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Disinhibition is one of the most distressing and difficult to treat neuropsychiatric symptoms of dementia. It involves socially inappropriate behaviours, such as hypersexual comments, inappropriate approaching of strangers and excessive jocularity. Disinhibition occurs in multiple dementia syndromes, including behavioural variant frontotemporal dementia, and dementia of the Alzheimers type. Morphometric similarity networks are a relatively new method for examining brain structure and can be used to calculate measures of network integrity on large scale brain networks and subnetworks such as the salience network and cognitive control network. In a cross-sectional study, we calculated morphometric similarity networks to determine whether disinhibition in behavioural variant frontotemporal dementia (n = 75) and dementia of the Alzheimers type (n = 111) was associated with reduced integrity of these networks independent of diagnosis. We found that presence of disinhibition, measured by the Neuropsychiatric Inventory Questionnaire, was associated with reduced global efficiency of the cognitive control network in both dementia of the Alzheimers type and behavioural variant frontotemporal dementia. Future research should replicate this transdiagnostic finding in other dementia diagnoses and imaging modalities, and investigate the potential for intervention at the level of the cognitive control network to target disinhibition.

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. [ABSTRACT FROM AUTHOR]

At present, no research criteria exist for the diagnosis of prodromal behavioural variant frontotemporal dementia (bvFTD), though early detection is of high research importance. Thus, we sought to develop and validate a proposed set of research criteria for prodromal bvFTD, termed 'mild behavioural and/or cognitive impairment in bvFTD' (MBCI-FTD). Participants included 72 participants deemed to have prodromal bvFTD; this comprised 55 carriers of a pathogenic mutation known to cause frontotemporal lobar degeneration, and 17 individuals with autopsy-confirmed frontotemporal lobar degeneration. All had mild behavioural and/or cognitive changes, as judged by an evaluating clinician. Based on extensive clinical workup, the prodromal bvFTD group was divided into a Development Group (n = 22) and a Validation Group (n = 50). The Development Group was selected to be the subset of the prodromal bvFTD group for whom we had the strongest longitudinal evidence of conversion to bvFTD, and was used to develop the MBCI-FTD criteria. The Validation Group was the remainder of the prodromal bvFTD group and was used as a separate sample on which to validate the criteria. Familial non-carriers were included as healthy controls (n = 165). The frequencies of behavioural and neuropsychiatric features, neuropsychological deficits, and social cognitive dysfunction in the prodromal bvFTD Development Group and healthy controls were assessed. Based on sensitivity and specificity analyses, seven core features were identified: apathy without moderate-severe dysphoria, behavioural disinhibition, irritability/agitation, reduced empathy/sympathy, repetitive behaviours (simple and/or complex), joviality/gregariousness, and appetite changes/hyperorality. Supportive features include a neuropsychological profile of impaired executive function or naming with intact orientation and visuospatial skills, reduced insight for cognitive or behavioural changes, and poor social cognition. Three core features or two core features plus one supportive feature are required for the diagnosis of possible MBCI-FTD; probable MBCI-FTD requires imaging or biomarker evidence, or a pathogenic genetic mutation. The proposed MBCI-FTD criteria correctly classified 95% of the prodromal bvFTD Development Group, and 74% of the prodromal bvFTD Validation Group, with a false positive rate of

Abstract Background Non-memory-led dementias such as posterior cortical atrophy (PCA), primary progressive aphasia (PPA) and behavioural variant frontotemporal dementia (bvFTD) are low prevalent and often affect individuals under the age of 65. Tailored educational and support resources for caregivers of people living with these dementia phenotypes are scarce and unevenly distributed geographically. Web-based educational programmes are emerging as promising alternatives to improve caregiver self-efficacy and well-being. Here, we present the protocol of a study aiming to assess the feasibility of a co-produced online educational programme for caregivers of people living PCA, PPA and bvFTD: the Better Living with Non-memory-led Dementia programme. Methods A randomised controlled feasibility trial will be conducted on a sample of 30 caregivers of people living with PCA, PPA and bvFTD. Participants will be recruited among members of the support organisation Rare Dementia Support (based at UCL in the UK). The intervention group will be given access to an 8-week co-produced web-based educational programme consisting of 6 modules addressing education about PCA, PPA and bvFTD and support strategies for the person with dementia and for the caregiver. The control group will receive treatment as usual (TAU). Feasibility will be measured through feasibility of recruitment, clinical measurement tools and acceptability. Clinical measures will be used to assess preliminary efficacy and data on completion rates, missing data and variability used to decide on measures to be included in a full-scale trial. Allocation ratio will be 2:1 (intervention:control) stratified by diagnosis. Feasibility of recruitment and acceptability will be assessed. Clinical measures will be administered at baseline and 8-week and 3-month post-randomisation. The control group will be offered access to the intervention at the completion of data collection. Participants will be unblinded, and all measures will be self-reported online. Discussion Online-delivered educational programmes show potential for improving care competency of caregivers and may contribute to overcoming geographical inequalities in local provision of support services. This pilot study will inform a fully powered international trial to determine the effectiveness of Better Living with Non-memory-led Dementia. Trial registration This trial has been registered prospectively on the Clinical Trials Registry on 1st September 2022, registration number NCT05525377.

Objective: Blood biomarkers of neuronal injury such as neurofilament light (NfL) show promise to improve diagnosis of neurodegenerative disorders and distinguish neurodegenerative from primary psychiatric disorders (PPD). This study investigated the diagnostic utility of plasma NfL to differentiate behavioural variant frontotemporal dementia (bvFTD, a neurodegenerative disorder commonly misdiagnosed initially as PPD), from PPD, and performance of large normative/reference data sets and models. Methods: Plasma NfL was analysed in major depressive disorder (MDD, n = 42), bipolar affective disorder (BPAD, n = 121), treatment-resistant schizophrenia (TRS, n = 82), bvFTD (n = 22), and compared to the reference cohort (Control Group 2, n = 1926, using GAMLSS modelling), and age-matched controls (Control Group 1, n = 96, using general linear models). Results: Large differences were seen between bvFTD (mean NfL 34.9 pg/mL) and all PPDs and controls (all < 11 pg/mL). NfL distinguished bvFTD from PPD with high accuracy, sensitivity (86%), and specificity (88%). GAMLSS models using reference Control Group 2 facilitated precision interpretation of individual levels, while performing equally to or outperforming models using local controls. Slightly higher NfL levels were found in BPAD, compared to controls and TRS. Conclusions: This study adds further evidence on the diagnostic utility of NfL to distinguish bvFTD from PPD of high clinical relevance to a bvFTD differential diagnosis, and includes the largest cohort of BPAD to date. Using large reference cohorts, GAMLSS modelling and the interactive Internet-based application we developed, may have important implications for future research and clinical translation. Studies are underway investigating utility of plasma NfL in diverse neurodegenerative and primary psychiatric conditions in real-world clinical settings. [ABSTRACT FROM AUTHOR]

Background: Non-memory-led dementias such as posterior cortical atrophy (PCA), primary progressive aphasia (PPA) and behavioural variant frontotemporal dementia (bvFTD) are low prevalent and often affect individuals under the age of 65. Tailored educational and support resources for caregivers of people living with these dementia phenotypes are scarce and unevenly distributed geographically. Web-based educational programmes are emerging as promising alternatives to improve caregiver self-efficacy and well-being. Here, we present the protocol of a study aiming to assess the feasibility of a co-produced online educational programme for caregivers of people living PCA, PPA and bvFTD: the Better Living with Non-memory-led Dementia programme. Methods: A randomised controlled feasibility trial will be conducted on a sample of 30 caregivers of people living with PCA, PPA and bvFTD. Participants will be recruited among members of the support organisation Rare Dementia Support (based at UCL in the UK). The intervention group will be given access to an 8-week co-produced web-based educational programme consisting of 6 modules addressing education about PCA, PPA and bvFTD and support strategies for the person with dementia and for the caregiver. The control group will receive treatment as usual (TAU). Feasibility will be measured through feasibility of recruitment, clinical measurement tools and acceptability. Clinical measures will be used to assess preliminary efficacy and data on completion rates, missing data and variability used to decide on measures to be included in a full-scale trial. Allocation ratio will be 2:1 (intervention:control) stratified by diagnosis. Feasibility of recruitment and acceptability will be assessed. Clinical measures will be administered at baseline and 8-week and 3-month post-randomisation. The control group will be offered access to the intervention at the completion of data collection. Participants will be unblinded, and all measures will be self-reported online. Discussion: Online-delivered educational programmes show potential for improving care competency of caregivers and may contribute to overcoming geographical inequalities in local provision of support services. This pilot study will inform a fully powered international trial to determine the effectiveness of Better Living with Non-memory-led Dementia. Trial registration: This trial has been registered prospectively on the Clinical Trials Registry on 1st September 2022, registration number NCT05525377. [ABSTRACT FROM AUTHOR]

