Sporadic bvFTD Research Articles

Neuropsychiatric Symptoms Cluster and Fluctuate Over Time in Behavioral Variant Frontotemporal Dementia.

Cognitive and behavioral phenomena define behavioral variant frontotemporal dementia (bvFTD), but neuropsychiatric symptoms (NPS) outside the core criteria are common throughout the illness. Identifying how NPS cluster in bvFTD may clarify the underlying neurobiology of bvFTD-related NPS and guide development of therapies. Participants (N=354) with sporadic and genetic bvFTD were enrolled in the ARTFL LEFFTDS Longitudinal Frontotemporal Lobar Degeneration Consortium. Dementia stage was defined as early (CDR® plus NACC FTLD ≤ 1) or advanced (CDR® plus NACC FTLD ≥ 1). Baseline and annual follow-up visit data were analyzed to compare NPS across stages of bvFTD. Psychiatric states were captured using the Neuropsychiatric Inventory-Questionnaire and Clinician Judgement of Symptoms. Polychoric cluster analysis was used to describe NPS clusters. NPS were highly prevalent (≥ 90%) in early and late bvFTD. Four NPS clusters were identified based on magnitude of factor loadings: affective, disinhibited, compulsive, and psychosis. Neuropsychiatric symptoms fluctuated across visits. In the affective cluster, depression and anxiety showed the least visit-to-visit stability. In the disinhibited cluster, elation showed the least stability. Symptoms in the psychosis and compulsive clusters (hallucinations, delusions, obsessions/compulsions, and hyperorality) were largely stable, persisting from visit-to-visit in more than 50% of cases. NPS in bvFTD are frequent and cluster into four discrete groups in bvFTD. These clusters may result from specific neural network disruptions that could serve as targets for future interventions. The fluctuating nature of NPS in bvFTD suggests that they are not reliable markers of disease progression or stage.

Vascular dysfunction in sporadic bvFTD: white matter hyperintensity and peripheral vascular biomarkers

BackgroundVascular dysfunction was recently reported to be involved in the pathophysiological process of neurodegenerative diseases, but its role in sporadic behavioral variant frontotemporal dementia (bvFTD) remains unclear. The aim of this study was to systematically explore vascular dysfunction, including changes in white matter hyperintensities (WMHs) and peripheral vascular markers in bvFTD.MethodsThirty-two patients with bvFTD who with no vascular risk factors were enrolled in this cross-sectional study and assessed using positron emission tomography/magnetic resonance (PET/MRI) imaging, peripheral plasma vascular/inflammation markers, and neuropsychological examinations. Group differences were tested using Student’s t-tests and Mann–Whitney U tests. A partial correlation analysis was implemented to explore the association between peripheral vascular markers, neuroimaging, and clinical measures.ResultsWMH was mainly distributed in anterior brain regions. All peripheral vascular factors including matrix metalloproteinases-1 (MMP-1), MMP-3, osteopontin, and pentraxin-3 were increased in the bvFTD group. WMH was associated with the peripheral vascular factor pentraxin-3. The plasma level of MMP-1 was negatively correlated with the gray matter metabolism of the frontal, temporal, insula, and basal ganglia brain regions. The WMHs in the frontal and limbic lobes were associated with plasma inflammation markers, disease severity, executive function, and behavior abnormality. Peripheral vascular markers were associated with the plasma inflammation markers.ConclusionsWMHs and abnormalities in peripheral vascular markers were found in patients with bvFTD. These were found to be associated with the disease-specific pattern of neurodegeneration, indicating that vascular dysfunction may be involved in the pathogenesis of bvFTD. This warrants further confirmation by postmortem autopsy. Targeting the vascular pathway might be a promising approach for potential therapy.

Investigating Epigenetic and Neuroimaging Profiles in Bipolar Disorder and Behavioral Variant Frontotemporal Dementia: An integrated epigenetic-neuroimaging approach

