Memantine for behavioral disturbances in frontotemporal dementia: a case series

BACKGROUND: Frontotemporal dementia (FTD) is one of the more common presenile dementias. Unlike Alzheimer disease, there are no approved medications to treat this debilitating condition. OBJECTIVE: To report the response of memantine on the behavioral manifestations of FTD. DESIGN: Case series of 3 patients diagnosed with FTD and treated with memantine. RESULTS: All 3 patients showed an improvement in total Neuropsychiatric Inventory score with specific improvements in the subscale scores of apathy, agitation, and anxiety. Memantine was well tolerated in all patients. CONCLUSIONS: This small case series supports the notion that memantine may have a beneficial effect on the neuropsychiatric symptoms of FTD and should be further studied in a prospective clinical trial.     

Diminished disgust reactivity in behavioral variant frontotemporal dementia

Frontotemporal dementia is a neurodegenerative disease that impacts emotion and social behavior. Using laboratory measures of emotional reactivity, our past work has found that reactivity to loud noises and to thematically simple happy and sad emotional films are preserved in the early stages of the disease while other emotional responses (e.g., embarrassment) are severely compromised. In the present study we examined disgust, an emotion whose function is to distance us from offending objects and situations. We measured disgust reactivity in 21 patients with behavioral variant frontotemporal dementia (bvFTD, a subtype of frontotemporal dementia characterized by emotional blunting) and 25 neurologically healthy controls. Disgust is an emotion of particular interest in bvFTD, due to caregiver and clinician reports that patients engage in acts that suggest this emotion may be compromised; in addition, the pattern of neurodegeneration in bvFTD includes atrophy of key frontotemporal structures (e.g., anterior insula) with known roles in visceral emotions such as disgust. In the present study, participants had their emotional facial behavior, physiology, and self-reported emotional experience measured while watching a disgust-eliciting film. We found that behavioral, physiological, and self-reported experiential responses were all reduced in bvFTD patients compared to controls (with behavioral and physiological differences still found after controlling for patients' cognitive deficits). We discuss the implications of these findings for bvFTD patients' problems in social functioning and their typical patterns of neurodegeneration.     

Emotional evaluation and memory in behavioral variant frontotemporal dementia

Behavioral variant frontotemporal dementia (bvFTD) affects emotional evaluation, but less is known regarding the patients’ ability to remember emotional stimuli. Here, bvFTD patients and age-matched controls studied positive, negative, and neutral pictures followed by a recognition memory test. Compared to controls, bvFTD patients showed a reduction in emotional evaluation of negative scenes, but not of positive or neutral scenes. Additionally, the patients showed an overall reduction in recognition memory accuracy, due to impaired recollection in the face of relatively preserved familiarity. These results show that bvFTD reduces the emotional evaluation of negative scenes and impairs overall recognition memory accuracy and recollection.     

Distribution of brain atrophy in behavioral variant frontotemporal dementia

Marked brain atrophy occurs in frontotemporal dementia (FTD) yet substantial variation between cases is seen. Recently, a four-level staging scheme which reflects increasing disease duration, severity of dementia and degree of neurodegeneration was described. In the present study, the extent and magnitude of atrophy in behavioral variant FTD and its relationship to disease duration and pathological subtype was further evaluated by quantifying the volume of 30 anatomically-defined regions. A validated point count technique was applied to 17 patients with FTD (9 Pick's disease, 6 dementia lacking distinctive histology, 2 FTD with motor neuron disease) and 21 controls. Atrophy was seen in all brain regions except the inferior frontal cortex and area 37. As might be expected, increasing severity of atrophy occurred with increasing disease duration and stage however measurable atrophy was more widespread than indicated by the staging scheme. Furthermore, severity of atrophy was not related to pathological subtype. Frontal, limbic and temporal regions appeared to be severely affected early in the disease process with temporal lobe atrophy the best predictor of disease duration. White matter, more posterior regions and the subcortex were affected later in the disease. These findings demonstrate a pattern of selective vulnerability which progresses over time. Furthermore, they demonstrate that although patients with a similar clinical subtype may have differing underlying histopathology, the pattern, severity and progression of brain atrophy is the same. This suggests that the regional pattern of neurodegeneration, rather than the type of histopathology influences the clinical syndrome in FTD.     

