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Background: Reported sex distributions differ between frontotemporal dementia (FTD) cohorts. Possible explanations are the evolving clinical criteria of FTD and its subtypes and the discovery of FTD causal genetic mutations that has resulted in varying demographics. Objective: Our aim was to determine the sex distribution of sporadic and genetic FTD cases and its subtypes in an international cohort. Methods: We included 910 patients with behavioral variant frontotemporal dementia (bvFTD; n = 654), non-fluent variant primary progressive aphasia (nfvPPA; n = 99), semantic variant primary progressive aphasia (svPPA; n = 117), and right temporal variant frontotemporal dementia (rtvFTD; n = 40). We compared sex distribution between genetic and sporadic FTD using χ2-tests. Results: The genetic FTD group consisted of 51.2% males, which did not differ from sporadic FTD (57.8% male, p = 0.08). In the sporadic bvFTD subgroup, males were predominant in contrast to genetic bvFTD (61.6% versus 52.9% males, p = 0.04). In the other clinical FTD subgroups, genetic cases were underrepresented and within the sporadic cases the sex distribution was somewhat equal. Conclusion: The higher male prevalence in sporadic bvFTD may provide important clues for its differential pathogenesis and warrants further research.

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.

Frontotemporal dementia (FTD) is a heterogeneous group of neurodegenerative brain disorders, primarily affecting the frontal and/or temporal lobes. Three main subtypes are recognised, each with distinct clinical and cognitive profiles: behavioural-variant FTD (bvFTD), semantic dementia (SD), and progressive nonfluent aphasia (PNFA). Subtype-specific cerebellar grey matter atrophy has been associated with cognitive dysfunction in FTD; however, the extent and severity of structural abnormalities in the cerebro-cerebellar circuits in these disorders has not been investigated. This study aimed to identify patterns of cerebellar white matter changes and their relations to cognitive deficits in the main FTD subtypes. Results revealed bilateral cerebellar white matter changes in all FTD subtypes compared with controls, with greater cerebellar white matter changes in bvFTD than SD and PNFA. Both afferent and efferent cerebellar pathways were associated with cognition. The profiles of the involvement of cerebellar pathways in cognition varied across FTD syndromes. In bvFTD, the output pathway of the cerebellum was only associated with measures of episodic memory. The input pathway was associated with measures of attention, working memory, visuospatial, episodic memory, executive function, and emotion. In SD, both the output and input pathways were associated with measures of working memory, language, and emotion. Finally, in PNFA, both the output and input pathway of the cerebellum were associated with attention, language, and executive function. Additionally, the input pathway was associated with working memory, visuospatial, and emotion. This study is the first to identify patterns of cerebellar white matter changes across FTD syndromes, which in turn relate to cognitive deficits. These findings extend our understanding of the cerebro-cerebellar networks and provide new insight into the role of cerebellar white matter in cognition.

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

Background: Mild cognitive impairment (MCI) in Parkinson’s disease (PD) is considered a risk factor for PD with dementia (PDD). Verbal fluency tasks are widely used to assess executive function in PDD. However, in cases of PD with MCI (PD-MCI), the relative diagnostic accuracy of different qualitative verbal fluency measures and their related neural mechanisms remain unknown. Objective: This study aimed to investigate the relative diagnostic accuracy of qualitative (clustering and switching) verbal fluency strategies and their correlates with functional imaging in PD-MCI. Methods: Forty-five patients with PD (26 with MCI and 19 without MCI) and 25 healthy controls underwent comprehensive neurocognitive testing and resting-state functional magnetic resonance imaging. MCI in patients with PD was diagnosed according to established clinical criteria. The diagnostic accuracy of verbal fluency measures was determined via receiver operating characteristic analysis. Changes in brain functional connectivity between groups and across clinical measures were assessed using seed-to-voxel analyses. Results: Patients with PD-MCI generated fewer words and switched less frequently in semantic and phonemic fluency tasks compared to other groups. Switching in semantic fluency showed high diagnostic accuracy for PD-MCI and was associated with reduced functional connectivity in the salience network. Conclusion: Our results indicate that reduced switching in semantic fluency tasks is a sensitive and specific marker for PD-MCI. Qualitative verbal fluency deficits and salience network dysfunction represent early clinical changes observed in PD-MCI.