Background and objectives: Early-stage behavioural variant frontotemporal dementia (bvFTD) is often misdiagnosed, highlighting the need for new diagnostic instruments. Based on the revised diagnostic criteria for bvFTD, we developed the Behavioural Dysfunction Questionnaire (BDQ). In this explorative study, we aimed to determine the best scoring and analytical method for the BDQ to discriminate between bvFTD and non-bvFTD patients. Materials and methods: 34 patients with early-stage bvFTD, 56 with early-stage Alzheimer's disease dementia (ADD) and 41 with major depressive disorder (MDD) were recruited. We calculated BDQ-items with or without inclusion of a time criterion: (a) without time criterion, (b) with 10 years' time criterion (symptom presence less than 10 years), and (c) with 3 years' time criterion (symptom presentation within the first 3 years). Using these three differently calculated items, we generated six variables, i.e. 3*2 [BDQ-Global Score (BDQ-GS; domains average score); BDQ-Global Domain Score (BDQ-GDS; domains categorical score)]. Then, we performed univariate and bivariate (BDQ-GS and BDQ-GDS combined) ROC analyses. Results: Models including BDQ-GS, BDQ-GDS or both variables combined discriminated similarly between groups. In contrast, models without time criterion or with 10 years' time criterion discriminated better than models including variables with 3 years' time criterion. These models discriminated highly (AUC = 85.98–87.78) between bvFTD and MDD and bvFTD and ADD, respectively. Conclusion: BDQ-scores without any time criterion discriminated highly between early-stage bvFTD and non-bvFTD groups, which could improve the early diagnosis of bvFTD. With its standardised procedure, the BDQ is also appropriate for repeated assessments. [ABSTRACT FROM AUTHOR]

Timely, accurate distinction between behavioural variant frontotemporal dementia (bvFTD) and primary psychiatric disorders (PPD) is a clinical challenge. Blood biomarkers such as neurofilament light chain (NfL) and glial fibrillary acidic protein (GFAP) have shown promise. Prior work has shown NfL helps distinguish FTD from PPD. Few studies have assessed NfL together with GFAP. We investigated plasma GFAP and NfL levels in participants with bvFTD, bipolar affective disorder (BPAD), major depressive disorder (MDD), treatment-resistant schizophrenia (TRS), healthy controls (HC), adjusting for age and sex. We compared ability of GFAP and NfL to distinguish bvFTD from PPD. Plasma GFAP levels were significantly (all p < 0.001) elevated in bvFTD (n = 22, mean (M) = 273 pg/mL) compared to BPAD (n = 121, M = 96 pg/mL), MDD (n = 42, M = 105 pg/mL), TRS (n = 82, M = 67.9 pg/mL), and HC (n = 120, M = 76.8 pg/mL). GFAP distinguished bvFTD from all PPD with an area under the curve (AUC) of 0.85, 95 % confidence interval [0.76, 0.95]. The optimal cut-off of 105 pg/mL was associated with 73 % specificity and 86 % sensitivity. NfL had AUC 0.95 [0.91, 0.99], 13.3 pg/mL cut-off, 88 % specificity, 86 % sensitivity, and was superior to GFAP (p = 0.02863) and combination of GFAP and NfL (p = 0.04726). This study found elevated GFAP levels in bvFTD compared to a large cohort of PPD, but NfL levels exhibited better performance in this distinction. These findings extend the literature on GFAP in bvFTD and build evidence for plasma NfL as a useful biomarker to assist with distinguishing bvFTD from PPD. Utilisation of NfL may improve timely and accurate diagnosis of bvFTD. • This study examined plasma glial fibrillary acidic protein (GFAP) levels in bvFTD and PPD. • GFAP was significantly elevated in bvFTD compared to a large group of diverse PPD. • This extends the literature on GFAP and astrocyte dysfunction in bvFTD. • Plasma neurofilament light chain (NfL) was superior to GFAP in distinguishing bvFTD from PPD. • This further establishes the role of NfL to assist in this common, often challenging clinical distinction. • Elevated GFAP in bipolar disorder and unipolar depression suggests possible neuroinflammation and reactive astrogliosis. [ABSTRACT FROM AUTHOR]

Background: Using multi-block methods we combined multimodal neuroimaging metrics of thalamic morphology, thalamic white matter tract diffusion metrics, and cortical thickness to examine changes in behavioural variant frontotemporal dementia. (bvFTD). Method: Twenty-three patients with sporadic bvFTD and 24 healthy controls underwent structural and diffusion MRI scans. Clinical severity was assessed using the Clinical Dementia Rating scale and behavioural severity using the Frontal Behaviour Inventory by patient caregivers. Thalamic volumes were manually segmented. Anterior and posterior thalamic radiation fractional anisotropy and mean diffusivity were extracted using Tract-Based Spatial Statistics. Finally, cortical thickness was assessed using Freesurfer. We used shape analyses, diffusion measures, and cortical thickness as features in sparse multi-block partial least squares (PLS) discriminatory analyses to classify participants within bvFTD or healthy control groups. Sparsity was tuned with five-fold cross-validation repeated 10 times. Final model fit was assessed using permutation testing. Additionally, sparse multi-block PLS was used to examine associations between imaging features and measures of dementia severity. Results: Bilateral anterior-dorsal thalamic atrophy, reduction in mean diffusivity of thalamic projections, and frontotemporal cortical thinning, were the main features predicting bvFTD group membership. The model had a sensitivity of 96%, specificity of 68%, and was statistically significant using permutation testing (p = 0.012). For measures of dementia severity, we found similar involvement of regional thalamic and cortical areas as in discrimination analyses, although more extensive thalamo-cortical white matter metric changes. Conclusions: Using multimodal neuroimaging, we demonstrate combined structural network dysfunction of anterior cortical regions, cortical-thalamic projections, and anterior thalamic regions in sporadic bvFTD.

BackgroundBehavioural Variant Frontotemporal Dementia (bvFTD) is a rapidly progressing neurodegenerative proteinopathy. Perivascular spaces (PVS) form a part of the brain’s glymphatic clearance system. When enlarged due to poor glymphatic clearance of toxic proteins, PVS become larger and more conspicuous on MRI. Therefore, enlarged PVS may be a useful biomarker of disease severity and progression in neurodegenerative proteinopathies such as bvFTD. This study aimed to determine the utility of PVS as a biomarker of disease progression in patients with bvFTD.Materials and methodsSerial baseline and week 52 MRIs acquired from ten patients with bvFTD prospectively recruited and followed in a Phase 1b open label trial of sodium selenate for bvFTD were used in this study. An automated algorithm quantified PVS on MRI, which was visually inspected and validated by a member of the study team. The number and volume of PVS were extracted and mixed models used to assess the relationship between PVS burden and other measures of disease (cognition, carer burden scale, protein biomarkers). Additional exploratory analysis investigated PVS burden in patients who appeared to not progress over the 12 months of selenate treatment (i.e., “non-progressors”).ResultsOverall, PVS cluster number (ß = −3.27, CI [−7.80 – 1.27], p = 0.267) and PVS volume (ß = −36.8, CI [−84.9 – 11.3], p = 0.171) did not change over the paired MRI scans 12 months apart. There was association between cognition total composite scores and the PVS burden (PVS cluster ß = −0.802e–3, CI [9.45e–3 – −6.60e–3, p ≤ 0.001; PVS volume ß = −1.30e–3, CI [−1.55e–3 – −1.05e–3], p ≤ 0.001), as well as between the change in the cognition total composite score and the change in PVS volume (ß = 4.36e–3, CI [1.33e–3 – 7.40e–3], p = 0.046) over the trial period. There was a significant association between CSF t-tau and the number of PVS clusters (ß = 2.845, CI [0.630 – 5.06], p = 0.036). Additionally, there was a significant relationship between the change in CSF t-tau and the change in the number of PVS (ß = 1.54, CI [0.918 – 2.16], p < 0.001) and PVS volume (ß = 13.8, CI [6.37 – 21.1], p = 0.003) over the trial period. An association was found between the change in NfL and the change in PVS volume (ß = 1.40, CI [0.272 – 2.52], p = 0.045) over time. Within the “non-progressor” group (n = 7), there was a significant relationship between the change in the CSF total-tau (t-tau) levels and the change in the PVS burden (PVS cluster (ß = 1.46, CI [0.577 – 2.34], p = 0.014; PVS volume ß = 14.6, CI [3.86 – 25.4], p = 0.032) over the trial period. Additionally, there was evidence of a significant relationship between the change in NfL levels and the change in the PVS burden over time (PVS cluster ß = 0.296, CI [0.229 – 0.361], p ≤ 0.001; PVS volume ß = 3.67, CI [2.42 – 4.92], p = 0.002).ConclusionAnalysis of serial MRI scans 12 months apart in patients with bvFTD demonstrated a relationship between PVS burden and disease severity as measured by the total cognitive composite score and CSF t-tau. Further studies are needed to confirm PVS as a robust marker of neurodegeneration in proteinopathies.

