Maturitas 79 (2014) 216–219

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Maturitas journal homepage: www.elsevier.com/locate/maturitas

Review

What is frontotemporal dementia? Alexander Kurz a,∗ , Carolin Kurz b , Kathryn Ellis c , Nicola T. Lautenschlager c,d a

Department of Psychiatry and Psychotherapy, Klinikum rechts der Isar, Technische Universität München, Munich, Germany Department of Neurology, Klinikum rechts der Isar, Technische Universität München, Munich, Germany c The Academic Unit for Psychiatry of Old Age, St. Vincent’s Health, Department of Psychiatry, University of Melbourne, Australia d School of Psychiatry and Clinical Neurosciences & WA Centre for Health and Ageing, University of Western Australia b

a r t i c l e

i n f o

Keywords: Frontotemporal dementia diagnosis neuropathology genetics management

a b s t r a c t Frontotemporal dementia (FTD) is the clinical manifestation of progressive nerve cell loss in the frontal and anterior temporal lobes. It represents the second most frequent form of early-onset dementia. The two major types of FTD are determined by the localisation of the underlying pathology. The behaviour variant is characterised by disinhibition, socially inappropriate manners, loss of empathy, blunting of affect and hyperorality. Key features of the language variant are either non-fluent effortful speech and grammatical errors or impaired word finding and loss of meaning of words and objects. Histopathological changes are characterised by the abnormal processing of proteins including microtubule associated protein Tau, transactive response DNA-binding protein, and tumour-associated protein fused in sarcoma. The familial forms of FTD are caused by mutations in 5 genes. The diagnosis of FTD rests on careful history and psychiatric, neuropsychological and neurological examination supported by laboratory assessments and brain imaging. The management requires an interdisciplinary approach involving the carer and using non-pharmacological approaches in the first line. Current antidementia drugs, including cholinesterase inhibitors and memantine, have no consistent positive effects in FTD. Behavioural symptoms may respond favourably to selective serotonergic antidepressants. Antipsychotic agents should be used with caution regarding motor, cardiovascular and mortality risks. © 2014 Published by Elsevier Ireland Ltd.

Contents 1. 2. 3. 4. 5. 6.

Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Historical outline . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Functions of the frontal and temporal lobes . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Clinical pictures and diagnosis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Neuropathology and genetics . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Management . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Contributors . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Competing interest . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Funding . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Ethical approval . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

1. Introduction Frontotemporal dementia (FTD) refers to a cluster of syndromes which result from degeneration of the frontal and temporal lobes. Two major clinical forms of FTD are commonly distinguished, a

∗ Corresponding author. Tel.: +49 89 41 40 4275; fax: +49 89 41 40 4923. E-mail address: [email protected] (A. Kurz). http://dx.doi.org/10.1016/j.maturitas.2014.07.001 0378-5122/© 2014 Published by Elsevier Ireland Ltd.

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behavioural type and a language type. The latter is subdivided into non-fluent variant and semantic variant primary progressive aphasia [1]. The initial presentations of the three syndromes reflect the different localisation of the underlying brain changes. However, upon progression convergence occurs indicating that eventually the frontal and temporal lobes are diffusely involved [2]. In a substantial fraction of cases movement disorders develop which shows that FTD is closely linked to extrapyramidal and motor neuron diseases [3]. FTD is the second most frequent form of presenile

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dementia following dementia in Alzheimer’s disease [4] with a prevalence of 15–22 per 100,000 in the age group between 45 and 65 years [5]. Diagnosis of FTD is demanding because behaviour and language changes are usually the first symptoms while memory or other cognitive impairment may be absent. Also, clinical management is challenging because currently no specific pharmacological or non-pharmacological treatments are available. The focus of clinical management is on the interdisciplinary management of behavioural changes and on carer support. 2. Historical outline Arnold Pick was the first to describe aphasic and apraxic syndromes resulting from focal atrophy of the frontal and temporal lobes [6]. Upon histopathological examination of such cases Alois Alzheimer found inflated neurons (Pick cells) and peculiar intraneuronal inclusions (Pick bodies) [7]. Georg Stertz provided a comprehensive account of the clinical symptoms of frontotemporal atrophy which is remarkably close to present-day descriptions [8]. The label ‘Pick’s disease’ was assigned to frontotemporal atrophy by Onari and Hugo Spatz [9]. The familial form of frontotemporal lobar degenerations with an autosomal dominant mode of transmission was observed by Torsten Sjögren [10]. The first insight into the molecular pathology of frontotemporal degenerations was the finding that Pick bodies contained the microtubule-associated protein Tau [11]. In 1994 research groups from Sweden and the UK coined the term ‘frontotemporal dementia’ and distinguished a non-specific and a Pick-type of histological changes [12]. These histological alterations were later also found in progressive aphasia [13]. In recent years there has been rapid progress regarding the molecular pathology and genetics of FTD, which has not as yet paralleled by significant advances in treatment. 3. Functions of the frontal and temporal lobes The frontal lobes, which include the prefrontal cortex (PFC) and the motor regions, comprise approximately 30% of the cortical surface of the human brain [14] and are involved in higher order cognitive abilities such as planning, decision making, reward regulation, social cognition and language processing, in addition to initiating and directing physical movement [15]. The PFC is linked with all areas of the neocortex and has connections to limbic and subcortical structures. The dorsolateral region of the PFC is the seat of executive functions such as working memory, cognitive flexibility, planning, attention, goal formation, goal-directed behaviour and reasoning [16]. Damage to this region results in executive