The GGGGCC hexanucleotide repeat expansion in the non-coding region of the chromosome 9 open reading frame 72 gene (C9orf72) is the most common genetic cause of familial frontotemporal dementia (FTD). This study aims to clarify the patterns of cerebellar atrophy in FTD patients with and without a C9orf72 repeat expansion compared with healthy controls and determine whether associations between cerebellar atrophy and cognition differ between patient groups.Thirty C9orf72 repeat expansion-positive FTD patients, 30 C9orf72 repeat expansion-negative FTD patients, and 30 age-, sex-, and education-matched healthy controls underwent brain MRI and cognitive assessments. Patient groups were matched for clinical diagnosis, disease duration, general cognition, and disease severity.Compared with controls, the C9orf72 positive group showed cerebellar changes bilaterally involving the lobules V, VI, Crus I, Crus II, VIIb, VIIIa, left VIIIb, and right lobules I-IV. All these changes were localised within the regions affected in the C9orf72 negative group. No significant differences were found between patient groups. Correlation analyses with a liberal threshold found the cerebellar integrity to be associated with attention, language, and executive function in the C9orf72 positive group. In the C9orf72 negative group, these associations included attention, working memory, language, episodic memory, and executive function.This study clarifies the impact of C9orf72 repeat expansion on cerebellar integrity in FTD. The findings reveal overlapping patterns of cerebellar atrophy in C9orf72 positive and negative groups. The associations with cognitive functions suggest that the type of pathology linked with cerebellar atrophy is another relevant variable to consider in future studies.

Background Frontotemporal dementia (FTD) is associated with complex changes in eating behavior and metabolism, which potentially affect disease pathogenesis and survival. It is currently not known if body composition changes and changes in fat deposition also exist in FTD, the relationship of these changes in eating behavior and appetite, and whether these changes are centrally mediated. Methods Body composition was measured in 28 people with behavioral‐variant frontotemporal dementia (bvFTD), 16 with Alzheimer’s disease (AD), and 19 healthy controls, using dual energy x‐ray absorptiometry. Changes in body composition were correlated to brain grey matter atrophy using voxel‐based morphometry on high‐resolution magnetic resonance imaging. Results Behavioral‐variant FTD was characterized by changes in body composition, with increased total fat mass, visceral adipose tissue area (VAT area), and android: gynoid ratio compared to control and AD participants (all P values

Aquired apraxia of speech is a disorder that impairs speech production, despite intact peripheral neuromotor function. Its pathomechanism remains to be established. Neurodegenerative lesion models provide an unequalled opportunity to explore the neural correlates of apraxia of speech, which is present in a subset of patients diagnosed with non-semantic variants of primary progressive aphasia. The normalized pairwise variability index, an acoustic measure of speech motor programming, has shown high sensitivity and specificity for apraxia of speech in cross-sectional studies. Here, we aimed to examine the strength of the pairwise variability index and overall word duration (i.e. articulation rate) as markers of progressive motor programming deficits in primary progressive aphasia with apraxia of speech. Seventy-nine individuals diagnosed with primary progressive aphasia (39 with non-fluent variant and 40 with logopenic variant) and 40 matched healthy controls participated. Patients were followed-up annually (range 1–6 years, median number of visits = 2). All participants completed a speech assessment task and a high-resolution MRI. Our analyses investigated trajectories of speech production (e.g. pairwise variablity index and word duration) and associations with cortical atrophy in the patients. At first presentation, word duration differentiated the nonfluent and logopenic cases statistically, but the range of scores overlapped substantially across groups. Longitudinally, we observed progressive deterioration in pairwise variability index and word duration specific to the non-fluent group only. The pairwise variability index showed particularly strong associations with progressive atrophy in speech motor programming brain regions. Of novelty, our results uncovered a key role of the right frontal gyrus in underpinning speech motor programming changes in non-fluent cases, highlighting the importance of right-brain regions in responding to progressive neurological changes in the speech motor network. Taken together, our findings validate the use of a new metric, the pairwise variability index, as a robust marker of apraxia of speech in contrast to more generic measures of speaking rate. Sensitive/specific neuroimaging biomarkers of the emergence and progression of speech impairments will be useful to inform theories of the pathomechanisms underpinning impaired speech motor control. Our findings justify developing more sensitive measures of rhythmic temporal control of speech that may enable confident detection of emerging speech disturbances and more sensitive tracking of intervention-related changes for pharmacological, neuromodulatory and behavioural interventions. A more reliable detection of speech disturbances has relevance for patient care, with predominance of progressive apraxia of speech a high-risk factor for later diagnosis of progressive supranuclear palsy or corticobasal degeneration., Landin-Romero et al. combined speech and neuroimaging analyses to validate the pairwise variability index, a simple temporal acoustic measure, in the assessment and monitoring of apraxia of speech in primary progressive aphasia. Additionally, findings highlight the role of established and new brain regions in supporting speech motor control., Graphical Abstract Graphical Abstract

