A neuroanatomical and cognitive model of impaired social behaviour in frontotemporal dementia.

Impaired social cognition is a core deficit in frontotemporal dementia (FTD). It is most commonly associated with the behavioural-variant of FTD, with atrophy of the orbitofrontal and ventromedial prefrontal cortex. Social cognitive changes are also common in semantic dementia, with atrophy centred on the anterior temporal lobes. The impairment of social behaviour in FTD has typically been attributed to damage to the orbitofrontal cortex and/or temporal poles and/or the uncinate fasciculus that connects them. However, the relative contributions of each region are unresolved. In this review, we present a unified neurocognitive model of controlled social behaviour that not only explains the observed impairment of social behaviours in FTD, but also assimilates both consistent and potentially contradictory findings from other patient groups, comparative neurology and normative cognitive neuroscience. We propose that impaired social behaviour results from damage to two cognitively- and anatomically-distinct components. The first component is social-semantic knowledge, a part of the general semantic-conceptual system supported by the anterior temporal lobes bilaterally. The second component is social control, supported by the orbitofrontal cortex, medial frontal cortex and ventrolateral frontal cortex, which interacts with social-semantic knowledge to guide and shape social behaviour.

Atrophy network mapping of clinical subtypes and main symptoms in frontotemporal dementia.

Frontotemporal dementia (FTD) is a disease of high heterogeneity, apathy and disinhibition present in all subtypes of FTD and imposes a significant burden on families/society. Traditional neuroimaging analysis has limitations in elucidating the network localization due to individual clinical and neuroanatomical variability. The study aims to identify the atrophy network map associated with different FTD clinical subtypes and determine the specific localization of the network for apathy and disinhibition. Eighty FTD patients [45 behavioural variant FTD (bvFTD) and 35 semantic variant progressive primary aphasia (svPPA)] and 58 healthy controls at Xuanwu Hospital were enrolled as Dataset 1; 112 FTD patients including 50 bvFTD, 32 svPPA and 30 non-fluent variant PPA (nfvPPA) cases, and 110 healthy controls from the Frontotemporal Lobar Degeneration Neuroimaging Initiative (FTLDNI) dataset were included as Dataset 2. Initially, single-subject atrophy maps were defined by comparing cortical thickness in each FTD patient versus healthy controls. Next, the network of brain regions functionally connected to each FTD patient's location of atrophy was determined using seed-based functional connectivity in a large (n = 1000) normative connectome. Finally, we used atrophy network mapping to define clinical subtype-specific network (45 bvFTD, 35 svPPA and 58 healthy controls in Dataset 1; 50 bvFTD, 32 svPPA, 30 nfvPPA and 110 healthy controls in Dataset 2) and symptom-specific networks [combined Datasets 1 and 2, apathy without depression versus non-apathy without depression (80:26), disinhibition versus non-disinhibition (88:68)]. We compare the result with matched symptom networks derived from patients with focal brain lesions or conjunction analysis. Through the analysis of two datasets, we identified heterogeneity in atrophy patterns among FTD patients. However, these atrophy patterns are connected to a common brain network. The primary regions affected by atrophy in FTD included the frontal and temporal lobes, particularly the anterior temporal lobe. bvFTD connects to frontal and temporal cortical areas, svPPA mainly impacts the anterior temporal region and nfvPPA targets the inferior frontal gyrus and precentral cortex regions. The apathy-specific network was localized in the orbital frontal cortex and ventral striatum, while the disinhibition-specific network was localized in the bilateral orbital frontal gyrus and right temporal lobe. Apathy and disinhibition atrophy networks resemble known motivational and criminal lesion networks, respectively. A significant correlation was found between the apathy/disinhibition scores and functional connectivity between atrophy maps and the peak of the networks. This study localizes the common network of clinical subtypes and main symptoms in FTD, guiding future FTD neuromodulation interventions.