Cognitive correlates of negative symptoms in behavioral variant frontotemporal dementia: implications for the frontal lobe syndrome

Although both behavioral disturbances and executive impairments of patients with the behavioral variant frontotemporal dementia (bvFTD) seem to depend on early neurodegenerative damages to the prefrontal cortex, the relationship between these two distinct clinical features has been only partially established and represents the focus of the current preliminary neuropsychological study. Ten subsequent bvFTD patients underwent a neuropsychiatric assessment with the Frontal Behavior Inventory and a neuropsychological battery focused on prefrontal functions. Significant correlations were found only between negative symptoms and measures of prevalent medial prefrontal functioning, i.e. decision making under ambiguity (Iowa gambling task) (r = ?0.887; p = 0.018) and affective theory of mind (reading the mind in the eyes task) (r = ?0.982; p = 0.017). This finding could preliminary support a “frontal lobe syndrome” hypothesis for negative symptoms of bvFTD patients, as proposed for negative symptoms of schizophrenia; the small sample size represents a limit and empirical findings need replication in larger samples of bvFTD patients.     

Neural correlates of episodic memory in behavioral variant frontotemporal dementia

Impaired episodic memory is currently an exclusion criterion for behavioral variant frontotemporal dementia (bv-FTD), although prior studies have shown that neuropsychological memory performance varies from very impaired to intact in such patients. Our study investigated i) whether this variability might be due to the admixture of true bv-FTD and phenocopy syndrome patients and ii) the neural correlates of episodic memory deficits in bvFTD. Groups of patients with true bvFTD (n = 14), phenocopy syndrome (n = 6), Alzheimer's disease (AD) (n = 14), and healthy controls (n = 15) underwent memory testing and had MRI scanning with ratings of regional brain atrophy. Phenocopy patients did not differ to controls on memory scores or atrophy ratings. By contrast, bvFTD and AD patients were impaired on both measures in comparison to controls and more importantly, bvFTD and AD did not differ on memory scores. Atrophy patterns differed, with AD showing typical medial temporal lobe atrophy, while bvFTD patients had predominantly prefrontal cortex atrophy. In bvFTD neuropsychological memory performance correlated with frontal atrophy ratings while in AD significant correlations were found between memory and both medial temporal lobe and frontal atrophy ratings. Taken together, out data shows that bvFTD patients can show a similar degree of episodic memory impairment on neuropsychological tests to AD patients, however, the neural correlates differ. The previously variable reported memory performance in bvFTD is likely due to the inclusion of phenocopy patients, who are mostly undistinguishable from controls. These findings have implications for the diagnosis of bvFTD.     

Functional network connectivity in the behavioral variant of frontotemporal dementia

Introduction

The aim of this study was to investigate, using resting state (RS) functional magnetic resonance imaging (fMRI), the functional connectivity within and among brain networks in patients with the behavioral variant of frontotemporal dementia (bvFTD), compared with healthy controls and patients with probable Alzheimer's disease (pAD).

Methods

Twelve bvFTD patients were compared with 30 controls and 18 pAD patients. Functional connectivity within the salience, default mode (DMN), executive (EXN), attention/working memory (ATT/WM), and dorsal attentional networks was assessed using independent component analysis. The temporal associations among RS networks (RSNs) were explored using the functional network connectivity toolbox.

Results

A decreased dorsal salience network (DSN) connectivity, mainly involving the anterior cingulum, was observed in bvFTD versus controls and pAD. BvFTD was also characterized by a decreased ventral salience network connectivity in the basal ganglia, and divergent connectivity effects versus controls in the dorsolateral prefrontal cortex (decreased) and precuneus (enhanced) within the right ATT/WM network. The dorsal attentional network had a decreased connectivity with the DMN and EXN in bvFTD versus controls, and a decreased connectivity with the DSN versus pAD.

Conclusions

RSN functional abnormalities occur in bvFTD, involving not only the salience network, but also the DMN and fronto-parietal network associated with ATT and WM modulation. The pattern of functional changes differs from that seen in pAD. The altered interactions among RSN observed in bvFTD and pAD may provide a new venue to explore the functional correlates of cognitive abnormalities in neurodegenerative and psychiatric disorders.     

Bupropion improved apathy in behavioral variant frontotemporal dementia: a case report

ABSTRACT

Apathy is a common neurobehavioral sign in cases of behavioral variant frontotemporal dementia. However, there is still no established sustained effective treatment. We present the case of a 65-year-old man with behavioral variant frontotemporal dementia who suffered from severe apathy, but his apathy improved after a 10-month period of bupropion treatment. His single photon emission computed tomography report also showed slight improvement. To the best of our knowledge, such a case with imaging evidence has never been reported. Further studies to correlate the effects of bupropion on apathy in behavioral variant frontotemporal dementia patients are clearly needed.     

