The genetics of frontotemporal dementia

This article describes the remarkable progress that has been made over the past decade in identifying the genetic contribution to frontotemporal dementia. The clinical and neuropathologic features of frontotemporal dementia with parkinsonism linked to chromosome 17 and the nature of the mutations in the progranulin and microtubule-associated protein tau genes are emphasized.     

The diagnosis of frontotemporal dementia

Frontotemporal Lobar Degeneration (FTDL) is a neurodegenerative disorder which is predominantly characterized by changes in behaviour and loss of cognitive abilities. Three major clinical syndromes have been identified, Frontotemporal dementia (FTD), in which changes in social behaviour predominate, Semantic Dementia (SD) which is characterized by a loss of semantic knowledge, and Primary Progressive Aphasia (PPA), a disorder of phonological and syntactic aspects of language. All subtypes of FTLD have insiduous onset and stepwise progression. The present review lists the clinical symptoms and main findings of the three FTLD-subtypes, and discusses the difficulties of their diagnosis and differential diagnosis. The diagnosis of FTLD is based on the clinical consensus criteria of the Lund and Manchester groups, neuroradiological and neuropsychological investigations.     

Neuroimaging of frontotemporal dementia

With the development of neuroimaging, frontal lobe atrophy has been demonstrated with increased frequency, first with structural studies (computed tomography and magnetic resonance imaging), then with functional images (Single photon emission computed tomography and Positron emission tomography).     

Neuropathology of frontotemporal dementia

The syndrome of progressive fronto-temporal dementia represents the clinical expression of several pathological processes, mostly degenerative, preferentially involving the frontal and temporal lobes. These processes include dementia with Pick bodies, cortico-basal degeneration, dementia with ITSNU (Inclusions Tau and Synuclein Negative, Ubiquitinated), also known as dementia of motorneuron disease type, dementia with basophilic inclusion bodies, and dementia lacking specific histopathology, and in addition all variants linked to mutations in the tau gene, located in chromosome 17. The term "Pick complex" encompasses these processes and their clinical manifestations, which in addition to fronto-temporal dementia include primary progressive aphasia and apraxic-motor syndromes. The pathologic processes are better discriminated by histopathology than distribution of atrophy, but the latter is the main determinant of the clinical presentation.     

The diagnosis and course of frontotemporal dementia

The course of frontotemporal dementia (FTD) is examined in a prospective, incipient clinical cohort. Three hundred nineteen patients were followed yearly for an average of 3.6 years. The relative frequencies at presentation were Behavioral variety (FTD-bv) 37.6%, Primary Progressive Aphasia (PPA) 31.6%, possible PPA 10.6%, Corticobasal Syndrome (CBDS) and Progressive Supranuclear Palsy (PSP) 8.1%, Semantic Dementia (SD) 6.6%, and possible FTD 5.3%. The age of onset was significantly lower in the FTD-bv and SD groups than in the rest, but survival and sex distribution was similar in all groups. The evolution is characterized by the appearance of additional FTD syndromes in two-thirds of the patients. A significant association of SD with FTD-bv and CBDS/PSP with PPA was found. The Frontal Behavioral Inventory was highly sensitive and specific for FTD-bv. Visuospatial function was preserved except in CBDS/PSP. The clinical diagnosis showed a positive predictive value of 87% against autopsy in 67 patients. Multiple syndromes increase the likelihood of FTD pathology. In conclusion, the clinical associations follow the tau-negative and tau-positive pathologic dichotomy to some extent, but there is too much overlap to consider the clinical groups or their associations separate diseases.     

Neuroimaging in frontotemporal dementia

Abstract

The term frontotemporal dementia (FTD) refers to a group of neurodegenerative disorders that are associated with atrophy of the frontal and temporal lobes, and present clinically with impairments of behaviour or language. Three main subtypes are described, behavioural variant FTD (bvFTD) and two subtypes of the language presentation (known as primary progressive aphasia or PPA) called semantic variant of PPA and non-fluent variant of PPA. Most imaging studies of FTD have used volumetric T1 magnetic resonance imaging (MRI) or positron emissions tomography imaging to identify patterns of grey matter atrophy or hypometabolism in these different subtypes, but more recently newer imaging techniques have been used to help define abnormalities in structural connectivity (white matter tract integrity using diffusion tensor imaging), functional connectivity (resting state networks using resting state functional MRI) and perfusion (using arterial spin labelling perfusion MRI) in FTD. These techniques have the potential to improve the differential diagnosis of FTD from other disorders and to provide more informative imaging signatures of FTD syndromes.     

