Behavioral Variant Frontotemporal Dementia Patients Research Articles

Uncovering the distinct macro-scale anatomy of dysexecutive and behavioural degenerative diseases.

There is a longstanding ambiguity regarding the clinical diagnosis of dementia syndromes predominantly targeting executive functions versus behaviour and personality. This is due to an incomplete understanding of the macro-scale anatomy underlying these symptomatologies, a partial overlap in clinical features and the fact that both phenotypes can emerge from the same pathology and vice versa. We collected data from a patient cohort of which 52 had dysexecutive Alzheimer's disease, 30 had behavioural variant frontotemporal dementia (bvFTD), seven met clinical criteria for bvFTD but had Alzheimer's disease pathology (behavioural Alzheimer's disease) and 28 had amnestic Alzheimer's disease. We first assessed group-wise differences in clinical and cognitive features and patterns of fluorodeoxyglucose (FDG) PET hypometabolism. We then performed a spectral decomposition of covariance between FDG-PET images to yield latent patterns of relative hypometabolism unbiased by diagnostic classification, which are referred to as 'eigenbrains'. These eigenbrains were subsequently linked to clinical and cognitive data and meta-analytic topics from a large external database of neuroimaging studies reflecting a wide range of mental functions. Finally, we performed a data-driven exploratory linear discriminant analysis to perform eigenbrain-based multiclass diagnostic predictions. Dysexecutive Alzheimer's disease and bvFTD patients were the youngest at symptom onset, followed by behavioural Alzheimer's disease, then amnestic Alzheimer's disease. Dysexecutive Alzheimer's disease patients had worse cognitive performance on nearly all cognitive domains compared with other groups, except verbal fluency which was equally impaired in dysexecutive Alzheimer's disease and bvFTD. Hypometabolism was observed in heteromodal cortices in dysexecutive Alzheimer's disease, temporo-parietal areas in amnestic Alzheimer's disease and frontotemporal areas in bvFTD and behavioural Alzheimer's disease. The unbiased spectral decomposition analysis revealed that relative hypometabolism in heteromodal cortices was associated with worse dysexecutive symptomatology and a lower likelihood of presenting with behaviour/personality problems, whereas relative hypometabolism in frontotemporal areas was associated with a higher likelihood of presenting with behaviour/personality problems but did not correlate with most cognitive measures. The linear discriminant analysis yielded an accuracy of 82.1% in predicting diagnostic category and did not misclassify any dysexecutive Alzheimer's disease patient for behavioural Alzheimer's disease and vice versa. Our results strongly suggest a double dissociation in that distinct macro-scale underpinnings underlie predominant dysexecutive versus personality/behavioural symptomatology in dementia syndromes. This has important implications for the implementation of criteria to diagnose and distinguish these diseases and supports the use of data-driven techniques to inform the classification of neurodegenerative diseases.

Zero the hero: Evidence for involvement of the ventromedial prefrontal cortex in affective bias for free items

Recent evidence from psycho-economics shows that when the price of an item decreases to the extent that it becomes available for free, one can observe a remarkable increase of subjective utility toward this item. This phenomenon, which is not observed for any other price but zero, has been termed the zero-price effect (ZPE). The ZPE is attributed to an affective heuristic where the positive affect elicited by the free status of an item provides a mental shortcut biasing choice towards that item. Given that the ZPE relies on affective processing, a key role of the ventromedial prefrontal cortex (vmPFC) has been proposed, yet neuroscientific studies of the ZPE remain scarce. This study aimed to explore the role of the vmPFC in the ZPE using a novel, within-subject assessment in participants with either an acquired (lesion patients) or degenerative (behavioural-variant frontotemporal dementia patients) lesion of the vmPFC, and age-matched healthy controls. All participants were asked to make a series of choices between pairs of items that varied in price. One choice trial involved an equal decrease of both item prices, such that one of the items was priced zero. In contrast to controls, patients with both vmPFC-lesion and behavioural-variant frontotemporal dementia showed marked reductions in zero-related changes of preference in pairs of gift-cards, but not for pairs of food items. Our findings suggest that affective evaluations driving the ZPE are altered in patients with focal or degenerative damage to the vmPFC. This supports the notion of a key role of the vmPFC in the ZPE and, more generally, the importance of this region in value-based affective decision-making. Our findings also highlight the potential utility of affective heuristic tasks in future clinical assessments.

