Alzheimer's disease and frontal variant of frontotemporal dementia

The aim of this study was to investigate whether a brief neuropsychological battery consisting of a limited number of cognitive tests and an evaluation of the behavioural domains intended to discriminate between frontotemporal dementia (fv–FTD) and Alzheimer's disease (AD), constitutes a useful instrument for making a differential clinical diagnosis between these two pathologies. Nineteen fv–FTD and 39 AD patients were compared on cognitive tasks (assessing memory, executive functions, language and constructional praxis) and on the NPI behavioural assessment. A stepwise discriminant analysis was performed to identify the linear combination of cognitive and behavioural measures able to best discriminate between the two groups. One test for each of the investigated cognitive domains (Delayed Prose Recall, FAS verbal fluency, Boston naming test, Rey's Figure A Copy) and the four subscales of the Neuropsychiatry Inventory (NPI) which best differentiated between fv–FTD and AD patients (apathy, disinhibition, euphoria, aberrant motor behaviour) were used. The analysis selected Rey's Figure A Copy, FAS verbal fluency and NPI apathy subscale as the best discriminants between fv–FTD and AD patients. The final equation assigned 73.7% of the fv–FTD patients and 94.7% of the AD patients to the correct diagnostic group. A validation study conducted on a new independent sample of 11 fv–FTD and 22 AD patients confirmed the high sensitivity (82.6 %) and specificity (81.8%) of the diagnostic equation in assigning fv–FTD and AD patients to the correct dementia group. Although both cognitive and behavioural differences exist between FTD and AD, previous studies have aimed at differentiating the two pathologies by considering the two aspects separately and discriminant analyses were focused only on neuropsychological or neuropsychiatric evaluations. The present results emphasise the importance of rating both cognitive and behavioural clinical features of the two syndromes as objectively as possible to improve differential diagnostic accuracy.     

A study of stereotypic behaviours in Alzheimer's disease and frontal and temporal variant frontotemporal dementia

OBJECTIVE: To document the prevalence and pattern of stereotypic behaviour in patients with Alzheimer's dementia and frontal and temporal variants of frontotemporal dementia. Secondly, to examine the relationship between stereotypic and other neuropsychiatric behaviours. METHODS: Patients with the following were studied; Alzheimer's disease (n=28), frontal variant frontotemporal dementia (fvFTD, n=18), and semantic dementia-the temporal lobe variant of FTD (n=13). All patients were assessed using the Neuropsychiatric Inventory (NPI), the Mini-Mental State Examination, Addenbrooke's Cognitive Examination, and the Clinical Dementia Rating scale. Patients were also rated on the newly devised Stereotypic and Ritualistic Behaviour (SRB) subscale, which was designed as an addendum to the NPI. RESULTS: There was no significant difference across diagnostic groups in terms of age, sex, or severity of cognitive deficits. The overall NPI was significantly higher in patients with fvFTD compared with the other two groups, but fvFTD and semantic dementia showed a similar, and significantly increased, prevalence of stereotypic behaviours on the SRB subscale. Within the FTD group as a whole these behaviours were more likely to be complex, whereas in Alzheimer's disease, when present, such behaviours tended to be more simple stereotypies or stimulus bound repetitive behaviours. Stereotypic behaviours were not correlated with either disease severity or the extent of cognitive impairment in the fvFTD group, but were in the other two diagnostic groups. CONCLUSION: Complex stereotypic behaviours are a core feature of the dementing syndrome in FTD and may reflect early and specific deficits in orbitofrontal circuitry and basal ganglia involvement.     