An altered sense of self-awareness and agency has been proposed to underlie symptoms of schizophrenia. In this study, we used the enfacement illusion paradigm - in which perception of another person's face leads to changes in perception of one's own peri-personal space - to examine the brain correlates of the sense of agency and its potential disruption in schizophrenia. Thirty-three schizophrenic patients and 27 healthy controls underwent fMRI scanning during performance of a task designed to elicit the enfacement illusion. Activations were examined using whole-brain analysis and also in an a priori identified region of interest (ROI) in the temporoparietal junction (TPJ), a region that has been described as involved in self/other differentiation and sense of agency. Both groups showed a pattern of cortical activation involving the pre and postcentral cortex, Rolandic operculum, insula, parietal, temporal and occipital cortex bilaterally as well as TPJ (but only right-side in patients). Examination of the TPJ ROI revealed significantly reduced activation on the left in the patients that was associated with poorer insight. The findings suggest brain functional abnormality in schizophrenia related to the formation or maintenance of processes related to self and/or agency. Decreased function in the TPJ may have a role in the impaired insight seen in patients with the disorder.

ObjectiveTo test the hypothesis that white matter hyperintensities (WMH) in behavioral-variant frontotemporal dementia (bvFTD) and Alzheimer disease (AD) are associated with disease variables such as disease severity, cortical atrophy, and cognition, we conducted a cross-sectional brain MRI study with volumetric and voxel-wise analyses.MethodsA total of 129 patients (64 bvFTD, 65 AD) and 66 controls underwent high-resolution brain MRI and clinical and neuropsychological examination. Genetic screening was conducted in 124 cases (54 bvFTD, 44 AD, 26 controls) and postmortem pathology was available in 18 cases (13 bvFTD, 5 AD). WMH were extracted using an automated segmentation algorithm and analyses of total volumes and spatial distribution were conducted. Group differences in total WMH volume and associations with vascular risk and disease severity were examined. Syndrome-specific voxel-wise associations between WMH, cortical atrophy, and performance across different cognitive domains were assessed.ResultsTotal WMH volumes were larger in patients with bvFTD than patients with AD and controls. In bvFTD, WMH volumes were associated with disease severity but not vascular risk. Patients with bvFTD and patients with AD showed distinct spatial patterns of WMH that mirrored characteristic patterns of cortical atrophy. Regional WMH load correlated with worse cognitive performance in discrete cognitive domains. WMH-related cognitive impairments were shared between syndromes, with additional associations found in bvFTD.ConclusionIncreased WMH are common in patients with bvFTD and patients with AD. Our findings suggest that WMH are partly independent of vascular pathology and associated with the neurodegenerative process. WMH occur in processes independent of and related to cortical atrophy. Furthermore, increased WMH in different regions contributes to cognitive deficits.

Mounting evidence suggests an association between cerebellar atrophy and cognitive impairment in the main frontotemporal dementia syndromes. In contrast, whether cerebellar atrophy is present in the motor syndromes associated with frontotemporal lobar degeneration (corticobasal syndrome and progressive supranuclear palsy) and the extent of its contribution to their cognitive profile remain poorly understood. The current study aimed to comprehensively chart profiles of cognitive impairment in relation to cerebellar atrophy in 49 dementia patients (corticobasal syndrome = 33; progressive supranuclear palsy = 16) compared to 33 age-, sex- and education-matched healthy controls. Relative to controls, corticobasal syndrome and progressive supranuclear palsy patients demonstrated characteristic cognitive impairment, spanning the majority of cognitive domains including attention and processing speed, language, working memory, and executive function with relative preservation of verbal and nonverbal memory. Voxel-based morphometry analysis revealed largely overlapping patterns of cerebellar atrophy in corticobasal syndrome and progressive supranuclear palsy relative to controls, primarily involving bilateral Crus II extending into adjacent lobules VIIb and VIIIa. After controlling for overall cerebral atrophy and disease duration, exploratory voxel-wise general linear model analysis revealed distinct cerebellar subregions differentially implicated across cognitive domains in each patient group. In corticobasal syndrome, reduction in grey matter intensity in the left Crus I was significantly correlated with executive dysfunction. In progressive supranuclear palsy, integrity of the vermis and adjacent right lobules I–IV was significantly associated with language performance. These results are consistent with the well-established role of Crus I in executive functions and provide further supporting evidence for vermal involvement in cognitive processing. The current study presents the first detailed exploration of the role of cerebellar atrophy in cognitive deficits in corticobasal syndrome and progressive supranuclear palsy, offering insights into the cerebellum’s contribution to cognitive processing even in neurodegenerative syndromes characterized by motor impairment., Voxel-based morphometry analysis revealed that cerebellar atrophy in the left Crus I was correlated with executive dysfunction in corticobasal syndrome, whereas the vermis and adjacent right lobules I–IV were associated with language performance in progressive supranuclear palsy, demonstrating cerebellar contributions to cognition even in neurodegenerative syndromes characterized by motor impairment., Graphical Abstract Graphical Abstract

