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An Evidence-Based Review of the Psychopathology of Frontotemporal Dementia: A Report of the ANPA Committee on Research

2008; American Psychiatric Association Publishing; Volume: 20; Issue: 2 Linguagem: Inglês

10.1176/jnp.2008.20.2.130

1545-7222

Mario F. Mendez, Edward C. Lauterbach, Shirlene Sampson,

Alzheimer's disease research and treatments

Back to table of contents Previous article Next article SPECIALFull AccessAn Evidence-Based Review of the Psychopathology of Frontotemporal Dementia: A Report of the ANPA Committee on ResearchMario F. Mendez M.D., Ph.D.Edward C. Lauterbach M.D.Shirlene M. Sampson M.D.Mario F. Mendez M.D., Ph.D.Edward C. Lauterbach M.D.Shirlene M. Sampson M.D.Published Online:1 Apr 2008AboutSectionsPDF/EPUB ToolsAdd to favoritesDownload CitationsTrack Citations ShareShare onFacebookTwitterLinked InEmail F rontotemporal dementia is a neurodegenerative disorder characterized by the development of neuropsychiatric symptoms. These behavioral changes most commonly emerge when patients are in their fifties, 1 – 3 although the age of onset for frontotemporal dementia can range from the third to the ninth decade. 1 , 4 Frontotemporal dementia is one of the most common dementias of early onset. Among dementia patients with an age of onset less than 65 years old, frontotemporal dementia accounts for 20%–50% of all cases. 3 , 5 – 7 Frontotemporal dementia results from frontotemporal lobar degeneration. On gross pathology, there is circumscribed and often asymmetric lobar atrophy of the frontal lobes, adjacent anterior temporal regions, or both. On microscopic examination, there are microvacuoles and gliosis with or without inclusion bodies. 8 – 10 The prior term of "Pick's disease" referred to frontotemporal lobar degeneration with argentophilic, tau-positive intranuclear inclusions (Pick bodies). 11 , 12 Most patients with frontotemporal dementia and related syndromes, however, lack tau-positive inclusions and may have tau-negative, ubiquitin-positive inclusions with TDP-43 protein. 13 , 14 Some patients have additional involvement of other areas of the nervous system resulting in parkinsonism, motor neuron disease, or corticobasal degeneration. 4 Clinically, frontotemporal lobar degenerations reflect the initial distribution of neuropathology and present as several clinical syndromes depending on their predominant presenting symptoms. 9 , 12 Neuropsychiatric behavioral changes define the clinical syndrome of frontotemporal dementia, which is the most common frontotemporal lobar degeneration. 1 Among 61 patients with pathologically proven frontotemporal lobar degeneration, 90% presented with behavioral disturbances consistent with frontotemporal dementia, including personality and social conduct disorder. 8 This review focuses on the clinical syndrome of frontotemporal dementia. Other frontotemporal lobar degeneration syndromes, such as primary or progressive nonfluent aphasia, semantic dementia, or several movement disorders, are discussed only where they overlap with frontotemporal dementia ( Figure 1 ). 15 , 16FIGURE 1. Schematic Showing the Clinical Variants of Frontotemporal Lobar Degeneration (FTLD) This report specifically reviews the noncognitive neuropsychiatric features of frontotemporal dementia. In contrast to Alzheimer's disease, during the first few years after onset, behavioral symptoms in frontotemporal dementia are more prominent and disruptive than memory or other cognitive deficits. 2 , 5 , 17 – 22 In the absence of diagnostic biomarkers, the clinical diagnosis depends on recognizing core, or necessary, behavioral features of frontotemporal dementia. 23 Yet, physicians frequently fail to recognize psychopathology as symptoms and misdiagnose these patients as having a primary psychiatric diagnosis. 