Frontotemporal dementia--Part I. History, prevalence, clinical forms

The authors report a comprehensive publication consisting of three parts going into the details of history, prevalence, clinical forms, differential diagnosis, genetics, molecular pathomechanism, pathology, clinical diagnosis and treatment of frontotemporal dementia (FTD). The first part of the present review deals with history, prevalence and clinical forms of FTD. The prototypical FTD with circumscribed atrophy was first described by Arnold Pick; Alois Alzheimer found the intraneural inclusions in the patients' brain. Later it was recognised that many patients had neither the atrophy nor the cellular changes, but genetic mutations have been identified. Frontotemporal dementia is a degenerative condition with unknown etiology in the frontal and anterior temporal lobes of the brain. It is a progressive neurobehavioral syndrome characterized by early decline in social interpersonal conduct, early impairment in the regulation of personal conduct, early emotional blunting, and early loss of insight. There are no reliable epidemiological studies on the prevalence of FTD, but it is well-accepted that FTD is a common cause for dementia before the age of 65 (it constitutes approximately five percent of all irreversible dementias). The nomenclature of the FTD has been confusing and continues to be. Three major clinical syndromes can be identified: 1 frontal variant FTD (dementia of frontal type) in which changes in social behavior and personality predominate, 2. in semantic dementia (progressive fluent aphasia) there is a breakdown in the conceptual database which underlies language production and comprehension, 3. in progressive nonfluent aphasia the phonologic and syntactic components of language are affected. The authors report two cases, which can point to clinical symptoms and forms, and mention the problems of the differential diagnosis and therapy.     

An investigation of moral judgement in frontotemporal dementia.

OBJECTIVE: To investigate the basis of disturbed moral judgment in patients with frontotemporal dementia (FTD). BACKGROUND: FTD is characterized by difficulty in modulating social behavior. Patients lack social propriety and may perform sociopathic acts. In addition, FTD patients often lack empathy for others. These findings suggest alterations in the nature of morality in patients with FTD. METHOD: We administered an inventory of moral knowledge and two moral dilemmas to 26 patients with the frontal variant of FTD, 26 patients with Alzheimer disease (AD), and 26 normal control subjects. The FTD patients met Consensus Criteria for FTD and had corroborative frontal abnormalities on functional neuroimaging. The FTD and AD patients were comparably impaired on dementia measures. RESULTS: All these groups showed the retention of knowledge for moral behavior and the ability to make "impersonal" moral judgments. In contrast, the FTD patients were impaired in their ability to make immediate, emotionally based moral judgments compared with the patients with AD and the normal control subjects. CONCLUSIONS: These findings are consistent with an attenuation of the automatic emotional identification with others that is part of the innate moral sense. Such a disturbance may result from neurodegenerative disease affecting the ventromedial frontal cortex.     

Accuracy of the clinical evaluation for frontotemporal dementia

BACKGROUND: Without a definitive clinical test, the early diagnosis of frontotemporal dementia (FTD) can be difficult. OBJECTIVE: To evaluate the accuracy of the clinical evaluation for FTD. DESIGN: Retrospective assessment of consensus criteria for FTD, neuropsychological measures, magnetic resonance images, and single-photon emission computed tomography/positron emission tomography (SPECT/PET) scans at baseline compared with a standard of subsequent clinical diagnosis after follow-up and reevaluation to year 2. SETTING: University hospital. PATIENTS: A total of 134 patients referred for clinical evaluation of suspected FTD. These patients had 1 or more core or supportive features of FTD in the absence of another etiology on initial assessment. MAIN OUTCOME MEASURES: Sensitivities, specificities, and predictive values of consensus criteria for FTD, magnetic resonance images, and SPECT/PET scans at initial assessment. RESULTS: The sensitivities and specificities for the diagnosis of FTD were 36.5% and 100.0% for consensus criteria, 63.5% and 70.4% for magnetic resonance images, and 90.5% and 74.6% for SPECT/PET scans, respectively. With a previous prevalence of nearly 50% for FTD, the positive predictive value was greatest for consensus criteria (100.0%), and the negative predictive value was greatest for SPECT/PET (89.8%). The initial neuropsychological results did not distinguish FTD, but the pattern of progression (worse naming and executive functions and preserved constructional ability) helped establish the diagnosis at year 2. CONCLUSIONS: Consensus criteria for FTD and neuropsychological measures lacked sensitivity for FTD; however, neuroimaging, particularly functional brain studies, greatly increased the sensitivity of detecting FTD. The clinical diagnosis of FTD needs to combine neuropsychiatric features with SPECT or PET findings while following the changes on neuropsychological tests.     

