Altered reward processing underpins emotional apathy in dementia.

INTRODUCTION: While apathy is broadly defined as a loss of motivation, it is increasingly recognised as a multidimensional syndrome spanning executive, emotional, and initiation domains. Emotional apathy is purportedly driven by deficits in using socioemotional rewards to guide behaviour, yet the link between these symptoms and reward processing, and their common neural correlates, has not been directly examined. METHODS: Sixty-four patients (33 behavioural-variant frontotemporal dementia, 14 Alzheimer's disease, 8 semantic dementia, 6 progressive nonfluent aphasia, 3 logopenic progressive aphasia) were classified into high (HEA; n = 36) and low (LEA; n = 28) emotional apathy groups based on emotional apathy subscale scores on the Dimensional Apathy Scale. Patients and age-matched healthy controls (n = 27) performed an instrumental reward learning task where they learned to associate cues with either social or monetary outcomes. RESULTS: HEA patients showed impaired learning on both the social and monetary reward conditions, relative to LEA patients (p = 0.016) and controls (p = 0.005). Conversely, the LEA group did not differ from controls (p = 0.925). Importantly, multiple regression analyses indicated that social reward learning significantly predicted emotional apathy. Voxel-based morphometry analyses revealed that emotional apathy and social reward learning were both associated with orbitofrontal cortex, ventral striatum, and insula atrophy. DISCUSSION: Our results demonstrate a unique link between impaired social reward learning and emotional apathy in dementia and reveal a shared neurobiological basis. Greater understanding of these neurocognitive mechanisms of reward processing will help improve the identification of emotional apathy in dementia and inform the development of novel interventions to address these symptoms.

Current Potential for Clinical Optimization of Social Cognition Assessment for Frontotemporal Dementia and Primary Psychiatric Disorders.

Dodich and colleagues recently reviewed the evidence supporting clinical use of social cognition assessment in behavioral variant frontotemporal dementia (Dodich et al., 2021). Here, we comment on their methods and present an initiative to address some of the limitations that emerged from their study. In particular, we established the social cognition workgroup within the Neuropsychiatric International Consortium Frontotemporal dementia (scNIC-FTD), aiming to validate social cognition assessment for diagnostic purposes and tracking of change across clinical situations.

Error profiles of facial emotion recognition in frontotemporal dementia and Alzheimer's disease.

OBJECTIVES: To identify the patterns of errors in facial emotion recognition in frontotemporal dementia (FTD) subtypes compared with Alzheimer's disease (AD) and healthy controls. DESIGN: Retrospective analysis. SETTING: Participants were recruited from FRONTIER, the frontotemporal dementia research group at the University of Sydney, Australia. PARTICIPANTS: A total of 356 participants (behavioral-variant FTD (bvFTD): 62, semantic dementia (SD)-left: 29, SD-right: 14, progressive non-fluent aphasia (PNFA): 21, AD: 76, controls: 90) were included. MEASUREMENTS: Facial emotion recognition was assessed using the Facial Affect Selection Task, a word-face matching task measuring recognition of the six basic emotions (anger, disgust, fear, happiness, sadness, and surprise), as well as neutral emotion, portrayed by black and white faces. RESULTS: Overall, all clinical groups performed significantly worse than controls with the exception of the PNFA subgroup (p = .051). The SD-right group scored worse than all other clinical groups (all p values < .027) and the bvFTD subgroup performed worse than the PNFA group (p < .001). The most frequent errors were in response to the facial emotions disgust (26.1%) and fear (22.9%). The primary error response to each target emotion was identified; patterns of errors were similar across all clinical groups. CONCLUSIONS: Facial emotion recognition is impaired in FTD and AD compared to healthy controls. Within FTD, bvFTD and SD-right are particularly impaired. Dementia groups cannot be distinguished based on error responses alone. Implications for future clinical diagnosis and research are discussed.

Gaps in clinical research in frontotemporal dementia: A call for diversity and disparities-focused research.