Radiogenomics of C9orf72 Expansion Carriers Reveals Global Transposable Element Derepression and Enables Prediction of Thalamic Atrophy and Clinical Impairment.

Hexanucleotide repeat expansion (HRE) within C9orf72 is the most common genetic cause of frontotemporal dementia (FTD). Thalamic atrophy occurs in both sporadic and familial FTD but is thought to distinctly affect HRE carriers. Separately, emerging evidence suggests widespread derepression of transposable elements (TEs) in the brain in several neurodegenerative diseases, including C9orf72 HRE-mediated FTD (C9-FTD). Whether TE activation can be measured in peripheral blood and how the reduction in peripheral C9orf72 expression observed in HRE carriers relates to atrophy and clinical impairment remain unknown. We used FreeSurfer software to assess the effects of C9orf72 HRE and clinical diagnosis (n = 78 individuals, male and female) on atrophy of thalamic nuclei. We also generated a novel, human, whole-blood RNA-sequencing dataset to determine the relationships among peripheral C9orf72 expression, TE activation, thalamic atrophy, and clinical severity (n = 114 individuals, male and female). We confirmed global thalamic atrophy and reduced C9orf72 expression in HRE carriers. Moreover, we identified disproportionate atrophy of the right mediodorsal lateral nucleus in HRE carriers and showed that C9orf72 expression associated with clinical severity, independent of thalamic atrophy. Strikingly, we found global peripheral activation of TEs, including the human endogenous LINE-1 element L1HS L1HS levels were associated with atrophy of multiple pulvinar nuclei, a thalamic region implicated in C9-FTD. Integration of peripheral transcriptomic and neuroimaging data from human HRE carriers revealed atrophy of specific thalamic nuclei, demonstrated that C9orf72 levels relate to clinical severity, and identified marked derepression of TEs, including L1HS, which predicted atrophy of FTD-relevant thalamic nuclei.SIGNIFICANCE STATEMENT Pathogenic repeat expansion in C9orf72 is the most frequent genetic cause of FTD and amyotrophic lateral sclerosis (ALS; C9-FTD/ALS). The clinical, neuroimaging, and pathologic features of C9-FTD/ALS are well characterized, whereas the intersections of transcriptomic dysregulation and brain structure remain largely unexplored. Herein, we used a novel radiogenomic approach to examine the relationship between peripheral blood transcriptomics and thalamic atrophy, a neuroimaging feature disproportionately impacted in C9-FTD/ALS. We confirmed reduction of C9orf72 in blood and found broad dysregulation of transposable elements-genetic elements typically repressed in the human genome-in symptomatic C9orf72 expansion carriers, which associated with atrophy of thalamic nuclei relevant to FTD. C9orf72 expression was also associated with clinical severity, suggesting that peripheral C9orf72 levels capture disease-relevant information.

A 3D convolutional neural network to classify subjects as Alzheimer's disease, frontotemporal dementia or healthy controls using brain 18F-FDG PET.

With the arrival of disease-modifying drugs, neurodegenerative diseases will require an accurate diagnosis for optimal treatment. Convolutional neural networks are powerful deep learning techniques that can provide great help to physicians in image analysis. The purpose of this study is to introduce and validate a 3D neural network for classification of Alzheimer's disease (AD), frontotemporal dementia (FTD) or cognitively normal (CN) subjects based on brain glucose metabolism. Retrospective [18F]-FDG-PET scans of 199 CE, 192 FTD and 200 CN subjects were collected from our local database, Alzheimer's disease and frontotemporal lobar degeneration neuroimaging initiatives. Training and test sets were created using randomization on a 90 %-10 % basis, and training of a 3D VGG16-like neural network was performed using data augmentation and cross-validation. Performance was compared to clinical interpretation by three specialists in the independent test set. Regions determining classification were identified in an occlusion experiment and Gradient-weighted Class Activation Mapping. Test set subjects were age- and sex-matched across categories. The model achieved an overall 89.8 % accuracy in predicting the class of test scans. Areas under the ROC curves were 93.3 % for AD, 95.3 % for FTD, and 99.9 % for CN. The physicians' consensus showed a 69.5 % accuracy, and there was substantial agreement between them (kappa = 0.61, 95 % CI: 0.49-0.73). To our knowledge, this is the first study to introduce a deep learning model able to discriminate AD and FTD based on [18F]-FDG PET scans, and to isolate CN subjects with excellent accuracy. These initial results are promising and hint at the potential for generalization to data from other centers.

