Behavioral-variant frontotemporal dementia: Distinct phenotypes with unique functional profiles

Objective: To identify distinct behavioral phenotypes of behavioral variant frontotemporal dementia (bvFTD), and elucidate differences in functional, neuroimaging, and progression to residential care placement. Methods: Eighty-eight patients with bvFTD were included in a cluster analysis applying levels of disinhibition and apathy (Cambridge Behavioural Inventory-Revised) to identify phenotypic subgroups. Between-group (Kruskal-Wallis; Mann-Whitney U) functional differences (Disability Assessment for Dementia), and time to residential care placement (survival analyses) were examined. Cortical thickness differences (whole brain MRI) were analyzed in bvFTD patients versus healthy controls (n=30) and between phenotypic subgroups. Results: Four phenotypic subgroups were identified: “Primary severe apathy” (n=26), “Severe apathy and disinhibition” (n=26), “Mild apathy and disinhibition” (n=27), “Primary severe disinhibition” (n= 9). Severely apathetic phenotypes were more functionally impaired and had more extensive brain atrophy than those with mild apathy or severe disinhibition alone. Further imaging analyses indicated that the right middle temporal region is critical for the development of disinhibition, an association that remains with disease progression and in the context of severe apathy. Finally, no difference in time to residential care admission was found between phenotypes. Conclusions: This study reveals that different clinical behavioral phenotypes of bvFTD have differing profiles of functional decline and distinct patterns of associated cortical changes. These findings emphasize the importance of apathy in functional impairment, highlight the role of the right temporal region in disinhibition and suggest that disability may be a sensitive outcome measure for treatments targeting reduction of apathy. These phenotypes could also support understanding of prognosis and clinical management

Energy expenditure in frontotemporal dementia: a behavioural and imaging study.

SEE FINGER DOI101093/AWW312 FOR A SCIENTIFIC COMMENTARY ON THIS ARTICLE: Abnormal eating behaviour and metabolic parameters including insulin resistance, dyslipidaemia and body mass index are increasingly recognized as important components of neurodegenerative disease and may contribute to survival. It has previously been established that behavioural variant frontotemporal dementia is associated with abnormal eating behaviour characterized by increased sweet preference. In this study, it was hypothesized that behavioural variant frontotemporal dementia might also be associated with altered energy expenditure. A cohort of 19 patients with behavioural variant frontotemporal dementia, 13 with Alzheimer's disease and 16 (age- and sex-matched) healthy control subjects were studied using Actiheart devices (CamNtech) to assess resting and stressed heart rate. Actiheart devices were fitted for 7 days to measure sleeping heart rate, activity levels, and resting, active and total energy expenditure. Using high resolution structural magnetic resonance imaging the neural correlates of increased resting heart rate were investigated including cortical thickness and region of interest analyses. In behavioural variant frontotemporal dementia, resting (P = 0.001), stressed (P = 0.037) and sleeping heart rate (P = 0.038) were increased compared to control subjects, and resting heart rate (P = 0.020) compared to Alzheimer disease patients. Behavioural variant frontotemporal dementia was associated with decreased activity levels compared to controls (P = 0.002) and increased resting energy expenditure (P = 0.045) and total energy expenditure (P = 0.035). Increased resting heart rate correlated with behavioural (Cambridge Behavioural Inventory) and cognitive measures (Addenbrooke's Cognitive Examination). Increased resting heart rate in behavioural variant frontotemporal dementia correlated with atrophy involving the mesial temporal cortex, insula, and amygdala, regions previously suggested to be involved exclusively in social and emotion processing in frontotemporal dementia. These neural correlates overlap the network involved in eating behaviour in frontotemporal dementia, suggesting a complex interaction between eating behaviour, autonomic function and energy homeostasis. As such the present study suggests that increased heart rate and autonomic changes are prevalent in behavioural variant frontotemporal dementia, and are associated with changes in energy expenditure. An understanding of these changes and neural correlates may have potential relevance to disease progression and prognosis.National Health and Medical Research Council of Australia (Grant IDs: 1037746, 1003139, 1022684), Australian Research Council Centre of Excellence in Cognition and its Disorders Memory Node (Grant ID: CE110001021), Royal Australasian College of Physicians (PhD scholar), MND Australia (PhD scholar), Wellcome Trust, Medical Research Council, European Research Council, National Institute for Health Research Cambridge Biomedical Research Centre, The Bernard Wolfe Endowment, Swiss National Science Foundation (Grant IDs: PBLAP3-145870, P3SMP3-155318)This is the author accepted manuscript. The final version is available from Oxford University Press via https://doi.org/10.1093/brain/aww26