The frontal assessment battery does not differentiate frontotemporal dementia from Alzheimer's disease

BACKGROUND: An early differentiation of Alzheimer's disease (AD) from frontotemporal dementia (FTD) is important, since these conditions are essentially different regarding prognosis and therapeutical approach. Until now, no single test is available which allows a reliable differentiation. The Frontal Assessment Battery (FAB) has been found to have good reliability in identifying an executive deficit in frontal syndromes and in extrapyramidal disorders. The ability of the FAB to distinguish AD from FTD in mildly demented patients is less clearly assessed. METHODS: We compared FAB scores in a consecutive series of 33 FTD (frontal variant) and 85 AD patients. RESULTS: FAB global scores in the two groups were very similar, also when considering only mildly demented subgroups [Mini Mental State Examination (MMSE) score > or = 20; 20 FTD and 38 AD patients]. Considering FAB subscores, only the 'go-no go' subtest showed a significant difference, reflecting a poorer inhibitory motor control in AD patients. FAB scores in the two groups of patients correlated with global cognitive decline (MMSE), and with executive and visuospatial test scores, showing good concurrent validity. CONCLUSION: The FAB does not differentiate patients with AD from those with FTD, like all other executive tests. However, it may be useful in the examination of executive function in AD, FTD and several other pathological conditions.     

Right temporal variant frontotemporal dementia with motor neuron disease

Patterns of atrophy in frontotemporal dementia (FTD) correlate with the clinical subtypes of behavioral variant FTD (bvFTD), semantic dementia, progressive non-fluent aphasia (PNFA) and FTD with motor neuron disease (FTD-MND). Right temporal variant FTD is associated with behavioral dyscontrol and semantic impairment, with tau abnormalities more common in right temporal bvFTD and TDP-43 accumulation in right temporal semantic dementia. However, no clinical and anatomical correlation has been described for patients with predominant right temporal atrophy and FTD-MND. Therefore, we performed a database screen for all patients diagnosed with FTD-MND at Mayo Clinic and reviewed their MRI scans to identify those with striking, dominant, right temporal lobe atrophy. For cases with volumetric MRI we performed voxel based morphometry and for those with brain tissue we performed pathological examination. Of three such patients identified, each patient had different presenting behavioral and/or aphasic characteristics. MRI, including diffusion tensor imaging in one patient, and FDG positron emission tomography revealed striking and dominant right temporal lobe atrophy, right corticospinal tract degeneration, and right temporal hypometabolism. Archived brain tissue was available in two patients; both demonstrating TDP-43 type 3 pathology (Mackenzie scheme) with predominant neuronal cytoplasmic inclusions. In one case, neurofibrillary tangles (Braak V) and neuritic plaques were also present in keeping with a diagnosis of Alzheimer’s disease. There appears to be an association between FTD-MND and severe right temporal lobe atrophy. Until further characterization of such cases are determined, they may be best classified as right temporal variant FTD-MND.     

Differential neuropsychological patterns of frontal variant frontotemporal dementia and Alzheimer's disease in a study of diagnostic concordance

Although the pathological hallmarks of Alzheimer's disease (AD) and frontal variant frontotemporal dementia (fvFTD) predict different cognitive patterns, many comparative neuropsychological studies showed no difference in the expected cognitive domains. Inconsistencies in diagnostic criteria, small cohorts of patients, and neuropsychological assessment may account for such findings. Moreover, discrepancies in memory and executive dysfunctions that are expected to distinguish AD and fvFTD may reflect the basic brain organization. Adhering to a strict concordance of clinical and neuroradiological criteria, we compared many patients with AD and fvFTD using a large neuropsychological battery. One hundred and thirty-nine patients with AD (n = 89) or fvFTD (n = 50) were retrospectively considered in order to verify the diagnostic congruence of clinical and neuroradiological aspects. On this basis, 117 patients with AD (n = 77) or fvFTD (n = 40) with similar duration and severity of dementia were selected. Ninety-one healthy subjects were also controlled. Mean scores in tests for abstract reasoning, planning, set shifting, initiative, verbal fluency, immediate and episodic memory, constructive, ideomotor and orofacial praxis, selective and divided attention, visuomotor coordination, and visual perception were evaluated. Separate analyses of variance and post hoc Bonferroni tests showed that, with respect to controls, both patient groups were significantly impaired in all neuropsychological tests. Compared to fvFTD patients, AD patients were significantly impaired in episodic memory, selective attention, visual perception, visuomotor coordination, and constructive praxis, whereas no differences were found in executive, intellective, and linguistic abilities between the two patient groups. Logistic regression analyses revealed that episodic memory significantly predicted the diagnosis of AD while no executive deficit was able to predict the diagnosis of fvFTD. To conclude, memory, attention, and visuoconstructive deficits may distinguish AD with respect to fvFTD, in accordance with the severe temporo-parietal-occipital degeneration characterizing AD, but no executive impairment is consistently able to identify a relative compromise in fvFTD. Executive functions impairments possibly reflect the altered spatial–temporal integration of the frontal lobes with different brain areas, which prevents a clear-cut cognitive-brain correlation.     