Frontotemporal dementia (FTD) is one of the leading causes of dementia before age 65 and often manifests as abnormal behavior (in behavioral variant FTD) or language impairment (in primary progressive aphasia). FTD's exact clinical presentation varies by culture, language, education, social norms, and other socioeconomic factors; current research and clinical practice, however, is mainly based on studies conducted in North America and Western Europe. Changes in diagnostic criteria and procedures as well as new or adapted cognitive tests are likely needed to take into consideration global diversity. This perspective paper by two professional interest areas of the Alzheimer's Association International Society to Advance Alzheimer's Research and Treatment examines how increasing global diversity impacts the clinical presentation, screening, assessment, and diagnosis of FTD and its treatment and care. It subsequently provides recommendations to address immediate needs to advance global FTD research and clinical practice.

Plasma Oxytocin Is Not Associated with Social Cognition or Behavior in Frontotemporal Dementia and Alzheimer's Disease Syndromes.

INTRODUCTION: Changes in social behavior and emotion processing are common in frontotemporal dementia (FTD) and semantic dementia (SD), and less so in Alzheimer's disease (AD). Recent research has investigated oxytocin as a potential treatment for these symptoms; however, whether plasma oxytocin is associated with social-emotional symptoms of dementia remains underexplored. METHODS: Thirty behavioral-variant FTD (bvFTD), 28 SD, 39 AD, and 24 controls underwent blood sampling to measure oxytocin. Participants completed an emotion processing battery. Carers completed the Cambridge Behavioral Inventory and the Neuropsychiatric Inventory. RESULTS: Patients with bvFTD were severely impaired in emotion processing and behavioral ratings, with milder impairment in SD and AD. No difference in plasma oxytocin was observed between groups (p = 0.632). No significant associations were found between oxytocin and social behavior or emotion processing (r values between -0.241 and 0.227, all p values >0.099). CONCLUSION: Our results indicate that plasma oxytocin is not reduced in dementia and is unrelated to social, emotional, and behavioral features. We noted high interindividual variability in our data; hence, future investigations should consider methodological influences such as serum versus saliva and diurnal variation on oxytocin function. These results demonstrate that current measurement measures of plasma oxytocin have limited utility in determining the role of oxytocin in FTD. Alternative oxytocin measures may prove more sensitive and should be considered when conducting clinical trials.

Adaptation, Validation and Preliminary Standardisation of the Frontal Systems Behaviour Scale - Apathy Subscale and the Dimensional Apathy Scale in Vietnamese Healthy Samples.

OBJECTIVE: Apathy, the reduction of motivation and goal-directed behaviour, is a ubiquitous behavioural syndrome in many neurological disorders. However, apathy measures are limited in non-English speaking countries. The present study aimed to develop a culturally appropriate version of the Vietnamese Frontal Systems Behavioural Scale-Apathy subscale (V-FrSBe-A) and Dimensional Apathy Scale (V-DAS), examine their internal reliability and construct validity (i.e., factor structure, convergent and divergent validity) in a Vietnamese healthy sample and establish preliminary normative cut-offs for clinical and research applications. METHOD: In total, 112 healthy subjects and 64 informants completed the self-report and informant report V-FrSBe-A and V-DAS, developed using a translation, back-translation and cultural adaptation procedure. McDonald's omega was applied to examine internal reliability. The internal structure of the V-DAS was evaluated using exploratory structural equation model. For both apathy scales, convergent validity was determined by correlations between scales and between informant and self-report versions. Regarding divergent validity, participants completed the Vietnamese Depression Anxiety Stress Scale-21 and V-FrSBe-Disinhibition for depression and disinhibition assessment. RESULTS: Both the V-FrSBe-A and V-DAS were reliable (ωt ≥ .74). Dimensional manifestations of apathy in executive, emotional and initiation domains were confirmed on the V-DAS. Both scales were also valid, convergent with each other and divergent from depression and disinhibition symptoms. Cut-off scores for both scales were higher than their English versions. CONCLUSION: The adapted V-FrSBe-A and V-DAS have good reliability and validity for the potential application in clinical groups to advance current knowledge about apathy transculturally and direct more effective clinical care for Vietnamese individuals with neurological disorders.

Examining the presence and nature of delusions in Alzheimer's disease and frontotemporal dementia syndromes.