Acquired extroversion associated with bitemporal variant of frontotemporal dementia

Frontotemporal dementia (FTD) is characterized by alterations in personality. The nature of the personality changes depend on the localization of the pathology. The authors present three patients with acquired extroversion who met criteria for FTD. All three patients exhibited predominant bilateral temporal involvement as determined with functional neuroimaging. Possible mechanisms for acquired extroversion in bitemporal FTD include bilateral amygdalar damage with decreased interpersonal fear or sense of threat, orbitofrontal-ventromedial damage with social disinhibition, and relative sparing of dorsolateral frontal and anterior cingulate regions with preserved interpersonal agency. FTD can be a vehicle for unraveling the basis of personality characteristics such as the introversion/extroversion dimension.     

Social cognition in frontotemporal dementia and Huntington's disease

Frontotemporal dementia (FTD) and Huntington's disease (HD) are degenerative disorders, with predominant involvement, respectively of frontal neocortex and striatum. Both conditions give rise to altered social conduct and breakdown in interpersonal relationships, although the factors underlying these changes remain poorly defined. The study used tests of theory of mind (interpretation of cartoons and stories and judgement of preference based on eye gaze) to explore the ability of patients with FTD and HD to interpret social situations and ascribe mental states to others. Performance in the FTD group was severely impaired on all tasks, regardless of whether the test condition required attribution of a mental state. The HD group showed a milder impairment in cartoon and story interpretation, and normal preference judgements. Qualitative differences in performance were demonstrated between groups. FTD patients made more concrete, literal interpretations, whereas HD patients were more likely to misconstrue situations. The findings are interpreted as demonstrating impaired theory of mind in FTD, as one component of widespread executive deficits. In HD the evidence does not suggest a fundamental loss of theory of mind, but rather a tendency to draw faulty inferences from social situations. It is concluded that social breakdown in FTD and HD may have a different underlying basis and that the frontal neocortex and striatum have distinct contributions to social behaviour.     

Frontotemporal dementia

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.     

Clinical aspects of frontotemporal dementia

Frontotemporal neurodegeneration can cause three typical clinical syndromes: frontotemporal dementia (FTD), primary progressive aphasia (PPA) and semantic dementia (SD). In the present paper we review these syndromes, highlighting FTD. Four case examples are presented. At the early stage of FTD changes of personality and social conduct are prominent, whereas cognitive functions are relatively well preserved. Since the usual dementia tests are not sufficiently sensitive to disclose non-cognitive symptoms, clinical diagnosis as well as differentiation from non-organic psychiatric disorders can be difficult. Detailed history, thorough clinical examination, and neuropsychological testing are required to establish the diagnosis. EEG and functional brain imaging may be helpful. The choice of therapeutic options for FTD is extremely limited. Medications may be used to treat neuropsychiatric symptoms. There is little experience with non-pharmacologic behaviour modification and milieu treatment approaches. The problems that FTD imposes on caregivers are dissimilar to those arising from Alzheimer's disease. Families receive little or no support so that early nursing home admission of patients is common.     