The tau gene locus and frontotemporal dementia

Frontotemporal lobar degeneration (FTLD) has become an increasingly recognised form of dementia. It has been demonstrated that a proportion of cases of FTLD result from mutations in the tau gene on chromosome 17. A pathological hallmark in the brains from patients with tau mutations is an accumulation of insoluble tau within neurons and glia that is considered neurotoxic. However, there are reports of families with FTLD linked to the tau locus on chromosome 17 in which no mutations have been found, and these families lack any accumulation of insoluble tau. Recently, two new tau mutations have been described that also appear to cause disease in the absence of any tau accumulation. The role of the tau locus and tau accumulation in contributing to the neurodegenerative process in chromosome-17-linked families without mutations and in families with tau mutations without insoluble tau is discussed.     

Misdemeanor in frontotemporal dementia

The nature and prevalence of misdemeanor in patients with dementia due to frontotemporal lobar degeneration has been described in a few case reports and in two small U.S. studies. Our clinical impression suggests that antisocial and aggressive behaviour are relatively frequent in this patient population. The objective of the present study was to verify this observation. For this purpose we developed a standardized questionnaire on misdemeanor in Frontotemporal Dementia. Using this instrument caregivers of 30 patients with Frontotemporal Dementia (FTD), 11 patients with Semantic dementia (SD) and 33 patients with Alzheimer-type dementia (AD) were interviewed. The interview included questions about theft, burglary, damaging other peoples' belongings, verbal or physical offence, bodily harm, drug abuse and use of weapons. Questions about the frequency of criminal behaviour, the amount of damages and consequences if applicable completed the questionnaire. Misdemeanor was found in half of the patients with FTD (15 out of 30) and in 7 out of 11 patients with SD, but only in one out of 33 patients with AD. The most frequent type of inappropriate behaviour was theft (13 patients), particularly shoplifting. 8 patients with FTD, 1 patient with SD and 1 patient with AD entered someone else's house without permission. 10 patients with FTD and 3 patients with SD but none of the patients with AD had physically threatened spouses, relatives or strangers. In one case another person was hurt.     

Clinical features of frontotemporal dementia

What was once called Pick's disease has three major anatomic variants. With all three, frontotemporal brain is selectively injured whereas posterior cortical regions are spared. These three clinical patterns include a bifrontal, slightly asymmetric subtype with more involvement of the right frontotemporal region called frontotemporal dementia or the frontal variant of FTD (fvFTD), a temporal-predominant subtype called the temporal variant of FTD or semantic dementia (SD), and a left frontal-predominant subtype called progressive nonfluent aphasia (PNFA). The three anatomic groups help to classify distinctive clinical syndromes with unique features. Careful study of these subtypes of frontotemporal dementia, using combinations of new quantitative neuroimaging, behavioral and physiological measures are yielding important information about the functioning of the brain's frontal and temporal regions. As we come to better understand the biologic basis for the three FTD clinical syndromes, new classification schemas may emerge, but our current clinical criteria serve as a strong guide to the diagnosis and separation of FTD from Alzheimer disease and other dementias.     

Clinical concept of frontotemporal dementia

The clinical concept of frontotemporal dementia is reviewed by discussing its relationships to several related concepts. These include dementia of the frontal lobe type, slowly progressive aphasia without dementia or primary progressive aphasia, semantic dementia and frontotemporal lobar degeneration. A number of examples of confusion in the terminology are also examined.     

