The Frontal Behavioral Inventory in the differential diagnosis of frontotemporal dementia.

A personality and behavioral disorder is an important and defining feature of frontal lobe dementia (FLD) or frontotemporal degeneration (FTD). The diagnosis usually depends on the progressive development of various behavioral symptoms rather than a set of neuropsychological measures. Quantification of the personality-behavior disorder is important for standardizing the diagnosis. An inventory was constructed to capture the major positive and negative behaviors and personality change, and it was administered prospectively to caregivers of 108 patients in a cognitive neurology clinic, at the time of first diagnostic assessment. The prevalence and extent of behavioral abnormality was quantitated in the clinic population of FLD, vascular dementia (VaD), Alzheimer's disease (AD), primary progressive aphasia (PPA), and depressive disorder (DD) patients. The mean scores of FLD patients were significantly above all other groups. Scores in VaD were also higher than in AD, PPA, and DD. Interrater reliability (Cohen's kappa of .90) and item consistency (a Cronbach alpha of .89) were both high. Perseveration, indifference, inattention, inappropriateness, and loss of insight rated highest in FLD, significantly different from all other groups. Apathy, aspontaneity, inflexibility, disorganization, impulsivity, personal neglect, and poor judgment were also significantly higher in FLD. Discriminant function correctly classified 92.7% versus all other patients (NON-FLD) in the study. A total of 18.8% of VaD patients were misclassified as FLD. Indifference, alien hand, and inappropriateness were the highest discriminant functions. Perseveration and verbal apraxia were important discriminatory items for FLD and PPA, respectively. The FBI is a standardized behavioral inventory useful to diagnose FLD, to differentiate it from other dementias, and to quantify the behavior disorder.     

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.     

Behavioral quantitation is more sensitive than cognitive testing in frontotemporal dementia

OBJECTIVE: To compare behavioral and cognitive testing in the clinical diagnosis of frontotemporal dementia (FTD). METHODS: A clinically defined cohort of FTD (n = 52) is compared with 52 Alzheimer disease (AD) patients on a Frontal Behavioral Inventory (FBI) and cognitive tests (e.g., Mini-Mental State Examination, Mattis Dementia Rating Scale, Western Aphasia Battery, Wechsler Intelligence Scale, Wechsler Memory Scale). Fourteen patients with FTD had autopsy confirmation, and their tests are also compared with the rest of the FTD population. RESULTS: The FTD and AD groups were matched in sex, duration, and severity of dementia. The total scores on the FBI showed the largest difference. Mini-Mental State Examination and Mattis Dementia Rating Scale total scores did not discriminate between the two groups. Memory subscores were lower in the AD group, and conceptualization and language-related scores were worse in the FTD group. Milder and earlier affected patients, who could carry on a large battery of neuropsychological tests, were much better distinguished by the FBI scores on discriminant function analysis. In contrast to 78% by the cognitive tests, 98% of the FTD and AD patients were differentiated by the FBI. CONCLUSIONS: Although memory scores were lower in AD and language scores in the FTD population, many of the cognitive tests do not distinguish between FTD and AD. On the other hand, a behavioral inventory is a useful adjunct in the diagnosis of FTD. Postmortem validation was carried out in a sizeable subset of the population, showing similar behavioral and cognitive data.     

A longitudinal study of language decline in Alzheimer's disease and frontotemporal dementia.

Language decline is usually the fastest and predominant change in primary progressive aphasia (PPA). In Alzheimer's disease (AD), it is usually associated with global cognitive deficits. Decreased speech output, reduced conversational initiation, echolalia, and changes in the pragmatics of conversation are seen in the behavioral variant of frontotemporal dementia (FTD-bv), however, the evolution of language disturbance in FTD-bv patients is rarely examined systematically with a standardized language battery. We aimed to longitudinally track the nature of language change in FTD-bv, PPA, and AD using a standardized measure of language functioning. We also explored the nature of language deficits between semantic dementia (SD) patients and the fluent subgroup of PPA patients. The Western Aphasia Battery was administered to 105 AD, 20 FTD-bv, 54 PPA, and 10 SD patients on 2 occasions with approximately 1 year between assessments. Ninety-nine of these patients were examined an additional year. FTD-bv and PPA patients showed a faster language decline than AD patients. The eventual overlap in language functioning in FTD-bv and PPA suggests that these syndromes belong to the same spectrum of disorders. In conclusion, longitudinal language assessment provides us with a unique understanding of the evolution and progression of language deterioration in various dementias.     