Negative and positive emotions are known to shape decision-making toward more or less impulsive responses, respectively. Decision-making and emotion processing are underpinned by shared brain regions including the ventromedial prefrontal cortex (vmPFC) and the amygdala. How these processes interact at the behavioral and brain levels is still unclear. We used a lesion model to address this question. Study participants included individuals diagnosed with behavioral-variant frontotemporal dementia (bvFTD, n = 18), who typically present deficits in decision-making/emotion processing and atrophy of the vmPFC, individuals with Alzheimer’s disease (AD, n = 12) who present with atrophy in limbic structures and age-matched healthy controls (CTRL, n = 15). Prior to each choice on the delay discounting task participants were cued with a positive, negative or neutral picture and asked to vividly imagine witnessing the event. As hypothesized, our findings showed that bvFTD patients were more impulsive than AD patients and CTRL and did not show any emotion-related modulation of delay discounting rate. In contrast, AD patients showed increased impulsivity when primed by negative emotion. This increased impulsivity was associated with reduced integrity of bilateral amygdala in AD but not in bvFTD. Altogether, our results indicate that decision-making and emotion interact at the level of the amygdala supporting findings from animal studies.

Introduction Timely 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. Methods We 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. Results Our method successfully combined multimodal imaging information with high accuracy (91%), sensitivity (83.7%), and specificity (96.6%). Discussion This 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., Highlights • A multimodal computational approach was implemented to identify patients with bvFTD. • We combined features from structural MRI data and fMRI-based functional connectivity. • Our approach was validated over 103 subjects from three different centers. • Our multimodal approach yielded high classification accuracy (91%) across centers. • Multimodal computational approaches may be useful complements for dementia diagnosis.

Eye movement desensitization and reprocessing (EMDR) is a relatively new psychotherapy that has gradually gained popularity for the treatment of post-traumatic stress disorder. In the present work, the standardised EMDR protocol is introduced, along with current hypotheses of its mechanism of action, as well as a critical review of the available literature on its clinical effectiveness in adult post-traumatic stress disorder. A systematic review of the published literature was performed using PubMed and PsycINFO databases with the keywords «eye movement desensitization and reprocessing» and «post-traumatic stress disorder» and its abbreviations «EMDR» and «PTSD». Fifteen randomised controlled trials of good methodological quality were selected. These studies compared EMDR with unspecific interventions, waiting lists, or specific therapies. Overall, the results of these studies suggest that EMDR is a useful, evidence-based tool for the treatment of post-traumatic stress disorder, in line with recent recommendations from different international health organisations.

Objective:To identify distinct behavioral phenotypes of behavioral-variant frontotemporal dementia (bvFTD) and to 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 patients with bvFTD vs 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), and primary severe disinhibition (n = 9). Patients with 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.

Biomarkers represent a critical research area in neurodegeneration disease as they can contribute to studying potential disease-modifying agents, fostering timely therapeutic interventions, and alleviating associated financial costs. Functional connectivity (FC) analysis represents a promising approach to identify early biomarkers in specific diseases. Yet, virtually no study has tested whether potential FC biomarkers prove to be reliable and reproducible across different centers. As such, their implementation remains uncertain due to multiple sources of variability across studies: the numerous international centers capable conducting FC research vary in their scanning equipment and their samples’ socio-cultural background, and, more troublingly still, no gold-standard method exists to analyze FC. In this unprecedented study, we aim to address both issues by performing the first multicenter FC research in the behavioral-variant frontotemporal dementia (bvFTD), and by assessing multiple FC approaches to propose a gold-standard method for analysis. We enrolled 52 bvFTD patients and 60 controls from three international clinics (with different fMRI recording parameters), and three additional neurological patient groups. To evaluate FC, we focused on seed analysis, inter-regional connectivity, and several graph-theory approaches. Only graph-theory analysis, based on weighted-matrices, yielded consistent differences between bvFTD and controls across centers. Also, graph metrics robustly discriminated bvFTD from the other neurological conditions. The consistency of our findings across heterogeneous contexts highlights graph-theory as a potential gold-standard approach for brain network analysis in bvFTD. Hum Brain Mapp, 2017. © 2017 Wiley Periodicals, Inc.