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

An Update on semantic dementia : genetics, imaging, and pathology

Progressive and relatively circumscribed loss of semantic knowledge, referred to as semantic dementia (SD) which falls under the broader umbrella of frontotemporal dementia, was officially identified as a clinical syndrome less than 50 years ago. Here, we review recent neuroimaging, pathological, and genetic research in SD. From a neuroimaging perspective, SD is characterised by hallmark asymmetrical atrophy of the anterior temporal pole and anterior fusiform gyrus, which is usually left lateralised. Functional magnetic resonance imaging (fMRI) studies have revealed widespread changes in connectivity, implicating the anterior temporal regions in semantic deficits in SD. Task-related fMRI have also demonstrated the relative preservation of frontal and parietal regions alongside preserved memory performance. In addition, recent longitudinal studies have demonstrated that, with disease progression, atrophy encroaches into the contralateral temporal pole and medial prefrontal cortices, which reflects emerging changes in behaviour and social cognition. Notably, unlike other frontotemporal dementia subtypes, recent research has demonstrated strong clinicopathological concordance in SD, with TDP43 type C as the most common pathological subtype. Moreover, an underlying genetic cause appears to be relatively rare in SD, with the majority of cases having a sporadic form of the disease. The relatively clear diagnosis, clinical course, and pathological homogeneity of SD make this syndrome a promising target for novel disease-modifying interventions. The development of neuroimaging markers of disease progression at the individual level is an important area of research for future studies to address, in order to assist with this endeavour.9 page(s

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 rela- tion 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 per- formance 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

On the right side? A longitudinal study of left- versus right-lateralized semantic dementia

The typical presentation of semantic dementia is associated with marked, left predominant anterior temporal lobe atrophy and with changes in language. About 30% of individuals, however, present with predominant right anterior temporal lobe atrophy, usually accompanied by behavioural changes and prosopagnosia. Here, we aimed to establish whether these initially distinct clinical presentations evolve into a similar syndrome at the neural and behavioural level. Thirty-one patients who presented with predominant anterior temporal lobe atrophy were included. Based on imaging, patients were categorized as either predominant left ( n = 22) or right ( n = 9) semantic dementia. Thirty-three Alzheimer’s disease patients and 25 healthy controls were included for comparison. Participants completed the Addenbrooke’s Cognitive Examination, a Face and Emotion Processing Battery and the Cambridge Behavioural Inventory, and underwent magnetic resonance imaging annually. Longitudinal neuroimaging analyses showed greater right temporal pole atrophy in left semantic dementia than Alzheimer’s disease, whereas right semantic dementia showed greater orbitofrontal and left temporal lobe atrophy than Alzheimer’s disease. Importantly, direct comparisons between semantic dementia groups revealed that over time, left semantic dementia showed progressive thinning in the right temporal pole, whereas right semantic dementia showed thinning in the orbitofrontal cortex and anterior cingulate. Behaviourally, longitudinal analyses revealed that general cognition declined in all patients. In contrast, patients with left and right semantic dementia showed greater emotion recognition decline than Alzheimer’s disease. In addition, left semantic dementia showed greater motivation loss than Alzheimer’s disease. Correlational analyses revealed that emotion recognition was associated with right temporal pole, right medial orbitofrontal and right fusiform integrity, while changes in motivation were associated with right temporal pole cortical thinning. While left and right semantic dementia show distinct profiles at presentation, both phenotypes develop deficits in emotion recognition and behaviour. These findings highlight the pervasive socio-emotional deficits in frontotemporal dementia, even in patients with an initial language presentation. These changes reflect right anterior temporal and orbitofrontal cortex degeneration, underscoring the role of these regions in social cognition and behaviour.13 page(s