OBJECTIVES: Abnormal beliefs and delusions have been reported in some people with dementia, however, the prevalence of delusions, and their neurocognitive basis has been underexplored. This study aimed to examine the presence, severity, content and neural correlates of delusions in a large, well-characterised cohort of dementia patients using a transdiagnostic, cross-sectional approach. METHODS: Four-hundred and eighty-seven people with dementia were recruited: 102 Alzheimer's disease, 136 behavioural-variant frontotemporal dementia, 154 primary progressive aphasia, 29 motor neurone disease, 46 corticobasal syndrome, 20 progressive supranuclear palsy. All patients underwent neuropsychological assessment and brain magnetic resonance imaging, and the Neuropsychiatric Inventory was conducted with an informant, by an experienced clinician. RESULTS: In our cohort, 48/487 patients (10.8%) had delusions. A diagnosis of behavioural-variant frontotemporal dementia (18.4%) and Alzheimer's disease (11.8%) were associated with increased risk of delusions. A positive gene mutation was observed in 11/27 people with delusions. Individuals with frequent delusions performed worse on the Addenbrooke's Cognitive Examination (p = 0.035), particularly on the orientation/attention (p = 0.022) and memory (p = 0.013) subtests. Voxel-based morphometry analyses found that increased delusional psychopathology was associated with reduced integrity of the right middle frontal gyrus, right planum temporale and left anterior temporal pole. CONCLUSION: Our results demonstrate that delusions are relatively common in dementia and uncover a unique cognitive and neural profile associated with the manifestation of delusions. Clinically, delusions may lead to delayed or misdiagnosis. Our results shed light on how to identify individuals at risk of neuropsychiatric features of dementia, a crucial first step to enable targeted symptom management.

Managing communication changes in persons with multiple sclerosis: Findings from qualitative focus groups.

BACKGROUND: There is growing recognition that communication can be affected in multiple sclerosis (MS) and can negatively impact relationships, employment and psychological well-being. Some persons with MS (PwMS) implement strategies to facilitate their communication; however, some do not. Most PwMS who report communication changes do not engage with speech-language pathology (SLP) services. This raises concerns that a large portion of communication changes associated with MS go under-recognized and unmanaged. Little is known about what PwMS want and need to facilitate effective communication. AIM: To explore what PwMS want and need to better manage their communication changes. METHODS & PROCEDURES: Three focus groups were conducted online using Zoom, with a total of 12 PwMS. Participants were an opportunistic sample of PwMS within Australia recruited via advertisements distributed to various MS organizations and clinics. Data were transcribed verbatim and analysed using thematic content analysis to provide a qualitative analysis of the data. OUTCOMES & RESULTS: Two main themes emerged: (1) accessible knowledge and a holistic approach; and (2) partnerships. Specifically, the identified wants and needs of participants included: (1) assessment; (2) information; (3) raising awareness; (4) support groups; (5) a whole-person approach to intervention; (6) geographically and economically accessible and navigable services; (7) effective patient-physician interactions; and (8) a multidisciplinary team-based approach (e.g., SLP, psychology, neuropsychology, occupational therapy). CONCLUSIONS & IMPLICATIONS: This study identified a wide range of unmet wants and needs of PwMS related to communication changes. Participants wanted improved collaborative partnerships with healthcare professionals to better manage their communication changes. For example, healthcare professionals could ask PwMS about potential communication changes, provide education and make appropriate referrals. Education and information provision could focus on communication changes in MS, factors that trigger or exacerbate communication changes, impacts, self-management strategies, and available supports and services. Specific implications for clinical practice and future research are suggested in this paper, including ideas for patient education materials and content, suggestions for communication-specific screening and information that could be shared in patient-physician interactions, the development of guidelines to systematically screen, assess, manage and monitor communication changes in MS, and the design of evidence-based communication interventions for this clinical population. The results from this study can be used to guide the design of supports and services to help PwMS better manage communication changes, with the aim to reduce the negative impacts. WHAT THIS PAPER ADDS: What is already known on this subject PwMS can experience communication changes across a range of domains, including speech, voice, fluency, expressive and receptive language, and cognitive-linguistic functions. These changes can have profound and far-reaching negative impacts on educational and vocational outcomes, social participation, relationships, psychological well-being, and quality of life. Most PwMS who report communication changes do not engage with SLP services. There has been little research exploring what PwMS want and need to help manage their communication changes. What this paper adds to the existing knowledge This research is the first study of its kind that sets out specifically to explore what PwMS want and need to better manage their communication changes. This study increases our understanding of, and provides valuable insights into, the specific types of supports and services PwMS desire to access, and the partnerships and kinds of interactions PwMS dream of having with healthcare professionals to manage these changes. This information can facilitate the development of future interventions to manage communication changes in MS. What are the potential or actual clinical implications of this work? PwMS wanted healthcare professionals to ask about potential communication changes, provide education and make appropriate referrals. When providing education and information on communication changes in MS, healthcare professionals should focus on covering symptoms, triggers, impacts, self-management strategies, and available supports and services. There is a timely need to develop guidelines and interventions to manage communication changes in MS to reduce their negative impacts.