An ecological approach to identify distinct neural correlates of disinhibition in frontotemporal dementia

Disinhibition is a core symptom of many neurodegenerative diseases, particularly frontotemporal dementia, and is a major cause of stress for caregivers. While a distinction between behavioural and cognitive disinhibition is common, an operational definition of behavioural disinhibition is still missing. Furthermore, conventional assessment of behavioural disinhibition, based on questionnaires completed by the caregivers, often lacks ecological validity. Therefore, their neuroanatomical correlates are non-univocal.In the present work, we used an original behavioural approach in a semi-ecological situation to assess two specific dimensions of behavioural disinhibition: compulsivity and social disinhibition. First, we investigated disinhibition profile in patients compared to controls. Then, to validate our approach, compulsivity and social disinhibition scores were correlated with classic cognitive tests measuring disinhibition (Hayling Test) and social cognition (mini-Social cognition & Emotional Assessment). Finally, we disentangled the anatomical networks underlying these two subtypes of behavioural disinhibition, taking in account the grey (voxel-based morphometry) and white matter (diffusion tensor imaging tractography). We included 17 behavioural variant frontotemporal dementia patients and 18 healthy controls.We identified patients as more compulsive and socially disinhibited than controls. We found that behavioural metrics in the semi-ecological task were related to cognitive performance: compulsivity correlated with the Hayling test and both compulsivity and social disinhibition were associated with the emotion recognition test. Based on voxel-based morphometry and tractography, compulsivity correlated with atrophy in the bilateral orbitofrontal cortex, the right temporal region and subcortical structures, as well as with alterations of the bilateral cingulum and uncinate fasciculus, the right inferior longitudinal fasciculus and the right arcuate fasciculus. Thus, the network of regions related to compulsivity matched the “semantic appraisal” network. Social disinhibition was associated with bilateral frontal atrophy and impairments in the forceps minor, the bilateral cingulum and the left uncinate fasciculus, regions corresponding to the frontal component of the “salience” network.Summarizing, this study validates our semi-ecological approach, through the identification of two subtypes of behavioural disinhibition, and highlights different neural networks underlying compulsivity and social disinhibition. Taken together, these findings are promising for clinical practice by providing a better characterisation of inhibition disorders, promoting their detection and consequently a more adapted management of patients.

Reduction of behavioural inhibition disorders in behavioural variant frontotemporal dementia patients observed under semi‐ecological conditions