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dysfunction, which becomes manifest when performing most higher level cognitive functions. The ventrolateral PFC is closely connected to the temporal lobe [17]. The fronto-temporal networks, which include Broca’s area in the inferior frontal gyrus and Wernicke’s area in the superior temporal gyrus, are not only critical to language processing [18] but also to the top-down control of behaviour [19]. Damage to these networks is associated with difficulty in comprehension and formulation of language as well as deficits in behaviour inhibition [20]. The functions of the ventromedial PFC range from emotional regulation, cognition focussed on the ‘self’ as an entity and social cognition to episodic and semantic memory. Damage to this region leads to impairment in decision making, diminished emotional responsivity, reduced shame and guilt, and poorly regulated anger and frustration, although knowledge regarding social conventions and moral rules may be preserved [21]. The motor cortex sits anterior to the central sulcus, with the primary motor cortex comprising a strip within the precentral gyrus. The primary motor cortex directs voluntary movements [22], whereas the premotor cortex is responsible for motor intentions, postural fixation and stabilisation. Damage to the motor areas results in loss of fine motor control and motor strength, spasticity, akinesia, limb apraxia, axial rigidity and increase in falls [23]. The temporal lobe represents the laterobasal part of the cortex. The medial temporal lobe comprises a system of anatomically related structures which are essential for episodic memory, including the hippocampal region, perirhinal entorhinal and parahippocampal cortices [24]. The anterior temporal lobe is connected to the inferior frontal region and with the motor speech output systems. These networks subserve receptive and expressive language processing, semantic memory and social concepts [25]. Left-sided lesions of the anterior temporal lobe are typically associated with semantic deficit and impaired comprehension. Right-sided damage results in abnormal social behaviour such as violence and theft, poor personal hygiene, impulsiveness, irritability, social ineptness, lack of empathy and disinhibition as well as stereotyped and repetitive behaviours. 4. Clinical pictures and diagnosis Degeneration of the frontal and temporal lobes leads to three characteristic patterns of symptoms which are determined by localisation of the brain lesions (Table 1). Symptom onset is usually before the age of 65 years, survival from symptom onset varies between 6 and 11 years [2]. Motor neuron involvement is associated with significantly poorer prognosis [26]. Symmetrical

Table 1 Clinical features of bvFTD, nfvPPA and svPPA. Syndrome

Behaviour

Cognition

Functional ability

Motor symptoms

Behavioural variant fronto-temporal dementia

Disinhibition; embarrassing and socially inappropriate behaviours; apathy; loss of empathy; perseverative, stereotyped or ritualistic behaviours; hyperorality Preservation of personality and social skills until late

Executive deficits; impaired social cognition; relative sparing of memory and visuospatial functions; reduced verbal output; lack of disease insight Effortful, halting speech; agrammatism; impaired comprehension of complex sentences

Activities of daily living impaired by executive dysfunction, impaired persistence and impulse control

Signs of progressive supranuclear palsy syndrome, corticobasal syndrome or amyotrophic lateral sclerosis syndrome

Activities of daily living impaired by deficits of verbal communication

Loss of sympathy and empty, mental rigidity, ritualistic behaviour, dietary change

Fluent but circumlocutory speech; impaired word finding, naming and single word comprehension; loss of the meaning of words and objects

Activities of daily living impaired by semantic deficits and problems with planning

Signs of progressive supranuclear palsy syndrome, corticobasal syndrome or amyotrophic lateral sclerosis syndrome; apraxia of speech None until late

Non-fluent variant primary progressive aphasia

Semantic variant primary progressive aphasia

Adapted from [27–32].