23 – 26 For this and other reasons, this review of the psychopathology of frontotemporal dementia aims to comprehensively review the literature and characterize the psychopathology of this disorder. METHODWe searched MEDLINE using the strategy: "frontotemporal dementia" OR "Pick's disease" OR "frontotemporal lobar degeneration" OR "frontal dementia" OR "frontal lobe dementia." We also searched PsychInfo with the same strategy. The searches reviewed clinical papers on frontotemporal lobar degeneration if they included frontotemporal dementia or syndromes that overlapped with this disorder. The searches were complete to the end of April 2007 and were not limited to the English language. We also reviewed pertinent sections of selected books and references in our files.We characterized our reports by type of behavior divided up into changes in personality, anxiety and compulsions, mood disorders, and psychosis. Using all pertinent studies, we summarized the evidence to date. This review focused on the clinical syndrome of frontotemporal dementia and not on the pathological diagnoses. Furthermore, we focused on personality, behavioral, and psychiatric manifestations rather than on memory, language, perceptual, executive, or other cognitive deficits. This review did not include most single case studies except where detailed studies were limited, as in the psychosis section. Although there were earlier behavioral descriptions, publications on the neuropsychiatric features of frontotemporal dementia did not appear in significant numbers until the early 1990s. The early case reports and papers culminated in the Clinical Consensus Criteria for FTD, 15 published in 1998, which, in effect, summarized the core and supportive behavioral features of frontotemporal dementia up to that date ( Table 1 ). There was still little systematic study of personality and behavior, however, until 2001 when Mychack et al. 27 outlined the need and potential methodologies for investigating the nature of personality and behavior in frontotemporal dementia. The subsequent years yielded a great many papers on the subject, employing a variety of measures and terminology ( Table 2 ). Much of this literature has struggled with the challenge of comparing frontotemporal dementia, a dementia whose criteria emphasize behavioral symptoms, with Alzheimer's disease, a dementia whose criteria emphasizes cognitive deficits. TABLE 1. Consensus Criteria for Frontotemporal DementiaTABLE 1. Consensus Criteria for Frontotemporal DementiaEnlarge tableTABLE 2. TerminologyTABLE 2. TerminologyEnlarge tableRESULTSWe obtained 504 citations from MEDLINE and PsychInfo. These citations were then reviewed for studies shedding light specifically on the noncognitive neuropsychiatric aspects of frontotemporal dementia and, with exceptions, not involving just a case report or a genetic kindred. We reviewed and included 192 articles as potentially relevant. After review, the studies were grouped into 10 behavioral categories, additional behaviors with limited literature, and treatment. The findings are summarized below.Neuropsychiatric SymptomsApathy-Abulia Apathy-abulia is the most common initial symptom of frontotemporal dementia and is present in the majority of patients as the disease progresses. 23 , 28 – 33 Among frontotemporal dementia patients, clinicians often mistake as depression the presence of apathy, or the lack of feeling or emotion, and abulia, or the loss of volition and initiative. 28 , 34 Miller et al. 21 initially reported two frontotemporal dementia patients with frontal hypoperfusion on single photon emission tomography (SPECT) who presented with "pseudodepression" attributable to apathy. The following year, Gustafson et al. 35 reviewed several hundred cases of dementias in a longitudinal prospective clinicopathological study. They identified 30 patients with frontotemporal dementia, all of whom developed apathy with amimia and mutism late in their course. In a careful retrospective review of nine patients with frontotemporal dementia, Galante et al. 36 confirmed that these patients became inactive with decreased behavioral initiation and spontaneity, loss of interest, and, ultimately, frank apathy. Eventually, several large series of outpatients, ranging from 50 to 74 patients, confirmed the presence of apathy-abulia in 62% to 89% of patients with frontotemporal dementia. 23 , 37 – 39 Comparative studies with the Neuropsychiatric Inventory show that apathy-abulia is more common, severe, and pervasive in frontotemporal dementia than in Alzheimer's disease. Investigators developed the Neuropsychiatric Inventory to evaluate patients with Alzheimer's disease on 12 behavioral features including delusions, hallucinations, agitation, dysphoria, anxiety, apathy, irritability, euphoria, disinhibition, aberrant motor behavior, night-time behavior disturbances, and appetite and eating abnormalities. 