Clinical and neuroimaging characterization of the first frontotemporal dementia family carrying the MAPT p.K298E mutation.

We present an in-depth clinical and neuroimaging analysis of a family carrying the MAPT K298E mutation associated with frontotemporal dementia (FTD). Initial identification of this mutation in a single clinical case led to a comprehensive investigation involving four affected siblings allowing to elucidate the mutation's phenotypic expression.A 60-year-old male presented with significant behavioral changes and progressed rapidly, exhibiting speech difficulties and cognitive decline. Neuroimaging via FDG-PET revealed asymmetrical frontotemporal hypometabolism. Three siblings subsequently showed varied but consistent clinical manifestations, including abnormal behavior, speech impairments, memory deficits, and motor symptoms correlating with asymmetric frontotemporal atrophy observed in MRI scans.Based on the genotype-phenotype correlation, we propose that the p.K298E mutation results in early-onset behavioral variant FTD, accompanied by a various constellation of speech and motor impairment.This detailed characterization expands the understanding of the p.K298E mutation's clinical and neuroimaging features, underlining its role in the pathogenesis of FTD. Further research is crucial to comprehensively delineate the clinical and epidemiological implications of the MAPT p.K298E mutation.

Causal relationship between imaging-derived phenotypes and neurodegenerative diseases: a Mendelian randomization study.

Neurodegenerative diseases are incurable conditions that lead to gradual and progressive deterioration of brain function in patients. With the aging population, the prevalence of these diseases is expected to increase, posing a significant economic burden on society. Imaging techniques play a crucial role in the diagnosis and monitoring of neurodegenerative diseases. This study utilized a two-sample Mendelian randomization (MR) analysis to assess the causal relationship between different imaging-derived phenotypes (IDP) in the brain and neurodegenerative diseases. Multiple MR methods were employed to minimize bias and obtain reliable estimates of the potential causal relationship between the variable exposures of interest and the outcomes. The study found potential causal relationships between different IDPs and Alzheimer's disease (AD), Parkinson's disease (PD), amyotrophic lateral sclerosis (ALS), multiple sclerosis (MS), and frontotemporal dementia (FTD). Specifically, the study identified potential causal relationships between 2 different types of IDPs and AD, 8 different types of IDPs and PD, 11 different types of imaging-derived phenotypes and ALS, 1 type of IDP and MS, and 1 type of IDP and FTD. This study provides new insights for the prevention, diagnosis, and treatment of neurodegenerative diseases, offering important clues for understanding the pathogenesis of these diseases and developing relevant intervention strategies.

Synaptic Loss in Frontotemporal Dementia Revealed by [11 C]UCB-J Positron Emission Tomography.