IntroductionDiscriminating between bipolar disorder (BD) and behavioral variant Frontotemporal Dementia (bvFTD) is a clinical challenge as it is still based on clinical judgement, which often leads to misdiagnosis. This challenge is particularly pronounced in cases involving the C9orf72 hexanucleotide expansion, a genetic factor responsible for a substantial portion of familial FTD cases, as in these patients the development of late psychoses is particularly frequent. Moreover, individuals with C9orf72 bvFTD are also characterized by behavioral changes that resemble those seen in late-life BD, especially during the early stages of the disease. This raises questions about whether the clinical similarities between BD and bvFTD are rooted in specific alterations within the brain networks involved in cognitive processing or in selective genetic and epigenetic mutations. In light of this, our recently published neuroimaging study has shed light on the presence of distinctive structural and metabolic characteristics in elderly individuals with BD and bvFTD. These findings offer valuable neurobiological insights that may lead to differentiate between bvFTD and elderly BD patients.ObjectivesBuilding on our previous research, this study further explores the existence of similar epigenetic expression patterns in plasma neural derived extra cellular vesicles (NDEs), such as miRNA and lncRNA, and seeks to correlate these epigenetic data with shared or distinct biological markers obtained through structural Magnetic Resonance Imaging and [18F]-fluorodeoxyglucose (FDG)-Positron Emission Tomography (PET).MethodsWe will plan to conduct statistical analyses on epigenetic and neuroimaging data on C9orf72 and sporadic bvFTD as well as on late-and early-onset BD patients and on healthy controls. Additionally, A PET study will be also performed on a subpopulation of these patients.ResultsOur hypothesis posits that selective epigenetic modifications may impact the brain’s structure and function, in a way that can change the glutamatergic neurotransmission in prefrontal regions, with subsequent indirect effects on subcortical areas.ConclusionsOur findings will not only help identifying the specific biological signatures of BD and bvFTD, which might have important implications not only in prevention but also in differential diagnosis and treatment, but also offer insights into potential targets for slowing the onset and progression of the structural alterations characterizing these disorders.Disclosure of InterestNone Declared

Memory Performance in Mild Sporadic and Familial Behavioral Variant Frontotemporal Dementia: Findings from the ALLFTD Consortium

AbstractBackgroundMemory impairment is generally considered minimal to absent in those with behavioral variant frontotemporal dementia (bvFTD). We sought to assess the frequencies of subjective and objective memory impairment in individuals with mild bvFTD according to consensus criteria.MethodAssessments were performed in mildly symptomatic bvFTD [defined by global FTLD Clinical Dementia Rating scale (CDR®+NACC FTLD) = 1] mutation carriers (Familial) and non‐mutation carriers (Sporadic) who are participants in the ARTFL LEFFTDS Longitudinal Frontotemporal Lobar Degeneration (ALLFTD, www.allftd.org) study. Mutation carriers had a pathogenic mutation in the MAPT, GRN or C9orf72 gene. The presence of subjective memory impairment was defined by a rating >0 on the memory domain of the CDR®+NACC FTLD. Evidence of objective memory impairment was based on performance across 7 memory measures, which include the National Alzheimer’s Coordinating Center Uniform Data Set Version 3 – Craft Story Immediate Recall (CSImm) and Delayed Recall (CSDel), Benson Figure Delayed Recall (BenDel), and the California Verbal Learning Test – Learning (CVLearn), Immediate Recall (CVImm), Delayed Recall (CVDel), and Recognition (CVRecog). Performance was considered abnormal for z‐scores ≤ ‐1.5.ResultData from 38 Familial (mean age 60±8 years, 61% male), and 109 Sporadic (mean age 63±7 years, 70% male) participants were analyzed. Memory ratings >0 on the CDR®+NACC FTLD were common for both Familial (84%) and Sporadic (88%). The frequencies of abnormal performance in the Familial vs Sporadic groups, respectively, per memory measure were: CSImm 43.8% vs 45.9%, p = 0.83; CSDel 46.9% vs 52.6%, p = 0.58; BenDel 29.4% vs 46.4%, p = 0.08; CVLearn 54.8% vs 39.8, p = 0.14; CVImm 64.5% vs 50%, p = 0.16, CVDel 80.6% vs 55.1%, p = 0.01, and CVRecog 51.6 vs 49%, p = 0.80. The frequencies of abnormal performance did not differ (all p>0.05) between Familial and Sporadic for ≥2 tests (79.3% vs 67.7%), ≥4 tests (55.2% vs 44.1%) and ≥6 tests (34.5% vs 31.2%).ConclusionThese data suggest that among those with a mild global severity of bvFTD features: 1) subjective and objective memory impairment are relatively frequent, and 2) the frequency of impairment across memory measures is largely similar between familial and sporadic bvFTD. The presence of memory impairment should not preclude a diagnosis of bvFTD.