40 Levy et al. 41 first used the Neuropsychiatric Inventory to compare 22 patients with frontotemporal dementia with 30 patients with Alzheimer's disease matched for dementia severity and found higher levels of apathy among those with frontotemporal dementia. Subsequently, Neuropsychiatric Inventory investigations reported apathy as one of the most common symptoms of frontotemporal dementia, present in approximately 95% of patients, 42 , 43 more severe and frequent in frontotemporal dementia compared to Alzheimer's disease, 44 – 46 and present in both mild and moderate-severe frontotemporal dementia. 47 Furthermore, in a discriminant analysis, Perri et al. 48 combined the Neuropsychiatric Inventory with neuropsychological testing to correctly assign 73.7% of 19 frontotemporal dementia patients and 94.7% of 39 Alzheimer's disease patients based on better Rey's Figure A Copy, worse performance on the Initial Letter Verbal Fluency Test (FAS), and greater Neuropsychiatric Inventory apathy subscale scores among the frontotemporal dementia patients. Additional scales and measures have further defined the frequency and nature of apathy-abulia in frontotemporal dementia. Bozeat et al. 49 reported apathy among 75% of 33 frontotemporal dementia patients using their own neuropsychiatric caregiver questionnaire. Kertesz et al. 50 confirmed that apathy and aspontaneity distinguish frontotemporal dementia from non-frontotemporal dementia groups using the Frontal Behavior Inventory, 51 – 52 an instrument that they felt would be more sensitive to frontotemporal dementia than the Neuropsychiatric Inventory. 50 Others found significantly more apathy and negative symptoms in frontotemporal dementia than in Alzheimer's disease, dementia with Lewy bodies, or mixed dementias. 53 , 54 Rankin and colleagues 55 used the Interpersonal Adjectives Scales, a self-report and caregiver questionnaire, to measure personality change in 16 patients with frontal variant frontotemporal dementia (fvFTD), with greater frontal volume loss, and 13 with temporal variant frontotemporal dementia (tvFTD), with greater anterior temporal volume loss, and in a comparison group of 16 patients with Alzheimer's disease. This, and a subsequent study with the Interpersonal Adjectives Scales, documented that fvFTD patients became aloof and introverted, unassured and socially submissive, and less dominant and assertive. 55 , 56 The presence of apathy-abulia in frontotemporal dementia correlates with orbitofrontal disease, extending from Brodmann's area 10 to the anterior cingulate cortex, especially on the right. Liu et al. 57 studied 51 patients with frontotemporal dementia and 20 normal comparison subjects, as well as 22 patients with Alzheimer's disease, using the Neuropsychiatric Inventory and MRI voxel-based morphometry. The fvFTD patients scored higher on apathy compared to the tvFTD patients or the Alzheimer's disease patients. In voxel-based morphometry MRI studies, apathy scores on the Neuropsychiatric Inventory correlated not only with right lateral orbitofrontal atrophy but also with anterior cingulate cortex atrophy and, possibly, caudate head/ventral striatal atrophy. 58 , 59 In SPECT and positron emission tomography (PET) studies, apathy in frontotemporal dementia correlated with right frontal hypoperfusion or frontal hypometabolism ( Figure 2 ). 30 , 60 In addition, apathy in fvFTD may be associated with PET hypometabolism in the orbitofrontal cortex and anterior cingulate cortex. 31 , 61 Investigators further reported orbitofrontal hypometabolism specifically in the right medial Brodmann's area 10 associated with apathy in a range of frontal-predominant disorders. 62FIGURE 2. PET Images of a Frontotemporal Dementia Patient with Predominant Apathy-AbuliaThe PET shows prominent frontal lobe hypometabolism.Disinhibition-Impulsivity Disinhibition-impulsivity is one of two major behavioral subtypes of frontotemporal dementia, along with apathy-abulia. 30 – 32 , 34 , 63 It is unclear from the literature how often disinhibition and impulsivity are dissociable or occur independently in frontotemporal dementia. Many clinical and clinicopathological reports describe disinhibition and a decreased ability to restrain impulses as prominent and early symptoms of frontotemporal dementia. 