OBJECTIVE: Synaptic loss is an early feature of neurodegenerative disease models, and is severe in post mortem clinical studies, including frontotemporal dementia. Positron emission tomography (PET) with radiotracers that bind to synaptic vesicle glycoprotein 2A enables quantification of synaptic density in vivo. This study used [11 C]UCB-J PET in participants with behavioral variant frontotemporal dementia (bvFTD), testing the hypothesis that synaptic loss is severe and related to clinical severity. METHODS: Eleven participants with clinically probable bvFTD and 25 age- and sex-matched healthy controls were included. Participants underwent dynamic [11 C]UCB-J PET, structural magnetic resonance imaging, and a neuropsychological battery, including the revised Addenbrooke Cognitive Examination, and INECO frontal screening. General linear models compared [11 C]UCB-J binding potential maps and gray matter volume between groups, and assessed associations between synaptic density and clinical severity in patients. Analyses were also performed using partial volume corrected [11 C]UCB-J binding potential from regions of interest (ROIs). RESULTS: Patients with bvFTD showed severe synaptic loss compared to controls. [11 C]UCB-J binding was reduced bilaterally in medial and dorsolateral frontal regions, inferior frontal gyri, anterior and posterior cingulate gyrus, insular cortex, and medial temporal lobe. Synaptic loss in the frontal and cingulate regions correlated significantly with cognitive impairments. Synaptic loss was more severe than atrophy. Results from ROI-based analyses mirrored the voxelwise results. INTERPRETATION: In accordance with preclinical models, and human postmortem evidence, there is widespread frontotemporal loss of synapses in symptomatic bvFTD, in proportion to severity. [11 C]UCB-J PET could support translational studies and experimental medicine strategies for new disease-modifying treatments for neurodegeneration. ANN NEUROL 2023;93:142-154.

The use of neuroimaging techniques in the early and differential diagnosis of dementia.

Dementia is a leading cause of disability and death worldwide. At present there is no disease modifying treatment for any of the most common types of dementia such as Alzheimer's disease (AD), Vascular dementia, Lewy Body Dementia (LBD) and Frontotemporal dementia (FTD). Early and accurate diagnosis of dementia subtype is critical to improving clinical care and developing better treatments. Structural and molecular imaging has contributed to a better understanding of the pathophysiology of neurodegenerative dementias and is increasingly being adopted into clinical practice for early and accurate diagnosis. In this review we summarise the contribution imaging has made with particular focus on multimodal magnetic resonance imaging (MRI) and positron emission tomography imaging (PET). Structural MRI is widely used in clinical practice and can help exclude reversible causes of memory problems but has relatively low sensitivity for the early and differential diagnosis of dementia subtypes. 18F-fluorodeoxyglucose PET has high sensitivity and specificity for AD and FTD, while PET with ligands for amyloid and tau can improve the differential diagnosis of AD and non-AD dementias, including recognition at prodromal stages. Dopaminergic imaging can assist with the diagnosis of LBD. The lack of a validated tracer for α-synuclein or TAR DNA-binding protein 43 (TDP-43) imaging remain notable gaps, though work is ongoing. Emerging PET tracers such as 11C-UCB-J for synaptic imaging may be sensitive early markers but overall larger longitudinal multi-centre cross diagnostic imaging studies are needed.

Cross-sectional study of patients with VCP multisystem proteinopathy 1 using dual-energy x-ray absorptiometry.

INTRODUCTION/AIMS: VCP multisystem proteinopathy 1 (MSP1), encompassing inclusion body myopathy (IBM), Paget's disease of bone (PDB) and frontotemporal dementia (FTD) (IBMPFD), features progressive muscle weakness, fatty infiltration, and disorganized bone structure in Pagetic bones. The aim of this study is to utilize dual-energy x-ray absorptiometry (DXA) parameters to examine it as a biomarker of muscle and bone disease in MSP1. METHODS: DXA scans were obtained in 28 patients to assess body composition parameters (bone mineral density [BMD], T-score, total fat, and lean mass) across different groups: total VCP disease (n = 19), including myopathy without Paget's ("myopathy"; n = 12) and myopathy with Paget's ("Paget"; n = 7), and unaffected first-degree relatives serving as controls (n = 6). RESULTS: In the VCP disease group, significant declines in left hip BMD and Z-scores were noted versus the control group (p ≤ .03). The VCP disease group showed decreased whole body lean mass % (p = .04), and increased total body fat % (p = .04) compared to controls. Subgroup comparisons indicated osteopenia in 33.3% and osteoporosis in 8.3% of the myopathy group, with 14.3% exhibiting osteopenia in the Paget group. Moreover, the Paget group displayed higher lumbar L1-L4 T-score values than the myopathy group. DISCUSSION: In MSP1, DXA revealed reduced bone and lean mass, and increased fat mass. These DXA insights could aid in monitoring disease progression of muscle loss and secondary osteopenia/osteoporosis in MSP1, providing value both clinically and in clinical research.