Apathy and disinhibition are common and highly distressing neuropsychiatric symptoms associated with negative outcomes in persons with dementia. This paper is a critical review of functional and structural neuroimaging studies of these symptoms transdiagnostically in dementia of the Alzheimer type, which is characterized by prominent amnesia early in the disease course, and behavioural variant frontotemporal dementia, characterized by early social-comportmental deficits. We describe the prevalence and clinical correlates of these symptoms and describe methodological issues, including difficulties with symptom definition and different measurement instruments. We highlight the heterogeneity of findings, noting however, a striking similarity of the set of brain regions implicated across clinical diagnoses and symptoms. These regions involve several key nodes of the salience network, and we describe the functions and anatomical connectivity of these brain areas, as well as present a new theoretical account of disinhibition in dementia. Future avenues for research are discussed, including the importance of transdiagnostic studies, measuring subdomains of apathy and disinhibition, and examining different units of analysis for deepening our understanding of the networks and mechanisms underlying these extremely distressing symptoms. [ABSTRACT FROM AUTHOR]

Abstract Background Current tasks measuring social cognition are usually ‘pen and paper’ tasks, have ceiling effects and include complicated test instructions that may be difficult to understand for those with cognitive impairment. We therefore aimed to develop a set of simple, instructionless, quantitative, tasks of emotion recognition using the methodology of eye tracking, with the subsequent aim of assessing their utility in individuals with behavioural variant frontotemporal dementia (bvFTD). Methods Using the Eyelink 1000 Plus eye tracker, 18 bvFTD and 22 controls completed tasks of simple and complex emotion recognition that involved viewing four images (one target face (simple) or pair of eyes (complex) and the others non-target) followed by a target emotion word and lastly the original four images alongside the emotion word. A dwell time change score was then calculated as the main outcome measure by subtracting the percentage dwell time for the target image before the emotion word appeared away from the percentage dwell time for the target image after the emotion word appeared. All participants also underwent a standard cognitive battery and volumetric T1-weighted magnetic resonance imaging. Results Analysis using a mixed effects model showed that the average (standard deviation) mean dwell time change score in the target interest area was 35 (27)% for the control group compared with only 4 (18)% for the bvFTD group (p

The TDP-43 type C pathological form of frontotemporal lobar degeneration is characterized by the presence of immunoreactive TDP-43 short and long dystrophic neurites, neuronal cytoplasmic inclusions, neuronal loss and gliosis and the absence of neuronal intranuclear inclusions. Frontotemporal lobar degeneration-TDP-type C cases are commonly associated with the semantic variant of primary progressive aphasia or behavioural variant frontotemporal dementia. Here, we provide detailed characterization of regional distributions of pathological TDP-43 and neuronal loss and gliosis in cortical and subcortical regions in 10 TDP-type C cases and investigate the relationship between inclusions and neuronal loss and gliosis. Specimens were obtained from the first 10 TDP-type C cases accessioned from the Northwestern Alzheimer's Disease Research Center (semantic variant of primary progressive aphasia, n = 7; behavioural variant frontotemporal dementia, n = 3). A total of 42 cortical (majority bilateral) and subcortical regions were immunostained with a phosphorylated TDP-43 antibody and/or stained with haematoxylin-eosin. Regions were evaluated for atrophy, and for long dystrophic neurites, short dystrophic neurites, neuronal cytoplasmic inclusions, and neuronal loss and gliosis using a semiquantitative 5-point scale. We calculated a 'neuron-to-inclusion' score (TDP-type C mean score - neuronal loss and gliosis mean score) for each region per case to assess the relationship between TDP-type C inclusions and neuronal loss and gliosis. Primary progressive aphasia cases demonstrated leftward asymmetry of cortical atrophy consistent with the aphasic phenotype. We also observed abundant inclusions and neurodegeneration in both cortical and subcortical regions, with certain subcortical regions emerging as particularly vulnerable to dystrophic neurites (e.g. amygdala, caudate and putamen). Interestingly, linear mixed models showed that regions with lowest TDP-type C pathology had high neuronal dropout, and conversely, regions with abundant pathology displayed relatively preserved neuronal densities (P < 0.05). This inverse relationship between the extent of TDP-positive inclusions and neuronal loss may reflect a process whereby inclusions disappear as their associated neurons are lost. Together, these findings offer insight into the putative substrates of neurodegeneration in unique dementia syndromes. [ABSTRACT FROM AUTHOR]

Social feedback can selectively enhance learning in diverse domains. Relevant neurocognitive mechanisms have been studied mainly in healthy persons, yielding correlational findings. Neurodegenerative lesion models, coupled with multimodal brain measures, can complement standard approaches by revealing direct multidimensional correlates of the phenomenon. To this end, we assessed socially reinforced and non-socially reinforced learning in 40 healthy participants as well as persons with behavioural variant frontotemporal dementia (n = 21), Parkinson's disease (n = 31) and Alzheimer's disease (n = 20). These conditions are typified by predominant deficits in social cognition, feedback-based learning and associative learning, respectively, although all three domains may be partly compromised in the other conditions. We combined a validated behavioural task with ongoing EEG signatures of implicit learning (medial frontal negativity) and offline MRI measures (voxel-based morphometry). In healthy participants, learning was facilitated by social feedback relative to non-social feedback. In comparison with controls, this effect was specifically impaired in behavioural variant frontotemporal dementia and Parkinson's disease, while unspecific learning deficits (across social and non-social conditions) were observed in Alzheimer's disease. EEG results showed increased medial frontal negativity in healthy controls during social feedback and learning. Such a modulation was selectively disrupted in behavioural variant frontotemporal dementia. Neuroanatomical results revealed extended temporo-parietal and fronto-limbic correlates of socially reinforced learning, with specific temporo-parietal associations in behavioural variant frontotemporal dementia and predominantly fronto-limbic regions in Alzheimer's disease. In contrast, non-socially reinforced learning was consistently linked to medial temporal/hippocampal regions. No associations with cortical volume were found in Parkinson's disease. Results are consistent with core social deficits in behavioural variant frontotemporal dementia, subtle disruptions in ongoing feedback-mechanisms and social processes in Parkinson's disease and generalized learning alterations in Alzheimer's disease. This multimodal approach highlights the impact of different neurodegenerative profiles on learning and social feedback. Our findings inform a promising theoretical and clinical agenda in the fields of social learning, socially reinforced learning and neurodegeneration. [ABSTRACT FROM AUTHOR]

Degraded semantic memory is a prominent feature of frontotemporal dementia (FTD). It is classically associated with semantic dementia and anterior temporal lobe (ATL) atrophy, but semantic knowledge can also be compromised in behavioural variant FTD. Motivated by understanding behavioural change in FTD, recent research has focused selectively on social-semantic knowledge, with proposals that the right ATL is specialized for social concepts. Previous studies have assessed very different types of social concepts and have not compared performance with that of matched non-social concepts. Consequently, it remains unclear to what extent various social concepts are (i) concurrently impaired in FTD, (ii) distinct from general semantic memory and (iii) differentially supported by the left and right ATL. This study assessed multiple aspects of social-semantic knowledge and general conceptual knowledge across cohorts with ATL damage arising from either neurodegeneration or resection. We assembled a test battery measuring knowledge of multiple types of social concept. Performance was compared with non-social general conceptual knowledge, measured using the Cambridge Semantic Memory Test Battery and other matched non-social-semantic tests. Our trans-diagnostic approach included behavioural variant FTD, semantic dementia and 'mixed' intermediate cases to capture the FTD clinical spectrum, as well as age-matched healthy controls. People with unilateral left or right ATL resection for temporal lobe epilepsy were also recruited to assess how selective damage to the left or right ATL impacts social- and non-social-semantic knowledge. Social- and non-social-semantic deficits were severe and highly correlated in FTD. Much milder impairments were found after unilateral ATL resection, with no left versus right differences in social-semantic knowledge or general semantic processing and with only naming showing a greater deficit following left versus right damage. A principal component analysis of all behavioural measures in the FTD cohort extracted three components, interpreted as capturing (i) FTD severity, (ii) semantic memory and (iii) executive function. Social and non-social measures both loaded heavily on the same semantic memory component, and scores on this factor were uniquely associated with bilateral ATL grey matter volume but not with the degree of ATL asymmetry. Together, these findings demonstrate that both social- and non-social-semantic knowledge degrade in FTD (semantic dementia and behavioural variant FTD) following bilateral ATL atrophy. We propose that social-semantic knowledge is part of a broader conceptual system underpinned by a bilaterally implemented, functionally unitary semantic hub in the ATLs. Our results also highlight the value of a trans-diagnostic approach for investigating the neuroanatomical underpinnings of cognitive deficits in FTD., Competing Interests: The authors report no competing interests., (© The Author(s) 2024. Published by Oxford University Press on behalf of the Guarantors of Brain.)