The scale for emotional blunting in patients with frontotemporal dementia

Emotional blunting may underlie many of the behavioral features of frontotemporal dementia (FTD). The Scale for Emotional Blunting (SEB) was evaluated in 12 patients with early FTD, 12 patients with Alzheimer's disease (AD), and 12 normal controls. There were overall group differences on the SEB, and the FTD patients had greater emotional blunting than the AD patients. The SEB had good inter-rater reliability and a sensitivity of 92%, and a specificity of 83.5% for FTD. These findings suggest that the SEB may be a good instrument for the early detection and quantification of emotional blunting in patient with FTD.     

The Scale for Emotional Blunting in Patients with Frontotemporal Dementia

Emotional blunting may underlie many of the behavioral features of frontotemporal dementia (FTD). The Scale for Emotional Blunting (SEB) was evaluated in 12 patients with early FTD, 12 patients with Alzheimer's disease (AD), and 12 normal controls. There were overall group differences on the SEB, and the FTD patients had greater emotional blunting than the AD patients. The SEB had good inter-rater reliability and a sensitivity of 92%, and a specificity of 83.5% for FTD. These findings suggest that the SEB may be a good instrument for the early detection and quantification of emotional blunting in patient with FTD.     

Neural correlates of the mini-SEA (Social cognition and Emotional Assessment) in behavioral variant frontotemporal dementia

Although Frontotemporal Dementia (FTD) is the second most common form of dementia after Alzheimer’s disease, its diagnosis remains particularly challenging today. This is particularly true for the behavioral variant (bvFTD), the most common phenotype of FTD, which is characterised by dramatic changes in personal and social conduct. Novel clinical cognitive tests have been recently proposed to diagnose and assess these patients. Among them, the mini-SEA (Social cognition & Emotional Assessment) has shown promising results. This quick clinical tool evaluates emotion recognition and theory of mind deficits, both recognized as hallmark features of bvFTD. In this study, we investigated the neural correlates of the mini-SEA in twenty bvFTD patients, using single photon emission computed tomography (SPECT) and focusing on the mPFC. Results showed that detection of faux pas during a theory of mind evaluation was related to rostral mPFC perfusion (BA 10) while recognition of emotion involved more dorsal regions within the mPFC (BA 9). As significant and early dysfunction of the mPFC has been extensively described in bvFTD, this study supports the use of the mini-SEA in evaluation and diagnosis purposes in bvFTD.     

Similar early clinical presentations in familial and non-familial frontotemporal dementia

BACKGROUND: It is unclear whether there are early clinical features that can distinguish between patients with familial and non-familial frontotemporal dementia (FTD). OBJECTIVE: To compare the clinical features of FTD cases who have tau gene mutations with those of cases with a family history of FTD but no tau gene mutation, and with sporadic cases with neither feature. METHODS AND RESULTS: Comparisons of the behavioural, cognitive, and motor features in 32 FTD patients (five positive for tau gene mutations, nine familial but tau negative, and 18 tau negative sporadic) showed that age of onset and duration to diagnosis did not differ between the groups. Apathy was not observed in tau mutation positive cases, and dysexecutive signs were more frequent in familial tau mutation negative cases. Memory deficits and behavioural changes were common in all groups. CONCLUSIONS: In comparison with other neurodegenerative conditions such as Alzheimer's disease and Parkinson's disease, neither tau gene mutations nor strong familial associations confer earlier disease susceptibility.     

Frontotemporal dementia: An attempt at clinical characteristics.

The clinical recognition of frontotemporal dementia (FTD) depends on its differentiation from Alzheimer's disease (AD). From 212 patients primarily diagnosed as probable AD, 24 cases with mild dementia, absence of disturbances the presence of which would have prevented a full neuropsychological assessment, and brain CT with detailed visualization of hippocampus atrophy were chosen. On the basis of neuropsychological examination the patients were divided into two groups: 11 cases with predominant deficit in frontal system tasks (FTD group) and 13 cases with changes in cognitive functions typical of AD (AD group). Age at onset, duration, behavioral changes, psychotic symptoms, depression, speech disorders, neurologic deficit and hippocampal atrophy were analyzed in both groups. Statistically significant differences for behavioral disturbances and hippocampal atrophy were found. Early behavioral changes and lack of early hippocampal atrophy on CT may be useful features for differentiating between FTD and AD, especially when SPECT is not available.     

