Christopher M. Kipps

Social reasoning, emotion and empathy in frontotemporal dementia

INTRODUCTION Social cognition is crucial for human interaction, and is markedly impaired in the frontal variant of frontotemporal dementia (fvFTD). The relationship of various aspects of social functioning, however, remains controversial in this group. METHODS Patients with fvFTD (n = 18), and matched controls (n = 13), were tested using tasks designed to assess their Theory of Mind (ToM), moral reasoning, emotion recognition and executive function. Caregivers documented changes in empathy compared to premorbid functioning. RESULTS We found marked impairments in the abilities of fvFTD patients, relative to controls, in ability to mentalise (ToM), which was evident on a cartoon test, but not on a story-based ToM task. Knowledge of social rules was intact, but moral reasoning was defective, and was due, in part, to an inability to rate the seriousness of moral and conventional transgressions appropriately. Executive function was impaired in this group, and compromised aspects of moral reasoning, but ToM performance was independent of this. Emotion recognition was globally impaired in fvFTD, but was particularly so for anger and disgust which may partly explain the difficulty these patients have with identifying social violations. Empathy, as rated by carers, was also shown to be abnormal. CONCLUSION It appears that social reasoning is disrupted in a number of ways in fvFTD, and the findings provide a basis for the understanding and further study of abnormal behaviour in this disease. The results are discussed in light of neuroimaging findings in studies of social cognition and the locus of pathology in fvFTD.

Understanding social dysfunction in the behavioural variant of frontotemporal dementia: the role of emotion and sarcasm processing

Social interaction is profoundly affected in the behavioural form of frontotemporal dementia (bvFTD) yet there are few means of objectively assessing this. Diagnosis of bvFTD is based on informant report, however a number of individuals with a clinical profile consistent with the disease have no imaging abnormality and seem to remain stable, with doubt about the presence of underlying neurodegenerative pathology. We aimed to quantify aspects of the behavioural disorder and link it to the underlying level of atrophy in socially relevant brain regions. We tested individuals with either bvFTD (N = 26) or Alzheimers disease (N = 9) and 16 controls using The Awareness of Social Inference Test (TASIT) to assess their ability to identify emotion and sarcasm in video vignettes. A subset of bvFTD patients (N = 21) and controls (N = 12) were scanned using MRI within 6 months of assessment. There was marked impairment in the ability of bvFTD patients whose scans showed abnormalities to recognize sarcastic, but not sincere statements. Their capacity to interpret negative emotion was also impaired, and this appeared to be a major factor underlying the deficit in sarcasm recognition. Clinically diagnosed bvFTD patients whose scans were normal, Alzheimers disease patients and controls had no difficulty in appreciating both types of statement. In a multivariate imaging analysis it was shown that the sarcasm (and emotion recognition) deficit was dependent on a circuit involving the lateral orbitofrontal cortex, insula, amygdala and temporal pole, particularly on the right. Performance on a more global test of cognitive function, the Addenbrookes Cognitive Examination did not have a unique association with these regions. The TASIT is an objective test of social dysfunction in bvFTD which indexes the frontotemporal volume loss in bvFTD patients and provides an objective measure for separating behavioural patients who are likely to decline from those who may remain stable. These results provide additional evidence for the role of the orbitofrontal cortex and related structures in the processing of socially relevant signals, particularly those where negative emotion recognition is important.

Diagnostic criteria for the behavioral variant of frontotemporal dementia (bvFTD): Current limitations and future directions

The most widely established diagnostic criteria for the behavioral variant of frontotemporal dementia have now been in use for almost a decade. Although consensus criteria have provided a much needed standard for frontotemporal dementia research, a growing body of evidence suggests that revisions are needed to improve their applicability. In this article, we discuss the limitations of current diagnostic criteria and propose the establishment of an international consortium to revise diagnostic and research criteria for the behavioral variant of frontotemporal dementia.

Activities of daily living in frontotemporal dementia and Alzheimer disease.

Objective: To evaluate activities of daily living (ADLs) in three clinical variants of frontotemporal dementia and the relationship to cognitive dysfunction. Methods: Fifty-nine patients and caregivers participated in this cross-sectional study: behavioral variant frontotemporal dementia (bv-FTD, n = 15), progressive nonfluent aphasia (PNFA, n = 10), semantic dementia (n = 15), and Alzheimer disease (AD, n = 19). Caregivers were interviewed with the Disability Assessment for Dementia (DAD) to provide two outcome measures about ADLs: basic and instrumental ADLs (BADLs, IADL). In addition, patients were rated on the Clinical Dementia Rating Scale (CDR), and performance on cognitive measures (Addenbrookes Cognitive Examination Revised [ACE-R]) was assessed. Results: On the DAD, the bv-FTD group was most affected (56% of normal), whereas PNFA and semantic dementia patients were least impaired (83% and 85%); AD was intermediate (76%). The opposite pattern was seen on the ACE-R, where PNFA and semantic dementia groups were most affected, and bv-FTD showed least impairment; AD was again intermediate. Scores on the DAD did not correlate with cognitive measures, CDR, or disease duration. We further analyzed which aspect of ADLs was most affected, and a unique pattern of deficits emerged for the bv-FTD group (initiation affected > planning > execution for BADLs). Conclusion: Frontotemporal dementia has a devastating effect on activities of daily living, which is of considerable importance to caregivers and not captured by bedside cognitive tests.