Contextual social cognition and the behavioral variant of frontotemporal dementia

The significance of social situations is commonly context-embedded. Although the role of context has been extensively studied in basic sensory processing or simple stimulus-response settings, its relevance for social cognition is unknown. We propose the social context network model (SCNM), a fronto-insular-temporal network responsible for processing social contextual effects. The SCNM may 1) update the context and use it to make predictions, 2) coordinate internal and external milieus, and 3) consolidate context-target associative learning. We suggest the behavioral variant of frontotemporal dementia (bvFTD) as a specific disorder in which the reported deficits in social cognition (e.g., facial recognition, empathy, decision-making, figurative language, theory of mind) can be described as context impairments due to deficits in the SCNM. Disruption of orbitofrontal-amygdala circuit, as well as the frontal, temporal, and insular atrophy in bVFTD, suggests a relationship between context-sensitive social cognition and SCNM. In considering context as an intrinsic part of social cognition, we highlight the need for a situated cognition approach in social cognition research as opposed to an abstract, universal, and decontextualized approach. The assessment of context-dependent social cognition paradigms, the SCNM, and their possible application to neuropsychiatric disorders may provide new insight into bvFTD and other related frontal disorders.     

Neuropsychiatric symptoms in behavioral variant frontotemporal dementia and primary progressive aphasia

Neuropsychiatric symptoms are well defined in behavioral variant frontotemporal dementia but are not as well studied in primary progressive aphasia. This study compared caregiver reported neuropsychiatric symptoms in these 2 forms of dementia at short and long disease duration. Patients with behavioral variant frontotemporal dementia had more symptoms than patients with primary progressive aphasia. However, when divided by duration of disease, patients with primary progressive aphasia with long duration had a similar number of symptoms to patients with behavioral variant frontotemporal dementia at either duration. Furthermore, this group of patients with primary progressive aphasia had more symptoms typical of behavioral variant frontotemporal dementia and less mood-related symptoms which were more common in patients with primary progressive aphasia with shorter duration. This study illustrates the emergence of neuropsychiatric symptoms as primary progressive aphasia progresses and highlights the increasing overlap with behavioral variant frontotemporal dementia because the disease affects areas outside of the language network.     

Frontal paralimbic network atrophy in very mild behavioral variant frontotemporal dementia

BACKGROUND: Behavioral variant frontotemporal dementia (bvFTD) strikes hardest at the frontal lobes, but the sites of earliest injury remain unclear. OBJECTIVE: To determine atrophy patterns in distinct clinical stages of bvFTD, testing the hypothesis that the mildest stage is restricted to frontal paralimbic cortex. DESIGN: A bvFTD cohort study. SETTING: University hospital dementia clinic. PARTICIPANTS: Patients with bvFTD with Clinical Dementia Rating (CDR) scale scores of 0.5 (n = 15), 1 (n = 15), or 2 to 3 (n = 15) age and sex matched to each other and to 45 healthy controls. MAIN OUTCOME MEASURES: Magnetic resonance voxel-based morphometry estimated gray matter and white matter atrophy at each disease stage compared with controls. RESULTS: Patients with a CDR score of 0.5 had gray matter loss in frontal paralimbic cortices, but atrophy also involved a network of anterior cortical and subcortical regions. A CDR score of 1 showed more extensive frontal gray matter atrophy and white matter losses in corpus callosum and brainstem. A CDR score of 2 to 3 showed additional posterior insula, hippocampus, and parietal involvement, with white matter atrophy in presumed frontal projection fibers. CONCLUSIONS: Very mild bvFTD targets a specific subset of frontal and insular regions. More advanced disease affects white matter and posterior gray matter structures densely interconnected with the sites of earliest injury.     

The behavioral variant of frontotemporal dementia: linking neuropathology to social cognition

The behavioral variant of frontotemporal dementia (bvFTD) is one of the most frequent neurodegenerative disorders with a presenile onset. It is characterized by a long phase of subclinical behavioral changes and social conduct disorders, associated with a progressive modification of personality. Recently, an international consortium of experts developed revised guidelines for its clinical diagnosis, which highlight the supportive role of biomarkers in the diagnostic process. According to new criteria, bvFTD can be classified in “possible” (requiring three of six specific clinical features), “probable” (in the presence of functional disability and typical neuroimaging features), and “with definite frontotemporal lobar degeneration” (requiring the presence of a known causal mutation or a histopathological confirmation). Familial aggregation is frequently reported in bvFTD and frontotemporal lobar degeneration in general, with an autosomal dominant transmission in about 10 % cases. The aim of this paper is to review and discuss recent advances in the knowledge of clinical, neuropsychological, and imaging features of bvFTD. We also briefly summarize the available genetic information about the frontotemporal lobar degeneration spectrum.     