Different TMS patterns of intracortical inhibition in early onset Alzheimer dementia and frontotemporal dementia.

OBJECTIVE: To investigate putative changes in cortical excitability of patients affected by early-onset mild dementia by means of transcranial magnetic stimulation (TMS) and to verify whether a peculiar neurophysiological profile may contribute to characterise Alzheimer's disease (AD) vs frontotemporal dementia (FTD). METHODS: Motor threshold and intracortical inhibition (ICI) and facilitation (ICF) after paired-pulse TMS (inter-stimulus intervals from 1 to 20 ms) were studied in two groups of early-onset demented patients with a neuropsychological profile suggestive of AD (n = 12) and FTD (n = 8). Twelve age-matched healthy subjects were considered as control group. In both patient groups, recordings were performed before and after a single oral dose of 4 mg galantamine. RESULTS: No significant difference in motor threshold was observed among the three studied groups. On the contrary, early-onset AD showed a significant reduction of ICI compared to control group, no changes were detected in FTD patients. No significant changes in ICF were found between both patient groups and healthy subjects. The acute administration of galantamine reversed the modified ICI in AD group. CONCLUSIONS: The differential pattern of ICI exhibited by early-onset AD vs FTD in the early stage of disease may represent a non-invasive, reproducible electrophysiological tool, which may contribute to early differential diagnosis and, possibly, to monitor therapeutic effectiveness. SIGNIFICANCE: The present results support the possibility that subtle, early modifications in intracortical circuitry features AD, but not FTD patients.     

Functional neuroimaging and presenting psychiatric features in frontotemporal dementia

BACKGROUND: Frontotemporal dementia (FTD) is a behavioural syndrome caused by degeneration of the frontal and anterior temporal lobes. Behavioural disturbances include psychiatric features. Whether patients with FTD present with psychiatric features varies with the initial neuroanatomical variability of FTD. OBJECTIVE: To identify presenting psychiatric changes not part of diagnostic criteria of FTD and contrast them with the degree of hemispheric asymmetry and frontal and temporal hypoperfusion on single photon emission computed tomography (SPECT) imaging. METHODS: 74 patients who met consensus criteria for FTD were evaluated at a two year follow up. All had brain SPECT on initial presentation. Results of an FTD psychiatric checklist were contrasted with ratings of regional hypoperfusion. RESULTS: The regions of predominant hypoperfusion did not correlate with differences on FTD demographic variables but were associated with presenting psychiatric features. Dysthymia and anxiety were associated with right temporal hypoperfusion. "Moria" or frivolous behaviour also occurred with temporal lobe changes, especially on the right. The only significant frontal lobe feature was the presence of a peculiar physical bearing in association with right frontal hypoperfusion. CONCLUSIONS: Patients with FTD may present with psychiatric changes distinct from the behavioural diagnostic criteria for this disorder. Early temporal involvement is associated with frivolous behaviour and right temporal involvement is associated with emotional disturbances. In contrast, those with right frontal disease may present with alterations in non-verbal behaviour.     

The Frontal Systems Behavior Scale discriminates frontotemporal dementia from Alzheimer’s disease

Frontotemporal dementia (FTD) is characterized by pronounced changes in affect, self-regulation, and social conduct. These behaviors can predate significant cognitive changes and can be the most disabling aspect of FTD, yet there are few scales designed to assess such changes. The Frontal Systems Behavior Scale (FrSBe) is a 46-item behavior rating scale that is intended to measure behavior associated with damage to the frontal systems of the brain, with subscales measuring Apathy, Disinhibition, and Executive Dysfunction. Thirty-four FTD patients and 34 matched patients with dementia of the Alzheimer’s type (DAT) were compared on the FrSBe in the present study. Both groups displayed increases in apathy and dysexecutive behaviors after the onset of dementia, but the FTD group exhibited significantly greater change in disinhibition. A discriminant analysis with just two scores from the FrSBe and a memory test correctly classified 81% of the patients into diagnostic group.     