Visual rating scales of atrophy to differentiate Frontotemporal dementia from Primary psychiatric disorder: results from DIPPA study

AbstractBackgroundAdult‐onset behavioral changes and altered executive functioning are frequently caused by behavioural variant of Frontotemporal dementia (bvFTD) or primary psychiatric disorders (PPD) which overlap in terms of clinical presentations but differ in terms of treatment and prognosis. The multi‐centre study DIPPA‐FTD aims to develop diagnostic and prognostic algorithms to help distinguish sporadic bvFTD from late‐onset PPD. Although atrophy on neuroimaging seems to be an appropriate discriminator between neurodegenerative and non‐neurodegenerative conditions, the sensitivity of frontotemporal atrophy for bvFTD is relatively low, whereas decreased brain volumes may be found in conditions like schizophrenia. The aim of the study is to identify a discriminative pattern of brain atrophy between bvFTD and PPD in a clinically applicable way.MethodThe DIPPA FTD consortium retrospectively collected patients with late onset behavioral disturbances after the age of 45 years, across 5 centers (Milan, Amsterdam, Munich, Sydney, Montreal). The subjects had been classified either as bvFTD or PPD according to current clinical criteria and the majority had clinical follow‐up. Among the patients collected in the project, only those with T1 MRI available were selected. A protocol of 9 visual rating scales of atrophy (orbitofrontal, anterior cingulate, anterior temporal, fronto‐insula, medial temporal, parietal, medial ventricular and axial ventricular) was applied by a rater blind for clinical and demographic infomation. The rater was asked to classify the subjects as bvFTD or PPD. A composite score of frontal, temporal and ventricular rating scales was also calculated.ResultThe MRIs of 323 subjects (211 bvFTD and 112 PPD) were analysed. Groupwise bvFTD cases showed significantly higher scores of atrophy for all the scales used. The rater accurately predicted 72% of the cases (Sens 0.70, Spec 0.76) while the composite score reached an accuracy of 76% (Sens 0.77 Spec 0.74). ROC curve analysis showed that fronto‐insula was the single most useful scale in the differentiation between bvFTD and PPD (AUC 0.80).ConclusionBrain atrophy has a significant role in the discrimination between bvFTD and PPD. The use of visual rating scales, and in particular the fronto‐insula one, could increase the diagnostic accuracy in the clinical setting.

Visual rating scales of atrophy to differentiate Frontotemporal dementia from Primary psychiatric disorder: results from DIPPA study

AbstractBackgroundAdult‐onset behavioral changes and altered executive functioning are frequently caused by behavioural variant of Frontotemporal dementia (bvFTD) or primary psychiatric disorders (PPD) which overlap in terms of clinical presentations but differ in terms of treatment and prognosis. The multi‐centre study DIPPA‐FTD aims to develop diagnostic and prognostic algorithms to help distinguish sporadic bvFTD from late‐onset PPD. Although atrophy on neuroimaging seems to be an appropriate discriminator between neurodegenerative and non‐neurodegenerative conditions, the sensitivity of frontotemporal atrophy for bvFTD is relatively low, whereas decreased brain volumes may be found in conditions like schizophrenia. The aim of the study is to identify a discriminative pattern of brain atrophy between bvFTD and PPD in a clinically applicable way.MethodThe DIPPA FTD consortium retrospectively collected patients with late onset behavioral disturbances after the age of 45 years, across 5 centers (Milan, Amsterdam, Munich, Sydney, Montreal). The subjects had been classified either as bvFTD or PPD according to current clinical criteria and the majority had clinical follow‐up. Among the patients collected in the project, only those with T1 MRI available were selected. A protocol of 9 visual rating scales of atrophy (orbitofrontal, anterior cingulate, anterior temporal, fronto‐insula, medial temporal, parietal, medial ventricular and axial ventricular) was applied by a rater blind for clinical and demographic infomation. The rater was asked to classify the subjects as bvFTD or PPD. A composite score of frontal, temporal and ventricular rating scales was also calculated.ResultThe MRIs of 323 subjects (211 bvFTD and 112 PPD) were analysed. Groupwise bvFTD cases showed significantly higher scores of atrophy for all the scales used. The rater accurately predicted 72% of the cases (Sens 0.70, Spec 0.76) while the composite score reached an accuracy of 76% (Sens 0.77 Spec 0.74). ROC curve analysis showed that fronto‐insula was the single most useful scale in the differentiation between bvFTD and PPD (AUC 0.80).ConclusionBrain atrophy has a significant role in the discrimination between bvFTD and PPD. The use of visual rating scales, and in particular the fronto‐insula one, could increase the diagnostic accuracy in the clinical setting.

Atrophy in behavioural variant frontotemporal dementia spans multiple large-scale prefrontal and temporal networks.