REM sleep behavior disorder in a patient with frontotemporal dementia

We describe a patient with frontotemporal dementia (FTD), a tauopathy, who also showed clinical and polysomnographic features of REM sleep behavior disorder (RBD). The patient is a 78-year-old male with a 1 year history of behavioral dysfunction involving emotion, character and social functioning. Brain imaging and the results of neuropsychological testing were consistent with a diagnosis of FTD. Sleep symptom onset occurred some years before the behavioral changes, and consisted of unpleasant dreams, vocalization, and prominent motor behaviors. A polysomnography confirmed the diagnosis of RBD. Our findings support the hypothesis that RBD, although more frequent in synucleinopathies, might be a pathological stage in the development of almost every neurodegenerative disorder in which the pathological process involves the cerebral structures that regulate muscle tone during REM sleep.     

Patterns of cerebral atrophy in primary progressive aphasia.

The authors illustrate the spectrum of clinical and imaging patterns in primary progressive aphasia (PPA), a syndrome of slowly progressive speech and language impairment occurring with neurodegenerative disease. Although PPA presents with relatively isolated impairment in language, many patients progress to global cognitive or behavioral dysfunction. The syndrome may be associated with frontotemporal dementia (FTD)- or Alzheimer disease (AD)-type changes. Authors describe the clinical presentation in three cases of PPA and analyze the pattern of cerebral atrophy in each case with voxel-based morphometry. Two patients presented with nonfluent progressive aphasia. Subtle differences in the clinical features were suggestive of FTD in one case and AD in the other. Neuroimaging revealed a predominance of frontal atrophy in the first case and temporo-parietal atrophy in the second. The third case presented with the syndrome of semantic dementia and showed the typical behavioral problems associated with FTD and a pattern of left-greater-than-right temporal atrophy. Different clinical syndromes in PPA are associated with different patterns of atrophy. In the future, combined analysis of imaging and clinical characteristics may allow more accurate etiologic diagnosis.     

The accuracy of clinical criteria for the diagnosis of frontotemporal dementia

The clinical diagnosis of frontotemporal dementia (FTD) can be challenging even to experienced clinicians. In the absence of a definitive clinical test, this diagnosis relies on behavioral criteria. Difficulty applying these criteria arise for four main reasons. First, FTD patients present with social and personality changes that defy the neuropsychological model of dementia. Second, FTD is not a single disorder but a spectrum of clinical syndromes with asymmetric and motor variants. Third, there may be qualitatively different symptoms during stages of FTD. Finally, pathologic and genetic variability contributes to the clinical variability. Future research should refine the clinical criteria for FTD using clinicopathological correlation in addition to working on the development of neurobiological markers.     

Prospective Evaluation of Behavioral Scales in the Behavioral Variant of Frontotemporal Dementia

Background: The Neuropsychiatric Inventory (NPI) and the Frontal Behavioral Inventory (FBI) are widely used in patients with the behavioral variant of frontotemporal dementia (bvFTD). Yet, few data are available on the long-term relevance of these scales. Material and Methods: Based on a bvFTD population that participated in the Memantine Clinical Trial (NCT00200538), we studied the evolution and correlation between scores obtained on behavioral scales (NPI and FBI), cognitive scales [Mini-Mental State Examination (MMSE) and Mattis Dementia Rating Scale (MDRS)] and a burden scale [Zarit Burden Inventory (ZBI)]. The assessments were performed at 1 year in 41 patients and at 2 years in 23 patients who agreed to participate in this open-label study. Results: The 2-year scores obtained on the FBI were significantly higher than the scores at inclusion while those obtained on the NPI did not change. There were significant correlations between the FBI, and the MDRS and MMSE, especially regarding the negative items. The ZBI correlated with behavioral scales at all stages for positive items. Conclusions: This study based on a large population shows that the FBI is a better tool than the NPI for the long-term assessment of bvFTD patients. Moreover, the FBI allows a distinction to be made between behavioral disturbances that involve cognitive functions from those which have an important impact on caregiver burden.     

