood flow pathology in progressive aphasia is most pronounced in the left hemisphere. (11)
Assessment of cognitive impairment
The cognitive symptoms, which appear early in FTD, may be difficult to evaluate due to the patient's emotional and behavioural changes. Distractibility and slightly reduced recent memory are common findings and remote memory is also impaired although to a lesser extent than in Alzheimer's didease. The patients show significant impairment on ‘frontal-lobe' tests such as the Wisconsin card sorting test, word fluency test, and the Stroop and trail-making tests. The early test profile is characterized by slow verbal production and relatively intact visuospatial ability, reasoning, and memory, while intellectual and motor speed are reduced. (39) Early Alzheimer's disease usually shows a relatively preserved verbal ability and simultaneous impairment of reasoning ability, verbal and spatial memory dysfunction, dysphasia, and dyspraxia.(39,40) Difficulties in understanding instructions are found early only in a minority of FTD cases. Misspelling and dyscalculia are sometimes reported early in FTD.
Discrimination between FTD and Alzheimer's disease can be based on a short test-battery (verbal ability, visuospatial ability, and verbal memory), when used in the context of a neuropsychological evaluation of qualitative as well as quantitative aspects of test performance. (39,41) Using a screening instrument based on frontal release signs, awareness of social/ethical dilemma in a short story, and the number of preservation errors, FTD was classified correctly in 83 per cent, validated against clinical diagnosis. (42) The Mini-Mental State Examination (43) does not reflect the FTD patient's true competence because of influence of motivational and behavioural factors. (44)
The deterioration of personality and behaviour in FTD contrasts with the comparatively spared spatial orientation, receptive speech, and practical ability.
Differential diagnosis between FTD and Alzheimer's disease and other dementias is often possible using well-defined clinical criteria, neuropsychological testing, and brain imaging.
The clinical differences between FTD and Alzheimer's disease are often obvious at an early stage. The initial stages of FTD are dominated by emotional and personality changes, and consequently severe dyspraxia, memory failure, and spatial disorientation develop comparatively late with the relative sparing of the temporoparietal occipital cortical areas. In contrast, early-onset Alzheimer's disease is characterized by memory failure, dyspraxia, dysgnosia, and impaired sense of locality, whereas habitual personality traits, social competence, and insight are better preserved in agreement with the consistent pattern of cortical involvement. A minority of Alzheimer's cases, about 5 per cent, show a marked frontal-lobe involvement at an early stage and consequently also present a frontal-lobe clinical pattern in addition to the temporoparietal symptoms. (38)
The PEMA syndrome with stereotypy of speech (palilalia), echolalia, late mutism, and amimia is typical of FTD and rare in Alzheimer's disease. Certain neurological features may also contribute to the differentiation between the two, for example generalized epileptic seizures, myoclonus, and logoclonia are more prevalent in Alzheimer's disease. Moreover, EEG may remain normal in FTD cases with evident signs of dementia while EEG in Alzheimer's disease is almost always pathological. The Klüver–Bucy syndrome in Alzheimer's disease is usually less complete than in FTD with less hypersexuality and utilization behaviour, supporting the suggestion that frontal as well as temporal lobe involvement is needed to produce the syndrome in humans. Imitating behaviour, seen as echolalia and repetition of other people's gestures, is more prevalent in FTD than in Alzheimer's disease.
Vascular dementia with frontal emphasis may be caused by selective incomplete white-matter infarction, Binswanger's disease, and frontal and strategic thalamic infarctions. The frontal-lobe dysfunction caused by vascular lesions may closely mimic the course of FTD, when developing gradually without dramatic onset on fluctuations. (38,45)
The clinical distinction between FTD and Huntington's disease may be difficult when personality changes and psychotic features dominate, and when the neurological characteristics of Huntington's disease are less obvious or appear late in the course. Brain imaging showing striatal involvement and genetic analysis may contribute to the diagnosis.
Progressive supranuclear palsy and the rare progressive subcortical gliosis may also show a frontal-lobe clinical and imaging pathology. (46,47) Corticobasal degeneration may also present with a dementia of frontal-lobe type in addition to the typical asymmetric akinetic–rigid dystonic syndrome. These three diseases have grown increasingly important because of studies suggesting a linkage to chromosome 17. (12)
Dementia of the frontal and frontal subcortical type is also found in Creutzfeldt–Jakob disease, (38) in the AIDS dementia complex, and in general paresis.