2 , 21 , 35 , 42 , 61 , 64 – 66 Among 63 frontotemporal lobar degeneration patients, Mourik et al. 43 described disinhibition in 52% of the patients on the Neuropsychiatric Inventory administered to their caregivers. Chow et al. 37 described disinhibition throughout the course of frontotemporal dementia among 62 patients evaluated retrospectively. Recently, Liscic et al. 67 reported their results on 48 autopsy-confirmed patients with frontotemporal lobar degeneration compared to 27 autopsy-confirmed patients with Alzheimer's disease. The frontotemporal lobar degeneration patients, most of whom had frontotemporal dementia, had much more disinhibition-impulsivity (23–25 patients; about 50%) compared to the Alzheimer's disease patients (1–3 patients; 4–11%). Comparative studies using scales and measures show that disinhibition-impulsivity discriminates frontotemporal dementia from other dementias. Multiple investigations using the Neuropsychiatric Inventory to compare frontotemporal dementia with Alzheimer's disease show higher disinhibition scores among the frontotemporal dementia patients, particularly with fvFTD, compared to patients with Alzheimer's disease, dementia with Lewy bodies, and vascular dementia. 41 , 44 , 48 , 57 , 68 , 69 Lopez et al. 70 evaluated DSM-III-R diagnoses in 20 patients with frontotemporal dementia and 40 patients with Alzheimer's disease and found disinhibition in six frontotemporal dementia patients (30%) compared to only two Alzheimer's disease patients (5%). Bathgate et al. 71 found greater disinhibition among 30 frontotemporal dementia patients compared to 75 Alzheimer's disease and 34 "cerebrovascular dementia" patients on a semistructured caregiver questionnaire. Bozeat et al. 49 found greater group levels of disinhibition among 33 frontotemporal dementia patients compared to 27 Alzheimer's disease patients using their neuropsychiatric questionnaire. The presence of disinhibition-impulsivity correlates with right-sided frontotemporal disease. Miller et al. 65 described behavioral disinhibition as one of the dominant, and often first, symptoms in five patients with predominant right frontotemporal involvement, and, in a retrospective comparison of 52 patients with frontotemporal dementia and 101 patients with Alzheimer's disease, Lindau et al. 64 found that disinhibition was greatest in the frontotemporal dementia patients with asymmetric right-sided involvement. In addition, Liu et al. 57 found that disinhibition on the Neuropsychiatric Inventory is associated with decreased right frontal volumes in frontotemporal dementia. In contrast, other investigations have described prominent disinhibited and impulsive behavior or frivolousness and inappropriate humor among frontotemporal dementia patients with bilateral or predominantly right anterior temporal involvement. 60 , 72 – 75 Kertesz 28 suggested that the disinhibited subtype of frontotemporal dementia results specifically from both orbitofrontal and anterior temporal involvement. Consistent with this formulation, subsequent PET and voxel-based morphometry studies among disinhibited frontotemporal dementia patients show an interconnected right hemisphere region of involvement extending from the posterior orbitofrontal cortex, subgenu cingulate, to the anterior temporal pole. 1 , 30 , 31 , 59 , 61 This region may be somewhat more posterior than the region for apathy-abulia, but more research is needed to clarify this difference. Loss of Insight and Self-Referential Behavior Early in frontotemporal dementia, patients lose awareness of their disability or the consequences of their behavior and cannot see themselves from others' point of view (perspective taking). Since being reported as part of the criteria for this disease, 5 , 15 , 38 , 71 , 76 , 77 there have been many clinical reports on loss of insight in frontotemporal dementia. Among 53 frontotemporal dementia patients, Mendez and Perryman 23 reported loss of insight in 58.5% at onset and in 100% 2 years later. Similarly, Passant et al. 25 found loss of insight in all 19 of their neuropathologically verified cases with frontotemporal dementia. Perrine et al. 78 showed loss of insight in frontotemporal dementia associated with loss of perspective taking (i.e., they cannot show how others see them). More recently, Evers et al. 79 evaluated the decreased insight in five of eight patients with frontotemporal dementia and suggested that there was primarily a loss of "emotional insight" from frontotemporal disease, rather than impairment in "cognitive insight." This loss of emotional insight resembles more of an anosodiaphoria, or indifference towards their illness rather than a true anosognosia, or ignorance of their symptoms. 