AbstractBackgroundBehavioural variant frontotemporal dementia (bvFTD) is characterised by a progressive deterioration of personality, social conduct and cognition. Especially, inhibition troubles are reported, impairing the daily lives of patients and caregivers. However, assessment and characterisation of disinhibition are still poorly known, leading to a limited management of these disorders. We aim to identify activities related to an increase or a decrease of behavioural disinhibition, in order to better apprehend these disorders and set up non‐pharmacological approaches to limit these troubles.MethodWe assess behavioural disinhibition in a semi‐ecological setting, noting occurrences of 16 behaviours – derived from clinical criteria of bvFTD – related to compulsivity, impulsivity or social disinhibition, in a population of 25 bvFTD and 25 healthy controls (HC). Subjects are placed in a waiting room during 45 minutes, instructions are to get comfortable and enjoy the room. During the scenario, they are firstly free to explore the room (Free Phase) and are then guided by a questionnaire to be filled in (Guided Phase). Duration of activity related behaviours and motor patterns are also collected to look for correlations with behavioural disinhibition scores.ResultTo date, we included 22 bvFTD and 24 HC. We found out that disinhibition behaviours are not constant during the scenario. BvFTD patients are less impulsive during the guided phase compared to the free phase (p=0.014, Wilcoxon test), and show more social disinhibition than HC during the free phase and at the end of the guided phase (p=0.014 and p=0.026 respectively, Mann‐Whitney U tests), but not during the guided phase. Compulsive behaviours remain unchanged. Moreover, looking for correlations between behavioural disinhibition and activity related behaviours or motor patterns, we found out that: 1) social disinhibition would be less present during activity (eg, reading), 2) there would be less compulsivity when patients are dealing with the questionnaire, and 3) impulsivity would increase during exploration of the room (eg, books).ConclusionThis study relying on a semi‐ecological setting highlights interesting areas for non‐pharmacological treatments of behavioural disturbances in bvFTD, consistent with previous studies encouraging concentration on a given task, hobbies or a tidy environment to reduce undesired behavioural symptoms in dementia.

Alterations of Cerebral Blood Flow Network in Behavioral Variant Frontotemporal Dementia patients with and without Apathy

Apathy is one of the core symptoms in behavioral variant of frontotemporal dementia (bvFTD), and increases patient's morbidity and caregiver's distress. In this study, we applied a graph theoretical analysis (GTA) to analyze the topological properties of cerebral blood flow (CBF) network in 64 bvFTD patients with and without apathy (47 bvFTD-apathy and 17 bvFTD-woapathy, respectively), and 20 normal controls (NCs) based on single photon emission tomography (SPECT). Compared with the NCs, both the bvFTD groups preserved global function and typical features of small-worldness, but exhibited the loss of hubs mainly distributed in the prefrontal cortex (PFC). Compared with bvFTD-woapathy, the bvFTD-apathy group exhibited additional loss of hubs in the ventral PFC areas, middle cingulate cortex, limbic and paralimbic system, and subcortical regions, but recruited hubs in the areas of angular gyrus, precuneus and posterior cingulate cortex. Overall, our findings support the hypothesis that the disruption of frontostriatal circuit is associated with apathy in bvFTD.

Argentinian/Chilean validation of the Spanish-language version of Addenbrooke's Cognitive Examination III for diagnosing dementia

BackgroundThe Addenbrooke's Cognitive Examination III (ACE-III), an adaptation of the ACE cognitive screening test, has been demonstrated to have high sensitivity and specificity in detecting cognitive impairment in patients with dementia and other neurological and psychiatric disorders. Although the Spanish-language version of the ACE-III has already been validated in Spain, it is yet to be validated in Latin America. The aim of this study was to validate the ACE-III test in an Argentinean and Chilean population. MethodsACE-III was administered to 70 patients with Alzheimer disease, 31 patients with behavioural variant frontotemporal dementia, and a control group of 139 healthy volunteers. Participants were recruited at centres in both countries. ResultsThe Spanish-language version of ACE-III was found to have good internal consistency (Cronbach's alpha=0.87). We found significant differences in total ACE-III scores between patients with Alzheimer disease and controls (P<.05) and between patients with Alzheimer disease and bvFTD (P<.05). With a cut-off point of 86, 98.6% of AD patients, 83.9% of behavioural variant frontotemporal dementia patients, and 84.2% of controls were correctly classified. ConclusionsThis study shows that the Spanish-language version of ACE-III continues to be an effective tool for detecting cognitive dysfunction in patients with dementia.