The objective of this study was to examine if patterns of resting-state brain activity and functional connectivity in cortical and subcortical regions in patients with early symptomatic amyotrophic lateral sclerosis (ALS) resemble those of behavioural variant frontotemporal dementia (bvFTD). In a cross-sectional design, eyes-closed resting-state magnetoencephalography (MEG) data of 34 ALS patients, 18 bvFTD patients and 18 age- and gender-matched healthy controls (HCs) were projected to source-space using an atlas-based beamformer. Group differences in peak frequency, band-specific oscillatory activity and functional connectivity (corrected amplitude envelope correlation) in 78 cortical regions and 12 subcortical regions were determined. False discovery rate was used to correct for multiple comparisons. BvFTD patients, as compared to ALS and HCs, showed lower relative beta power in parietal, occipital, temporal and nearly all subcortical regions. Compared to HCs, patients with ALS and patients with bvFTD had a higher delta (0.5–4 Hz) and gamma (30–48 Hz) band resting-state functional connectivity in a high number of overlapping regions in the frontal lobe and in limbic and subcortical regions. Higher delta band connectivity was widespread in the bvFTD patients compared to HCs. ALS showed a more widespread higher gamma band functional connectivity compared to bvFTD. In conclusion, MEG in early symptomatic ALS patients shows resting-state functional connectivity changes in frontal, limbic and subcortical regions that overlap considerably with bvFTD. The findings show the potential of MEG to detect brain changes in early symptomatic phases of ALS and contribute to our understanding of the disease spectrum, with ALS and bvFTD at the two extreme ends.

Studies on caregiver burden in patients with frontotemporal lobar degeneration are rare, differ methodologically and show variable results. Single center longitudinal pilot study on caregiver burden and potential risk factors in patients with behavioural variant frontotemporal dementia (bvFTD) and semantic (svPPA) and non-fluent variants (nfvPPA) primary progressive aphasia. Forty-six bvFTD, nine svPPA, and six nfvPPA patients and caring relatives were analysed for up to 2 years using the Mini-Mental State Examination as global measure for cognitive performance, Frontal Assessment Battery (frontal lobe functions), Frontal Behavioural Inventory (personality and behaviour), Neuropsychiatric Inventory (dementia-related neuropsychiatric symptoms), Barthel Index and Lawton IADL Scale (basic and instrumental activities of daily living), the Caregiver Strain Index (CSI), and in most participants also the Zarit Burden Interview (ZBI). CSI baseline sum scores were highest in bvFTD (mean ± SD 5.5 ± 3.4, median 5, IQR 6), intermediate in svPPA (2.9 ± 2.3; 3; 3.5) and low in nfvPPA (1.6 ± 2.1; 1; 2). Similar differences of caregiver burden were found using the ZBI. During follow-up, CSI and ZBI sum scores deteriorated in svPPA, not in bvFTD and nfvPPA, and correlated significantly with personality and behaviour, neuropsychiatric symptoms, caregiver age, and instrumental, but not basic activities of daily living, Mini-Mental State Examination scores or frontal lobe functions. This study reveals differences in caregiver burden in variants of frontotemporal lobar degeneration. Caregivers should be systematically asked for caregiver burden from the time of the diagnosis to provide comprehensive support in time. [ABSTRACT FROM AUTHOR]

Amyotrophic lateral sclerosis and behavioural variant frontotemporal dementia are two different diseases recognized to overlap at clinical, pathological and genetic characteristics. Both conditions are traditionally known for relative sparing of episodic memory. However, recent studies have disputed that with the report of patients presenting with marked episodic memory impairment. Besides that, structural and functional changes in temporal lobe regions responsible for episodic memory processing are often detected in neuroimaging studies of both conditions. In this study, we investigated the gray matter features associated with the Papez circuit in amyotrophic lateral sclerosis, behavioural variant frontotemporal dementia and healthy controls to further explore similarities and differences between the two conditions. Our non-demented amyotrophic lateral sclerosis patients showed no episodic memory deficits measured by a short-term delayed recall test while no changes in gray matter of the Papez circuit were found. Compared with the amyotrophic lateral sclerosis group, the behavioural variant frontotemporal dementia group had lower performance on the short-term delayed recall test and marked atrophy in gray matter of the Papez circuit. Bilateral atrophy of entorhinal cortex and mammillary bodies distinguished behavioural variant frontotemporal dementia from amyotrophic lateral sclerosis patients as well as atrophy in left cingulate, left hippocampus and right parahippocampal gyrus. Taken together, our results suggest that sub-regions of the Papez circuit could be differently affected in amyotrophic lateral sclerosis and behavioural variant frontotemporal dementia. [ABSTRACT FROM AUTHOR]

Cooperative social behaviour in humans hinges upon our unique ability to make appropriate moral decisions in accordance with our ethical values. The complexity of the neurocognitive mechanisms underlying moral reasoning is revealed when this capacity breaks down. Patients with the behavioural variant of frontotemporal dementia (bvFTD) display striking moral transgressions in the context of atrophy to frontotemporal regions supporting affective and social conceptual processing. Developmental studies have highlighted the importance of social knowledge to moral decision making in children, yet the role of social knowledge in relation to moral reasoning impairments in neurodegeneration has largely been overlooked. Here, we sought to examine the role of affective and social conceptual processes in personal moral reasoning in bvFTD, and their relationship to the integrity and structural connectivity of frontotemporal brain regions. Personal moral reasoning across varying degrees of conflict was assessed in 26 bvFTD patients and compared with demographically matched Alzheimer's disease patients (n = 14), and healthy older adults (n = 22). Following each moral decision, we directly probed participants' subjective emotional experience as an index of their affective response, while social norm knowledge was assessed via an independent task. While groups did not differ significantly in terms of their moral decisions, bvFTD patients reported feeling 'better' about their decisions than healthy control subjects. In other words, although bvFTD patients could adjudicate between different courses of action in the moral scenarios, their affective responses to these decisions were highly irregular. This blunted emotional reaction was exclusive to the personal high-conflict condition, with 61.5% of bvFTD patients reporting feeling 'extremely good' about their decisions, and was correlated with reduced knowledge of socially acceptable behaviour. Voxel-based morphometry analyses revealed a distributed network of frontal, subcortical, and lateral temporal grey matter regions involved in the attenuated affective response to moral conflict in bvFTD. Crucially, diffusion-tensor imaging implicated the uncinate fasciculus as the pathway by which social conceptual knowledge may influence emotional reactions to personal high-conflict moral dilemmas in bvFTD. Our findings suggest that altered moral behaviour in bvFTD reflects the dynamic interplay between degraded social conceptual knowledge and blunted affective responsiveness, attributable to atrophy of, and impaired information transfer between, frontal and temporal cortices. Delineating the mechanisms of impaired morality in bvFTD provides crucial clinical information for understanding and treating this challenging symptom, which may help pave the way for targeted behavioural interventions. [ABSTRACT FROM AUTHOR]

Background: Current tasks measuring social cognition are usually 'pen and paper' tasks, have ceiling effects and include complicated test instructions that may be difficult to understand for those with cognitive impairment. We therefore aimed to develop a set of simple, instructionless, quantitative, tasks of emotion recognition using the methodology of eye tracking, with the subsequent aim of assessing their utility in individuals with behavioural variant frontotemporal dementia (bvFTD). Methods: Using the Eyelink 1000 Plus eye tracker, 18 bvFTD and 22 controls completed tasks of simple and complex emotion recognition that involved viewing four images (one target face (simple) or pair of eyes (complex) and the others non-target) followed by a target emotion word and lastly the original four images alongside the emotion word. A dwell time change score was then calculated as the main outcome measure by subtracting the percentage dwell time for the target image before the emotion word appeared away from the percentage dwell time for the target image after the emotion word appeared. All participants also underwent a standard cognitive battery and volumetric T1-weighted magnetic resonance imaging. Results: Analysis using a mixed effects model showed that the average (standard deviation) mean dwell time change score in the target interest area was 35 (27)% for the control group compared with only 4 (18)% for the bvFTD group (p < 0.05) for the simple emotion recognition task, and 15 (26)% for the control group compared with only 2 (18)% for the bvFTD group (p < 0.05) for the complex emotion recognition task. Worse performance in the bvFTD group correlated with atrophy in the right ventromedial prefrontal and orbitofrontal cortices, brain regions previously implicated in social cognition. Conclusions: In summary, eye tracking is a viable tool for assessing social cognition in individuals with bvFTD, being well-tolerated and able to overcome some of the problems associated with standard psychometric tasks. [ABSTRACT FROM AUTHOR]

Behavioural variant frontotemporal dementia (bvFTD) is characterized by an absence of obvious cognitive impairment and presence of symptoms such as disinhibition, social inappropriateness, personality changes, hyper-sexuality, and hyper-orality. Affected individuals do not feel concerned enough about their actions to be deterred from violating social norms, and their antisocial behaviours are most likely caused by the neurodegenerative processes in the frontal and anterior temporal lobes. BvFTD patients present a challenge for the traditional notion of autonomy and the medical and criminal justice systems. Antisocial behaviour is often the earliest recognized manifestation of bvFTD. Given that the symptoms are not specific and that atrophy of the frontal lobes is only observable with structural neuroimaging in the later stages of the disease, it is hard to ascertain their autonomy. Recently proposed re-conceptualizations of autonomy (Dworkin's, Jaworska's, and Dubljević's) can, however, be sufficiently redefined to provide explicit rules and offer nuanced guidance in such cases. A combination of notions of autonomy gives the most nuanced guidance with three modifications: 1) including socio-moral judgement in the notion of "normal cognitive competence," 2) excluding in-principle un-endorsable ideals from the notion of "capacity to value," and 3) redefining ideal-typical degrees of compulsion (mild, severe, and total). [ABSTRACT FROM AUTHOR]