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.     

Screening for dysfunction in the children of outpatients at a psychopharmacology clinic

OBJECTIVE: The goals of this study were 1) to determine whether the use of the Pediatric Symptom Checklist in an adult-oriented psychiatric practice was feasible, 2) to determine if scores indicative of dysfunction on the Pediatric Symptom Checklist were associated with parental or background factors, 3) to determine whether children flagged by their scores on the Pediatric Symptom Checklist were receiving psychiatric services, and 4) to compare the psychosocial dysfunction in this group of children with that found in children screened as part of routine pediatric visits. METHOD: Adult outpatients in a hospital's clinical psychopharmacology unit were asked to complete the Pediatric Symptom Checklist regarding their children. These patients were the parents of 100 school-aged children. Factors such as the parents' diagnoses and demographic variables were also examined. RESULTS: The Pediatric Symptom Checklist was readily accepted by parents and fit easily into the routine of general psychiatric practice. Significantly more of the children of these outpatients than of children in comparable pediatric offices had scores indicative of psychiatric dysfunction (scores above the cutoff). Children of parents who were single, of low socioeconomic status, or with a diagnosis of personality (especially borderline) or mood disorder were more likely to have scores above the cutoff. More than a third of the children who had scores above the cutoff on the Pediatric Symptom Checklist were not currently receiving psychiatric services. CONCLUSIONS: The Pediatric Symptom Checklist provided a rapid and simple method for general psychiatrists to identify psychosocial dysfunction in their patients' children.     

Profiles of decline in activities of daily living in non-Alzheimer dementia

Assessment of functional ability is an essential component in the clinical diagnosis of dementia. Most studies have primarily focused on disability due to Alzheimer disease (AD), and less is known about profiles of functional impairment in other dementia syndromes. Functional ability was assessed in individuals in the early stages of AD (N=100), the behavioral variant of frontotemporal dementia (FTD) (N=57), and primary progressive aphasia (PPA) (N=61), using the activities of daily living questionnaire (Johnson et al, 2004). The average duration of illness for the 3 groups ranged from 3.4 to 3.9 years. Overall level of functional impairment and the profile of abilities across subscales of Self-Care, Household Care, Employment and Recreation, Shopping and Money, Travel, and Communication were examined. Results showed that overall functional ability was moderately impaired in AD and FTD, and mildly impaired in PPA. For all groups, more complex ADLs were impaired early on, with relative preservation of self-care activities. The Communication score was the least impaired next to Self-Care for FTD and AD, and the most impaired for PPA patients. The activities of daily living questionnaire may capture aspects of preserved functioning that are not apparent from patients' scores on cognitive tests, especially for those with aphasia.     

The Philadelphia Brief Assessment of Cognition (PBAC): a validated screening measure for dementia

The Philadelphia Brief Assessment of the Cognition (PBAC) is a brief dementia-screening instrument. The PBAC assesses five cognitive domains: working memory/executive control; lexical retrieval/language; visuospatial/visuoconstructional operations; verbal/visual episodic memory; and behavior/social comportment. A revised version of the PBAC was administered to 198 participants including patients with Alzheimer's disease (AD) (n=46) and four groups of patients with frontotemporal dementia (FTD) syndromes: behavioral-variant FTD (bvFTD; n=65), semantic-variant primary progressive aphasia (PPA) (svPPA; n=22), non-fluent/agrammatic-variant PPA (nfaPPA; n=23), and corticobasal syndrome (CBS; n=42), and a group of normal controls (n=15). The total PBAC score was highly correlated with the MMSE. The criterion validity of the PBAC was assessed relative to standard neuropsychological test performance. Using standard neuropsychological test performance as a criterion, the total PBAC score accurately identified the presence and severity of dementia. Intra-class correlations between PBAC subscales and standard neuropsychological tests were highly significant. PBAC subscales demonstrated good clinical utility in distinguishing AD and FTD subtypes using receiver operating characteristic analysis and standard diagnostic performance statistics to determine optimal subscale cut scores. The PBAC is a valid tool and able to assesses differential patterns neuropsychological/behavioral impairment in a broad range of neurodegenerative conditions.     