The Lund–Manchester consensus (Table 1) is recommended as guidelines for clinical recognition of FTD. Guidelines for diagnosis of dementia, such as the NINCDS-ADRDA criteria for diagnosis of Alzheimer's disease, (48) may easily lead to the inclusion of FTD and Pick cases in the Alzheimer's group. DSM-IV presents Pick's disease as ‘One of the pathologically distinct etiologies among the heterogeneous group of dementing processes that are associated with frontotemporal brain atrophy. The specific diagnosis of a frontal-lobe dementia such as Pick's disease is usually established at autopsy with a pathological finding of characteristic intraneuronal argentophilic Pick inclusion bodies'. Moreover, the frontal-lobe dementias are ‘characterized clinically by changes in personality early in course, deterioration of social skills, emotional blunting, behavioural inhibition, and prominent language abnormalities. Difficulties with memory, apraxia and other features of dementia usually follow later in the course.' (1)
ICD-10 (49) describes ‘Dementia in Pick's disease' as ‘a progressive dementia, commencing in middle life (usually between 50 to 60 years) characterized by slowly progressive changes of character and social deterioration, followed by impairment of intellect memory and language functions with apathy, euphoria and (occasionally) extrapyramidal phenomena. The social and behavioural manifestations often precede frank memory impairment.' ICD-10 points out that Pick's disease is a non-Alzheimer degenerative brain disease, but it does not introduce the concepts of frontal-lobe dementia or FTD.
Aetiology and pathogenesis
The aetiology and pathogenesis of FLD and Pick's disease and the relationship between the diseases are unknown. About 40 to 50 per cent of patients with FLD have a history of similar disorder in a first-degree relative. (18,21) A Swedish pedigree with FTD in 10 out of 21 family members in three generations has been described. (50) Typical FLD was confirmed post-mortem in three cases. There is at present no solid proof of an autosomal dominant inheritance in the majority of studies of Pick's disease. A linkage to chromosome 17q21–22 has been found in 13 families with an autosomal dominantly inherited FTDP-17. (12) The FTDP-17 locus has been mapped to a region where the tau gene also lies. Pathological tau proteins may therefore be of pathophysiological significance in FTD, Alzheimer's disease, and other degenerative dementias. (29) Another possible gene has been indicated by mapping to chromosome 3 in a Danish family with dementia of frontal-lobe type. (51) Conflicting results exist concerning the relation of FLD to chromosome 19 and the ApoE allele pattern has been reported. (52) A prion aetiology has been excluded in FLD and also in FTDP-17. (29) The pattern of degeneration in FTD may be related to selective vulnerability of different brain regions to factors such as oxidative stress, environmental toxins, neurotransmittor dysfunction, and certain mutations.
FTD patients tend to develop low and orthostatic blood pressure, but the pathological changes do not indicate an association with anoxic or ischaemic damage.
There are few systematic neurochemical studies of FTD. No alternations in cholinergic markers have been found in Pick's disease, FLD, or motor neurone disease with dementia. (9,10,20) Nigrostriatal dopamine decrease and reduction of serotonin receptors and substance P levels in substantia nigra and frontal cortex have been found in Pick's disease. (53,54) Cerebrospinal fluid analysis has shown reduced somatostatin levels both in FTD and Alzheimer's disease, while delta-sleep-inducing peptide was significantly reduced in Alzheimer's disease but not in FTD, and the corticotrophin-releasing factor was significantly reduced in FTD but not in Alzheimer's disease. (55) Pathological tau proteins have been found in the frontotemporal cortex in FTD despite the absence of neurofibrillary lesions. (56)
Treatment and care
FTD is a heterogeneous group, but with important clinical features and robably also aetiological factors in common. Early diagnosis is a prerequisite for adequate treatment and care of the patient and for information and support for the family and other carers involved.