Distinct neural signatures of pulvinar in C9orf72 amyotrophic lateral sclerosis mutation carriers and noncarriers.

BACKGROUND AND PURPOSE: Thalamic alterations have been reported as a major feature in presymptomatic and symptomatic patients carrying the C9orf72 mutation across the frontotemporal dementia-amyotrophic lateral sclerosis (ALS) spectrum. Specifically, the pulvinar, a high-order thalamic nucleus and timekeeper for large-scale cortical networks, has been hypothesized to be involved in C9orf72-related neurodegenerative diseases. We investigated whether pulvinar volume can be useful for differential diagnosis in ALS C9orf72 mutation carriers and noncarriers and how underlying functional connectivity changes affect this region. METHODS: We studied 19 ALS C9orf72 mutation carriers (ALSC9+) accurately matched with wild-type ALS (ALSC9-) and ALS mimic (ALSmimic) patients using structural and resting-state functional magnetic resonance imaging data. Pulvinar volume was computed using automatic segmentation. Seed-to-voxel functional connectivity analyses were performed using seeds from a pulvinar functional parcellation. RESULTS: Pulvinar structural integrity had high discriminative values for ALSC9+ patients compared to ALSmimic (area under the curve [AUC] = 0.86) and ALSC9- (AUC = 0.77) patients, yielding a volume cutpoint of approximately 0.23%. Compared to ALSmimic, ALSC9- showed increased anterior, inferior, and lateral pulvinar connections with bilateral occipital-temporal-parietal regions, whereas ALSC9+ showed no differences. ALSC9+ patients when compared to ALSC9- patients showed reduced pulvinar-occipital connectivity for anterior and inferior pulvinar seeds. CONCLUSIONS: Pulvinar volume could be a differential biomarker closely related to the C9orf72 mutation. A pulvinar-cortical circuit dysfunction might play a critical role in disease progression and development, in both the genetic phenotype and ALS wild-type patients.

Spatial and Temporal Relationships Between Atrophy and Hypometabolism in Behavioral-Variant Frontotemporal Dementia.

PURPOSE: Individuals with behavioral-variant frontotemporal dementia (bvFTD) show changes in brain structure as assessed by MRI and brain function assessed by 18FDG-PET hypometabolism. However, current understanding of the spatial and temporal interplay between these measures remains limited. METHODS: Here, we examined longitudinal atrophy and hypometabolism relationships in 15 bvFTD subjects with 2 to 4 follow-up MRI and PET scans (56 visits total). Subject-specific slopes of atrophy and hypometabolism over time were extracted across brain regions and correlated with baseline measures both locally, via Pearson correlations, and nonlocally, via sparse canonical correlation analyses (SCCA). RESULTS: Notably, we identified a robust link between initial hypometabolism and subsequent cortical atrophy rate changes in bvFTD subjects. Network-level exploration unveiled alignment between baseline hypometabolism and ensuing atrophy rates in the dorsal attention, language, and default mode networks. SCCA identified 2 significant and highly localized components depicting the connection between baseline hypometabolism and atrophy slope over time. The first centered around bilateral orbitofrontal, frontopolar, and medial prefrontal lobes, whereas the second concentrated in the left temporal lobe and precuneus. CONCLUSIONS: This study highlights 18FDG-PET as a dependable predictor of forthcoming atrophy in spatially adjacent brain regions for individuals with bvFTD.