Clinical and pathological diagnosis of frontotemporal dementia: report of the Work Group on Frontotemporal Dementia and Pick's Disease.

An international group of clinical and basic scientists participated in the Frontotemporal Dementia and Pick's Disease Criteria Conference at the National Institutes of Health in Bethesda, Md, on July 7, 2000, to reassess clinical and neuropathological criteria for the diagnosis of frontotemporal dementia (FTD). Previous criteria for FTD have primarily been designed for research purposes. The goal of this meeting was to propose guidelines that would enable clinicians (particularly neurologists, psychiatrists, and neuropsychologists) to recognize patients with FTD and, if appropriate, to expedite their referral to a diagnostic center. In addition, recommendations for the neuropathological criteria of FTD were reviewed, relative to classical neuropathology and modern molecular biology.     

The advantages of frontotemporal degeneration drug development (part 2 of frontotemporal degeneration: The next therapeutic frontier)

Frontotemporal degeneration (FTD) encompasses a spectrum of related neurodegenerative disorders with behavioral, language, and motor phenotypes for which there are currently no effective therapies. This is the second of two articles that summarize the presentations and discussions that occurred at two symposia in 2011 sponsored by the Frontotemporal Degeneration Treatment Study Group, a collaborative group of academic and industry researchers that is devoted to developing treatments for FTD. This article discusses the current status of FTD clinical research that is relevant to the conduct of clinical trials, and why FTD research may be an attractive pathway for developing therapies for neurodegenerative disorders. The clinical and molecular features of FTD, including rapid disease progression and relatively pure molecular pathology, suggest that there are advantages to developing drugs for FTD as compared with other dementias. FTD qualifies as orphan indication, providing additional advantages for drug development. Two recent sets of consensus diagnostic criteria will facilitate the identification of patients with FTD, and a variety of neuropsychological, functional, and behavioral scales have been shown to be sensitive to disease progression. Moreover, quantitative neuroimaging measurements demonstrate progressive brain atrophy in FTD at rates that may surpass Alzheimer's disease. Finally, the similarities between FTD and other neurodegenerative diseases with drug development efforts already underway suggest that FTD researchers will be able to draw on this experience to create a road map for FTD drug development. We conclude that FTD research has reached sufficient maturity to pursue clinical development of specific FTD therapies.     

Changes in dietary or eating behavior in frontotemporal dementia versus Alzheimer's disease

BACKGROUND: Changes in dietary or eating behavior are common in dementia and may help distinguish between different dementing illnesses. Objective: To evaluate and characterize differences in dietary and eating behavior among patients with early frontotemporal dementia (FTD) versus Alzheimer's disease (AD). METHODS: This study administered the Food-Related Problems Questionnaire (FRPQ) to caregivers of 16 patients with FTD and 16 comparable patients with AD. The FRPQ was evaluated at initial presentation when patients presented for a diagnostic evaluation. RESULTS: Compared with the AD patients, the FTD patients had significantly more changes on the FRPQ. Subscale analysis indicated that the FTD patients showed impairment of observed satiety, improper taking of food, and inappropriate responses when food was not available. CONCLUSIONS: The use of food-related questionnaires, such as the FRPQ, can help distinguish FTD patients, early in their course, from those with AD and can further characterize the altered dietary and eating behavior.     

Which neuropsychiatric and behavioural features distinguish frontal and temporal variants of frontotemporal dementia from Alzheimer's disease?