The right temporal lobe variant of frontotemporal dementia

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

Face and emotion processing in frontal variant frontotemporal dementia.

Lavenu et al. [Alzheimer Dis. Assoc. Disorder 5 (1999) 96] have shown that patients with frontotemporal dementia (FTD) show impaired recognition of facial expressions. It is not clear, however, whether these deficits arise from an impairment affecting face processing generally, emotion processing generally, or facial expression recognition alone. We address this issue by testing six patients with frontal variant frontotemporal dementia (fvFTD) on a series of face perception tasks (including facial identity and facial expression recognition), and a test of vocal emotion recognition. In general, the fvFTD participants showed impaired recognition of facial expressions in the context of preserved recognition of facial identity. In addition, however, deficits were also observed for the vocal emotion recognition task. These results are consistent with the idea that fvFTD affects the recognition of emotional signals from multiple modalities rather than facial expression processing alone. It is plausible that the emotion recognition impairments observed contribute to the abnormal social behaviour that is characteristic of this condition.     

Measuring and modifying abnormal social cognition in frontal variant frontotemporal dementia

We describe a 57-year-old man (MW) with frontal variant frontotemporal dementia (fv-FTD) who presented with a long history of drinking problem and marital disharmony followed by gradual changes in personality with disinhibition, stereotypic checking, overeating and a decline in self-care. Structural MRI imaging confirmed marked frontal atrophy involving particularly the ventromedial region. Performance on standard tests of frontal executive function was largely unremarkable and MW obtained a perfect score on the Mini-Mental State Examination (MMSE). In contrast, an experimental battery of tasks designed to evaluate theory of mind (ToM) revealed marked deficits. MW's challenging and disruptive behaviours, notably obsessive checking of car suspension by rocking, and wandering, responded to behavioural modification regimes adapted from the neurorehabilitation literature. In conclusion, deficits in ToM may underline the gross abnormalities in social conduct, which characterise fv-FTD; ToM appears to dissociate from frontal executive function; and behavioural modification approaches can be of benefit in this disorder.     

Differences in structural covariance brain networks between behavioral variant frontotemporal dementia and Alzheimer's disease

Disease‐specific patterns of gray matter atrophy in Alzheimer's disease (AD) and behavioral variant frontotemporal dementia (bvFTD) overlap with distinct structural covariance networks (SCNs) in cognitively healthy controls. This suggests that both types of dementia target specific structural networks. Here, we study SCNs in AD and bvFTD. We used structural magnetic resonance imaging data of 31 AD patients, 24 bvFTD patients, and 30 controls from two centers specialized in dementia. Ten SCNs were defined based on structural covariance of gray matter density using independent component analysis. We studied group differences in SCNs using F‐tests, with Bonferroni corrected t‐tests, adjusted for age, gender, and study center. Associations with cognitive performance were studied using linear regression analyses. Cross‐sectional group differences were found in three SCNs (all P < 0.0025). In bvFTD, we observed decreased anterior cingulate network integrity compared with AD and controls. Patients with AD showed decreased precuneal network integrity compared with bvFTD and controls, and decreased hippocampal network and anterior cingulate network integrity compared with controls. In AD, we found an association between precuneal network integrity and global cognitive performance (P = 0.0043). Our findings show that AD and bvFTD target different SCNs. The comparison of both types of dementia showed decreased precuneal (i.e., default mode) network integrity in AD and decreased anterior cingulate (i.e., salience) network integrity in bvFTD. This confirms the hypothesis that AD and bvFTD have distinct anatomical networks of degeneration and shows that structural covariance gives valuable insights in the understanding of network pathology in dementia. Hum Brain Mapp 37:978–988, 2016. © 2015 Wiley Periodicals, Inc .     