Clinical significance of lobar atrophy in frontotemporal dementia: application of an MRI visual rating scale.

Background/Aims: The status of imaging findings in the clinical diagnosis of frontotemporal dementia (FTD) remains uncertain; while they may be supportive of a diagnosis of frontotemporal dementia, they are not mandatory. Our aim was to assess patterns of lobar atrophy in a large sample of clinically defined, prospectively studied, patients using a magnetic resonance image (MRI) rating scale, to (1) determine whether imaging findings warrant a more prominent position in FTD diagnosis and (2) correlate the extent of lobar atrophy with clinical data. Methods: We adapted a recently devised post mortem rating scale for FTD to rate lobar atrophy on MRI scans. The areas rated included the frontal cortex and both anterior and posterior temporal regions bilaterally. All available brain scans from all patients seen in the Cambridge Dementia Clinic (n = 258) diagnosed as having FTD, together with controls (n = 20), were used to assess the reliability of the method. A subset of these (n = 121) were used for clinico-anatomic analysis. Results: The scale proved quick and reliable (intra-, inter-rater k = 0.80, 0.67). MRI scans were abnormal in the majority of patients (75%), with focal atrophy present in 100% of semantic dementia (SD) patients. By contrast, nearly half (47%) of the patients with clinical behavioural variant FTD had scans within the normal range. Behavioural cases with normal scans generally had fewer cognitive deficits and milder functional impairment than those with abnormal scans, yet displayed a clinically indistinguishable behavioural syndrome. They were not, however, simply at an earlier stage of the disease. Conclusions: MRI findings should form part of the diagnostic criteria for SD; the absence of atrophy on MRI in many behavioural cases raises the prospect that the behavioural syndrome of FTD is not specific for patients with a neurodegenerative disease.

Executive function in progressive and nonprogressive behavioral variant frontotemporal dementia

Background: Recent studies suggest that behavioral variant frontotemporal dementia (bv-FTD) patients differ in their prognosis with fast-progressing and very slow–progressing cases. We investigated executive and behavioral profiles of progressive and nonprogressive bv-FTD patients to establish diagnostic markers discriminating the two groups. Methods: A range of neuropsychological and behavioral tests were used. Mean overlap-based statistical analyses and logistic regression analyses were performed to distinguish progressive from nonprogressive bv-FTD cases. Results: Although progressors and nonprogressors showed similar behavioral profiles, they were distinguishable by their performance on executive tasks. The nonprogressors’ performance on all tests was with the normal range, whereas the progressors were consistently impaired on four tests: Digit Span Backward, Hayling Test of inhibitory control, Letter Fluency, and Trails B. Logistic regression showed that 86% of patients could be classified on the basis of Digit Span and Hayling subscores. Conclusions: Contrary to some prior reports, behavioral variant frontotemporal dementia (bv-FTD) patients who progress over time are typically impaired on executive tasks at first presentation, although an important minority of true FTD patients perform normally. Previous inconsistencies are explicable by the mixture of patients with progressing FTD and phenocopy cases.

Combined magnetic resonance imaging and positron emission tomography brain imaging in behavioural variant frontotemporal degeneration: refining the clinical phenotype

In patients with the behavioural variant of frontotemporal dementia, prognosis is often surprisingly good when there is normal structural imaging at presentation. Imaging abnormalities are not, however, mandatory for diagnosis, which in the absence of suitable biomarkers, remains entirely clinical. We aimed to test whether cases with normal structural imaging have hypometabolism suggestive of underlying neurodegeneration, or whether it is likely that such patients are false positive diagnoses of behavioural variant frontotemporal dementia. Patients with this disease (n = 24) and age-matched controls (n = 12) underwent both magnetic resonance imaging (MRI) and quantitative fluorodeoxyglucose-positron emission tomography (FDG-PET) scanning, together with clinical and behavioural assessments. Regions of interest were used to calculate metabolic rate in frontotemporal and control regions. Using a semi-quantitative visual rating scale, patients were divided into MRI-abnormal (n = 15) and MRI-normal groups (n = 9). There was definite frontotemporal hypometabolism in the MRI-abnormal group (particularly in the mesial and orbitofrontal regions) even after accounting for brain volume loss, whereas the MRI-normal group was similar to controls in all regions. In contrast, cognitive and behavioural indices did not separate the two behavioural variant frontotemporal dementia patient groups. The results suggest that the clinical syndrome of the behavioural variant of frontotemporal dementia may not be specific for a neurodegenerative disease, and we hypothesize the existence of a phenocopy. A number of alternative neuropsychiatric and developmental explanations are discussed. We advise caution in diagnosing the illness in patients without imaging abnormalities, and propose that imaging findings are included in criteria for diagnosis.