Objective: A significant proportion of patients with behavioural variant frontotemporal dementia (bvFTD) show memory impairments similar to patients with Alzheimer's disease (AD), making them prone to misdiagnosis in early disease stages. Our objective was to establish a rapid and efficient memory measure that enhances discrimination between patients with dementia due to Alzheimer's disease and amnestic presentations of behavioural variant frontotemporal dementia. Method: Word list learning data of patients with diagnoses of AD and both amnestic and non-amnestic presentations of bvFTD were analysed. The overall recall rate and the relative contributions of the first two (primacy items) and last two words (recency items) to recall performance were compared between groups. Results: Overall recall rate was indistinguishable between patients with AD and amnestic bvFTD. However, AD patients' recall was mostly driven by recency items, whereas amnestic bvFTD patients' performance was mostly driven by primacy items. Conclusion: We conclude that obtaining a simple recency dominance index from a single, 15-item word list memory trial can help discriminate patients with AD from patients with bvFTD, even if they present with similarly severe memory impairment. [ABSTRACT FROM AUTHOR]

Music is highly efficient at evoking autobiographical memories in both healthy and neurological populations. Music evoked autobiographical memories (MEAMs) are preserved in people with Alzheimer's Dementia (AD), and occur at the same frequency as in healthy people. To date there has been no investigation of the integrity of MEAMs in people with non-AD dementia. This study provides the first characterisation of the frequency and specificity of MEAMs and photo evoked autobiographical memories (PEAMs) in 6 people with Behavioural variant frontotemporal dementia (Bv-FTD). We found significantly reduced frequency and specificity of MEAMs and PEAMs in people with Bv-FTD compared with healthy elderly. This supports the known decline in autobiographical memory function in this population, and the integral role of medial frontal regions in the retrieval of MEAMs. Our findings highlight that the mnemonic effects of music vary between people with different types of dementia, which has implications for dementia care. [ABSTRACT FROM AUTHOR]

Objective: Cognitive tests of inhibitory control show variable results for the differential diagnosis between behavioural variant of Frontotemporal Dementia (bvFTD) and Alzheimer's disease (AD). We compared the diagnostic accuracies of tests of inhibitory control and of a behavioural questionnaire, to distinguish bvFTD from AD. Methods: Three groups of participants were enrolled: 27 bvFTD patients, 25 AD patients, and 24 healthy controls. Groups were matched for gender, education, and socio-economic level. Participants underwent a comprehensive neuropsychological assessment of inhibitory control, including Hayling Test, Stroop, the Five Digits Test (FDT) and the Delay Discounting Task (DDT). Caregivers completed the Barratt Impulsiveness Scale 11th version (BIS-11). Results: bvFTD and AD groups showed no difference in the tasks of inhibitory control, while the caregiver questionnaire revealed that bvFTD patients were significantly more impulsive (BIS-11: bvFTD 76.1+9.5, AD 62.9+13, p <.001). Conclusions: Neuropsychological tests of inhibitory control failed to distinguish bvFTD from AD. On the contrary, impulsivity caregiver-completed questionnaire provided good distinction between bvFTD and AD. These results highlight the current limits of cognitive measures of inhibitory control for the differential diagnosis between bvFTD and AD, whereas questionnaire information appears more reliable and in line with clinical diagnostics. [ABSTRACT FROM AUTHOR]

Background and purpose: Predicting the course of behavioural variant frontotemporal dementia (bvFTD) remains a major clinical challenge. This study aimed to identify factors that predict survival and clinical progression in bvFTD. Methods: Consecutive patients with clinically probable bvFTD were prospectively followed up over an 8‐year period. Baseline neuropsychological variables, presence of a known pathogenic frontotemporal dementia gene mutation and a systematic visual magnetic resonance imaging assessment at baseline were examined as candidate predictors using multivariate modelling. Results: After screening 121 cases, the study cohort consisted of 75 patients with probable bvFTD, with a mean age of 60.8 ± 8.5 years, followed up for a mean duration of 7.2 ± 3.5 years from symptom onset. Median survival time from disease onset was 10.8 years and median survival, prior to transition to nursing home, was 8.9 years. A total of 25 of the 75 patients died during the study follow‐up period. Survival without dependence was predicted by shorter disease duration at presentation (hazard ratio, 0.49, P = 0.001), greater atrophy in the anterior cingulate cortex (hazard ratio, 1.75, P = 0.047), older age (hazard ratio, 1.07, P = 0.026) and a higher burden of behavioural symptoms (hazard ratio, 1.04, P = 0.015). In terms of disease progression, presence of a known pathogenic frontotemporal dementia mutation (β = 0.46, P < 0.001) was the strongest predictor of progression. Deficits in letter fluency (β = −0.43, P = 0.017) and greater atrophy in the motor cortex (β = 0.51, P = 0.03) were also associated with faster progression. Conclusions: This study provides novel clinical predictors of survival and progression in bvFTD. Our findings are likely to have an impact on prognostication and care planning in this difficult disease. [ABSTRACT FROM AUTHOR]

Background/Aims: The C9ORF72 expansion is known to cause frontotemporal lobar degeneration (FTLD) and amyotrophic lateral sclerosis (ALS). We aim to identify the prevalence of the C9ORF72 expansion in idiopathic normal pressure hydrocephalus (iNPH). Methods: We analysed the C9ORF72 expansion in a large cohort of patients with possible iNPH (n = 487) and cognitively intact elderly controls (n = 432; age > 65 years). Results: While the C9ORF72 expansion was detected in 1.6% (n = 8/487) of cases with possible iNPH, no control subject was found to carry the mutation. The mean age at onset of symptoms of C9ORF72 expansion carriers was 59 years (range: 52–67 years), 11 years less than non-carriers (p = 0.0002). The most frequent initial/main symptom pertained to gait difficulties. Despite identified mutation, only 3 of the patients fulfilled the criteria for the FTLD-ALS spectrum. Clinically significant shunt response was detected in 6 out of 7 shunted C9ORF72 expansion carriers. Conclusion: This is the first study cohort identifying the underlying C9ORF72 expansion in patients with iNPH providing evidence for the potential comorbidity between iNPH and the FTLD-ALS spectrum. Analysis of the C9ORF72 expansion should be considered for patients with probable iNPH presenting with frontal atrophy and personality changes or other severe psychiatric symptoms. [ABSTRACT FROM AUTHOR]

Antemortem behavioural and anatomic abnormalities have largely been associated with right hemisphere disease in behavioural-variant frontotemporal dementia, but post-mortem neuropathological examination of bilateral hemispheres remains to be defined. Here we measured the severity of post-mortem pathology in both grey and white matter using a validated digital image analysis method in four cortical regions sampled from each hemisphere in 26 patients with behavioural-variant frontotemporal dementia, including those with frontotemporal degeneration (i.e. tau = 9, TDP-43 = 14, or FUS = 1 proteinopathy) or Alzheimer's pathology (n = 2). We calculated an asymmetry index based on the difference in measured pathology from each left-right sample pair. Analysis of the absolute value of the asymmetry index (i.e. degree of asymmetry independent of direction) revealed asymmetric pathology for both grey and white matter in all four regions sampled in frontototemporal degeneration patients with tau or TDP-43 pathology (P ≤ 0.01). Direct interhemispheric comparisons of regional pathology measurements within-subjects in the combined tauopathy and TDP-43 proteinopathy group found higher pathology in the right orbitofrontal grey matter compared to the left (P < 0.01) and increased pathology in ventrolateral temporal lobe grey matter of the left hemisphere compared to the right (P < 0.02). Preliminary group-wise comparisons between tauopathy and TDP-43 proteinopathy groups found differences in patterns of interhemispheric burden of grey and white matter regional pathology, with greater relative white matter pathology in tauopathies. To test the association of pathology measurement with ante-mortem observations, we performed exploratory analyses in the subset of patients with imaging data (n = 15) and found a direct association for increasing pathologic burden with decreasing cortical thickness in frontotemporal regions on ante-mortem imaging in tauopathy (P = 0.001) and a trend for TDP-43 proteinopathy (P = 0.06). Exploratory clinicopathological correlations demonstrated an association of socially-inappropriate behaviours with asymmetric right orbitofrontal grey matter pathology, and reduced semantically-guided category naming fluency was associated asymmetric white matter pathology in the left ventrolateral temporal region. We conclude that pathologic disease burden is distributed asymmetrically in behavioural-variant frontotemporal dementia, although not universally in the right hemisphere, and this asymmetry contributes to the clinical heterogeneity of the disorder. The basis for this asymmetric profile is enigmatic but may reflect distinct species or strains of tau and TDP-43 pathologies with propensities to spread by distinct cell- and region-specific mechanisms. Patterns of region-specific pathology in the right hemisphere as well as the left hemisphere may play a role in antemortem clinical observations, and these observations may contribute to antemortem identification of molecular pathology in frontotemporal degeneration. [ABSTRACT FROM AUTHOR]