80 In comparative studies, the loss of insight or self-awareness is worse in frontotemporal dementia than in other dementia syndromes. Eslinger et al. 81 used the Brock Adaptive Function Inventory and Apathy Evaluation Scale to evaluate 27 frontotemporal lobar degeneration patients, 11 Alzheimer's disease patients, and 11 comparison subjects. Their frontotemporal dementia sample as a whole showed significantly less behavioral self-awareness and self-knowledge than the Alzheimer's disease and healthy comparison samples. Pijnenburg et al. 82 retrospectively reviewed the case notes of 46 patients diagnosed with frontotemporal lobar degeneration (21 with frontotemporal dementia). In contrast to the other patients, the majority of the frontotemporal dementia patients presented without complaints or awareness of symptoms. Moretti et al. 83 compared frontotemporal dementia versus vascular dementia (subcortical) and found that frontotemporal dementia had a total lack of insight, whereas it was more intact in vascular dementia. Finally, O'Keeffe et al. 84 investigated loss of insight in 14 frontotemporal dementia patients compared to 11 corticobasal degeneration and 10 progressive supranuclear palsy patients. Although all groups had decreased insight, the frontotemporal dementia patient group was most impaired in "emergent awareness" or detection of their errors. The loss of insight in frontotemporal dementia is part of a spectrum of loss of self-referential behaviors such as self-consciousness, self-perception, stable self-concepts, self-criticism or reflection, awareness of personality changes, or self-conscious responses. 56 , 78 , 80 , 81 Snowden et al. 32 characterized frontotemporal dementia patients as lacking self-conscious emotions, and Bathgate et al. 71 characterized frontotemporal dementia patients as selfish. Using an autobiographical memory task, Piolino et al. 85 found a group deficit of autonoetic consciousness (self-perception) in 15 fvFTD patients. In a unique report, Miller et al. 86 showed that stable self-concepts, such as religion and political affiliation, can be altered with the development of frontotemporal dementia. Rankin et al. 56 used the Interpersonal Adjectives Scales to compare self-awareness of personality and personality changes in 12 fvFTD patients, 10 patients with Alzheimer's disease, and 11 comparison subjects. In this and other studies, the frontotemporal dementia patients exaggerated positive qualities, minimized negative ones, and were generally unaware of their personality change (or current personality). 56 , 81 Finally, Sturm et al. 87 examined the response of 30 frontotemporal lobar degeneration patients and 23 cognitively normal comparison subjects to a loud, unexpected acoustic startle stimulus (115-dB burst of white noise). Results indicated that frontotemporal lobar degeneration patients and comparison subjects had similar responses to the startle except for significantly fewer facial signs of embarrassment or self-conscious responses among the frontotemporal lobar degeneration patients. The presence of loss of insight and self-referential behavior correlates with right frontal involvement in frontotemporal dementia. 86 On SPECT scans of frontotemporal dementia patients, loss of insight is associated with hypoperfusion in the right hemisphere, particularly the frontal lobe. 60 , 80 Furthermore, loss of insight was significantly more common with right (54.6%) versus left (13.9%) temporal atrophy; 88 however, involvement of the left temporal lobe may result in anosognosia for their social disability. Sturm et al.'s 87 findings are consistent with neural loss in the medial prefrontal cortex, which may play an important role in the production of self-conscious emotions as self-awareness activates the medial prefrontal cortex during active recollection of one's past and during passive self-reflection. 