Frontotemporal dementia

doi:10.1016/S1474-4422(05)70223-4

The Lancet Neurology

Volume 4, Issue 11, November 2005, Pages 771-780

https://doi.org/10.1016/S1474-4422(05)70223-4 Get rights and content

Summary

Frontotemporal dementia (FTD) is a focal clinical syndrome characterised by profound changes in personality and social conduct and associated with circumscribed degeneration of the prefrontal and anterior temporal cortex. Onset is typically in the middle years of life and survival is about 8 years. The presence of microtubule-associated-protein-tau-based pathological features in some patients and the discovery, in some familial cases, of mutations in the tau gene links FTD to other forms of tauopathy, such as progressive supranuclear palsy and corticobasal degeneration. However, more than half of all patients with FTD, including some with a strong family history, show no apparent abnormality in the tau gene or protein, indicating pathological and aetiological heterogeneity. FTD provides a challenge both for clinical management and for theoretical understanding of its neurobiological substrate.

Introduction

Frontotemporal dementia (FTD) is the most common of a group of clinical syndromes associated with circumscribed degeneration of the prefrontal and anterior temporal lobes (figure 1) and non-Alzheimer disease type pathology, which has been called frontotemporal lobar degeneration (FTLD). Behavioural changes are the presenting feature and dominate the clinical picture throughout the disease course.1, 2, 3, 4, 5, 6 Qualitative changes in language and cognitive impairments in executive function also occur. The absence of early neurological signs and findings of focal abnormalities in the frontotemporal lobes on neuroimaging, contribute to the clinical diagnosis (table).

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Terminology and clinical criteria

Use of the term FTD is not consistent. The term was introduced by workers in Lund (Sweden) and Manchester (UK) to refer specifically to the progressive behavioural syndrome.⁷ The term—which superseded labels such as frontal-lobe dementia and dementia of frontal type—drew attention to the fact that the behavioural disorder is invariably associated with atrophy of both frontal and anterior temporal lobes. Some patients also develop motor-neuron disease (MND),8, 9 a syndrome designated FTD-MND.⁹

Neuropathological characteristics

FTLD comprises atrophy of the prefrontal and anterior temporal neocortex. Differences in topographical distribution of atrophy determine the clinical syndromes of FTD, semantic dementia, and progressive aphasia (figure 2). Routine histology shows microvacuolation of the outer cortical laminae (microvacuolar-type features), due to large neuronal cell loss, or less commonly, transcortical gliosis.

Immunohistochemical analysis defines four major types of pathological features (figure 3). (1)

Epidemiology

Prevalence studies of FTD are currently limited. One study, based on 17 patients with clinically diagnosed FTD in the Cambridge area of the UK, reported a prevalence of 15 cases per 100 000 in people age 45–64 years.³⁴ A study from the Netherlands of 245 patients with FTD in the Zuid-Holland province (the Netherlands), reported much lower prevalence: 3·6 per 100 000 at age 50–59 years, rising to 9·4 per 100 000 at age 60–69 years, and falling to 3·8 per 100 000 at age 70–79 years.³⁵ The high

Demographics

A study of 245 patients from the Netherlands indicated an equal distribution of FTD among men and women (49% men, 51% women), similar to findings in the Manchester series of 210 patients (50% men, 50% women).4, 35 Age at onset is typically 45–65 years, with a mean in the 50s.4, 34, 35 However, pathologically confirmed and clinically presumed FTD has been recorded in individuals as young as 21 years and as old as 85 years.38, 39 Age at onset in familial and sporadic cases does not differ

Behavioural changes

Abnormal behaviour is, by definition, the dominant feature of FTD (table). Changes in affect and lack of concern and insight are strong discriminators between FTD, Alzheimer's disease, and vascular dementia.44, 45, 46 Patients lack appropriate basic emotions, such as sadness, and social emotions, such as sympathy and empathy. Other strong discriminators are the presence of repetitive, stereotyped behaviours (motor mannerisms, repeated use of a phrase or saying, complex behavioural routines)4, 22

Physical signs and investigations

FTD is commonly associated with an early absence of neurological signs (table).⁴ However, primitive reflexes and striatal signs of akinesia and rigidity emerge with progression of disease. Muscular wasting occurs in the few patients who develop MND. Myoclonus, cortico-spinal weakness and ataxia are absent.

On electroencephalogram, an absence of slow waves is commonly thought of as valuable in differentiating between FTD and Alzheimer's disease.3, 4, 82 However, this differentiating feature has

Genetics

In 1998, research showed that familial FTD, linked to a chromosome-17 locus, was associated with mutations in tau.89, 90 Since then, further families and mutations in tau have been identified (figure 4)—about 35 different mutations in around 100 families in total. The tau mutations can be classified according to whether their primary effect is exerted either at the level of the translated protein or on alternative RNA splicing of tau involving exon 10, or both.

Treatment

Pharmacological treatments for FTD are limited. Data from neurochemical studies of necropsied brains133, 134 and functional imaging using PET135, 136 have indicated abnormalities in serotonin metabolism, which have led to clinical trials of drugs with serotoninergic effects. The results of trials of modulation of serotonin in FTD using selective serotonin reuptake inhibitors have been equivocal.137, 138, 139, 140, 141 Interestingly, concentrations of serotonin and its metabolites are high in

Conclusions

Growth in interest in FTD in recent years indicates the rapid advances in the understanding of its pathological and molecular basis. Better understanding has, however, revealed increased complexity. FTD is associated with distinct histological features, different immunochemical characteristics, and different genetic bases. FTD presents a challenge for management. There is a need for better symptomatic treatment and better resources for care of these patients and their families.

Search strategy and selection criteria

References for this review were identified in March, 2005, by searches of the PubMed database between 1995 and 2005 using the term “frontotemporal dementia”. Articles were also identified from the authors' personal files. Only papers published in English were reviewed. Articles were selected on the basis of their originality and relevance.

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