Diagnostic utility of brain MRI volumetry in comparing traumatic brain injury, Alzheimer disease and behavioral variant frontotemporal dementia.

BACKGROUND: Brain MRI with volumetric quantification, MRI volumetry, can improve diagnostic delineation of patients with neurocognitive disorders by identifying brain atrophy that may not be evident on visual assessments. OBJECTIVE: To investigate diagnostic utility of MRI volumetry in traumatic brain injury (TBI), early-onset Alzheimer disease (EOAD), late-onset Alzheimer disease, and behavioral variant frontotemporal dementia (bvFTD). METHOD: We utilized 137 participants of TBI (n = 40), EOAD (n = 45), LOAD (n = 32), and bvFTD (n = 20). Participants had 3D T1 brain MRI imaging amendable to MRI volumetry. Scan volumes were analyzed with Neuroreader. One-way ANOVA compared brain volumes across diagnostic groups. Discriminant analysis was done with leave-one-out cross validation on Neuroreader metrics to determine diagnostic delineation across groups. RESULT: LOAD was the oldest compared to other groups (F = 27.5, p < .001). There were no statistically significant differences in sex (p = .58) with women comprising 54.7% of the entire cohort. EOAD and LOAD had the lowest Mini-Mental State Exam (MMSE) scores compared to TBI (p = .04 for EOAD and p = .01 for LOAD). LOAD had lowest hippocampal volumes (Left Hippocampus F = 13.1, Right Hippocampus F = 7.3, p < .001), low white matter volume in TBI (F = 5.9, p < .001), lower left parietal lobe volume in EOAD (F = 9.4, p < .001), and lower total gray matter volume in bvFTD (F = 32.8, p < .001) and caudate atrophy (F = 1737.5, p < .001). Areas under the curve ranged from 92.3 to 100%, sensitivity between 82.2 and 100%, specificity of 78.1-100%. TBI was the most accurately delineated diagnosis. Predictive features included caudate, frontal, parietal, temporal lobar and total white matter volumes. CONCLUSION: We identified the diagnostic utility of regional volumetric differences across multiple neurocognitive disorders. Brain MRI volumetry is widely available and can be applied in distinguishing these disorders.

Socioemotional Dysfunction From Temporal Lobe Involvement in Frontotemporal Dementia: A Preliminary Report.

OBJECTIVE: Socioemotional changes, rather than cognitive impairments, are the feature that defines behavioral variant frontotemporal dementia (bvFTD). Investigators have attributed the socioemotional changes in bvFTD and other dementias to frontal lobe dysfunction; however, recent work implies a further contribution from right anterior temporal disease. The authors evaluated relationships between regional brain atrophy and socioemotional changes in both bvFTD and early-onset Alzheimer's disease (EOAD). METHODS: This study explored the neuroanatomical correlations of performance on the Socioemotional Dysfunction Scale (SDS), an instrument previously shown to document socioemotional changes in bvFTD, among 13 patients with bvFTD not preselected for anterior temporal involvement and 16 age-matched patients with early-onset Alzheimer's disease (EOAD). SDS scores were correlated with volumes of regions of interest assessed with tensor-based morphometric analysis of MRI images. RESULTS: As expected, the bvFTD group had significantly higher SDS scores overall and smaller frontal regions compared with the EOAD group, which in turn had smaller volumes in temporoparietal regions. SDS scores significantly correlated with lateral anterior temporal lobe (ATL) atrophy, and a regression analysis that controlled for diagnosis indicated that SDS scores predicted lateral ATL volume. Within the bvFTD group, higher SDS scores were associated with smaller lateral and right ATL regions, as well as a smaller orbitofrontal cortex. Within the EOAD group, higher SDS scores were associated with a smaller right parietal cortex. CONCLUSIONS: This study confirms that, in addition to orbitofrontal disease, there is a prominent right and lateral ATL origin of socioemotional changes in bvFTD and further suggests that right parietal involvement contributes to socioemotional changes in EOAD.