Behaviour in frontotemporal dementia, Alzheimer's disease and vascular dementia

OBJECTIVES: The study aimed to increase understanding of behavioural changes in frontotemporal dementia (FTD) and identify features that best differentiate FTD from Alzheimer's disease (AD) and cerebrovascular dementia (CvD). METHODS: A semi-structured questionnaire was administered to carers of 30 FTD, 75 AD and 34 CvD patients. RESULTS: Behavioural changes that strongly discriminated FTD from AD and to a lesser extent CvD were loss of emotions and insight, selfishness, disinhibition, personal neglect, gluttony and sweet food preference, wandering, motor and verbal stereotypies, loss of pain, echolalia and mutism. Irritability, hyposexuality and hypersomnia did not discriminate. Emotional, eating and stereotyped behaviours correctly classified 95% of patients using regression analysis. CONCLUSIONS: Behavioural characteristics accurately differentiate FTD from AD and CvD. The findings highlight the particular importance of affective change in FTD, and underline the role of the frontotemporal lobes in emotion.     

False-belief understanding in frontotemporal dementia and Alzheimer's disease

The ability to understand other people's behavior in terms of mental states, such as beliefs, desires, and intentions, is central to social interaction. It has been argued that the interpersonal problems of patients with behavioral variant of frontotemporal dementia (FTD-b) are due to a dysfunction of that system. We used first- and second-order false-belief tasks to assess theory-of-mind reasoning in a group of patients with FTD-b and a cognitively matched group of patients with Alzheimer's disease (AD). Both patient groups were equally impaired relative to a healthy elderly group in the cognitively demanding second-order false-belief tasks, revealing that cognitive demands are an important factor in false-belief task performance. Both patient groups reached ceiling performance in the first-order false-belief tasks with minimal cognitive demands, despite the striking difference in their social graces. These results suggest that a conceptual deficit in theory of mind-as measured by the false-belief task-is not at the core of the differences between FTD-b and AD.     

Different apathy clinical profile and neural correlates in behavioral variant frontotemporal dementia and Alzheimer's disease

Objectives

Apathy is one of the most common and disabling syndromes of dementia. Clinical apathy expression and neuroanatomical basis of apathy seem to differ between behavioral variant frontotemporal dementia (bvFTD) and Alzheimer's disease (AD), although evidence is scarce and poorly understood. Our main purposes were to compare the clinical apathy profile from patients with bvFTD and AD and analyze the relationship between apathy and brain metabolism measured using positron emission tomography imaging with ¹⁸F fluorodeoxyglucose (FDG‐PET).

Methods

Forty‐two bvFTD, 42 AD, and 30 healthy volunteers without cognitive or behavioral complaints were included. Apathy was defined using Robert's 2009 diagnostic criteria, and specific apathy characteristics were assessed with the Lille Apathy Rating Scale. All participants underwent FDG‐PET brain scan to provide data for voxel‐based morphometric analysis.

Results

Multivariate analysis showed that subjects affected by bvFTD displayed greater impairment of emotional apathy and self‐awareness in comparison with AD sample. Additionally, FDG‐PET imaging analyses revealed that apathy was associated with different neuroanatomical substrates in each dementia group: left lateral prefrontal, medial frontal/anterior cingulate, lateral orbitofrontal and anterior insular cortices in bvFTD, and right anterior cingulate in AD.

Conclusions

These results support that apathy is a complex syndrome, with different clinical expressions across different pathological conditions. Those differences in qualitative aspects of apathy seem to be associated with differences in the damage sites, as shown by our FDG‐PET imaging analysis. Our findings provide a better knowledge about pathophysiology of apathy in dementia, which could have practical implications for therapeutic management. Copyright © 2017 John Wiley & Sons, Ltd.     