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ventromedial frontal and anterior temporal atrophy causes the behavioural variant of FTD (bvFTD), which features behavioural changes, cognitive decline and significant impairment of everyday tasks [27]. Behavioural abnormalities include disinhibition, social inappropriateness, apathy, loss of empathy, jocularity, blunting of affect, repetitive behaviours and hyperorality. Echolalia reduced verbal output and mutism may occur at later stages. Cognitive deterioration involves fluency, mental flexibility, response inhibition, social cognition and disease insight. Memory and visuospatial abilities remain relatively spared [28]. Impairment of activities of daily living is due to executive dysfunction but may also be caused by difficulty starting, ordering and switching between tasks, controlling impulses and pursuing goals [29]. Symmetric atrophy of the inferior frontal and anterior temporal lobe results in the non-fluent variant of primary progressive aphasia (nfvPPA) which is characterised by word finding difficulty, effortful and halting speech, paraphasias, grammatical errors and limited comprehension of complex sentences [30]. Activities of daily living are compromised by impaired verbal communication. Aphasia may be accompanied by defective motor planning and programming of speech (apraxia of speech) [31]. Asymmetric (left > right) atrophy of the anterior and inferior temporal lobe is associated with the semantic variant of primary progressive aphasia (svPPA, semantic dementia). It is marked by fluent but circumlocutory speech, impaired word finding, naming and single-word comprehension, as well as loss of word and object meaning [32]. Behavioural changes include egocentricity and fixed daily routines including peculiar food preferences. Activities of daily living are compromised by semantic problems and by impaired planning and problem solving [33]. In each of the three syndromes concomitant movement abnormality may develop including features of progressive supranuclear palsy, corticobasal degeneration and amyotrophic lateral sclerosis, indicating that the pathology involves deep grey matter, brainstem and motor neurons [3]. The diagnosis of FTD requires careful history taking from an informant. Alternative causes of cognitive and functional decline such, as cerebrovascular disease, endocrine or metabolic disorders, must be excluded. A thorough neurological examination is essential to identify concomitant movement disorders. The neuropsychological evaluation should address memory, attention, language, visuoconstruction and executive functions. The diagnosis is supported by neuroimaging findings of frontotemporal atrophy, hypoperfusion or hypometabolism. Cerebrospinal fluid biomarkers (A␤1-42, Tau, phosphorylated Tau) may help to differentiate FTD and AD dementia. Differential diagnosis should also consider psychiatric disorders which may exhibit similar FTD symptoms, such as depression, bipolar disorder, schizophrenia and attention deficit hyperactivity disorder [34]. 5. Neuropathology and genetics The three FTD variants can be associated with four types of histopathology. They show neuronal loss and astrocytic gliosis as common features but differ with regard to the abnormal processing and deposition of specific proteins. Three major proteins are involved, namely microtubule-associated protein Tau, transactive response DNA-binding protein (TDP) and tumour-associated protein fused in sarcoma (FUS). The Tau type comprises classical Pick’s disease with inflated neurons and Pick bodies [35]. There are no consistent associations between the clinical syndromes and the molecular signatures [1] (Fig. 1). A family history of FTD is found in 30–50% of cases, with one third of pedigrees showing an autosomal dominant mode of transmission [36]. Mutations in five unrelated genes have been identified and cause most but not all of the familial FTD cases. These include the genes for microtubuleassociated protein Tau (MAPT), chromosome 9 open reading frame

Fig. 1. Relationships between clinical syndromes, abnormal proteins and altered genes (adapted from [1]). bvFTD, Behavioural-variant frontotemporal dementia; nfvPPA, Non-fluent variant primary progressive aphasia; svPPA, Semantic variant primary progressive aphasia; TDP, transactive DNA-binding protein, FUS, Tumourassociated protein fused in sarcoma; MAPT, Microtubule-associated protein Tau, GRN, Progranulin, Cporf72, Chromosome 9 open reading frame 72; VCP, Valosin containing protein, CHMP2B, Charged multivesicular body protein 2B.

72 (C9orf72), progranulin (GRN), charged multivesicular body protein 2B (CHMP2B) and valosin containing protein (VCP). MAPT mutations are associated with Tau-type pathology, whereas GRN, VCP and C9orf72 mutations lead to TDP-type histological changes. CHMP2B mutations are responsible for the fourth type of pathology with yet unidentified protein deposition. The role of the FUS gene in the aetiology of FTD is uncertain since most cases showing FUS-type pathology are sporadic (Fig. 1). Predictive testing for these mutations in asymptomatic individuals requires consultation with a geneticist and psychological counselling [37]. 6. Management Unfortunately no pharmacological compounds are currently available which alter the development or progression of FTD. Open label studies of cholinesterase inhibitors (ChEI) in FTD showed inconsistent or no benefits [38]. Adverse events of ChEI include reversible worsening of disinhibition or compulsiveness and increased risk of aspiration in individuals with additional motor neuron disease. The recent revision of the guidelines for clinical practice with anti-dementia drugs from the British Association for Psychopharmacology does not recommend the use of ChEI for FTD [39]. Trials with memantine in FTD were also unable to demonstrate any significant benefits. However, several reports indicate that ChEI and memantine are prescribed regularly for FTD in clinical practice [40]. There is some evidence that selective serotonin reuptake inhibitors (SSRI) may help with behavioural symptoms such as apathy, disinhibition, hyperorality, repetitive behaviours and sexually inappropriate behaviours [41]. Antipsychotics are often used in clinical practice for FTD to manage severe agitation, disinhibition and psychotic symptoms, especially when non-pharmacological strategies have failed or when there is an increased safety risk for patients or carers. Clinical benefits need to be weighed against the increased risk of extrapyramidal side effects, cerebrovascular events and mortality [42]. In light of the limited options regarding drug treatment, the focus of clinical management is on non-pharmacological strategies and carer support. Due to the prominent behavioural dysfunction the safety for patient and carer should be monitored regarding the areas of driving, financial management, dietary oversight, safety around the home, potential for criminal behaviour and suicide prevention [43]. It is common that carers experience significant caregiver burden. Therefore, establishing a therapeutic partnership between carer and the clinical team with identifying and addressing the individual stressors and needs of carers is crucial for an effective management plan [44]. Regarding non-pharmacological intervention various approaches such as skill-based compensation