Volumetric study of lobar atrophy in Pick complex and Alzheimer's disease

BACKGROUND: Lobar atrophy is an important neuroimaging feature of Pick complex (PiC). However, differences in patterns of focal brain atrophy between PiC and Alzheimer's disease (AD), and among PiC subgroups, have not been studied quantitatively. OBJECTIVE: To compare volumetric measures among primary progressive aphasia (PPA), frontotemporal dementia (FTD) and AD; to assess association between brain atrophy and cognition. PATIENTS: Seventeen patients with PPA, 11 with FTD and 24 with probable AD were studied. METHODS: We measured total and regional volume quantitatively using MRI and computerized volumetry. Contributing factors were controlled statistically or by adopting brain volume ratios. We investigated the classifying power of volumetry and correlated regional brain volume with cognitive and language test scores. RESULTS: The ratio for fronto-temporo-central region was smaller on the left in PPA and on the right in FTD. AD and some PPA patients had smaller parietal lobes. The frontal ratios correctly classified 93% of PPA and FTD patients, but only 50% of the entire PiC and AD patients. Language-dependent examinations correlated with the left fronto-temporal volume. CONCLUSIONS: Brain atrophy differs in PPA, FTD and AD, but there is some morphological overlap between PiC and AD in parietal volumes. Focal brain atrophy is most consistently associated with language impairments.     

Neuropsychological patterns in right versus left frontotemporal dementia.

Patients with frontotemporal dementia (FTD) often present with an asymmetric left or right-sided anterior cerebral perfusion abnormality that is associated with differential behavioral symptoms. However, whether patients with primarily right versus left FTD also have unique neuropsychological characteristics has not been previously investigated. Comparisons of 11 patients with right-sided FTD and 11 with left FTD indicated that the 2 patient groups showed relatively distinct cognitive profiles. Patients with right FTD exhibited relatively worse performance on PIQ than VIQ, and on select nonverbal executive tasks relative to their verbal analogs (e.g., design fluency < word generation; Picture Arrangement < word sequencing). In contrast, patients with left FTD showed the opposite pattern. In addition, the 2 patient groups differed on several absolute test scores; patients with right FTD demonstrated more errors and perseverative responses, and worse percent conceptual level responses, on the Wisconsin Card Sorting Test, while the left FTD patients obtained significantly worse scores on the Boston Naming Test, and Stroop word reading and color naming. Verbal and nonverbal memory, mental speed, visual perceptual-constructional skill, and IQ subtest scaled scores did not significantly differ between groups. These data indicate that FTD should not be viewed as a unitary disorder, and that neuropsychological testing holds promise for the differential diagnosis of right versus left FTD.     

The Philadelphia Brief Assessment of Cognition (PBAC): A Validated Screening Measure for Dementia

The Philadelphia Brief Assessment of the Cognition (PBAC) is a brief dementia-screening instrument. The PBAC assesses five cognitive domains: working memory/executive control; lexical retrieval/language; visuospatial/visuoconstructional operations; verbal/visual episodic memory; and behavior/social comportment. A revised version of the PBAC was administered to 198 participants including patients with Alzheimer's disease (AD) (n?=?46) and four groups of patients with frontotemporal dementia (FTD) syndromes: behavioral-variant FTD (bvFTD; n?=?65), semantic-variant primary progressive aphasia (PPA) (svPPA; n?=?22), non-fluent/agrammatic-variant PPA (nfaPPA; n?=?23), and corticobasal syndrome (CBS; n?=?42), and a group of normal controls (n?=?15). The total PBAC score was highly correlated with the MMSE. The criterion validity of the PBAC was assessed relative to standard neuropsychological test performance. Using standard neuropsychological test performance as a criterion, the total PBAC score accurately identified the presence and severity of dementia. Intra-class correlations between PBAC subscales and standard neuropsychological tests were highly significant. PBAC subscales demonstrated good clinical utility in distinguishing AD and FTD subtypes using receiver operating characteristic analysis and standard diagnostic performance statistics to determine optimal subscale cut scores. The PBAC is a valid tool and able to assesses differential patterns neuropsychological/behavioral impairment in a broad range of neurodegenerative conditions.     