Eyetracking technology has had limited application in the dementia field to date, with most studies attempting to discriminate syndrome subgroups on the basis of basic oculomotor functions rather than higher-order cognitive abilities. Eyetracking-based tasks may also offer opportunities to reduce or ameliorate problems associated with standard paper-and-pencil cognitive tests such as the complexity and linguistic demands of verbal test instructions, and the problems of tiredness and attention associated with lengthy tasks that generate few data points at a slow rate. In the present paper we adapted the Brixton spatial anticipation test to a computerized instruction-less version where oculomotor metrics, rather than overt verbal responses, were taken into account as indicators of high level cognitive functions. Twelve bvFTD (in whom spatial anticipation deficits were expected), six SD patients (in whom deficits were predicted to be less frequent) and 38 healthy controls were presented with a 10 × 7 matrix of white circles. During each trial (N = 24) a black dot moved across seven positions on the screen, following 12 different patterns. Participants’ eye movements were recorded. Frequentist statistical analysis of standard eye movement metrics were complemented by a Bayesian machine learning (ML) approach in which raw eyetracking time series datasets were examined to explore the ability to discriminate diagnostic group performance not only on the overall performance but also on individual trials. The original pen and paper Brixton test identified a spatial anticipation deficit in 7/12 (58%) of bvFTD and in 2/6 (33%) of SD patients. The eyetracking frequentist approach reported the deficit in 11/12 (92%) of bvFTD and in none (0%) of the SD patients. The machine learning approach had the main advantage of identifying significant differences from controls in 24/24 individual trials for bvFTD patients and in only 12/24 for SD patients. Results indicate that the fine grained rich datasets obtained from eyetracking metrics can inform us about high level cognitive functions in dementia, such as spatial anticipation. The ML approach can help identify conditions where subtle deficits are present and, potentially, contribute to test optimisation and the reduction of testing times. The absence of instructions also favoured a better distinction between different clinical groups of patients and can help provide valuable disease-specific markers. [ABSTRACT FROM AUTHOR]

Although converging evidence has positioned the human cerebellum as an important relay for intact cognitive and neuropsychiatric processing, changes in this large structure remain mostly overlooked in behavioural variant frontotemporal dementia (bvFTD), a disease which is characterized by cognitive and neuropsychiatric deficits. The present study assessed whether degeneration in specific cerebellar subregions associate with indices of cognition and neuropsychiatric performance in bvFTD. Our results demonstrate a relationship between cognitive and neuropsychiatric decline across various domains of memory, language, emotion, executive, visuospatial function and motivation and the degree of grey matter degeneration in cerebellar lobules V-VII. Most notably, bilateral cerebellar lobule VII and the posterior vermis emerged as distinct for memory processes, the right cerebellar hemisphere underpinned emotion, and the posterior vermis was highlighted in language dysfunction in bvFTD. Based on cortico-cerebellar connectivity maps, these findings in the cerebellum are consistent with the neural connections with the cortices involved in these domains in patients with bvFTD. Overall, the present study underscores the significance of cortical-cerebellar networks associated with cognition and neuropsychiatric dysfunction in bvFTD.

A decline in instrumental activities of daily living has been described as the earliest functional deficit in patients with neurodegenerative disease. It embraces specific competencies such as: “ recalling the date and telephone calls, orienting to new places, remembering the location of objects at home, understanding conversation and the plot of a movie, keeping belongings in order, doing mental calculations and handling money, remembering appointments and shopping lists and performing clerical work ”. Since changes in instrumental daily living activities are one of the descriptors of behavioural-variant frontotemporal dementia, we decided to investigate the neural correlates of a reduced awareness in this specific domain in twenty-three consecutive behavioural-variant frontotemporal dementia patients. Gray matter volume changes associated with a reduced awareness for the instrumental domain, assessed using a validated caregiver-patient discrepancy questionnaire, were examined. Interestingly, we found disabilities in instrumental daily living activities and a reduced awareness of these to be related to medial prefrontal cortex atrophy, where the mid-cingulate cortices, dorsal anterior insula and cuneous play an important role. Importantly, if the executive system does not function correctly, the comparator mechanism of action self-monitoring does not detect mismatches between the current and previous performance states stored in the personal database, and produces a reduced awareness for the instrumental domain. [ABSTRACT FROM AUTHOR]

Adherence to social norms is compromised in a variety of neuropsychiatric conditions. Functional neuroimaging studies have investigated social norm compliance in healthy individuals, leading to the identification of a network of fronto-subcortical regions that underpins this ability. However, there is a lack of corroborative evidence from human lesion models investigating the structural anatomy of norm compliance across this fronto-subcortical network. To address this, we developed a neuroeconomic task to investigate social norm compliance in a neurodegenerative lesion model: behavioural variant frontotemporal dementia, a condition characterized by gross social dysfunction. The task assessed norm compliance across three behaviours that are well-studied in the neuroeconomics literature: fairness, prosocial and punishing behaviours. We administered our novel version of the Ultimatum Game in 22 patients with behavioural variant frontotemporal dementia and 22 age-matched controls, to assess how decision-making behaviour was modulated in response to (i) fairness of monetary offers; and (ii) social context of monetary offers designed to produce either prosocial or punishing behaviours. Voxel-based morphometry was used to characterize patterns of grey matter atrophy associated with task performance. Acceptance rates between patients and controls were equivalent when only fairness was manipulated. However, patients were impaired in modulating their decisions in response to social contextual information. Patients' performance in the punishment condition was consistent with a reduced tendency to engage in punishment; this was associated with decreased grey matter volume in the anterior cingulate, orbitofrontal cortex, left dorsolateral prefrontal cortex and right inferior frontal gyrus. In the prosocial condition, patients' performance suggested a reduced expression of prosocial behaviour, associated with decreased grey matter in the anterior insula, lateral orbitofrontal cortex, anterior cingulate and dorsal striatum. Acceptance rates in the Ultimatum Game were also significantly related to impairments in the everyday expression of empathic concern. In conclusion, we demonstrate that compliance to basic social norms (fairness) can be maintained in behavioural variant frontotemporal dementia; however, more complex normative behaviours (prosociality, punishment) that require integration of social contextual information are disrupted in association with atrophy in key fronto-striatal regions. These results suggest that the integration of social contextual information to guide normative behaviour is uniquely impaired in behavioural variant frontotemporal dementia, and may explain other common features of the condition including gullibility and impaired empathy. Our findings also converge with previous functional neuroimaging investigations in healthy individuals and provide the first description of the structural anatomy of social norm compliance in a neurodegenerative lesion model. [ABSTRACT FROM AUTHOR]

The pathological sequestration of TAR DNA-binding protein 43 (TDP-43, encoded by TARDBP) into cytoplasmic pathological inclusions characterizes the distinct clinical syndromes of amyotrophic lateral sclerosis and behavioural variant frontotemporal dementia, while also co-occurring in a proportion of patients with Alzheimer's disease, suggesting that the regional concentration of TDP-43 pathology has most relevance to specific clinical phenotypes. This has been reflected in the three different pathological staging schemes for TDP-43 pathology in these different clinical syndromes, with none of these staging schemes including a preclinical phase similar to that which has proven beneficial in other neurodegenerative diseases. To apply each of these three staging schemes for TDP-43 pathology, the clinical phenotype must be known undermining the potential predictive value of the pathological examination. The present study set out to test whether a more unified approach could accurately predict clinical phenotypes based solely on the regional presence and severity of TDP-43 pathology. The selection of brain regions of interest was based on key regions routinely sampled for neuropathological assessment under current consensus criteria that have also been used in the three TDP-43 staging schemes. The severity of TDP-43 pathology in these regions of interest was assessed in four clinicopathological phenotypes: amyotrophic lateral sclerosis (n = 27, 47-78 years, 15 males), behavioural variant frontotemporal dementia (n = 15, 49-82 years, seven males), Alzheimer's disease (n = 26, 51-90 years, 11 males) and cognitively normal elderly individuals (n = 17, 80-103 years, nine males). Our results demonstrate that the presence of TDP-43 in the hypoglossal nucleus discriminates patients with amyotrophic lateral sclerosis with an accuracy of 98%. The severity of TDP-43 deposited in the anterior cingulate cortex identifies patients with behavioural variant frontotemporal dementia with an accuracy of 99%. This identification of regional pathology associated with distinct clinical phenotypes suggests key regions on which probabilistic pathological criteria, similar to those currently available for Alzheimer's disease and dementia with Lewy bodies, can be developed for TDP-43 proteinopathies. We propose and validate a simplified probabilistic statement that involves grading the presence of TDP-43 in the hypoglossal nucleus and the severity of TDP-43 in the anterior cingulate for the pathological identification of TDP-43 proteinopathy cases with clinical amyotrophic lateral sclerosis and behavioural variant frontotemporal dementia. [ABSTRACT FROM AUTHOR]