Dynamic brain fluctuations outperform connectivity measures and mirror pathophysiological profiles across dementia subtypes: A multicenter study.

From molecular mechanisms to global brain networks, atypical fluctuations are the hallmark of neurodegeneration. Yet, traditional fMRI research on resting-state networks (RSNs) has favored static and average connectivity methods, which by overlooking the fluctuation dynamics triggered by neurodegeneration, have yielded inconsistent results. The present multicenter study introduces a data-driven machine learning pipeline based on dynamic connectivity fluctuation analysis (DCFA) on RS-fMRI data from 300 participants belonging to three groups: behavioral variant frontotemporal dementia (bvFTD) patients, Alzheimer's disease (AD) patients, and healthy controls. We considered non-linear oscillatory patterns across combined and individual resting-state networks (RSNs), namely: the salience network (SN), mostly affected in bvFTD; the default mode network (DMN), mostly affected in AD; the executive network (EN), partially compromised in both conditions; the motor network (MN); and the visual network (VN). These RSNs were entered as features for dementia classification using a recent robust machine learning approach (a Bayesian hyperparameter tuned Gradient Boosting Machines (GBM) algorithm), across four independent datasets with different MR scanners and recording parameters. The machine learning classification accuracy analysis revealed a systematic and unique tailored architecture of RSN disruption. The classification accuracy ranking showed that the most affected networks for bvFTD were the SN + EN network pair (mean accuracy = 86.43%, AUC = 0.91, sensitivity = 86.45%, specificity = 87.54%); for AD, the DMN + EN network pair (mean accuracy = 86.63%, AUC = 0.89, sensitivity = 88.37%, specificity = 84.62%); and for the bvFTD vs. AD classification, the DMN + SN network pair (mean accuracy = 82.67%, AUC = 0.86, sensitivity = 81.27%, specificity = 83.01%). Moreover, the DFCA classification systematically outperformed canonical connectivity approaches (including both static and linear dynamic connectivity). Our findings suggest that non-linear dynamical fluctuations surpass two traditional seed-based functional connectivity approaches and provide a pathophysiological characterization of global brain networks in neurodegenerative conditions (AD and bvFTD) across multicenter data.

Recommendations to distinguish behavioural variant frontotemporal dementia from psychiatric disorders.

The behavioural variant of frontotemporal dementia (bvFTD) is a frequent cause of early-onset dementia. The diagnosis of bvFTD remains challenging because of the limited accuracy of neuroimaging in the early disease stages and the absence of molecular biomarkers, and therefore relies predominantly on clinical assessment. BvFTD shows significant symptomatic overlap with non-degenerative primary psychiatric disorders including major depressive disorder, bipolar disorder, schizophrenia, obsessive-compulsive disorder, autism spectrum disorders and even personality disorders. To date, ∼50% of patients with bvFTD receive a prior psychiatric diagnosis, and average diagnostic delay is up to 5-6 years from symptom onset. It is also not uncommon for patients with primary psychiatric disorders to be wrongly diagnosed with bvFTD. The Neuropsychiatric International Consortium for Frontotemporal Dementia was recently established to determine the current best clinical practice and set up an international collaboration to share a common dataset for future research. The goal of the present paper was to review the existing literature on the diagnosis of bvFTD and its differential diagnosis with primary psychiatric disorders to provide consensus recommendations on the clinical assessment. A systematic literature search with a narrative review was performed to determine all bvFTD-related diagnostic evidence for the following topics: bvFTD history taking, psychiatric assessment, clinical scales, physical and neurological examination, bedside cognitive tests, neuropsychological assessment, social cognition, structural neuroimaging, functional neuroimaging, CSF and genetic testing. For each topic, responsible team members proposed a set of minimal requirements, optimal clinical recommendations, and tools requiring further research or those that should be developed. Recommendations were listed if they reached a ≥ 85% expert consensus based on an online survey among all consortium participants. New recommendations include performing at least one formal social cognition test in the standard neuropsychological battery for bvFTD. We emphasize the importance of 3D-T1 brain MRI with a standardized review protocol including validated visual atrophy rating scales, and to consider volumetric analyses if available. We clarify the role of 18F-fluorodeoxyglucose PET for the exclusion of bvFTD when normal, whereas non-specific regional metabolism abnormalities should not be over-interpreted in the case of a psychiatric differential diagnosis. We highlight the potential role of serum or CSF neurofilament light chain to differentiate bvFTD from primary psychiatric disorders. Finally, based on the increasing literature and clinical experience, the consortium determined that screening for C9orf72 mutation should be performed in all possible/probable bvFTD cases or suspected cases with strong psychiatric features.