The identification of a neurodegenerative disorder's distributed pattern of atrophy-or atrophy 'signature'-can lend insights into the cortical networks that degenerate in individuals with specific constellations of symptoms. In addition, this signature can be used as a biomarker to support early diagnoses and to potentially reveal pathological changes associated with said disorder. Here, we characterized the cortical atrophy signature of behavioural variant frontotemporal dementia (bvFTD). We used a data-driven approach to estimate cortical thickness using surface-based analyses in two independent, sporadic bvFTD samples (n = 30 and n = 71, total n = 101), using age- and gender-matched cognitively and behaviourally normal individuals. We found highly similar patterns of cortical atrophy across the two independent samples, supporting the reliability of our bvFTD signature. Next, we investigated whether our bvFTD signature targets specific large-scale cortical networks, as is the case for other neurodegenerative disorders. We specifically asked whether the bvFTD signature topographically overlaps with the salience network, as previous reports have suggested. We hypothesized that because phenotypic presentations of bvFTD are diverse, this would not be the case, and that the signature would cross canonical network boundaries. Consistent with our hypothesis, the bvFTD signature spanned rostral portions of multiple networks, including the default mode, limbic, frontoparietal control and salience networks. We then tested whether the signature comprised multiple anatomical subtypes, which themselves overlapped with specific networks. To explore this, we performed a hierarchical clustering analysis. This yielded three clusters, only one of which extensively overlapped with a canonical network (the limbic network). Taken together, these findings argue against the hypothesis that the salience network is preferentially affected in bvFTD, but rather suggest that-at least in patients who meet diagnostic criteria for the full-blown syndrome-neurodegeneration in bvFTD encompasses a distributed set of prefrontal, insular and anterior temporal nodes of multiple large-scale brain networks, in keeping with the phenotypic diversity of this disorder.

Multisite ALLFTD study modeling progressive empathy loss from the earliest stages of behavioral variant frontotemporal dementia.

Empathy relies on fronto-cingular and temporal networks that are selectively vulnerable in behavioral variant frontotemporal dementia (bvFTD). This study modeled when in the disease process empathy changes begin, and how they progress. Four hundred thirty-one individuals with asymptomatic genetic FTD (n=114), genetic and sporadic bvFTD (n=317), and 163 asymptomatic non-carrier controls were enrolled. In sub-samples, we investigated empathy measured by the informant-based Interpersonal Reactivity Index (IRI) at each disease stage and over time (n=91), and its correspondence to underlying atrophy (n=51). Empathic concern (estimate=4.38, 95% confidence interval [CI]=2.79, 5.97; p<0.001) and perspective taking (estimate=5.64, 95% CI=3.81, 7.48; p<0.001) scores declined between the asymptomatic and very mild symptomatic stages regardless of pathogenic variant status. More rapid loss of empathy corresponded with subcortical atrophy. Loss of empathy is an early and progressive symptom of bvFTD that is measurable by IRI informant ratings and can be used to monitor behavior in neuropsychiatry practice and treatment trials.

Structural and microstructural thalamocortical network disruption in sporadic behavioural variant frontotemporal dementia

BackgroundUsing 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). MethodTwenty-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. ResultsBilateral 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. ConclusionsUsing multimodal neuroimaging, we demonstrate combined structural network dysfunction of anterior cortical regions, cortical-thalamic projections, and anterior thalamic regions in sporadic bvFTD.

Relationship Between Sporadic Behavioral Variant Frontotemporal Dementia and Primary Psychiatric Disorders: A Study in Families.

Background: Because the behavioral variant of frontotemporal dementia (bvFTD) shows major clinical overlap with primary psychiatric disorders (PPD) that affect similar neuroanatomical circuits, a common genetic vulnerability between FTD and PPD was hypothesized. Aims: We studied whether PPD are more prevalent in families of patients with sporadic frontotemporal dementia compared with healthy controls (HC), subjects with Alzheimer’s disease (AD), and individuals with bipolar disorder (BD). Methods: In this case-control study performed between January 2013 and February 2019, we investigated the first-degree family history concerning depression, psychosis (including schizophrenia), BD, and autism spectrum disorder for 73 bvFTD patients, 153 patients with BD, 108 patients with AD, and 101 HC with a semistructured questionnaire (QFTD-NL 1.0) according to DSM-IV, DSM-5, or ICD-10 criteria. Results: Patients with bvFTD had a 2.58-fold higher odds of having a first-degree family member with depression compared to HC (P = .04). Furthermore, they showed 3.26-fold higher odds of having a first-degree relative with psychosis compared to HC (P = .09). Conclusions: Our results implicate a link between dementia, including sporadic bvFTD, and depression. Further study into the genetic overlap between bvFTD and PPD might provide clues to targeting common disease mechanisms.