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.

Patients carrying the mutation p.R406W in MAPT present with non-conforming phenotypic spectrum.

The missense mutation p.R406W in microtubule-associated protein tau leads to frontotemporal lobar degeneration with an amnestic, Alzheimer's disease-like phenotype with an autosomal dominant pattern of inheritance. In 2003, we described the pedigree of a Belgian family, labelled ADG, with 28 p.R406W patients. Over 18 years follow-up, we extended the family with 10 p.R406W carriers and provided an in-depth clinical description of the patients. Additionally, genetic screening was used to identify p.R406W carriers in Belgian cohorts of frontotemporal dementia and Alzheimer's disease patients and to calculate p.R406W frequency. In the frontotemporal dementia cohort, we found four p.R406W carriers (n = 647, 0.62%) and three in the Alzheimer's disease cohort (n = 1134, 0.26%). Haplotype sharing analysis showed evidence of a shared haplotype suggesting that they are descendants of a common ancestor. Of the p.R406W patients, we describe characteristics of neuropsychological, imaging and fluid biomarkers as well as neuropathologic examination. Intriguingly, the phenotypic spectrum among the p.R406W patients ranged from typical behavioural variant frontotemporal dementia to clinical Alzheimer's disease, based on CSF biomarker analysis and amyloid PET scan. Heterogeneous overlap syndromes existed in between, with highly common neuropsychiatric symptoms like disinhibition and aggressiveness, which occurred in 100% of frontotemporal dementia and 58% of clinical Alzheimer's disease patients. This was also the case for memory problems, 89% in frontotemporal dementia and 100% in clinical Alzheimer's disease patients. Median age at death was significantly lower in patients with frontotemporal dementia (68 years) compared to clinical Alzheimer's disease patients (79 years), although the sizes of the sub-cohorts are limited and do not allow prognostic predictions. Post-mortem brain analysis of one p.R406W patient with behavioural variant frontotemporal dementia revealed frontotemporal lobar degeneration with tau pathology. Notably, neuropathological investigation showed only 3R tau isoforms in the absence of 4R tau reactivity, an unusual finding in microtubule-associated protein tau-related frontotemporal lobar degeneration. No traces of amyloid pathology were present. Prevalence of the p.R406W mutation was relatively high in both frontotemporal dementia and Alzheimer's disease Belgian patient cohorts. These findings grant new insights into genotype-phenotype correlations of p.R406W carriers. They may help in further unravelling of the pathophysiology of this tauopathy and in facilitating the identification of patients with p.R406W-related frontotemporal lobar degeneration, both in clinical diagnostic and research settings.

Frontal allographic agraphia in a patient with behavioral variant frontotemporal dementia.

We report a patient with behavioral variant frontotemporal dementia who developed agraphia, irritability, perseverative and stereotyped behavior, and dietary changes. MRI revealed bilateral frontal convexity atrophy. Neuropsychological examination showed fluent aphasia with perseverative allographic agraphia, mild semantic impairment, and dysexecutive syndrome. Allographic agraphia featured unidirectional conversion from hiragana (cursive form of Japanese phonograms) and kanji (Japanese morphograms) to katakana (square form of Japanese phonograms), as opposed to mutual (bidirectional) conversion between hiragana and katakana in parieto-occipital gyri lesions. Furthermore, all letters of the word were converted and this whole-word conversion may be characteristic of perseverative behavior in frontotemporal dementia.

Incongruent gray matter atrophy and functional connectivity of striatal subregions in behavioral variant frontotemporal dementia.