Dementia in Latin America: Paving the way toward a regional action plan.

Across Latin American and Caribbean countries (LACs), the fight against dementia faces pressing challenges, such as heterogeneity, diversity, political instability, and socioeconomic disparities. These can be addressed more effectively in a collaborative setting that fosters open exchange of knowledge. In this work, the Latin American and Caribbean Consortium on Dementia (LAC-CD) proposes an agenda for integration to deliver a Knowledge to Action Framework (KtAF). First, we summarize evidence-based strategies (epidemiology, genetics, biomarkers, clinical trials, nonpharmacological interventions, networking, and translational research) and align them to current global strategies to translate regional knowledge into transformative actions. Then we characterize key sources of complexity (genetic isolates, admixture in populations, environmental factors, and barriers to effective interventions), map them to the above challenges, and provide the basic mosaics of knowledge toward a KtAF. Finally, we describe strategies supporting the knowledge creation stage that underpins the translational impact of KtAF.

Evaluating the reliability of neurocognitive biomarkers of neurodegenerative diseases across countries: A machine learning approach.

Accurate early diagnosis of neurodegenerative diseases represents a growing challenge for current clinical practice. Promisingly, current tools can be complemented by computational decision-support methods to objectively analyze multidimensional measures and increase diagnostic confidence. Yet, widespread application of these tools cannot be recommended unless they are proven to perform consistently and reproducibly across samples from different countries. We implemented machine-learning algorithms to evaluate the prediction power of neurocognitive biomarkers (behavioral and imaging measures) for classifying two neurodegenerative conditions -Alzheimer Disease (AD) and behavioral variant frontotemporal dementia (bvFTD)- across three different countries (>200 participants). We use machine-learning tools integrating multimodal measures such as cognitive scores (executive functions and cognitive screening) and brain atrophy volume (voxel based morphometry from fronto-temporo-insular regions in bvFTD, and temporo-parietal regions in AD) to identify the most relevant features in predicting the incidence of the diseases. In the Country-1 cohort, predictions of AD and bvFTD became maximally improved upon inclusion of cognitive screenings outcomes combined with atrophy levels. Multimodal training data from this cohort allowed predicting both AD and bvFTD in the other two novel datasets from other countries with high accuracy (>90%), demonstrating the robustness of the approach as well as the differential specificity and reliability of behavioral and neural markers for each condition. In sum, this is the first study, across centers and countries, to validate the predictive power of cognitive signatures combined with atrophy levels for contrastive neurodegenerative conditions, validating a benchmark for future assessments of reliability and reproducibility.

Frontotemporal dementias: main syndromes and underlying brain changes.

PURPOSE OF REVIEW: Frontotemporal dementia (FTD) is a rare dementia, that accounts for about 15% of all dementia cases. Despite consensus diagnostic criteria, FTD remains difficult to diagnose in life because of its complex and variable clinical phenomenology and heterogeneous disorders. This review provides an update on the current knowledge of the main FTD syndromes -- the behavioural variant, semantic variant, and nonfluent/agrammatic variant-- their brain abnormalities and genetic profiles. RECENT FINDINGS: The complexity of the clinical features in FTD has become increasingly apparent, particularly in the domain of behaviour. Such behaviour changes are now also being recognized in the language variants of FTD. Initial interest on emotion processing and social cognition is now complemented by studies on other behavioural disturbance, that spans gambling, antisocial behaviours, repetitive behaviours, and apathy. At a biological level, novel pathological subcategories continue to be identified. From a genetic viewpoint, abnormalities in three genes explain nearly three quarters of familial cases of FTD. SUMMARY: In the absence of effective drug treatments, novel approaches are needed to target some of the most disabling features of FTD, such as language loss or behaviour disturbance. Recent interventions appear promising but will require confirmation.