Network structure and transcriptomic vulnerability shape atrophy in frontotemporal dementia.

Connections among brain regions allow pathological perturbations to spread from a single source region to multiple regions. Patterns of neurodegeneration in multiple diseases, including behavioural variant of frontotemporal dementia (bvFTD), resemble the large-scale functional systems, but how bvFTD-related atrophy patterns relate to structural network organization remains unknown. Here we investigate whether neurodegeneration patterns in sporadic and genetic bvFTD are conditioned by connectome architecture. Regional atrophy patterns were estimated in both genetic bvFTD (75 patients, 247 controls) and sporadic bvFTD (70 patients, 123 controls). First, we identified distributed atrophy patterns in bvFTD, mainly targeting areas associated with the limbic intrinsic network and insular cytoarchitectonic class. Regional atrophy was significantly correlated with atrophy of structurally- and functionally-connected neighbours, demonstrating that network structure shapes atrophy patterns. The anterior insula was identified as the predominant group epicentre of brain atrophy using data-driven and simulation-based methods, with some secondary regions in frontal ventromedial and antero-medial temporal areas. We found that FTD-related genes, namely C9orf72 and TARDBP, confer local transcriptomic vulnerability to the disease, modulating the propagation of pathology through the connectome. Collectively, our results demonstrate that atrophy patterns in sporadic and genetic bvFTD are jointly shaped by global connectome architecture and local transcriptomic vulnerability, providing an explanation as to how heterogenous pathological entities can lead to the same clinical syndrome.

Atrophy patterns in sporadic and genetic behavioral variant frontotemporal dementia reflect brain network architecture

AbstractBackgroundConnections among brain regions allow pathological perturbations to spread from a single source node to multiple nodes. Patterns of neurodegeneration in multiple diseases, including behavioral variant of frontotemporal dementia (bvFTD), resemble the network architecture (Seeley et al., 2009, Neuron), but how bvFTD‐related atrophy patterns relate to the network organization remains unknown. Here we investigate whether neurodegeneration patterns in sporadic and genetic bvFTD are conditioned by connectome architecture, such that connected regions display similar atrophy patterns.MethodDeformation‐based morphometry (DBM) was used to estimate regional changes in tissue volume density from T1‐weighted magnetic resonance images of 75 genetic bvFTD patients and 247 healthy controls (GENFI, http://genfi.org.uk/). We used linear mixed effects model to obtain a bvFTD‐related atrophy map, controlling for age, sex and aquision site. Structural and functional connectivity (SC and FC), derived from an independent sample of 70 healthy participants (Griffa et al., 2019, Zenodo), were used to estimate mean neighbor atrophy values of each region. Relationship between node and neighbor atrophy was examined by correlating neighbor atrophy with nodal atrophy. Statistical significance of the analyses was assessed using a spatial autocorrelation‐preserving null model. Analyses were replicated in an independent dataset (FTLDNI, AG032306) with 70 sporadic bvFTD patients and 123 healthy controls.ResultDistributed atrophy patterns were observed in bvFTD, mainly targeting areas associated with limbic intrinsic network and insular cytoarchitectonic class (Fig 1a). A node’s atrophy was significantly correlated with atrophy of its connected neighbors (e.g. high resolution: r=0.58, p=0.006 and r=0.54, p=0.0006, for SC‐ and FC‐ defined neighbors respectively) (Fig 2c). Relationship between node and neighbor atrophy was consistent across resolutions and greater in empirical networks compared to null networks. While a number of frontotemporal regions were identified as potential disease epicenters, anterior insula was the most likely one. Results were consistent in the sporadic cohort (Fig 1b&amp;2d).ConclusionUsing connectivity models and rigorous statistical analyses that account for spatial autocorrelation, we demonstrate that bvFTD‐related neurodegeneration is conditioned by connectome architecture, accounting for 30‐40% of variance in atrophy. Atrophy is most profound in regions associated with insular cortex.