Optic nerve thinning and neurosensory retinal degeneration in the rTg4510 mouse model of frontotemporal dementia

Visual impairments, such as difficulties in reading and finding objects, perceiving depth and structure from motion, and impaired stereopsis, have been reported in tauopathy disorders, such as frontotemporal dementia (FTD). These impairments however have been previously attributed to cortical pathologies rather than changes in the neurosensory retina or the optic nerve. Here, we examined tau pathology in the neurosensory retina of the rTg(tauP301L)4510 mouse model of FTD. Optic nerve pathology in mice was also assessed using MRI, and corresponding measurements taken in a cohort of five FTD sufferers and five healthy controls. rTg(tauP301L)4510 mice were imaged (T2-weighted MRI) prior to being terminally anesthetized and eyes and brains removed for immunohistochemical and histological analysis. Central and peripheral retinal labelling of tau and phosphorylated tau (pTau) was quantified and retinal layer thicknesses and cell numbers assessed. MR volumetric changes of specific brain regions and the optic nerve were compared to tau accumulation and cell loss in the visual pathway. In addition, the optic nerves of a cohort of healthy controls and behavioural variant FTD patients, were segmented from T1- and T2-weighted images for volumetric study. Accumulation of tau and pTau were observed in both the central and peripheral retinal ganglion cell (RGC), inner plexiform and inner nuclear layers of the neurosensory retina of rTg(tauP301L)4510 mice. This pathology was associated with reduced nuclear density (− 24.9 ± 3.4%) of the central RGC layer, and a reduced volume (− 19.3 ± 4.6%) and elevated T2 signal (+ 27.1 ± 1.8%) in the optic nerve of the transgenic mice. Significant atrophy of the cortex (containing the visual cortex) was observed but not in other area associated with visual processing, e.g. the lateral geniculate nucleus or superior colliculus. Atrophic changes in optic nerve volume were similarly observed in FTD patients (− 36.6 ± 2.6%). The association between tau-induced changes in the neurosensory retina and reduced optic nerve volume in mice, combined with the observation of optic nerve atrophy in clinical FTD suggests that ophthalmic tau pathology may also exist in the eyes of FTD patients. If tau pathology and neurodegeneration in the retina were to reflect the degree of cortical tau burden, then cost-effective and non-invasive imaging of the neurosensory retina could provide valuable biomarkers in tauopathy. Further work should aim to validate whether these observations are fully translatable to a clinical scenario, which would recommend follow-up retinal and optic nerve examination in FTD.

Validación argentino-chilena de la versión en español del test Addenbrooke's Cognitive Examination III para el diagnóstico de demencia

BackgroundThe Addenbrooke's Cognitive Examination III (ACE-III), an adaptation of the ACE cognitive screening test, has been demonstrated to have high sensitivity and specificity in detecting cognitive impairment in patients with dementia and other neurological and psychiatric disorders. Although the Spanish-language version of the ACE-III has already been validated in Spain, it is yet to be validated in Latin America. The aim of this study was to validate the ACE-III test in an Argentinean and Chilean population. MethodsACE-III was administered to 70 patients with Alzheimer disease, 31 patients with behavioural variant frontotemporal dementia, and a control group of 139 healthy volunteers. Participants were recruited at centres in both countries. ResultsThe Spanish-language version of ACE-III was found to have good internal consistency (Cronbach's alpha=0.87). We found significant differences in total ACE-III scores between patients with Alzheimer disease and controls (p< .05) and between patients with Alzheimer disease and bvFTD (p< .05). With a cut-off point of 86, 98.6% of AD patients, 83.9% of behavioural variant frontotemporal dementia patients, and 84.2% of controls were correctly classified. ConclusionsThis study shows that the Spanish-language version of ACE-III continues to be an effective tool for detecting cognitive dysfunction in patients with dementia.

Theory of mind impairment in patients with behavioural variant fronto-temporal dementia (bv-FTD) increases caregiver burden.