There is presently no specific pharmacological treatment for the underlying degenerative disease, but symptomatic treatment may be effective for the patient's anxiety, depressed mood, restlessness, aggressiveness, hallucinations, and delusions. However, the FTD patient may be extremely sensitive to psychotropic medication with disturbing side-effects and paradoxical reactions. The important consequence of the diagnostic process is the possibility of understanding and explaining the patient's strange behaviour, and to differentiate from early-onset Alzheimer's disease for which pharmacological treatment is now available. FTD patients are often restless and show stereotyped movements with a strong need for physical activity, which, as well as the comparatively preserved memory, and spatial and practicable abilities, should be channelled in a meaningful way, rather than restricted.
A well-structured programme for daily activities, considering the patient's premorbid personality and interests, may be rewarding and minimize the need for pharmacological treatment. Daily activities should be carried out together with someone well aware of the patient's difficulties to plan, initiate, and control emotions and behaviour. The long duration of the dementing process and the awareness of hereditary factors have a strong impact on family members, who need information, support, and training through many critical years. Prevailing psychotic features and unpredictable aggressive behaviour should managed by special psychiatric or psychogeriatric services for diagnosis, treatment, living, and care.
1. American Psychiatric Association (1994). Diagnostic and statistical manual of mental disorders (4th edn). American Psychiatric Association, Washington, DC.
2. Brun, A., Englund, E., Gustafson, L., et al. (1994). Consensus statement—clinical and neuropathological criteria for frontotemporal dementia. Journal of Neurology, Neurosurgery and Psychiatry 57, 416–18.
3. Pick, A. (1892). Über die Beziehungen der senilen Hirnatrophie zur Aphasie. Prager Medizinische Wochenschrift, 17, 165–7.
4. Alzheimer, A. (1911). Über eigenartige Krankheitsfälle des späteren Alters. Zeitschrift für die Gesamte Neurologie und Psychiatrie 4, 356–85.
5. Schneider, C. (1927). Über Picksche Krankheit. Monatschrift für Psychiatrie und Neurologie, 65, 230–75.
6. Brun, A. (1987). Frontal lobe degeneration of non-Alzheimer type. I. Neuropathology. Archives of Gerontology and Geriatrics, 6, 193–207.
7. Gustafson, L. (1987). Frontal lobe degeneration of non-Alzheimer type. II. Clinical picture and differential diagnosis. Archives of Gerontology and Geriatrics, 6, 209–23.
8. Neary, D., Snowden, J.S., Northern, B., and Goulding, P.J. (1988). Dementia of frontal lobe type. Journal of Neurology, Neurosurgery and Psychiatry, 51, 353–61.
9. Knopman, D.S., Mastri, A.R., Frey, W.H., Sung, J.H., and Rustan, T. (1990). Dementia lacking distinctive histologic features. A common non-Alzheimer degenerative dementia. Neurology, 40, 251–6.
10. Clark, A.W., White, C.L. III, and Manz, J.H. (1986). Primary degenerative dementia without Alzheimer pathology. Canadian Journal of Neurological Sciences, 13, 462–70.
11. Neary, D., Snowden, J.S., and Mann, D.M.A. (1993). The clinical pathological correlates of lobar atrophy. Dementia, 4, 154–9.
12. Hutton, M., Lendon, C.L., Rizzu, P., et al. (1998). Association of missence and 5'-splice-site mutation in tau with the inherited dementia FTDP-17. Nature, 393, 702–5.
13. Delacourte, A., Robitaille, Y., Sergeant, N., et al. (1996). Specific pathological tau protein varaints characterize Pick's disease. Journal of Neuropathology and Experimental Neurology, 55, 159–68.
14. Brun, A. (1993). Frontal lobe degeneration of non-Alzheimer type, revisited. I. Neuropathology. Archives of Gerontology and Geriatrics, 4, 126–31.
15. Englund, E. and Brun, A. (1987). Frontal lobe degeneration of non-Alzheimer type. II. White matter changes. Archives of Gerontology and Geriatrics, 6, 235–43.
16. Mitsuyama, Y. (1993). Presenile dementia with motor neuron disease. Dementia, 4, 137–42.
17. Jellinger, K., Danielczyk, W., Fischer, P., and Gabriel, E. (1990). Clinicopathological analysis of dementia disorders in the elderly. Journal of the Neurological Sciences, 95, 239–58.