Pathological manifestation of human endogenous retrovirus K in frontotemporal dementia

BackgroundBehavioral variant frontotemporal dementia (bvFTD) is a common form of younger-onset dementia with a proportion of cases overlapping pathologically and genetically with amyotrophic lateral sclerosis (ALS). Previous studies have identified that the human endogenous retrovirus K (HERV-K) is elevated in ALS serum and is associated with ALS TDP-43 pathology. In contrast, little is known about HERV-K changes in bvFTD. Here, we investigated the possible role of HERV-K in bvFTD.MethodsWe measured the HERV-K env gene in sporadic bvFTD (N = 63), sporadic ALS (N = 89), and control (N = 21) serum by ddPCR. We also analyzed HERV-K env, by qPCR, and the HERV-K reverse transcriptase protein, by confocal immunofluorescence microscopy, in the disease-affected superior frontal cortex of bvFTD with TDP-43 pathology.ResultsHere, we show that HERV-K env levels are significantly elevated (P = 3.5 × 10−6) in bvFTD compared to control serum, differentiating cases with an AUC value of 0.867. HERV-K env levels are also specifically elevated in the superior frontal cortex of bvFTD with TDP-43 pathology, with the HERV-K reverse transcriptase protein and TDP-43 deposit localized to the neuronal cytoplasm. Furthermore, in a neuronal cell line overexpression of TDP-43 induces HERV-K env transcription.ConclusionsThese results suggest that manifestation of HERV-K is associated with bvFTD TDP-43 pathology. Analysis of HERV-K in bvFTD may provide insight into an unrecognized but targetable perturbed pathology.

Differences in sex distribution between genetic and sporadic FTD

AbstractBackgroundThe reported sex distribution differs 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 have resulted in variable findings. Our aim was to determine the sex distribution in a large international retrospective cohort of sporadic and genetic FTD.MethodWe included patients with probable and definite behavioural variant frontotemporal dementia (bvFTD), non‐fluent variant primary progressive aphasia (nfvPPA), semantic variant primary progressive aphasia (svPPA) and right temporal variant frontotemporal dementia (rtvFTD) from the Amsterdam Dementia Cohort, the Montreal Neurological Institute Cohort, the University of Ulm and Technical University of Munich Cohort (part of the German Consortium of Frontotemporal Lobal Degeneration), the Policlinico Milan Cohort and the Sydney FRONTIER Cohort. We compared sex distribution between genetic and sporadic FTD using χ2 tests.ResultA total of 910 subjects were included (56.3% male), of whom 654 had bvFTD, 99 nfvPPA, 117 svPPA and 40 rtvFTD. Of these, 215 had genetic FTD and the sex distribution was equal (51.2% male), which did not differ significantly from sporadic FTD (57.8% male, χ2 p=0.081). In the sporadic bvFTD subgroup, we found a male predominance (61.6% males compared to 52.9% males in the bvFTD genetic group, χ 2 p=0.04). No sex distribution differences between sporadic and genetic cases were found in the other clinical FTD subgroups (all p&gt;0.05).ConclusionDifferences in sex distribution between genetic and sporadic behavioural variant of FTD may provide important clues for its differential pathogenesis and warrants further research.

Atrophy in bvFTD spans multiple large‐scale networks in prefrontal and temporal cortex

AbstractBackgroundConverging evidence suggests that neurodegenerative disorders preferentially affect specific large‐scale neural networks 1. This is thought to explain common phenotypic presentations of these conditions. For example, atrophy patterns in Alzheimer’s disease target episodic memory circuits2. Examination of network‐specific neurodegeneration could lend insight into how these conditions spread within vulnerable cortical systems 3. Behavioral variant Frontotemporal Dementia (bvFTD) is most commonly linked to degeneration in the salience network, with clinical presentations of bvFTD explained as deficits in salience processing 4,5. However, phenotypic presentations of bvFTD are diverse6 and this syndrome is caused by varied proteinopathies and gene mutations7. As such, we hypothesized that bvFTD patients would exhibit atrophy patterns that cross canonical network boundaries within prefrontal and temporal cortex.MethodWe estimated cortical thickness using surface‐based analyses described in our previous studies2 in two independent sporadic bvFTD samples: a Massachusetts General Hospital sample (n=30) and a sample derived from the Frontotemporal Lobar Degeneration Neuroimaging Initiative (NIFD) (n=60; excluding cases contributed by MGH). Cortical thickness in these samples were then compared to that measured in two groups of age and gender matched controls (n=71 and n=133, respectively). In order to estimate individual network atrophy in bvFTD, we then compared the resultant cortical thickness maps to the topography of seven large‐scale cortical networks derived from the Yeo et al. 2011 parcellation8.ResultWe found highly similar patterns of cortical atrophy across the two independent samples. In both samples, cortical atrophy in bvFTD was not confined to the salience network, but also spanned rostral portions of the default‐mode network (including the hippocampal formation), the limbic (semantic appraisal) network, and rostral nodes of the frontoparietal control network. Moreover, regions exhibiting the most prominent atrophy included anterior temporal regions, not only the salience network.ConclusionThese findings argue against the hypothesis that bvFTD preferentially affects the salience network and instead underscores the distributed impact this syndrome has across prefrontal and anterior temporal cortical circuits. This heterogeneity could reflect the diverse neuropathological etiologies giving rise to the cognitive‐behavioral syndrome of bvFTD. Future efforts should be directed toward examining selectively‐vulnerable circuits in bvFTD syndromes associated with specific molecular pathologies.