The effects of choral singing on communication impairments in acquired brain injury: A systematic review.

BACKGROUND: Acquired brain injury (ABI), such as Parkinson's disease, dementia or stroke, can result in communication difficulties that lead to an impoverished ability to connect meaningfully with others. Choral singing is a complex task that uses multiple brain regions which are also responsible for language and communication skills. The potential therapeutic effects of group singing on communication-related outcomes across ABI aetiologies have not been systematically reviewed. AIMS: To examine whether participation in group singing over multiple sessions improves speech, voice, language and/or communication skills in individuals with ABI-related communication disorders. METHODS & PROCEDURES: A database search was undertaken according to the PRISMA guidelines. Search terms included: stroke OR Parkinson* OR dementia OR 'acquired brain injury' AND choir OR choral OR singing OR sing OR 'choral sing* ' OR group adj3 singing OR community adj3 singing AND speech OR language OR communication. MAIN CONTRIBUTION: A total of 11 studies were included. Nine were quantitative, including one randomized and one non-randomized control trial, and two were mixed method. Nine studies were scored as level IV (uncontrolled) on the American Academy of Neurology (AAN) Classification of Evidence Matrix and two as level III (e.g., lack of blinded assessors). Eight examined speech and voice skills in Parkinson's disease, two functional communication skills in post-stroke aphasia and one communication between individuals with dementia and a significant other. One level III control trials provided evidence for a therapeutic effect of group singing on communication in individuals with Parkinson's disease. CONCLUSIONS & IMPLICATIONS: Currently, there is only one study providing support for using group singing to improve speech and voice skills in people with Parkinson's disease, and no studies of adequate quality indicating positive effects on language and functional communication abilities in ABI. Further research using more rigorous experimental designs is required to determine whether group singing can influence communication skills in ABI. What this paper adds What is already known on the subject Music activates widespread, bilateral cortical and subcortical brain regions. Group singing is increasingly understood to have positive benefits on quality of life and health-related well-being in both healthy and clinical populations. Given the crossover in neural networks between singing, speech and language, singing activities are also thought to have positive effect of communication impairments secondary to ABI. However, to date, the research evidence supporting the application of group singing for communication impairments in ABI has not been summarized. What this paper adds to existing knowledge A total of 11 studies have looked at communication outcomes after group singing in ABI. For most of these, the quality of evidence was low (AAN level IV). It also highlights that there is a bias in the literature towards the studying individuals with Parkinson's disease (i.e., nine of the 11 studies). What are the potential or actual clinical implications of this work? This review concludes that, currently, there is emerging evidence to support positive effects of a group singing for speech and voice symptoms in individuals with Parkinson's disease, when provided using the Tamplin protocol. However, there is not yet any evidence for communication benefits for individuals with aphasia or dementia.

Facial expressiveness and physiological arousal in frontotemporal dementia: Phenotypic clinical profiles and neural correlates.

Early theories of emotion processing propose an interplay between autonomic function and cognitive appraisal of emotions. Patients with frontotemporal dementia show profound social cognition deficits and atrophy in regions implicated in autonomic emotional responses (insula, amygdala, prefrontal cortex), yet objective measures of facial expressiveness and physiological arousal have been relatively unexplored. We investigated psychophysiological responses (surface facial electromyography (EMG); skin conductance level (SCL)) to emotional stimuli in 25 behavioural-variant frontotemporal dementia (bvFTD) patients, 14 semantic dementia (SD) patients, and 24 healthy older controls, while viewing emotionally positive, neutral, or negative video clips. Voxel-based morphometry was conducted to identify neural correlates of responses. Unlike controls, patients with bvFTD did not show differential facial EMG responses according to emotion condition, whereas SD patients showed increased zygomaticus responses to both positive and neutral videos. Controls showed greater arousal (SCL) when viewing positive and negative videos; however, both bvFTD and SD groups showed no change in SCL across conditions. Regardless of group membership, right insula damage was associated with dampened zygomaticus responses to positive film stimuli. Change in arousal (SCL) was associated with lower integrity of the caudate, amygdala, and temporal pole. Our results demonstrate that while bvFTD patients show an overall dampening of responses, SD patients appear to show incongruous facial emotional expressions. Abnormal responding is related to cortical and subcortical brain atrophy. These results identify potential mechanisms for the abnormal social behaviour in bvFTD and SD and demonstrate that psychophysiological responses are an important mechanism underpinning normal socioemotional functioning.