Background Clinical differentiation between Alzheimer's disease (AD) and behavioural-variant frontotemporal dementia (bvFTD) is challenging due to overlapping clinical features at presentation. Whilst diagnostic criteria for both disorders incorporate evidence of frontal and temporal cortical atrophy, understanding of the progression of atrophy in these disorders is limited. This study aimed to elucidate common and disease-specific progressive changes in cortical and subcortical brain structures in AD and bvFTD. Methods Forty-one AD, 37 bvFTD and 33 healthy controls underwent baseline MRI and of these longitudinal follow-up was obtained for 20 AD and 20 bvFTD (1 to 4 years). A total of 87 AD and 70 bvFTD consecutive scans were included in the study. The trajectories of progression in cortical and subcortical structures were identified with FreeSurfer and linear mixed effect modelling. Results The results uncovered cortical and subcortical disease-specific trajectories of neurodegeneration in AD and bvFTD. Specifically, direct comparisons between patient groups revealed that over time AD showed greater cortical atrophy in the inferior parietal and posterior cingulate cortex than bvFTD. Conversely, bvFTD patients showed greater atrophy in the striatum than AD over time. Conclusions These results indicate that atrophy in the posterior cingulate and the striatum diverges with disease progression in these dementia syndromes and may represent a potential diagnostic biomarker for tracking rates of progression of AD and bvFTD. These findings may help inform future drug trials by identifying appropriate outcome measures to quantify drug efficacy and their ability to modulate disease progression over time.

Background A key finding underlying the continuum of psychosis concept is the presence of psychotic-like experiences (PLEs) in healthy subjects. However, it remains uncertain to what extent these experiences are related to the genetic risk for schizophrenia and how far they actually resemble attenuated forms of psychotic symptoms. Methods Forty-nine adults with no history of mental illness in first-degree relatives and 59 siblings of patients with schizophrenia were rated on the psychosis section of the Computerized Diagnostic Interview Schedule IV (C DIS-IV) and the Rust Inventory of Schizotypal Cognitions (RISC). Those who rated positive on the CDIS-IV were re-interviewed using the lifetime version of the Present State Examination 9th edition (PSE-9) and the Structured interview for Schizotypy (SIS). Results Seventeen (34.69%) of the non-relatives and 22 (37.29%) of the relatives responded positively to one or more of the psychosis questions on the DIS. This difference was not significant. RISC scores were also similar between the groups. At follow-up interview with the PSE-9, 13/40 PLEs (32.50%) in the non-relatives were classified as possible or probable psychotic symptoms compared to 11/46 (23.91%) in the relatives. Using liberal symptom thresholds, 5 of those who attended the follow-up interview (2 non-relatives and 3 relatives) met SIS criteria for schizotypal personality disorder. Conclusions Rates of PLEs, however considered, do not differ substantially between relatives and non-relatives of patients with schizophrenia. Only a minority of PLEs picked up by screening interviews resemble attenuated forms of psychotic symptoms.

Background: Brain structural and functional changes in bipolar disorder (BD) are well-established findings, but it is uncertain whether these changes are already present in first episode mania (FEM).Methods: We compared 31 FEM subjects, with 31 healthy individuals matched for age, sex, and premorbid IQ. Whole-brain voxel-wise morphometry, functional magnetic resonance imaging during the n-back task, and a functional connectivity analysis were performed.Results: There were no volumetric differences between the 2 groups. During the 2-back task, FEM patients did not perform differently from controls and activated similar regions, but they showed less deactivation in the ventromedial prefrontal cortex (vmPFC), the anterior hub of the default mode network (DMN). They showed preserved functional connectivity between the vmPFC and other regions of the DMN, but increased connectivity with the superior frontal gyrus.Conclusions: The absence of volumetric changes in FEM patients suggests that these changes could be related to progression of the illness. On the other hand, the failure of deactivation of the anterior hub of the DMN is present from the onset of the illness and may represent a core pathophysiological feature of BD.

To track neural correlates of naming performance with disease progression, we estimated key areas affected in nonfluent/agrammatic (nfvPPA) and logopenic (lvPPA) primary progressive aphasia variants over time and changes in naming correlates over time. Twenty-nine non-semantic PPA participants (17 nfvPPA and 12 lvPPA) were selected based upon current diagnostic criteria and PiB-PET status and conducted a confrontation-naming task and a structural MRI. Linear mixed-effect models implemented in FreeSurfer were used for tracking cortical thickness and epicenters of atrophy over time. Using averaged cortical thickness of epicenters and naming performance as variables of interest, two sets of multivariate analyses were conducted to compare atrophy progression and naming correlates across groups. While all PPA participants demonstrated naming deterioration and progressive cortical thinning in the left temporal lobe and the left inferior frontal gyrus, the lvPPA cohort showed greater naming deterioration and thinning in the left posterior inferior parietal cortex over time than it did the nfvPPA cohort. The multivariate analyses confirmed a widespread cortical thinning in lvPPA over time, but a more rapid thinning in the right superior frontal gyrus of nfvPPA participants. Impaired naming correlated with common cortical regions in both groups. These regions included the left anterior superior temporal gyrus and the posterior middle temporal gyrus, which was primarily affected in lvPPA. Non-semantic PPA variants initially present with separate epicenters of atrophy and different spatial-temporal patterns of neurodegeneration over time, but the common involvement in key cortical regions of the left temporal lobe accounts for naming deterioration in both groups.