The neuropsychological correlates of pathological lying: evidence from behavioral variant frontotemporal dementia

To assess the neuropsychological bases of deception in a case of pathological lying. Pathological lying describes a clinical picture in which an individual repeatedly and apparently compulsively tells false stories. Developmental studies and neuroimaging studies suggested that executive functions and Theory of Mind are necessary for deception and that a dysfunctional prefrontal cortex may be involved in pathological lying. A patient presenting a pattern of behavioral alterations, including pathological lying, underwent a neurological, neuroradiological, neuropsychiatric, and neuropsychological examination. Psychopathological symptoms and cognitive deficits (executive functions and Theory of Mind) were suggestive of a behavioral variant frontotemporal dementia (bvFTD), while the lack of prefrontal hypometabolism was suggestive of a bvFTD phenocopy syndrome. This first observation of pathological lying as a symptom of bvFTD contributes to characterize its spectrum of psychopathological features. Moreover, this clinical case contributed to describe the possible neurocognitive deficits involved in the development of pathological lying. Further studies are needed to investigate how a prefrontal impairment affecting executive functions and Theory of Mind may cause a susceptibility to pathological lying.     

Progression in frontotemporal dementia: identifying a benign behavioral variant by magnetic resonance imaging

OBJECTIVE: To assess the clinical course and prognosis in patients with behavioral-variant frontotemporal dementia (FTD) lacking evidence of brain atrophy on magnetic resonance imaging (MRI). DESIGN: Patients were enrolled into this prospective cohort study over a period of 15 years; cognitive status, duration of symptoms, and behavioral indexes were recorded. Brain MRIs were rated using a standardized scale. SETTING: Regional early-onset dementia clinic. PARTICIPANTS: Thirty-one participants diagnosed clinically with behavioral-variant FTD. Intervention Rating of MRIs. MAIN OUTCOME MEASURES: Death or institutionalization after a minimum of 3 years' follow-up indicated poor prognosis, while the ability to live independently was regarded as a good prognosis for the purpose of survival (Kaplan-Meier) and discriminant function analysis. RESULTS: Patients with normal or borderline MRI findings (n = 15) showed significantly longer survival to institutionalization or death than those (n = 16) with definite frontotemporal atrophy (mean +/- SE, 9.3 +/- 1.7 years vs 3.0 +/- 0.7 years; P<.01). Using groups defined by 3-year outcome (good or bad prognosis), cerebral atrophy predicted poor outcome while age, symptom duration, cognitive performance, behavioral impairment, and overall disability at baseline did not. CONCLUSIONS: Patients with FTD with normal MRI results follow a more benign course than cases with atrophy at presentation. The substrate of the behavioral symptoms in such cases may differ from the neurodegenerative pathological features typically associated with FTD.     

Neural correlates of empathic impairment in the behavioral variant of frontotemporal dementia

ObjectiveLoss of empathy is a symptom of the behavioral variant of frontotemporal dementia (bvFTD), constituting a clue for early diagnosis. In this study, we directly compared two empathy components (intention attribution [IA] and emotion attribution [EA]), correlating them with possible specific patterns of gray-matter density reduction within the mentalizing network.MethodsWe evaluated IA and EA in 18 mild bvFTD patients compared with 36 healthy controls (HCs) using a single nonverbal test. A subgroup entered a voxel-based morphometry study.ResultsCompared with HC, bvFTD patients showed IA and EA impairments. EA performance correlated with gray-matter reduction in the right amygdala, left insula, and posterior-superior temporal sulcus extending into the temporoparietal junction.ConclusionWe proved an empathic impairment, with the ability to infer emotional states showing the most severe deficit. These results provide further evidence of selective disease-specific vulnerability of the limbic and frontoinsular network in bvFTD and highlight the usefulness of empathy assessment in early patients.     

The mini-mental state examination in behavioral variant frontotemporal dementia and primary progressive aphasia

There is little information regarding the usefulness of the Mini-Mental State Examination (MMSE) for tracking progression of non-Alzheimer's disease dementias. This study examined the utility of the MMSE in capturing disease severity in the behavioral variant frontotemporal dementia (bvFTD) and primary progressive aphasia (PPA), 2 nonamnestic clinical dementia syndromes. Retrospective data from 41 bvFTD and 30 PPA patients were analyzed. bvFTD patients' change in MMSE scores over time was significantly correlated with change over time on a measure of activities of daily living. In contrast, PPA patients' MMSE scores showed greater decline over time than scores on the activities of daily living scale. Results suggest that the MMSE score, heavily dependent on language skill, overestimates dementia severity in PPA patients. However, the score may be a more accurate measure of functional impairment in bvFTD due to the influence of their executive function and attentional deficits on MMSE performance.