Differences in Sex Distribution Between Genetic and Sporadic Frontotemporal Dementia.

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.

The Frequency of Genetic Mutations Associated With Behavioral Variant Frontotemporal Dementia in Chinese Han Patients.

BackgroundBehavioral variant frontotemporal dementia (bvFTD) is a clinically heterogeneous syndrome with high heredity. However, the frequencies of mutations associated with bvFTD have yet to be determined. The aim of the current study was to investigate the frequency of Chinese Han patients harboring genetic bvFTD variants.MethodsA total of 49 bvFTD patients selected from our frontotemporal lobar degeneration database, including 14 familial cases belonging to eight families and 35 sporadic cases were consecutively recruited from July 2014 to December 2019 at Xuanwu Hospital (Beijing, China). Whole-exome sequencing (WES) was performed and repeat-primed PCR was used to test samples for the C9orf72 hexanucleotide repeat expansion mutation. The frequency of genetic variants and the pathogenicity of the novel variants were analyzed.ResultsTen pathogenic or likely pathogenic variants were identified in 17 bvFTD patients, including C9orf72 repeat expansions, six previously reported mutations and three novel mutations (MAPT p. R5C, p. D54N, GRN p. P451L). Genetic mutations accounted for 27.9% (12/43) of total cases, 87.5% (7/8) of patients with familial bvFTD, and 14.3% (5/35) with sporadic bvFTD. Pathogenic variants mostly occurred in MAPT gene (20.9%, 9/43), followed by C9orf72 repeat expansions (2.3%, 1/43), GRN gene (2.3%, 1/43) and FUS gene (2.3%, 1/43).ConclusionThere was a high prevalence of genetic variants in Chinese bvFTD patients, highlighting the necessity of genetic testing for bvFTD.

Clinician‐reported features in MBI/MCI and early dementia in genetic FTLD

AbstractBackgroundFrontotemporal dementia (FTD) can present with significant phenotypic heterogeneity. Most cases of sporadic FTD do not present for diagnosis until functional impairment is evident, making it difficult to identify and characterize the earliest features of FTD. Focusing on participants from families with known FTD‐causing pathogenic mutations allows for the characterization of the earliest features of FTD in genetic carriers.MethodThe ARTFL and LEFFTDS consortia (AG063911, AG045390, NS092089, AG016976) are joint, multi‐center cohort studies of patients with FTLD, including symptomatic and asymptomatic family members. For this study, a subset of ARTFL/LEFFTDS participants from families with known genetic mutations were selected if they were determined by a study physician to have (a) a phenotype of Mild Behavioral / Cognitive Impairment (MBI/MCI) and CDR®+NACC‐FTLD = 0.5 (44 participants, 19 C9orf72, 12 GRN, 13 MAPT mutations), or (b) CDR®+NACC‐FTLD = 1 (33 participants, 16 C9orf72, 10 GRN, 7 MAPT mutations). We examined the NACC Uniform Data Set (UDS) B9F form, bvFTD criteria. Pearson chi‐squared tests compared the frequency of identified bvFTD features between MBI/MCI and bvFTD participants.ResultThe most common bvFTD diagnostic criteria features questionably or definitely present in the 44 MBI/MCI participants were Apathy and Disinhibition, both at 30% (Within the early FTLD group: Apathy at 70% and Disinhibition at 72%). Neuropsychological testing deficits consistent with bvFTD were present in 27% (72%), and loss of empathy in 25% (72%). Impaired daily functioning was next at 16% (81%), Ritualistic behaviors were observed in 7%, (36%) and Hyperorality in 5% (33%). Chi‐squared tests revealed significant differences between the two groups for all features, with the largest numerical and statistical difference in impaired daily functioning.ConclusionApathy and Disinhibition were the most common neuropsychiatric symptoms noted in FLTD MBI/MCI. Development of impairments in daily functioning best distinguished the MBI/MCI and FTLD groups. This may be related to the requirement of functional impairment for the diagnosis of dementia. The relative frequency of different features in early dementia of genetic FTLD is similar to that reported in sporadic bvFTD. As more longitudinal data is collected, within‐subject assessment of the development of features in genetic bvFTD over time will be instructive.