Background Structural pathology in the hippocampus is well-documented in schizophrenia, but brain functional changes have not been consistently found. We used spatial navigation in a virtual reality environment, a task that is known to produce robust hippocampal activation in healthy subjects, to examine task-related activations and de-activations in the disorder. Methods Twenty-seven DSM IV schizophrenia patients and 32 healthy controls underwent fMRI while they navigated to a goal through a virtual reality town. Activations and de-activations were examined at the whole brain level and also using a region-of-interest (ROI) in the hippocampus. Results Spatial navigation was associated with activation in the posterior hippocampus and parahippocampal gyrus plus widespread neocortical areas. The patients showed reduced activation compared to the controls in the left dorsolateral prefrontal cortex (DLPFC) and the left occipital/temporal cortex. No differences in hippocampal activation were seen either at the whole-brain level or in the ROI analysis. The patients showed failure of de-activation affecting some but not all subregions of the default mode network. Conclusions Schizophrenia is associated with task-related hypoactivation in the DLPFC during spatial navigation, but not with functional changes in the hippocampus. The failure of de-activation also found adds to evidence for default mode network dysfunction in the disorder.

Schizophrenia is considered a disorder of abnormal brain connectivity. Although whole brain maps of averaged bivariate voxel correlations have been successfully applied to study connectivity abnormalities in schizophrenia these maps do not adequately explore the multivariate nature of brain connectivity. Here we adapt a novel method for high-dimensional regression (supervised principal component regression) to estimate brain maps of multivariate non redundant connectivity (NRC) from resting functional Magnetic Resonance Imaging (fMRI) data of 116 patients with schizophrenia and 122 matched controls. Disorder related differences in NRC involved caudate hyper-connectivity and hypo-connectivity of several cortical areas such as the dorsal cingulate, the cuneus and the right postcentral cortex. These abnormalities were coupled with abnormalities in the amplitude of signal fluctuations and, to a minor extent, with differences in the dimensionality of connectivity patterns as quantified by the number of supervised principal components. Second level seed correlation analyses linked the observed abnormalities to an additional set of brain regions relevant to schizophrenia such as the thalamus and the temporal cortex. The non redundant connectivity maps proposed here are a new tool that will complement the information provided by other already available voxel based whole brain connectivity measures.

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.

Background Midline brain abnormalities might increase susceptibility to both first-episode and chronic mental disorder. Evidence of cavum vergae (CV) abnormality in mental disorders is scarce. Methods The presence of CV was assessed by a researcher blind to clinical information in a cross-disorder sample of 639 patients with mood and psychotic disorders and in 223 healthy controls. Homogeneous magnetic resonance imaging methods of acquisition and assessment were applied. Results Seven out of 639 patients with mood or psychotic disorders were detected with CV which corresponds to a prevalence of 1.1%. There were no concurrent cases of CV in the healthy control group. Identified cases which are briefly described were diagnosed from bipolar I disorder ( n =2), delusional disorder ( n =1), brief psychotic disorder ( n =1) and schizoaffective disorder ( n =3). Patients with CV had descriptively lower current IQ, executive functioning and memory scores in relation to patients without CV but this was not statistically significant. Limitations Effects of medication and lack of statistical power of the CV patient group. Conclusions Midline brain abnormalities, such as CV, might represent an unspecific risk factor for the development of severe mental disorders.

The authors apologize for misspelling the last name of the author Ratnavalli Ellajosyula. This has now been corrected.

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

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

Amann BL, Canales-Rodriguez EJ, Madre M, Radua J, Monte G,Alonso-Lana S, Landin-Romero R, Moreno-Alcazar A,Bonnin CM, Sarro S, Ortiz-Gil J, Gomar JJ, Moro N,Fernandez-Corcuera P, Goikolea JM, Blanch J, Salvador R, Vieta E,McKenna PJ, Pomarol-Clotet E. Brain structural changes inschizoaffective disorder compared to schizophrenia and bipolar disorder.Objective: Brain structural changes in schizoaffective disorder, and howfar they resemble those seen in schizophrenia and bipolar disorder, haveonly been studied to a limited extent.Method: Forty-five patients meeting DSM-IV and RDC criteria forschizoaffective disorder, groups of patients with 45 matchedschizophrenia and bipolar disorder, and 45 matched healthy controlswere examined using voxel-based morphometry (VBM).Results: Analyses comparing each patient group with the healthycontrol subjects found that the patients with schizoaffective disorderand the patients with schizophrenia showed widespread andoverlapping areas of significant volume reduction, but the patients withbipolar disorder did not. A subsequent analysis compared the combinedgroup of patients with the controls followed by extraction of clusters. Inregions where the patients differed significantly from the controls, nosignificant differences in mean volume between patients withschizoaffective disorder and patients with schizophrenia in any of fiveregions of volume reduction were found, but mean volumes in thepatients with bipolar disorder were significantly smaller in three of five.Conclusion: The findings provide evidence that, in terms of structuralgray matter brain abnormality, schizoaffective disorder resemblesschizophrenia more than bipolar disorder.