Cerebellar atrophy and its contribution to cognition in frontotemporal dementias.

OBJECTIVE: Increasing evidence suggests that cerebellar damage impacts on cognitive functions. Frontotemporal dementias (FTDs) are neurodegenerative brain conditions, primarily affecting the frontal and/or temporal lobe. Three main phenotypes are recognized, each with a distinct clinical and cognitive profile: behavioral-variant FTD (bvFTD), semantic dementia (SD), and progressive nonfluent aphasia (PNFA). The severity of cerebellar changes and their relation to cognition in FTD, however, remain unclear. This study aimed to establish cerebellar gray matter changes on magnetic resonance imaging (MRI) and their relation to profiles of cognitive deficits in FTD subtypes. METHODS: Ninety-six FTD patients (45 bvFTD, 28 SD, and 23 PNFA), meeting current clinical diagnostic criteria, and 35 age-, sex-, and education-matched controls underwent brain MRI and cognitive assessment. Cerebral and cerebellar gray matter integrity were investigated using voxel-based morphometry. RESULTS: Compared with controls, widespread bilateral cerebellar changes were observed in all FTD subtypes, with the greatest atrophy present in bvFTD. Significant associations were found between cerebellar integrity and cognitive performance in attention and working memory in bvFTD, visuospatial function in SD, and language-motor function in PNFA. Bilateral atrophy of crus and lobule VI were most commonly associated with cognitive deficits, irrespective of FTD phenotype. INTERPRETATION: This study is the first to identify distinct patterns of cerebellar atrophy across FTD syndromes, which in turn relate to discrete cognitive dysfunctions, after accounting for the effect of cerebral atrophy. These findings extend our understanding of the cerebellum and point to its involvement across an array of processes beyond the domain of motor function. Ann Neurol 2018;83:98-109.

The Cerebellum in Frontotemporal Dementia: a Meta-Analysis of Neuroimaging Studies.

Frontotemporal dementia (FTD) is a neurodegenerative brain disorder primarily affecting the frontal and/or temporal lobes. Three main subtypes have been recognized: behavioural-variant FTD (bvFTD), semantic dementia (SD), and progressive nonfluent aphasia (PNFA), each of which has a distinct clinical and cognitive profile. Although the role of the cerebellum in cognition is increasingly accepted, knowledge of cerebellar changes across neuroimaging modalities and their contribution to behavioural and cognitive changes in FTD syndromes is currently scant. We conducted an anatomical/activation likelihood estimation (ALE) meta-analysis in 53 neuroimaging studies (structural MRI: 42; positron emission tomography: 6; functional MRI: 4; single-photon emission computed tomography: 1) to identify the patterns of cerebellar changes and their relations to profiles of behavioural and cognitive deficits in FTD syndromes. Overall, widespread bilateral cerebellar changes were found in FTD and notably the patterns were subtype specific. In bvFTD, ALE peaks were identified in the bilateral Crus, left lobule VI, right lobules VIIb and VIIIb. In SD, focal cerebellar changes were located in the left Crus I and lobule VI. A separate ALE meta-analysis on PNFA studies was not performed due to the limited number of studies available. In addition, the ALE analysis indicated that bilateral Crus I and Crus II were associated with behavioural disruption and cognitive dysfunction. This ALE meta-analysis provides the quantification of the location and extent of cerebellar changes across the main FTD syndromes, which in turn provides evidence of cerebellar contributions to behavioural and cognitive changes in FTD. These results bring new insights into the mechanisms mediating FTD symptomatology.

A new framework for conceptualizing symptoms in frontotemporal dementia: from animal models to the clinic.