Although converging evidence has positioned the human cerebellum as an important relay for intact cognitive and neuropsychiatric processing, changes in this large structure remain mostly overlooked in behavioural variant frontotemporal dementia (bvFTD), a disease which is characterized by cognitive and neuropsychiatric deficits. The present study assessed whether degeneration in specific cerebellar subregions associate with indices of cognition and neuropsychiatric performance in bvFTD. Our results demonstrate a relationship between cognitive and neuropsychiatric decline across various domains of memory, language, emotion, executive, visuospatial function and motivation and the degree of grey matter degeneration in cerebellar lobules V-VII. Most notably, bilateral cerebellar lobule VII and the posterior vermis emerged as distinct for memory processes, the right cerebellar hemisphere underpinned emotion, and the posterior vermis was highlighted in language dysfunction in bvFTD. Based on cortico-cerebellar connectivity maps, these findings in the cerebellum are consistent with the neural connections with the cortices involved in these domains in patients with bvFTD. Overall, the present study underscores the significance of cortical-cerebellar networks associated with cognition and neuropsychiatric dysfunction in bvFTD. [ABSTRACT FROM AUTHOR]

Background.To investigate trajectories of cognitive decline in patients with different types of dementia compared to controls in a longitudinal study.Method.In 199 patients with Alzheimer's disease (AD), 10 with vascular dementia (VaD), 26 with dementia with Lewy bodies (DLB), 20 with behavioural variant frontotemporal dementia (bvFTD), 15 with language variant frontotemporal dementia (lvFTD) and 112 controls we assessed five cognitive domains: memory, language, attention, executive and visuospatial functioning, and global cognition (Mini-Mental State Examination, MMSE). All subjects had at least two neuropsychological assessments (median 2, range 2–7). Neuropsychological data were standardized into z scores using baseline performance of controls as reference. Linear mixed models (LMMs) were used to estimate baseline cognitive functioning and cognitive decline over time for each group, adjusted for age, gender and education.Results.At baseline, patients with dementia performed worse than controls in all cognitive domains (p < 0.05) except visuospatial functioning, which was only impaired in patients with AD and DLB (p < 0.001). During follow-up, patients with AD declined in all cognitive domains (p < 0.001). DLB showed decline in every cognitive domain except language and global cognition. bvFTD showed rapid decline in memory, language, attention and executive functioning (all p < 0.01) whereas visuospatial functioning remained fairly stable. lvFTD declined mostly in attention and executive functioning (p < 0.01). VaD showed decline in attention and executive functioning.Conclusions.We show cognitive trajectories of different types of dementia. These estimations of natural disease course have important value for the design of clinical trials as neuropsychological measures are increasingly being used as outcome measures. [ABSTRACT FROM AUTHOR]

Background : Distinguishing behavioural variant frontotemporal dementia (bvFTD) from non-neurodegenerative 'non-progressor' mimics of frontal lobe dysfunction, can be one of the most challenging clinical dilemmas. A biomarker of neuronal injury, neurofilament light chain (NfL), could reduce misdiagnosis and delay. Methods : Cerebrospinal fluid (CSF) NfL, amyloid beta 1–42 (AB42), total and phosphorylated tau (T-tau, P-tau) levels were examined in patients with an initial diagnosis of bvFTD. Based on follow-up information, patients were categorised as Progressors or Non-Progressors: further subtyped into Non-Progressor Revised (non-neurological/neurodegenerative final diagnosis), and Non-Progressor Static (static deficits, not fully explained by non-neurological/neurodegenerative causes). Results : Forty-three patients were included: 20 Progressors, 23 Non-Progressors (15 Non-Progressor Revised, 8 Non-Progressor Static), and 20 controls. NfL concentrations were lower in Non-Progressors (Non-Progressors Mean, M = 554 pg/mL, 95%CI:[461, 675], Non-Progressor Revised M = 459 pg/mL, 95%CI:[385, 539], and Non-Progressor Static M = 730 pg/mL, 95%CI:[516, 940]), compared to Progressors (M = 2397 pg/mL, 95%CI:[1607, 3332]). NfL distinguished Progressors from Non-Progressors with the highest accuracy (area under the curve 0.92, 90%/87% sensitivity/specificity, 86%/91% positive/negative predictive value, 88% accuracy). Non-Progressor Static tended to have higher T-tau and P-tau levels compared to Non-Progressor Revised Diagnoses. Conclusion : This study demonstrated strong diagnostic utility of CSF NfL to distinguish bvFTD from non-progressor variants, at baseline, with high accuracy, in a real-world clinical setting. This has important clinical implications, to improve outcomes for patients and clinicians facing this challenging clinical dilemma, healthcare services, and clinical trials. Further research is required to investigate heterogeneity within the non-progressor group and potential diagnostic algorithms, and prospective studies are underway assessing plasma NfL. • Accurate diagnosis of behavioural variant frontotemporal dementia is challenging. • bvFTD is commonly misdiagnosed, and distinguishing from non-progressor mimics is challenging. • The biomarker of neuronal injury, neurofilament light, improves diagnostic confidence in bvFTD. [ABSTRACT FROM AUTHOR]

Theory of mind reasoning—the ability to understand someone else’s mental states, such as beliefs, intentions and desires—is crucial in social interaction. It has been suggested that a theory of mind deficit may account for some of the abnormalities in interpersonal behaviour that characterize patients affected by behavioural variant frontotemporal dementia. However, there are conflicting reports as to whether understanding someone else’s mind is a key difference between behavioural variant frontotemporal dementia and other neurodegenerative conditions such as Alzheimer’s disease. Literature data on the relationship between theory of mind abilities and executive functions are also contradictory. These disparities may be due to underestimation of the fractionation within theory of mind components. A recent theoretical framework suggests that taking someone else’s mental perspective requires two distinct processes: inferring someone else’s belief and inhibiting one’s own belief, with involvement of the temporoparietal and right frontal cortices, respectively. Therefore, we performed a neuropsychological and neuroimaging study to investigate the hypothesis whereby distinct cognitive deficits could impair theory of mind reasoning in patients with Alzheimer’s disease and patients with behavioural variant frontotemporal dementia. We used a three-option false belief task to assess theory of mind components in 11 patients with behavioural variant frontotemporal dementia, 12 patients with Alzheimer’s disease and 20 healthy elderly control subjects. The patients with behavioural variant frontotemporal dementia and those with Alzheimer’s disease were matched for age, gender, education and global cognitive impairment. [18F]-fluorodeoxyglucose-positron emission tomography imaging was used to investigate neural correlates of theory of mind reasoning deficits. Performance in the three-option false belief task revealed differential impairments in the components of theory of mind reasoning; patients with Alzheimer’s disease had a predominant deficit in inferring someone else’s belief, whereas patients with behavioural variant frontotemporal dementia were selectively impaired in inhibiting their own mental perspective. Moreover, inhibiting one’s own perspective was strongly correlated with inhibition in a Stroop task but not with other subprocesses of executive functions. This finding suggests that self-perspective inhibition may depend on cognitive processes that are not specific to the social domain. Last, the severity of the deficit in inferring someone else’s beliefs correlated significantly over all subjects with hypometabolism in the left temporoparietal junction, whereas the severity of the deficit in self-perspective inhibition correlated significantly with hypometabolism in the right lateral prefrontal cortex. In conclusion, our findings provided clinical and imaging evidence to support differential deficits in two components of theory of mind reasoning (subserved by distinct brain regions) in patients with Alzheimer’s disease and patients with behavioural variant frontotemporal dementia. [ABSTRACT FROM AUTHOR]

Behavioural variant frontotemporal dementia can present with episodic memory deficits as severe as those in Alzheimer’s disease. Little is known of the integrity of grey matter areas and white matter tracts of the Papez memory circuit in these diseases. The integrity of the Papez circuit (hippocampus, fornix, mammillary bodies, anterior thalamus, cingulate cortex) was investigated in vivo and at post-mortem in behavioural variant frontotemporal dementia and Alzheimer’s disease cohorts using voxel-based morphometry, diffusion tensor imaging and manual volumetric tracing. Our findings indicate that behavioural variant frontotemporal dementia and Alzheimer’s disease show similar degrees of hippocampal atrophy in vivo, but patients with behavioural variant frontotemporal dementia show greater hippocampal atrophy at post-mortem, with the frontotemporal lobar degeneration with TDP-43 inclusions subtype being particularly affected. Cingulate cortex findings show an expected atrophy pattern with behavioural variant frontotemporal dementia being affected more anteriorly and Alzheimer’s disease showing more posterior atrophy. More importantly, subcortical Papez circuit regions (fornix and anterior thalamus) were affected in behavioural variant frontotemporal dementia only, with atrophy in these regions determining the degree of amnesia in behavioural variant frontotemporal dementia. Hippocampal atrophy does not appear to be an efficient diagnostic marker for underlying behavioural variant frontotemporal dementia or Alzheimer’s disease pathology, although for behavioural variant frontotemporal dementia, episodic memory deficits in conjunction with marked hippocampal atrophy emerge as potential biomarkers for frontotemporal lobar degeneration with TDP-43 inclusions pathology. Sub-regions of the Papez circuit were differentially affected in behavioural variant frontotemporal dementia and Alzheimer’s disease with subcortical regions determining the degree of episodic memory deficits in behavioural variant frontotemporal dementia. Subcortical atrophy should be taken into account when establishing whether the severe amnesia observed in a patient is likely to be due to behavioural variant frontotemporal dementia or Alzheimer’s disease pathology. [ABSTRACT FROM AUTHOR]