The right temporal lobe variant of frontotemporal dementia

The right temporal variant of frontotemporal lobar degeneration (Rtv-FTLD) is a focal degenerative condition affecting predominantly the right temporal lobe. The aim of this study was to further characterize the profile of cognitive impairment and the neuroanatomical basis of Rtv-FTLD patients without behavioural disturbances. A group of three patients with this syndrome had a detailed neuropsychological assessment, along with Voxel-Based Morphometry (VBM) of their brain to determine location of cortical atrophy. VBM analyses showed a pattern of atrophy that was predominant in the right hemisphere and concerned primarily the right anterior temporal lobe region. Patients carried out a test of famous people in which their ability to recognize, name and provide semantic information about famous persons from their faces, their voices and their names was investigated. They all showed a severe defect in recognizing, naming and identifying famous people irrespective of modality. Therefore, their inability to recognize famous people resulted from a multimodal defect (semantic). These results highlight the semantic nature of the defect, and suggest that the anterior right temporal lobe may have a prominent role in processing person-based semantic knowledge. This study helps in further understanding the neuropsychological profile of patients with Rtv-FTLD.     

Clinical manifestation of frontotemporal dementia

Frontotemporal dementia is a degenerative disease, usually of presenile onset, frequently with positive family history, whose main clinical features are early social and personal behavioral disturbances, cognitive defects mainly in attention, language and executive functions, personality disorders and blunt, unconcerned and subdepressive affect. Anatomic and functional neuroimaging shows atrophy and functional defects in anterior brain regions, and the EEG is persistently normal. Although frontotemporal dementia has been confounded with Alzheimer's disease for long time, it can be identified on clinical grounds in order to perform new therapeutic trials.     

Medical management of frontotemporal dementia

There are no Food and Drug Administration (FDA)-approved medications for the medical management of frontotemporal dementia and its related disorders, so all management recommendations are necessarily off-label and borrowed from experience with Alzheimer's disease, psychiatric disease, and related medical illnesses. Six areas of pharmacotherapeutic consideration are prevention (primary and secondary), intellectual decline, behavioral disorders (such as depression, anxiety, and psychosis), sleep disorders, frequently associated disorders (including motor neuron disease), and abrupt decline. In addition to pharmacotherapy, important lifestyle issues confronting the clinician include driving cessation, securing any weapons maintained at home, assisted living, and caregiver burnout.     

Two cases of frontotemporal dementia

Frontotemporal dementias represent the third most common cause of primer degenerative dementias next to Alzheimer's disease and Lewy body disease. Frontotemporal dementia constitutes 10-20% of all praesenilis dementias. The authors present the results of the 10 years' clinical, neuropsychological, neuropathological examinations and brain imaging with the examples of two cases. At the early stage of frontotemporal dementia changes of personality and social conduct are prominent, whereas cognitive functions are relatively well preserved. The usual dementia tests are not sufficiently sensitive to disclose non-cognitive symptoms. Clinical diagnosis as well as differentiation from functional psychiatric disorders can be difficult. Brain imaging present the frontal and the anterior temporal lobe atrophy and selective hypometabolism in these areas. The typical onset is between at the age 50 and 65 years. It is very rare under the age of 30. The symptoms of two patients started at the age of 42-44. The first diagnosis was post traumatic stress disorder. Later stereotyped behaviour, mental rigidity, hyperorality, irritability, progressive reduction of speech and vegetative dysfunctions appeared. Besides the affecting of the irresistibly worsening symptoms and the medical care requiring strength and inventiveness, the authentic informing of the relatives is also a challenge. The caregivers have special relationship with the patients and their relatives.     

Clinical subtypes of frontotemporal dementia

Three distinctive clinical presentations can occur in frontotemporal dementia (FTD): disinhibited, apathetic and stereotypic subtypes. Each one shows a specific pattern of clinical, neuropsychological and neuroimaging findings, besides manifesting the core features of this form of dementia. We report three clinical cases, each one an example of a subtype of FTD, that were evaluated by neuropsychological and neuroimaging methods. Even the reported cases being a prototype of a specific subgroup, they can share some features with the others subtypes. According to this, patients with predominantly disinhibited or stereotypic behavior can also show apathy, in much the same way as predominantly apathetic or disinhibited patients can manifest stereotypic ritualistic behavior. The final stage of FTD is generally dominated by apathetic behavior.