Schizoaffective patients can have neurocognitive deficits and default mode network dysfunction while being acutely ill. It remains unclear to what extent these abnormalities persist when they go into clinical remission. Memory and executive function were tested in 22 acutely ill schizoaffective patients; they also underwent fMRI scanning during performance of the n-back working memory test. The same measures were obtained after they had been in remission for ≥ 2 months. Twenty-two matched healthy individuals were also examined. In clinical remission, schizomanic patients showed an improvement of memory but not of executive function, while schizodepressive patients did not change in either domain. All schizoaffective patients in clinical remission showed memory and executive impairment compared to the controls. On fMRI, acutely ill schizomanic patients had reversible frontal hypo-activation when compared to clinical remission, while activation patterns in ill and remitted schizodepressive patients were similar. The whole group of schizoaffective patients in clinical remission showed a failure of de-activation in the medial frontal gyrus compared to the healthy controls. There was evidence for memory improvement and state dependent changes in activation in schizomanic patients across relapse and remission. Medial frontal failure of de-activation in remitted schizoaffective patients, which probably reflects default mode network dysfunction, appears to be a state independent feature of the illness.

Background.Functional imaging studies in relatives of schizophrenic patients have had inconsistent findings, particularly with respect to altered dorsolateral prefrontal cortex activation. Some recent studies have also suggested that failure of deactivation may be seen.Method.A total of 28 patients with schizophrenia, 28 of their siblings and 56 healthy controls underwent functional magnetic resonance imaging during performance of the n-back working memory task. An analysis of variance was fitted to individual whole-brain maps from each set of patient–relative–matched pair of controls. Clusters of significant difference among the groups were then used as regions of interest to compare mean activations and deactivations among the groups.Results.In all, five clusters of significant differences were found. The schizophrenic patients, but not the relatives, showed reduced activation compared with the controls in the lateral frontal cortex bilaterally, the left basal ganglia and the cerebellum. In contrast, both the patients and the relatives showed significant failure of deactivation compared with the healthy controls in the medial frontal cortex, with the relatives also showing less failure than the patients. Failure of deactivation was not associated with schizotypy scores or presence of psychotic-like experiences in the relatives.Conclusions.Both schizophrenic patients and their relatives show altered task-related deactivation in the medial frontal cortex. This in turn suggests that default mode network dysfunction may function as a trait marker for schizophrenia.

Background Many studies having shown significant improvements in non-social and social cognitive performance in smoking FEP patients compared to non-smoking FEP patients. The findings are controversial. This study analyzed the effects of tobacco use on non-social and social cognitive function in a large group of FEP patients and a matched healthy control group. Methods A sample of 335 patients with FEP and 253 healthy controls was divided into four subgroups: control tobacco users (CTU), control non-tobacco users (CNTU), patient tobacco users (PTU) and patient non-tobacco users (PNTU). Demographic variables, tobacco use variables (presence or absence, frequency and duration of tobacco use), neurocognitive (non-social) performance and social cognition were assessed. Results Comparison of 4 subgroups in non-social cognitive function revealed significant differences after controlling for covariables in executive functions (F = 13.45; p ≤0.001) and working memory domains (F = 4.30; p = 0.005). CTU and CNTU subgroups scored higher in all the domains compared to the PTU and the PNTU subgroups respectively. Social cognitive function was also significantly different within the four subgroups, with control subgroups showing better social cognition than patient subgroups. Significant differences in the executive functions domain were observed when comparing PTU and CTU groups (F = 19.60; p ≤0.001). No significant differences were revealed in the comparison between the patient groups. Conclusions This large study suggests that tobacco use in FEP patients is not related to better non-social or social cognitive performance.

Background/Aims: Although some patients with primary progressive aphasia (PPA) exhibit novel or improved skills after the onset of dementia, these changes have yet to be quantified. Therefore, this study systematically explored and identified the emergence of positive behaviours after dementia onset. Methods: This study included 48 carers of patients with PPA: 12 nonfluent/agrammatic PPA (nfvPPA), 22 semantic variant PPA (svPPA), and 14 logopenic variant PPA (lvPPA). The presence and frequency of positive behaviour changes after dementia onset were established using the Hypersensory and Social/Emotional Scale (HSS). Results: Scores on Sensitivity to Details, Visuospatial Activities, and Music Activities differed significantly among the groups. More specifically, svPPA was associated with increased visuospatial activity, but only in the mild stage of the disease; nfvPPA was associated with increased visuospatial activity and decreased music activity, while lvPPA exhibited the reverse profile. Conclusions: The results demonstrate that subsets of PPA patients show novel or increased positive behaviours following dementia onset, and differences among subtypes may be helpful for improving diagnostic accuracy. Additionally, harnessing these skills may improve the quality of life of both patients and carers.