Disinhibition is a common behavioural symptom in frontotemporal dementia but its neural correlates are still debated. In the current study, we investigated the grey and white matter neural correlates of disinhibition in a sample of behavioural variant frontotemporal dementia (n = 14) and patients with Alzheimer's disease (n = 15). We employed an objective (Hayling Test of inhibitory functioning) and subjective/carer-based (Neuropsychiatric Inventory) measure of disinhibition to reveal convergent evidence of disinhibitory behaviour. Mean and overlap-based statistical analyses were conducted to investigate profiles of performance in patients with behavioural variant frontotemporal dementia, Alzheimer's disease and controls. Hayling Test and Neuropsychiatric Inventory scores were entered as covariates in a grey matter voxel-based morphometry, as well as in a white matter diffusion tensor imaging analysis to determine the underlying grey and white matter correlates. Patients with behavioural variant frontotemporal dementia showed more disinhibition on both behavioural measures in comparison to patients with Alzheimer's disease and controls. Voxel-based morphometry results revealed that atrophy in orbitofrontal/subgenual, medial prefrontal cortex and anterior temporal lobe areas covaried with total errors score of the Hayling Test. Similarly, the Neuropsychiatric Inventory disinhibition frequency score correlated with atrophy in orbitofrontal cortex and temporal pole brain regions. The orbitofrontal atrophy related to the objective (Hayling Test) and subjective (Neuropsychiatric Inventory) measures of disinhibition was partially overlapping. Diffusion tensor imaging analysis revealed that white matter integrity fractional anisotropy values of the white matter tracts connecting the identified grey matter regions, namely uncinate fasciculus, forceps minor and genu of the corpus callosum, correlated well with the total error score of the Hayling Test. Our results show that a network of orbitofrontal, anterior temporal and mesial frontal brain regions and their connecting white matter tracts are involved in inhibitory functioning. Further, we find convergent evidence for objective and subjective disinhibition measures that the orbitofrontal/subgenual brain region is critical for adapting and maintaining normal behaviour. [ABSTRACT FROM PUBLISHER]

Based on the recent literature and collective experience, an international consortium developed revised guidelines for the diagnosis of behavioural variant frontotemporal dementia. The validation process retrospectively reviewed clinical records and compared the sensitivity of proposed and earlier criteria in a multi-site sample of patients with pathologically verified frontotemporal lobar degeneration. According to the revised criteria, ‘possible’ behavioural variant frontotemporal dementia requires three of six clinically discriminating features (disinhibition, apathy/inertia, loss of sympathy/empathy, perseverative/compulsive behaviours, hyperorality and dysexecutive neuropsychological profile). ‘Probable’ behavioural variant frontotemporal dementia adds functional disability and characteristic neuroimaging, while behavioural variant frontotemporal dementia ‘with definite frontotemporal lobar degeneration’ requires histopathological confirmation or a pathogenic mutation. Sixteen brain banks contributed cases meeting histopathological criteria for frontotemporal lobar degeneration and a clinical diagnosis of behavioural variant frontotemporal dementia, Alzheimer’s disease, dementia with Lewy bodies or vascular dementia at presentation. Cases with predominant primary progressive aphasia or extra-pyramidal syndromes were excluded. In these autopsy-confirmed cases, an experienced neurologist or psychiatrist ascertained clinical features necessary for making a diagnosis according to previous and proposed criteria at presentation. Of 137 cases where features were available for both proposed and previously established criteria, 118 (86%) met ‘possible’ criteria, and 104 (76%) met criteria for ‘probable’ behavioural variant frontotemporal dementia. In contrast, 72 cases (53%) met previously established criteria for the syndrome (P < 0.001 for comparison with ‘possible’ and ‘probable’ criteria). Patients who failed to meet revised criteria were significantly older and most had atypical presentations with marked memory impairment. In conclusion, the revised criteria for behavioural variant frontotemporal dementia improve diagnostic accuracy compared with previously established criteria in a sample with known frontotemporal lobar degeneration. Greater sensitivity of the proposed criteria may reflect the optimized diagnostic features, less restrictive exclusion features and a flexible structure that accommodates different initial clinical presentations. Future studies will be needed to establish the reliability and specificity of these revised diagnostic guidelines. [ABSTRACT FROM PUBLISHER]

The behavioural variant of frontotemporal dementia is a progressive neurodegenerative syndrome characterized by changes in personality and behaviour. It is typically associated with frontal lobe atrophy, although patterns of atrophy are heterogeneous. The objective of this study was to examine case-by-case variability in patterns of grey matter atrophy in subjects with the behavioural variant of frontotemporal dementia and to investigate whether behavioural variant of frontotemporal dementia can be divided into distinct anatomical subtypes. Sixty-six subjects that fulfilled clinical criteria for a diagnosis of the behavioural variant of frontotemporal dementia with a volumetric magnetic resonance imaging scan were identified. Grey matter volumes were obtained for 26 regions of interest, covering frontal, temporal and parietal lobes, striatum, insula and supplemental motor area, using the automated anatomical labelling atlas. Regional volumes were divided by total grey matter volume. A hierarchical agglomerative cluster analysis using Ward's clustering linkage method was performed to cluster the behavioural variant of frontotemporal dementia subjects into different anatomical clusters. Voxel-based morphometry was used to assess patterns of grey matter loss in each identified cluster of subjects compared to an age and gender-matched control group at P < 0.05 (family-wise error corrected). We identified four potentially useful clusters with distinct patterns of grey matter loss, which we posit represent anatomical subtypes of the behavioural variant of frontotemporal dementia. Two of these subtypes were associated with temporal lobe volume loss, with one subtype showing loss restricted to temporal lobe regions (temporal-dominant subtype) and the other showing grey matter loss in the temporal lobes as well as frontal and parietal lobes (temporofrontoparietal subtype). Another two subtypes were characterized by a large amount of frontal lobe volume loss, with one subtype showing grey matter loss in the frontal lobes as well as loss of the temporal lobes (frontotemporal subtype) and the other subtype showing loss relatively restricted to the frontal lobes (frontal-dominant subtype). These four subtypes differed on clinical measures of executive function, episodic memory and confrontation naming. There were also associations between the four subtypes and genetic or pathological diagnoses which were obtained in 48% of the cohort. The clusters did not differ in behavioural severity as measured by the Neuropsychiatric Inventory; supporting the original classification of the behavioural variant of frontotemporal dementia in these subjects. Our findings suggest behavioural variant of frontotemporal dementia can therefore be subdivided into four different anatomical subtypes. [ABSTRACT FROM PUBLISHER]

Spontaneous intracranial hypotension is uncommon and results from a cerebrospinal fluid (CSF) leak. We describe the case of a marathon runner who presented with postural headache attributable to CSF venous fistulation originating from a lower thoracic nerve root cyst. Subsequent investigations confirmed a unifying de novo diagnosis of human leukocyte antigen B27-associated syndrome. With unmitigated CSF loss over the following 3 months, the patient became bedbound and developed rapidly progressive behavioural variant frontotemporal dementia. Behavioural changes were somewhat reversible on restoration of CSF volume after surgical intervention. [ABSTRACT FROM AUTHOR]

The behavioural variant of frontotemporal dementia is a clinical syndrome characterized by changes in behaviour, cognition and functional ability. Although atrophy in frontal and temporal regions would appear to be a defining feature, neuroimaging studies have identified volumetric differences distributed across large parts of the cortex, giving rise to a classification into distinct neuroanatomical subtypes. Here, we extended these neuroimaging studies to examine how distributed patterns of cortical atrophy map onto brain network hubs. We used baseline structural magnetic resonance imaging data collected from 213 behavioural variant of frontotemporal dementia patients meeting consensus diagnostic criteria and having definite evidence of frontal and/or temporal lobe atrophy from a global clinical trial conducted in 70 sites in Canada, United States of America, Australia, Asia and Europe. These were compared with data from 244 healthy elderly subjects from a well-characterized cohort study. We have used statistical methods of hierarchical agglomerative clustering of 68 regional cortical and subcortical volumes (34 in each hemisphere) to determine the reproducibility of previously described neuroanatomical subtypes in a global study. We have also attempted to link the structural findings to clinical features defined systematically using well-validated clinical scales (Addenbrooke's Cognitive Examination Revised, the Mini-Mental Status Examination, the Frontotemporal Dementia Rating Scale and the Functional Assessment Questionnaire) and subscales derived from them. Whilst we can confirm that the subtypes are robust, they have limited value in explaining the clinical heterogeneity of the syndrome. We have found that a common pattern of degeneration affecting a small number of subcortical, limbic and frontal nodes within highly connected networks (most previously identified as rich club members or functional binding nodes) is shared by all the anatomical subtypes. Degeneration in these core regions is correlated with cognitive and functional impairment, but less so with behavioural impairment. These findings suggest that degeneration in highly connected basal, limbic and frontal networks is a core feature of the behavioural variant of frontotemporal dementia phenotype irrespective of neuroanatomical and clinical heterogeneity, and may underly the impairment of integration in cognition, function and behaviour responsible for the loss of insight that characterizes the syndrome., (© The Author(s) (2021). Published by Oxford University Press on behalf of the Guarantors of Brain.)