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methods, environmental modifications to improve function, integration of carers in the rehabilitation process as well as support and activity groups have shown promising results [45]. Speech therapy can be helpful especially in the language variants [46]. Individually tailored exercise and physical therapy should be part of a management plan when parkinsonism and mobility problems are present [47]. Effective management of FTD is challenging and, if possible, should be planned using a multidisciplinary approach [48]. Contributors None. Competing interest The authors declare no conflict of interest. Funding The authors have received no funding for the article. Ethical approval Ethical approval was not required for this work. References [1] Sieben A, Van Langenhove T, Engelborghs S, et al. The genetics and neuropathology of frontotemporal lobar degeneration. Acta Neuropathol 2012;124:353–72. [2] Seltman R, Matthews B. Frontotemporal lobar degeneration: epidemiology, pathology, diagnosis and management. CNS Drugs 2012;26:841–70. [3] Rohan Z, Matej R. Current concepts in the classification and diagnosis of frontotemporal lobar degenerations. Arch Pathol Lab Med 2014;138:132–8. [4] Ratnavalli E, Brayne C, Dawson K, Hodges JR. The prevalence of frontotemporal dementia. Neurology 2002;58:1615–21. [5] Onyike CU, Diehl-Schmid J. The epidemiology of frontotemporal dementia. Int Rev Psychiatr 2013;25:130–7. [6] Pick A. Über einen weiteren Symptomenkomplex im Rahmen der Dementia senilis, bedingt durch umschriebene stärkere Hirnatrophie (gemischte Apraxie). Monatsschr Psychiatr 1906;19:97–108. [7] Alzheimer A. Über eigenartige Krankheitsfälle des späteren Alters. Z ges Neurol Psychiatr 1911:4. [8] Stertz G. Über die Picksche Atrophie. Z ges Neurol Psychiatr 1926;101:729–47. [9] Onari K, Spatz H. Anatomische Beiträge zur Lehre von der Pickschen umschribenen Großhirnrinden-Atrophie (“Picksche Kranheit”). Z ges Neurol Psychiatr 1926;101:470–511. [10] Sjögren. A genetic study of morbus Alzheimer and morbus Pick. Acta Psychiat Scand Suppl 1952;82:9–66. [11] Pollock NJ, Mirra SS, Binder LI, Hansen LA, Wood JG. Filamentous aggregates in Pick’s disease, progressive supranuclear palsy, and Alzheimer’s disease share antigenic determinants with microtubule-associated protein, Tau. Lancet 1986;328:1211. [12] Brun A, Englund B, Gustafson L. Clinical and neuropathological criteria for frontotemporal dementia. J Neurol Neurosurg Pschiatr 1994;57:416–8. [13] Mesulam MM. Slowly progressive aphasia without generalized dementia. Ann Neurol 1982;11:592–8. [14] Miller BL, Cummings JL. The human frontal lobes second edition: functions and disorders (Science and practice of neuropsychology). 2nd ed. New York: The Guilford Press; 2006. [15] Buchsbaum MS. Frontal Cortex Function. Am J Psychiatr 2004;161:2178–80. [16] Jurado MB, Rosselli M. The elusive nature of executive functions: a review of our current understanding. Neuropsychol Rev 2007;17:213–33. [17] Friederici AD. The brain basis of language processing: from structure to function. Physiol Rev 2011;91:1357–92. [18] Faw B. Pre-frontal executive committee for perception, working memory, attention, long-term memory, motor control, and thinking: a tutorial review. Conscious Cognit 2003;12:83–139.

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What is frontotemporal dementia?

Frontotemporal dementia (FTD) is the clinical manifestation of progressive nerve cell loss in the frontal and anterior temporal lobes. It represents t...
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