Dissociation of social cognition and executive function in frontal variant frontotemporal dementia

In this paper, we adopt a neurodevelopmental stance to examining frontal variant frontotemporal dementia (fv-FTD) by using experimental procedures from the literature on the growth of social behaviour in children to examine the deficits in social reasoning which may underpin behavioural disturbance in fv-FTD. We present the case of a 47-year-old man with a diagnosis of fv-FTD and severe antisocial behaviour. Tests of general neuropsychology and of executive function were performed. In addition, the patient, JM, was assessed on tasks which test theory of mind. Theory of mind develops in distinct stages through childhood and is a core ability to represent the thoughts and feelings of others, independent of the level of intellectual ability. The results indicate relatively intact general neuropsychological and executive function, but extremely poor performance on tasks of theory of mind. This indicates a dissociation of social cognition and executive function suggesting that in psychiatric presentations of fv-FTD there may be a fundamental deficit in theory of mind independent of the level of executive function. The implications of this finding for diagnostic procedures and possible behavioural management are discussed.     

Complex compulsive behaviour in the temporal variant of frontotemporal dementia

Objective As metabolic and structural changes in frontotemporal-subcortical pathways have been reported in patients with obsessive-compulsive disorders, we investigated the correlation between complex compulsive behaviour (CCB) and the distribution of atrophy in a group of 90 patients with frontotemporal dementia (FTD). Methods CCB was defined as complex, intentional, and time consuming repetitive behaviour, which was distinguished from simple compulsive behaviour (SCB), such as verbal and motor repetitions and utilisation behaviour. Cortical atrophy on CT and/or MRI was semi-quantitatively assessed in frontal, temporal, parietal and occipital regions, and the pattern of atrophy was compared between patients with and without CCB or SCB. Linear measures were used to establish the presence of caudate atrophy (bicaudate ratio) and ventricular enlargement (bifrontal ratio). Results CCB was reported in 18 (21 %) and SCB in 53 (61 %) FTD patients. Frontotemporal atrophy was present in 64 patients (74 %), and predominant temporal atrophy in 23 (26 %). The pattern of atrophy was asymmetric in 25 patients (29 %). Logistic regression analysis showed that temporal lobe atrophy (p < 0.005), as well as asymmetry of atrophy (p < 0.05) were independently associated with CCB, after adjusting for age at onset, gender, duration of symptoms at the time of imaging, severity of atrophy, and bicaudate and bifrontal ratio. No relationship was found between the presence of SCB and the distribution of atrophy, although patients with SCB tended to have more caudate atrophy (p < 0.1). Conclusion Temporal lobe atrophy appears to mediate CCB in patients with FTD, especially if asymmetry of atrophy is present. Future studies with quantitative and volumetric measurements of the cortical and subcortical structures may further clarify the aetiology of CCB in FTD. Received: 29 November 2000, Received in revised form: 8 March 2001, Accepted: 25 March 2001     

Retrieval mechanisms for autobiographical memories: insights from the frontal variant of frontotemporal dementia

Very few studies have investigated autobiographical memory in the frontal variant of frontotemporal dementia (fv-FTD). The aim of this study was therefore to unravel the mechanisms of autobiographical memory disruption in general and in the anterograde and retrograde components of amnesia in particular, in patients suffering from fv-FTD. An autobiographical memory task assessing overall (AM) and strictly episodic memories (EM) from five lifetime periods covering the entire lifespan revealed the absence of a temporal gradient for both scores, suggesting the existence of a retrieval deficit. An analysis of the correlation between these two scores and a general cognitive assessment of executive function, working, episodic (i.e. new learning ability) and semantic memory, and behavioural changes highlighted the considerable involvement of executive function, semantic memory and, to a lesser degree, episodic memory and behavioural changes. Moreover, step-wise regression analyses performed on the EM score revealed that the executive function was a better predictor of the retrograde component than of the anterograde component, which was linked principally to new episodic learning ability. All these results confirm the impact of executive dysfunction on autobiographical deficits in fv-FTD, and suggest that the mechanisms at the root of autobiographical memory disruption may also involve difficulties in new episodic learning and semantic storage, though this may be due to the fact that we studied an advanced form of fv-FTD.