Diminished impulsivity in older patients with borderline personality disorder

OBJECTIVE: The aim of this study was to test, in terms of impulsivity, the hypothesis that borderline personality disorder "burns out" with age. METHOD: Linear regression analyses, with age as a predictor variable, were conducted on subsection scores of the Revised Diagnostic Interview for Borderlines (DIB-R) for 123 individuals with a diagnosis of borderline personality disorder who were accepted into an outpatient-based psychotherapy program. The subsection scores of the DIB-R allow quantification of the core features of the disorder: affective disturbance, relationship disturbance, cognitive disturbance, and impulsive behavior. RESULTS: Older patients with borderline personality disorder showed less impulsivity than younger patients, but there was no difference in terms of affect disturbance, identity disturbance, and interpersonal problems. CONCLUSIONS: The view that borderline personality disorder burns out with age is supported in terms of impulsivity.     

Clinical features of frontotemporal dementia due to the intronic tau 10(+16) mutation

OBJECTIVE: To describe the clinical features of nine British families with neuropathologically verified frontotemporal dementia (FTD) due to the intronic tau exon 10(+16) mutation. METHODS: Retrospective chart reviews of family members with FTD belonging to nine tau 10(+16) mutation pedigrees in whom neuropathologic examination had been carried out. APOE genotype was determined for those patients for whom DNA was available. RESULTS: The median age at onset was 50 years (range 37 to 59 years; n = 30). The median age at death was 61 years (range 42 to 72 years; n = 33). The median duration of the disease was 11 years (range 3 to 22 years; n = 25) for those who have died and is 17 years (range 15 to 23 years; n = 3) for those living. The most common presenting symptom was disinhibition (n = 23). A minority presented with frontal dysexecutive symptoms, apathy, impairment of episodic memory, or depression. All of these patients subsequently developed personality and behavioral change. Memory impairment, language deficits, ritualistic behavior, hyperphagia, and hyperorality were frequent symptoms. Parkinsonism, neuroleptic sensitivity, or primitive reflexes were present in half of the patients, where these data were available. The clinical features of ALS were absent. Neuropathologic examination of 12 patients demonstrated the hallmark tau-positive neuronal and glial inclusions. APOE genotype did not account for the considerable variation in age at onset, age at death, duration of disease, or severity of estimated brain atrophy. CONCLUSIONS: All cases fulfilled the clinical criteria for a diagnosis of FTD. Despite similar clinical phenotypes, there was considerable variation in age at onset and duration of disease both between and within families, suggesting the presence of an effect due to other genetic or environmental factors.     

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.     

Thalamic nuclei in frontotemporal dementia: Mediodorsal nucleus involvement is universal but pulvinar atrophy is unique to C9orf72

Thalamic atrophy is a common feature across all forms of FTD but little is known about specific nuclei involvement. We aimed to investigate in vivo atrophy of the thalamic nuclei across the FTD spectrum. A cohort of 402 FTD patients (age: mean(SD) 64.3(8.2) years; disease duration: 4.8(2.8) years) was compared with 104 age‐matched controls (age: 62.5(10.4) years), using an automated segmentation of T1‐weighted MRIs to extract volumes of 14 thalamic nuclei. Stratification was performed by clinical diagnosis (180 behavioural variant FTD (bvFTD), 85 semantic variant primary progressive aphasia (svPPA), 114 nonfluent variant PPA (nfvPPA), 15 PPA not otherwise specified (PPA‐NOS), and 8 with associated motor neurone disease (FTD‐MND), genetic diagnosis (27 MAPT, 28 C9orf72, 18 GRN), and pathological confirmation (37 tauopathy, 38 TDP‐43opathy, 4 FUSopathy). The mediodorsal nucleus (MD) was the only nucleus affected in all FTD subgroups (16–33% smaller than controls). The laterodorsal nucleus was also particularly affected in genetic cases (28–38%), TDP‐43 type A (47%), tau‐CBD (44%), and FTD‐MND (53%). The pulvinar was affected only in the C9orf72 group (16%). Both the lateral and medial geniculate nuclei were also affected in the genetic cases (10–20%), particularly the LGN in C9orf72 expansion carriers. Use of individual thalamic nuclei volumes provided higher accuracy in discriminating between FTD groups than the whole thalamic volume. The MD is the only structure affected across all FTD groups. Differential involvement of the thalamic nuclei among FTD forms is seen, with a unique pattern of atrophy in the pulvinar in C9orf72 expansion carriers.