The effects of the COVID-19 pandemic on neuropsychiatric symptoms in dementia and carer mental health: an international multicentre study

As a global health emergency, the rapid spread of the novel coronavirus disease (COVID-19) led to the implementation of widespread restrictions (e.g., quarantine, physical/social distancing measures). However, while these restrictions reduce the viral spread of COVID-19, they may exacerbate behavioural and cognitive symptoms in dementia patients and increase pressure on caregiving. Here, we aimed to assess the impact of COVID-19 and related restrictions on both carers and people living with dementia across the world. We conducted an international survey (Australia, Germany, Spain, and the Netherlands) to assess the impact of COVID-19 on carers and people living with dementia. People with dementia experienced worsened neuropsychiatric symptoms since the outbreak of COVID-19, most commonly, depression, apathy, delusions, anxiety, irritability, and agitation. Regression analyses revealed that limited understanding of the COVID-19 situation and not living with the carer was associated with worsened neuropsychiatric symptoms. Carers also reported a decline in their own mental health, increased stress and reduced social networks as a result of COVID-19 and related restrictions. Regression analyses revealed uncertainty about the future and loneliness were associated with worsened carer mental health. Findings from this study will inform strategies for the development of support services and compassionate protocols that meet the evolving needs of those living with dementia and their carers

The effects of the COVID-19 pandemic on neuropsychiatric symptoms in dementia and carer mental health: an international multicentre study

As a global health emergency, the rapid spread of the novel coronavirus disease (COVID-19) led to the implementation of widespread restrictions (e.g., quarantine, physical/social distancing measures). However, while these restrictions reduce the viral spread of COVID-19, they may exacerbate behavioural and cognitive symptoms in dementia patients and increase pressure on caregiving. Here, we aimed to assess the impact of COVID-19 and related restrictions on both carers and people living with dementia across the world. We conducted an international survey (Australia, Germany, Spain, and the Netherlands) to assess the impact of COVID-19 on carers and people living with dementia. People with dementia experienced worsened neuropsychiatric symptoms since the outbreak of COVID-19, most commonly, depression, apathy, delusions, anxiety, irritability, and agitation. Regression analyses revealed that limited understanding of the COVID-19 situation and not living with the carer was associated with worsened neuropsychiatric symptoms. Carers also reported a decline in their own mental health, increased stress and reduced social networks as a result of COVID-19 and related restrictions. Regression analyses revealed uncertainty about the future and loneliness were associated with worsened carer mental health. Findings from this study will inform strategies for the development of support services and compassionate protocols that meet the evolving needs of those living with dementia and their carers

Robust automated computational approach for classifying frontotemporal neurodegeneration: Multimodal/multicenter neuroimaging.

IntroductionTimely diagnosis of behavioral variant frontotemporal dementia (bvFTD) remains challenging because it depends on clinical expertise and potentially ambiguous diagnostic guidelines. Recent recommendations highlight the role of multimodal neuroimaging and machine learning methods as complementary tools to address this problem.MethodsWe developed an automatic, cross-center, multimodal computational approach for robust classification of patients with bvFTD and healthy controls. We analyzed structural magnetic resonance imaging and resting-state functional connectivity from 44 patients with bvFTD and 60 healthy controls (across three imaging centers with different acquisition protocols) using a fully automated processing pipeline, including site normalization, native space feature extraction, and a random forest classifier.ResultsOur method successfully combined multimodal imaging information with high accuracy (91%), sensitivity (83.7%), and specificity (96.6%).DiscussionThis multimodal approach enhanced the system's performance and provided a clinically informative method for neuroimaging analysis. This underscores the relevance of combining multimodal imaging and machine learning as a gold standard for dementia diagnosis