Altres ajuts: Plan Nacional 2013-2016 with a Miguel Servet Research Contract (MS14/00041). We acknowledge also the generous support by the Centro de Investigación Biomédica en Red de Salud Mental (CIBERSAM), Madrid, Spain. Up to 60% of patients with bipolar disorder (BD) have a history of traumatic events, which is associated with greater episode severity, higher risk of comorbidity and higher relapse rates. Trauma-focused treatment strategies for BD are thus necessary but studies are currently scarce. The aim of this study is to examine whether Eye Movement Desensitization and Reprocessing (EMDR) therapy focusing on adherence, insight, de-idealisation of manic symptoms, prodromal symptoms and mood stabilization can reduce episode severity and relapse rates and increase cognitive performance and functioning in patients with BD. This is a single-blind, randomized controlled, multicentre trial in which 82 patients with BD and a history of traumatic events will be recruited and randomly allocated to one of two treatment arms: EMDR therapy or supportive therapy. Patients in both groups will receive 20 psychotherapeutic sessions, 60 min each, during 6 months. The primary outcome is a reduction of affective episodes after 12 and 24 months in favour of the EMDR group. As secondary outcome we postulate a greater reduction in affective symptoms in the EMDR group (as measured by the Bipolar Depression Rating Scale, the Young Mania Rating Scale and the Clinical Global Impression Scale modified for BD), and a better performance in cognitive state, social cognition and functioning (as measured by the Screen for Cognitive Impairment in Psychiatry, The Mayer-Salovey-Caruso Emotional Intelligence Test and the Functioning Assessment Short Test, respectively). Traumatic events will be evaluated by The Holmes-Rahe Life Stress Inventory, the Clinician-administered PTSD Scale and the Impact of Event Scale. The results of this study will provide evidence whether a specific EMDR protocol for patients with BD is effective in reducing affective episodes, affective symptoms and functional, cognitive and trauma symptoms. The trial is registered at ClinicalTrials.gov, identifier: . Registered on 3 December 2015. The online version of this article (doi:10.1186/s13063-017-1910-y) contains supplementary material, which is available to authorized users.

Biomarkers represent a critical research area in neurodegeneration disease as they can contribute to studying potential disease‐modifying agents, fostering timely therapeutic interventions, and alleviating associated financial costs. Functional connectivity (FC) analysis represents a promising approach to identify early biomarkers in specific diseases. Yet, virtually no study has tested whether potential FC biomarkers prove to be reliable and reproducible across different centers. As such, their implementation remains uncertain due to multiple sources of variability across studies: the numerous international centers capable conducting FC research vary in their scanning equipment and their samples’ socio‐cultural background, and, more troublingly still, no gold‐standard method exists to analyze FC. In this unprecedented study, we aim to address both issues by performing the first multicenter FC research in the behavioral‐variant frontotemporal dementia (bvFTD), and by assessing multiple FC approaches to propose a gold‐standard method for analysis. We enrolled 52 bvFTD patients and 60 controls from three international clinics (with different fMRI recording parameters), and three additional neurological patient groups. To evaluate FC, we focused on seed analysis, inter‐regional connectivity, and several graph‐theory approaches. Only graph‐theory analysis, based on weighted‐matrices, yielded consistent differences between bvFTD and controls across centers. Also, graph metrics robustly discriminated bvFTD from the other neurological conditions. The consistency of our findings across heterogeneous contexts highlights graph‐theory as a potential gold‐standard approach for brain network analysis in bvFTD. Hum Brain Mapp 38:3804–3822, 2017. © 2017 Wiley Periodicals, Inc.

Functional imaging studies have implicated the hippocampus and parahippocampal gyrus in cue-guided spatial navigation, but also many other regions. Furthermore, little is known about de-activations that take place during performance of navigation tasks, something that is of interest given that the hippocampus is a component of the default mode network, which de-activates during attention-demanding tasks. In this study 22 healthy subjects underwent whole-brain functional Magnetic Resonance Imaging (fMRI) while they navigated toward a previously learned goal in a virtual reality environment. At a threshold of p0.05 corrected, the subjects showed a pattern of widespread cortical activations, including the parahippocampal and retrosplenial cortex and also parts of the frontal, temporal and occipital cortex. Hippocampal activation, however, was restricted to the posterior portion of the structure bilaterally. De-activations were seen in the medial frontal cortex and other regions of the default mode network, but not in the posterior cingulate cortex/precuneus. The findings support the involvement of the hippocampus in cue-guided navigation, but suggest that its posterior regions are particularly important. Cue-guided spatial navigation is associated with de-activation in some but not all parts of the default mode network.

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.