18. Gustafson, L. (1993). Clinical picture of frontal lobe degeneration of non-Alzheimer type. Dementia, 4, 143–8.
19. Neary, D. (1990). Dementia of frontal lobe type. Journal of the American Geriatrics Society. 38, 71–2.
20. Markesbery, W.R. (1998). Pick's disease. In Neuropathology of dementing disorders (ed. W.R. Markesbery), pp. 142–57. Arnold, London.
21. Stevens, M., Van Duijn, C.M., Kamphorts, W., et al. (1998). Familial aggregation in fronto-temporal dementia, Neurology, 50, 1541–5.
22. Pasquier, F., Lebert, F., and Amouyel, P. (1995). In Les démences frontotemporales, épidémiologie (ed F. Pasquier and F. Lebert), pp. 23–9. Masson, Paris.
23. Lopez, O.L., Becker, J.T., and De Kosky, S.T. (1994). Dementia accompanying motor neuron disease. Dementia, 5, 42–7.
24. Salazar, A.M., Masters, C.L., Gajdusek, D.C., and Gibbs, C.J. (1983). Syndromes of amyotrophic lateral sclerosis and dementia: relation to transmissible Creutzfeldt–Jakob's disease. Annual Neurology, 14, 17–26.
25. Lebert, F., Pasquier, F., and Petit, H. (1995). Personality traits and frontal lobe dementia. International Journal of Geriatric Psychiatry, 10, 1046–9.
26. Cummings, J.L. and Duchen, L.W. (1981). Klüver–Bucy syndrome in Pick's disease: clinical and pathological correlations. Neurology, 31, 1415–22.
27. Van Mansfelt, J. (1954). Pick's disease. A syndrome of lobar, cerebral atrophy; its clinico-anatomical and histopathological types. Unpublished Thesis, Enschede, Utrecht.
28. Lynch, T., Sano, M., Marder, K.S., et al. (1994). Clinical characteristics of a family with chromosome 17-linked disinhibition–dementia– parkinsonism–amyotrophy complex. Neurology, 44, 1878–84.
29. Foster, N.L., Wilhelmsen, K., Sima, A.A.F., Jones, M.Z., D'Amato, C., and Gildman, S. (1997). Frontotemporal dementia and parkinsonism linked to chromosome 17: a consensus. Annals of Neurology, 41, 706–15.
30. Passant, U., Warkentin, S., and Gustafson, L. (1997). Orthostatic hypotension and low blood pressure in organic dementia: a study of prevalence and related clinical characteristics. International Journal of Geriatric Psychiatry, 12, 395–403.
31. Neary, D., Snowden, J.S., and Mann, D.M.A. (1990). Frontal lobe dementia and motor neuron disease. Journal of Neurology, Neurosurgery and Psychiatry, 53, 23–32.
32. Rosén, I., Gustafson, L., and Risberg, J. (1993). Multichannel EEG frequency analysis and somatosensory-evoked potentials in patients with different types of organic dementia. Dementia, 4, 43–9.
33. Förstl, H., Hentschel, F., Besthorn, C., et al. (1994). Frontal und temporal beginnende Hirnatrophie. Nervenarzt, 65, 611–18.
34. Larsson, E.-M., Passant, U., Sundgren, P.C., et al. Magnetic resonance imaging and histopathology in dementia, clinically of frontotemporal type. Dementia and Geriatric Cognitive Disorders, in press.
35. Risberg, J. and Gustafson, L. (1997). Regional cerebral blood flow measurements in the clinical evaluation of demented patients. Dementia and Geriatric Cognitive Disorders, 8, 92–7.
36. Miller, B.L., Laurent, I., Li, J., et al. (1995). Atrophy-corrected cerebral blood flow in frontotemporal dementia. In Facts and research in geriatrics (ed. A. Bruno, F. Chollet, and B.J. Vellas), pp. 93–103. Springer, New York.
37. Ludolph, A.C., Langen, K.J., Regard, M., et al. (1992). Frontal lobe function in amyotrophic lateral sclerosis: an neuropatholgoical and positron emission tomography study. Acta Neurologica Scandinavica, 82, 81–9.