87 Finally, a recent multi-center study of lack of awareness in frontotemporal dementia compared to Alzheimer's disease suggested that greater loss of awareness in frontotemporal dementia corresponds to the degree of frontally-mediated atrophy. 89Decreased Emotion and Empathy In general, frontotemporal dementia patients lack emotional warmth and appear emotionally shallow and indifferent. 32 , 65 , 90 , 91 , 92 In a large series, Le Ber et al. 61 document changes in affect and emotional development among patients with frontotemporal dementia, and Snowden et al. 32 found that emotional unresponsiveness, including reduced response to pain, was pervasive among frontotemporal dementia patients. Using the Interpersonal Reactivity Index, a measure of cognitive and emotional empathy, Lough et al. 93 reported decreased empathic concern and decreased perspective taking in frontotemporal dementia, and Eslinger et al. 94 reported decreased self-awareness of empathy. In experiments, the emotional deficit in frontotemporal dementia spares emotional reactivity and the recognition of happiness, but impairs the recognition of negative emotions such as sadness and fear and the experience of self-conscious emotions such as embarrassment and shame. 78 , 90 In comparative studies, emotional blunting and loss of empathy are worse in frontotemporal dementia than in Alzheimer's disease and vascular dementia. Among 30 patients with frontotemporal dementia and 30 patients with Alzheimer's disease, Miller et al. 46 reported more patients with emotional unconcern in the frontotemporal dementia group (N=24, 80.0%) compared to the Alzheimer's disease group (N=6, 20.0%). 46 Barber et al. 95 found less emotional reaction to handicaps on a retrospective informant questionnaire in 18 subjects with pathologically proven frontotemporal dementia than in 20 subjects with Alzheimer's disease. Likewise, among 30 frontotemporal dementia patients, 75 Alzheimer's disease patients, and 34 vascular dementia patients, Bathgate et al. 71 reported greater loss of emotions among the frontotemporal dementia patients. Two studies that used the Scale for Emotional Blunting recorded higher emotional blunting scores in frontotemporal dementia than in Alzheimer's disease. 53 , 75 Two other studies using the Interpersonal Reactivity Index reported significantly more impaired cognitive (perspective taking) and emotional (emotional contagion) empathy in frontotemporal dementia compared to other dementia groups. 96 , 97 In frontotemporal dementia, decreased empathy is associated with right anterior temporal disease. Case studies or series of tvFTD found loss of empathy, fixed facial expressions unresponsive to situations, and emotional distancing and blunting, particularly with right-sided disease, 72 , 73 , 98 , 99 and the speech of right hemispheric frontotemporal dementia patients was less relevant to emotionally loaded pictures than that of left hemisphere patients. 100 In studies using the Interpersonal Adjectives Scales or the Interpersonal Reactivity Index, Rankin et al. 55 showed that tvFTD patients were particularly prone to interpersonal coldness compared to fvFTD patients and had decreased emotional contagion or emotional response to another's distress. 97 On voxel-based morphometry MRI, empathy correlated with a right medial frontotemporal network, particularly emotional empathy with the right ventromedial and anterior temporal areas. 96 , 97 Moreover, among artists with predominant right temporal frontotemporal dementia, Mendez and Perryman 101 report decreases in empathy reflected in alterations in their caricatures of others, and, using distorted and morphed face tasks, Mendez and Lim 102 showed that frontotemporal dementia patients with predominant right frontotemporal involvement tended to have decreased empathic awareness. Violation of Social and Moral Norms Frontotemporal dementia patients have disturbed social and moral behavior. Social changes that differ from the patient's premorbid behavior most commonly include social inadequacy or awkwardness, tactlessness, disagreeableness, decreased propriety and manners, unacceptable physical contact, or improper verbal or physical acts. 15 , 23 , 36 , 64 , 103 In a retrospective study of 19 neuropathologically verified patients with frontotemporal dementia, Passant et al. 25 found impaired social interactions in all patients, including offensive language in ten, physical aggression in eight, and many