OBJECTIVES: To investigate the prevalence of changes in mood, personality, and behaviour in frontotemporal dementia (FTD) and Alzheimer's disease (AD) and hence, which features reliably distinguish between them. To establish whether the frontal and temporal variants of FTD are characterised by different behavioural changes. METHODS: A questionnaire was designed to assess a wide range of neuropsychiatric changes; it incorporated features reported in previous studies of FTD and components of the neuropsychiatric inventory.(1) This was completed by 37 carers of patients with Alzheimer's disease (AD) and 33 patients with frontotemporal dementia (FTD), comprising 20 with temporal variant FTD (tv FTD) or semantic dementia and 13 with frontal variant FTD (fv FTD). An exploratory principal components factor analysis and discriminant function analysis was applied. RESULTS: Factor analysis showed four robust and meaningful symptom clusters: factor 1-stereotypic and eating behaviour; factor 2-executive dysfunction and self care; factor 3-mood changes; factor 4-loss of social awareness. Only stereotypic and altered eating behaviour and loss of social awareness reliably differentiated AD from FTD with no effect of disease severity. By contrast, executive dysfunction, poor self care, and restlessness showed a significant effect of disease severity only, with the more impaired patients scoring more highly. Changes in mood were found to be equally prevalent in the three patient groups. Analysis of individual symptoms showed increased rates of mental rigidity and depression in the patients with semantic dementia compared with those with fv FTD. Conversely, the latter group showed greater disinhibition. Discriminant function analysis correctly classified 71.4% overall and 86.5% of the patients with AD. CONCLUSIONS: This questionnaire disclosed striking differences between patients with FTD and AD, but only stereotypic behaviour, changes in eating preference, disinhibition, and features of poor social awareness reliably separated the groups. The patients with fv FTD and semantic dementia were behaviourally very similar, reflecting the involvement of a common network, the ventral frontal lobe, temporal pole, and amygdala. Dysexecutive symptoms and poor self care were found to be affected by the severity of the disease, reflecting perhaps spread to dorsolateral prefrontal areas relatively late in the course of both FTD and AD. This questionnaire may be of value in the diagnosis and the monitoring of therapies.     

Dementia with lewy bodies: findings from an international multicentre study

OBJECTIVES: To describe the baseline demographic, neuropsychiatric and neurological data of a large selected clinical sample of patients with dementia with Lewy Bodies (DLB) from an international multicentre trial with rivastigmine. To examine the usefulness of the Consensus Criteria for the diagnosis of DLB in different countries. METHODS: Seventeen centres from Spain, the UK and Italy recruited patients diagnosed clinically as probable DLB according to recent Consensus Criteria (McKeith et al., 1996). A standard clinical protocol including inclusion/exclusion criteria, collection of demographic and medical data, cognitive (Mini Mental State Examination: MMSE), motor (Unified Parkinson's Disease Rating Scale: UPDRS) and neuropsychiatric (Neuropsychiatric Inventory: NPI) examinations, was applied after obtaining informed consent. Data were summarised and compared across countries with uni- and multivariate analyses. RESULTS: One hundred and twenty patients were recruited: 56.7% males, mean (SD) age 73.9 (6.4) years, range 57 - 87 years. Sixty percent fulfilled all three core diagnostic features of DLB, and 40% only two ('parkinsonism' 92.4%, 'cognitive fluctuations' 89.1%, 'visual hallucinations' 77.3%). 'Systematised delusions' (46%) and 'repeated falls' (42%) were the most frequent supportive diagnostic features. There were no differences across countries in demographic, diagnostic or clinical features. Patients showed a wide range of psychopathology which was weakly correlated with cognitive impairment. Some mild extrapyramidal signs (EPS) were observed in most patients. CONCLUSIONS: The Consensus Criteria for DLB can be consistently applied across many different sites for multicentre studies. 'Parkinsonism' and 'cognitive fluctuations' as core features and 'systematised delusions' and 'repeated falls' as supportive features are the most frequent diagnostic clues. Neuropsychiatric disturbances, in particular apathy, delusions, hallucinations and anxiety, and mild symmetric EPS are frequent in DLB and are only related weakly to cognitive impairment.