38. Brun, A. and Gustafson, L. (1991). Psychopathology and frontal lobe involvement in organic dementia. In Alzheimer's disease: basic mechanisms, diagnosis and therapeutic strategies (ed. K. Iqbal, D.R.C. McLachlan, B. Winblad, and H.M. Wisnewski), pp. 27–33. Wiley, Chichester.
39. Johanson, A. and Hagberg, B. (1989). Psychometric characteristics in patients with frontal lobe degeneration of non-Alzheimer type. Archives of Gerontology and Geriatrics, 8, 29–137.
40. Frisoni, G.B., Pizzolato, G., Geroldi, C., Rossato, A., Bianchetti, A., and Trabuceti, M. (1995). Dementia of the frontal type: neuropsychological and (99Tc)-HMPAO SPET features. Journal of Geriatric Psychiatry and Neurology, 8, 42–8.
41. Elfgren, C., Brun, A., Gustafson, L., et al. (1994). Neuropsychological tests as discriminators between dementia of Alzheimer type and frontotemporal dementia. International Journal of Geriatric Psychiatry, 9, 635–42.
42. Gregory, C.A., Orrell, M., Sahakian, B., and Hodges, J.R. (1997). Can frontotemporal dementia and Alzheimer's disease be differentiated using a brief battery of tests? International Journal of Geriatric Psychiatry, 12, 375–83.
43. Folstein, M.F., Folstein, S.E., and McHugh, P.R. (1975). ‘Mini-Mental State'. A practical method for grading the cognitive state of patients for the clinician. Journal of Psychiatric Research, 12, 189–98.
44. Pasquier, F. (1996). Neuropsychological features and cognitive assessment in frontotemporal dementia. In Frontotemporal dementia (ed. D. Pasquier, F. Lebert, and P. Scheltens), pp. 46–69. ICG, The Netherlands.
45. Benson, D.F. (1993). Progressive frontal dysfunction. Dementia, 4, 149–53.
46. Esmonde, T., Giles, E., Xuereb, J., and Hodges, J. (1996). Progressive supranuclear palsy presenting with dynamic aphasia. Journal of Neurology, Neurosurgery and Psychiatry, 60, 403–10.
47. d'Antona, R., Baron, J.C., Samson, Y., et al. (1985). Subcortical dementia. Brain, 108, 785–99.
48. McKhann, G., Drachmann, D.A., Folstein, M., Katzmann, R., Price, D., and Stadlan, E.M. (1984). Clinical diagnosis of Alzheimer's disease: report of the NINCDS-ADRDA Work Group. Neurology, 34, 939–44.
49. World Health Organization (1992). The ICD-10 classification of mental and behavioural disorders. Clinical descriptions and diagnostic guidelines. World Health Organization, Geneva.
50. Passant, U., Gustafson, L., and Brun, A. (1993). Spectrum of frontal lobe dementia in a Swedish Family. Dementia, 4, 160–2.
51. Brown, J., Asworth, A., Gydesen, S., et al. (1995). Familial non-specific dementia maps to chromosome 3. Human Molecular Genetics, 4, 1625–8.
52. Pickering-Brown, S.M., Siddons, M., Mann, D.M.A., Owen, F., Neary, D., and Snowden, J.S. (1995). Apolipoprotein E allelic frequencies in patients with lobar atrophy. Neuroscience Letters, 188, 205–7.
53. Kanazawa, I., Kwak, S., Sasaki, H., et al. (1988). Studies on neurotransmitter markers of the basal ganglia in Pick's disease, with special reference to dopamine reduction. Journal of the Neurological Sciences, 83, 63–74.
54. Francis, P.T., Holmes, C., Webster, M-T., Stratmann, G.C., Procter, A.W., and Bowen, D.M. (1993). Preliminary neurochemical findings in non-Alzheimer dementia due to lobar atrophy. Dementia, 4, 172–7.
55. Edvinsson, L., Minthon, L., Ekman, R., and Gustafson, L. (1993). Neuropeptides in cerebrospinal fluid of patients with Alzheimer's disease and dementia in frontotemporal lobe degeneration. Dementia, 4, 167–71.
56. Vermersch, P., David, J.P., Frigard, B., et al. (1995). Cortical mapping of Alzheimer pathology in brains of aged non-demented subjects. Neuropsychopharmacology and Biological Psychiatry, 19, 1035–47.