Theory of mind (ToM), the capacity to infer the intention, beliefs and emotional states of others, is frequently impaired in behavioural variant fronto-temporal dementia patients (bv-FTDp); however, its impact on caregiver burden is unexplored. National Institute of Neurological Disorders and Stroke, National Institutes of Health. bv-FTDp (n = 28), a subgroup of their caregivers (n = 20) and healthy controls (n = 32). we applied a faux-pas (FP) task as a ToM measure in bv-FTDp and healthy controls and the Zarit Burden Interview as a measure of burden in patients' caregivers. Patients underwent structural MRI; we used voxel-based morphometry to examine relationships between regional atrophy and ToM impairment and caregiver burden. FP task performance was impaired in bv-FTDp and negatively associated with caregiver burden. Atrophy was found in areas involved in ToM. Caregiver burden increased with greater atrophy in left lateral premotor cortex, a region associated in animal models with the presence of mirror neurons, possibly involved in empathy. ToM impairment in bv-FTDp is associated with increased caregiver burden.

MRI patterns of atrophy and hypoperfusion associations across brain regions in frontotemporal dementia

Magnetic Resonance Imaging (MRI) provides various imaging modes to study the brain. We tested the benefits of a joint analysis of multimodality MRI data in combination with a large-scale analysis that involved simultaneously all image voxels using joint independent components analysis (jICA) and compared the outcome to results using conventional voxel-by-voxel unimodality tests. Specifically, we designed a jICA to decompose multimodality MRI data into independent components that explain joint variations between the image modalities as well as variations across brain regions. We tested the jICA design on structural and perfusion-weighted MRI data from 12 patients diagnosed with behavioral variant frontotemporal dementia (bvFTD) and 12 cognitively normal elderly individuals. While unimodality analyses showed widespread brain atrophy and hypoperfusion in the patients, jICA further revealed two significant joint components of variations between atrophy and hypoperfusion across brain regions. The 1st joint component revealed associated brain atrophy and hypoperfusion predominantly in the right brain hemisphere in behavioral variant frontotemporal dementia, and the 2nd joint component revealed greater atrophy relative to hypoperfusion affecting predominantly the left hemisphere in behavioral variant frontotemporal dementia. The patterns are consistent with the clinical symptoms of behavioral variant frontotemporal dementia that relate to asymmetric compromises of the left and right brain hemispheres. The joint components also revealed that that structural alterations can be associated with physiological alterations in spatially separated but potentially connected brain regions. Finally, jICA outperformed voxel-by-voxel unimodal tests significantly in terms of an effect size, separating the behavioral variant frontotemporal dementia patients from the controls. Taken together, the results demonstrate the benefit of multimodality MRI in conjunction with jICA for mapping neurodegeneration, which may lead ultimately to an improved diagnosis of behavioral variant frontotemporal dementia and other forms of neurodegenerative diseases.

Utility of an abbreviated version of the executive and social cognition battery in the detection of executive deficits in early behavioral variant frontotemporal dementia patients

The detection of executive deficits in early behavioral variant frontotemporal dementia (bvFTD) is crucial, as impairments in the executive domain constitute an important diagnostic feature of the newly proposed diagnostic criteria for bvFTD. Our group has recently demonstrated that classical executive tests fail to detect the executive deficits of a subgroup of early bvFTD patients. When administered an executive and social cognition battery (ESCB) that includes tasks that mimic everyday scenarios (e.g., affective decision-making, planning and organization, theory of mind), however, the performance of those bvFTD patients differed significantly from that of controls. One limitation of the ESCB is its lengthy nature (approximately 90 min). For this reason, the present study analyzes the usefulness of alternative shorter versions of this battery. We propose one particular two-task combination that demands approximately 30 min for its administration and scoring, and which presents similar discriminatory accuracy as that of the complete ESCB, while maintaining its significantly superior capacity to detect subtle executive deficits in bvFTD patients relative to classical executive tests. We suggest that, in clinical settings where tools, time, or human resources are scarce, this abbreviated ESCB may be useful in the detection of subtle yet impairing executive impairments of patients with bvFTD.