Sensitivity of current criteria for the diagnosis of behavioral variant frontotemporal dementia

Background: Diagnosis of behavioral variant frontotemporal dementia (bvFTD) relies on criteria that are constraining and potentially ambiguous. Some features are open to clinical interpretation and their prevalence unknown. This study investigated the sensitivity of current diagnostic criteria in a large group of patients with bvFTD. Methods: Forty-five patients with clear evidence of bvFTD as judged by progressive clinical decline (>3 years) with marked frontal features and significant frontal brain atrophy on brain MRI were included. Thirty-two have died; pathologic confirmation of frontotemporal lobar degeneration was found in all 18 coming to autopsy. We established the prevalence of core and supportive diagnostic features at presentation and with disease progression. Results: Only 25/45 patients (56%) showed all five core features necessary for a diagnosis of bvFTD at initial presentation and 33/45 (73%) as their disease progressed. Two core features, emotional blunting and loss of insight, were never observed in 25% and 13% of cases. Executive dysfunction, hyperorality, mental inflexibility, and distractibility were the only supportive features present in >50% of cases at initial presentation. Although not a diagnostic feature, impaired activities of daily living was present in 33/45 patients (73%). Conclusions: Strict application of the criteria misses a significant proportion of patients. Many supportive features have low prevalence and are clinically not useful. Revision of the criteria to include level of certainty (definite, probable, possible) dependent on the number of features present and the presence of ancillary information (e.g., brain atrophy, neuropsychological abnormalities, impaired activities of daily living) is encouraged. ACE = Addenbrooke’s Cognitive Examination; ADL = activities of daily living; bvFTD = behavioral variant frontotemporal dementia; MMSE = Mini-Mental State Examination.

Nonprogressive behavioural frontotemporal dementia:Recent developments and clinical implications of the 'bvFTD phenocopy syndrome'

PURPOSE OF REVIEW The clinical features of behavioural variant frontotemporal dementia (bvFTD) are well established; however, recent work has identified patients fulfilling diagnostic criteria for the disease who do not appear to progress clinically. This review describes means of distinguishing this group at an early stage from patients who are likely to deteriorate. RECENT FINDINGS Despite indistinguishable clinical profiles, studies in a cohort of bvFTD patients showed a particularly good prognosis in a subgroup of predominantly male patients in whom initial structural imaging was normal. This could not be explained by differences in disease duration, and was confirmed by subsequent PET studies. Retrospective review of clinical data in these groups verified that the current clinical diagnostic criteria are both insensitive to true progressive bvFTD, particularly in the early stages, and also poorly specific. In contrast, measures of activity of daily living performance, executive function and tests of social cognition appear to have better discriminatory value for patients who show clear clinical progression, with many individual diagnoses verified by post mortem examination in this group. SUMMARY It remains doubtful that the nonprogressive group have a neurodegenerative disease. The implication for the current clinical diagnostic criteria and their proposed revision is discussed.

Is the pathology of corticobasal syndrome predictable in life

Corticobasal syndrome (CBS) has been associated with a heterogeneous spectrum of pathologies with an increasing number of reports of Alzheimers type pathology. There is, however, no means of predicting pathology of CBS in vivo at present. We compared the clinical features of patients presenting with CBS who have either pathologic changes of classic corticobasal degeneration (CBD) or Alzheimers disease (AD) at post‐mortem to identify predictors of the specific pathological processes in life. Twelve patients with CBS were followed prospectively; six had AD and six had classic CBD neuropathology. After review of the presenting clinical features, we identified nine potential predictor variables, compared their frequency in the two groups, and performed a discriminant function analysis. Initial episodic memory complaints and poor performance on the combined orientation‐memory subtest of the Addenbrookes Cognitive Examination (ACE) reliably predicted AD pathology while varying combinations of early frontal‐lobe type behavioral symptoms, nonfluent language disturbance, orobuccal apraxia, and utilization behavior predicted CBD pathology ante‐mortem. CBS is frequently associated with Alzheimers disease pathology. Early episodic memory impairment versus early behavioral symptomatology appears to best predict AD or CBD pathology in life.