Neuropsychological features of progranulin-associated frontotemporal dementia: a nested case-control study.

The distinction between sporadic and genetic behavioural-variant frontotemporal dementia (bvFTD) regarding some neuropsychological (NP) features remains challenging. Specifically, progranulin (GRN)-associated bvFTD frequently presents with early episodic memory impairment and some degree of parietal dysfunction which are supporters of Alzheimer's disease (AD) diagnosis. In this context, we aimed to characterize the NP profile of GRN-bvFTD as compared to sporadic-bvFTD and AD in patients with mild dementia (Mini-Mental State Examination score ≥ 17 and Clinical Dementia Rating Scale score ≤ 1. We identified 21 patients at Centro Hospitalar e Universitário de Coimbra, Portugal with GRN mutations belonging to fifteen different families. As our focus was bvFTD variants, FTD-related aphasic forms (3 patients) were excluded. The remaining 18 GRN-bvFTD were further matched with 18 sporadic-bvFTD and 18 AD patients according to disease staging, age and education. All patients completed the Mini-Mental State Examination, Montreal Cognitive Assessment (MoCA) and a comprehensive NP assessment battery. Results were converted into z-scores. Differences between groups in individual NP measures and NP domains were assessed through non-parametric tests (Kruskal-Wallis test analysis) and eta squared (ŋ2) was calculated as a measure of effect size. Group comparisons show that GRN patients have worse performances on verbal retrieval processes (P = 0.039, ŋ2 = 0.110) and visuoconstructive abilities (P = 0.039, ŋ2 = 0.190) than sporadic bvFTD forms. When compared to AD, GRN patients present a higher impairment in frontal (P = 0.001, ŋ2 = 0.211) and parietal (P = 0.041, ŋ2 = 0.129) measures and a better performance in memory tasks (P = 0.020, ŋ2 = 0.120). Sporadic-bvFTD forms are worse than AD in frontal measures (P = 0.032, ŋ2 = 0.200), being better in both memory (P = 0.010, ŋ2 = 0.131) and visuospatial skills (P = 0.023, ŋ2 = 0.231). Considering these results, we conclude that GRN-bvFTD patients present a NP profile that associates the typical patterns of FTD and AD deficits. This is particularly expressive in visuoconstructive abilities, which was the more discriminative feature between groups, followed by episodic verbal memory. This study was approved by the Institutional Ethics Committee of Centro Hospitalar e Universitário de Coimbra, Portugal (CE-029/2019) on June 24, 2019.

Modeling of Frontotemporal Dementia Using iPSC Technology.

Frontotemporal dementia (FTD) is caused by the progressive degeneration of the frontal and temporal lobes of the brain. Behavioral variant FTD (bvFTD) is the most common clinical subtype of FTD and pathological subtypes of bvFTD are known as FTD-tau, transactive response (TAR) DNA-binding protein 43 (TDP-43), and fused in sarcoma (FUS). Pathological mechanisms of bvFTD are largely unknown. In this study, we investigated the expression of pathological markers, such as p-Tau, TDP-43, and FUS, in the induced pluripotent stem-cell-derived neurons (iPSN) from two sporadic bvFTD patients and one normal subject. We also used an FTD-patient-derived iPSC-line-carrying microtubule-associated protein tau (MAPT) P301L point mutation as positive control for p-Tau expression. Staurosporine (STS) was used to induce cellular stress in order to investigate dynamic cellular responses related to the cell death pathway. As a result, the expression of active caspase-3 was highly increased in the bvFTD-iPSNs compared with control iPSNs in the STS-treated conditions. Other cell-death-related proteins, including Bcl-2-associated X protein (Bax)/Bcl-2 and cytochrome C, were also increased in the bvFTD-iPSNs. Moreover, we observed abnormal expression patterns of TDP-43 and FUS in the bvFTD-iPSNs compared with control iPSNs. We suggest that the iPSC technology might serve as a potential tool to demonstrate neurodegenerative phenotypes of bvFTD, which will be useful for studying pathological mechanisms for FTD as well as related drug screening in the future.