A neuropsychological battery to detect specific executive and social cognitive impairments in early frontotemporal dementia

Traditional cognitive tests may not be sensitive for the early detection of executive and social cognitive impairments in the behavioural variant of frontotemporal dementia. The aim of this study was to detect specific executive and social cognitive deficits in patients with early behavioural variant frontotemporal dementia using a battery of tests previously shown to be sensitive to frontal lobe dysfunction. Behavioural variant frontotemporal dementia patients and paired controls were assessed with a complete standard neuropsychological battery evaluating attention, memory, visuospatial abilities, language and executive functions. All participants were then assessed with our Executive and Social Cognition Battery, which included Theory of Mind tests (Mind in the Eyes, Faux Pas), the Hotel Task, Multiple Errands Task-hospital version and the Iowa Gambling Task for complex decision-making. Patients were divided into two groups according to their Addenbrooke's Cognitive Examination scores, a measure of general cognitive status. Low Addenbrooke's Cognitive Examination patients differed from controls on most tasks of the standard battery and the Executive and Social Cognition Battery. While high Addenbrooke's Cognitive Examination patients did not differ from controls on most traditional neuropsychological tests, significant differences were found between this high-functioning behavioural variant of frontotemporal dementia group and controls on most measures of our Executive and Social Cognition Battery. Our results suggest that the Executive and Social Cognition Battery used in this study is more sensitive in detecting executive and social cognitive impairment deficits in early behavioural variant of frontotemporal dementia than the classical cognitive measures.

Activities of Daily Living in Behavioral Variant Frontotemporal Dementia

Patients with the behavioral variant of frontotemporal dementia have marked impairment in everyday life, yet little is known about factors underlying this impairment. Moreover, a recently identified subgroup with normal brain imaging has an excellent prognosis (phenocopy cases) and their performance on activities of daily living (ADL) tasks is unknown. Eighteen behavioral variant frontotemporal dementia patients were assessed on 2 ADL measures, the Disability Assessment for Dementia, a caregiver-based interview, and the Assessment of Motor and Process Skills, a performance-based instrument. Behavior change, global cognition, executive function, and magnetic resonance imaging brain atrophy were also evaluated. There was no association between the 2 ADL measures. A model combining the Addenbrooke's Cognitive Examination Revised (global cognition) and Frontal Systems Behavior Scale (frontal dysfunction) explained the variance on ADL performance. A qualitative rating distinguished between pathologic and phenocopy patients better than the performance-based assessment. Degree of frontal dysfunction and overall dementia determined the level of ADL impairment. The phenocopy patients were clearly distinguishable when evaluated using a performance-based, and even better with a qualitative rating assessment.

Clinical Features of Pathologic Subtypes of Behavioral-Variant Frontotemporal Dementia

To identify clinical features in behavioral-variant frontotemporal dementia that may help predict tau-positive pathology. Clinical and historical features of patients with pathologically confirmed tau-positive and tau-negative frontotemporal lobar degeneration from 1970 to 2006 were retrospectively reviewed in a blinded fashion. The initial clinical features of those patients who eventually met consensus criteria for frontotemporal dementia were examined using univariate and cluster analyses to explore characteristics that may be associated with tau pathology. Fifty-six patients (24 tau-positive cases) were included in the analysis. There was no difference in demographics between the tau-positive and tau-negative cases. Univariate analysis showed that poor planning and/or judgment was more commonly associated with tau-positive pathology (P = .03). Cluster analysis using behavioral characteristics identified 2 groups of patients: cluster 1 contained mainly tau-positive cases (57%) and cluster 2 was mostly tau-negative cases (71%). Poor planning and/or judgment was a common presenting sign in the first group (P < .001), while the second group was more likely to present with impaired regulation of personal conduct (P < .001) and a decline in personal hygiene (P = .005). Poor planning and/or judgment was associated with behavioral-variant frontotemporal dementia patients who had tau-positive pathology. The constellation of impaired personal conduct and a paucity of dysexecutive symptoms identified tau-negative patients.