Behavioural-variant frontotemporal dementia is characterized by a number of ostensibly disparate clinical features, which have largely been considered independently. This update proposes an integrated conceptual framework for these symptoms, by bringing together findings from animal studies, functional neuroimaging and behavioural neurology. The combined evidence indicates that many of the clinical symptoms--such as altered eating behaviour; overspending and susceptibility to scams; reduced empathy and socially inappropriate behaviour; apathy and stereotyped/ritualistic behaviour--can be conceptualized as a common underlying deficiency in goal-directed behaviour and the concomitant emergence of habits. This view is supported by similarities between the characteristic patterns of frontostriatal and insular atrophy in behavioural-variant frontotemporal dementia and the circuitry of homologous brain regions responsible for goal-directed and habitual behaviour in animals. Appreciating the impact of disturbance in goal-directed behaviour provides a new, integrated understanding of the common mechanisms underpinning prototypical clinical symptoms in behavioural-variant frontotemporal dementia. Furthermore, by drawing parallels between animal and clinical research, this translational approach has important implications for the development and evaluation of novel therapeutic treatments, from animal models through to behavioural interventions and clinical trials in humans.10.1093/brain/awy123_video1awy123media15796485557001.

Beyond the face: how context modulates emotion processing in frontotemporal dementia subtypes.

The importance of assessing social cognition to characterize dementia syndromes is increasingly recognized, with lower social cognition capacity associated with reduced functional independence and greater carer burden. Emotion recognition is impaired in both behavioural-variant frontotemporal dementia and semantic dementia, yet the social and behavioural changes observed in these syndromes in everyday situations varies. To date, most studies have investigated isolated, context-free stimuli indexing recognition of facial emotions only. Here, we aimed to investigate how contextual information (i.e. emotional body language) influences emotion recognition, within the framework of the Social Context Network Model. Thirty-one patients with frontotemporal dementia (19 behavioural-variant frontotemporal dementia; 12 semantic dementia) and 20 healthy age- and education-matched controls were assessed on three tasks which varied contextual cues: (i) face alone; (ii) context alone; and (iii) face embedded in context. Voxel-based morphometry was used to identify neural correlates of task performance. Our results demonstrated that both behavioural-variant frontotemporal dementia and semantic dementia patients performed worse than controls in recognizing emotions from face alone and context alone. Importantly, performance differed when faces were presented in context. While both behavioural-variant frontotemporal dementia and semantic dementia patients performed similarly to controls on congruent items (i.e. face emotion and body emotion are the same) (P-values > 0.05), patients with behavioural-variant frontotemporal dementia performed worse than both controls (P < 0.001) and patients with semantic dementia (P = 0.044) for incongruent items (i.e. face emotion and body emotion are different). Neuroimaging analyses revealed that abnormal contextual influence was associated with lower integrity of the right parahippocampal gyrus/amygdala and left precentral gyrus. Together, these results indicate that patients with behavioural-variant frontotemporal dementia are over-reliant on external contextual information. Conversely, in semantic dementia and controls, contextual influence varies, with the degree of contextual influence appearing to be mediated, at least in part, by the facial expression depicted. The profile in behavioural-variant frontotemporal dementia is reminiscent of the 'environmental dependency syndrome' described in frontal lesion patients. It also converges with recent evidence of abnormal face perception in this group. From a theoretical perspective, our findings demonstrate that the capacity to incorporate contextual body language is dependent on the integrity of both contextual association brain regions (i.e. parahippocampal gyrus), as well as regions necessary for processing dynamic body movements. Clinically, these results open new avenues for rehabilitation of social impairments in dementia.

Frontal variant of Alzheimer's disease masquerading as behavioural-variant frontotemporal dementia: a case study comparison.

The current clinical diagnostic criteria for Alzheimer's disease (AD) recognize an atypical, non-amnestic presentation of AD, characterized by prominent executive dysfunction. Increasing evidence, however, indicates that the clinical phenotype of this so-called "frontal-variant" of AD (fv-AD) includes behavioral symptoms and deficits in social cognition, together with disproportionate frontal lobe atrophy. As these features resemble those characteristic of behavioral-variant frontotemporal dementia (bvFTD), differential diagnosis can be challenging. Here, we report a case of fv-AD who met clinical diagnostic criteria bvFTD, but had in vivo amyloid neuroimaging evidence of AD pathology. We compare this case against two individuals who were clinically diagnosed with bvFTD and early-onset AD, with in vivo amyloid neuroimaging confirmation of pathology. We highlight the challenges in differential diagnosis by contrasting their behavioral, cognitive and structural neuroimaging findings.