Previous studies on the striatum demonstrated that it is involved in the regulation of cognitive function and psychiatric symptoms in patients with behavioral variant frontotemporal dementia (bvFTD). Multiple lines of evidence have shown that striatal subregions have their own functions. However, the results of the existing studies on striatal subregions are inconsistent and unclear. In this study, we found that structural imaging analysis revealed that the bvFTD patients had smaller volumes of striatal subregions than the controls. We found that the degree of atrophy varied across the striatal subregions. Additionally, the right striatal subregions were significantly more atrophic than the left in bvFTD. Functional imaging analysis revealed that bvFTD patients exhibited different changed patterns of resting-state functional connectivity (RSFC) when striatal subregions were selected as regions of interest (ROI). The RSFC extending range on the right ROIs was more significant than on the left in the same subregion. Interestingly, the RSFC of the subregions extending to the insula were consistent. In addition, the left dorsolateral putamen may be involved in executive function regulation. This suggests that incongruence in striatal subregions may be critical to the bvFTD characteristics.

Genetic overlap between cortical brain morphometry and frontotemporal dementia risk.

Frontotemporal dementia (FTD) has a complex genetic etiology, where the precise mechanisms underlying the selective vulnerability of brain regions remain unknown. We leveraged summary-based data from genome-wide association studies (GWAS) and performed LD score regression to estimate pairwise genetic correlations between FTD risk and cortical brain imaging. Then, we isolated specific genomic loci with a shared etiology between FTD and brain structure. We also performed functional annotation, summary-data-based Mendelian randomization for eQTL using human peripheral blood and brain tissue data, and evaluated the gene expression in mice targeted brain regions to better understand the dynamics of the FTD candidate genes. Pairwise genetic correlation estimates between FTD and brain morphology measures were high but not statistically significant. We identified 5 brain regions with a strong genetic correlation (rg > 0.45) with FTD risk. Functional annotation identified 8 protein-coding genes. Building upon these findings, we show in a mouse model of FTD that cortical N-ethylmaleimide sensitive factor (NSF) expression decreases with age. Our results highlight the molecular and genetic overlap between brain morphology and higher risk for FTD, specifically for the right inferior parietal surface area and right medial orbitofrontal cortical thickness. In addition, our findings implicate NSF gene expression in the etiology of FTD.

Prevalence, treatment, and neural correlates of apathy in different forms of dementia: a narrative review.

OBJECTIVES: The aim of this review is to provide an overview on prevalence and clinical tools for the diagnosis of apathy, as well as on neurophysiological and neuroimaging findings obtained from studies in patients with apathy in different forms of dementia, including Alzheimer's disease (AD), vascular (VaD) and mixed dementia, frontotemporal dementia (FTD), and Parkinson's disease dementia (PDD). METHODS: Randomized controlled trials, non-randomized controlled trials, controlled before-after studies, and interrupted time series from four databases (WebOfScience, Scopus, Pubmed, and PsycINFO) addressing apathy in adults or older people aged over 65 years of age affected by dementia were included. RESULTS: The prevalence of apathy was 26-82% for AD, 28.6-91.7 for VaD, 29-97.5% in PDD, and 54.8-88.0 in FTD. The assessment of apathy was not consistent in the reviewed studies. Methylphenidate was the most successful pharmacological treatment for apathy. Neurobiological studies highlighted the relationship between both structural and functional brain areas and the presence or severity of apathy. CONCLUSION: Apathy is a very common disorder in all types of dementia, although it is often underdiagnosed and undertreated. Further studies are needed to investigate its diagnosis and management. A consensus on the different evaluation scales should be achieved.

The use of an anterior-posterior atrophy index to distinguish Alzheimer's disease from frontotemporal disorders: an automated volumetric MRI Study.

BACKGROUND: Alzheimer's disease (AD) and frontotemporal dementia (FTD) require different treatments. Since clinical presentation can be nuanced, imaging biomarkers aid in diagnosis. Automated software such as Neuroreader (NR) provides volumetric imaging data, and indices between anterior and posterior brain areas have proven useful in distinguishing dementia subtypes in research cohorts. Existing indices are complex and require further validation in clinical settings. PURPOSE: To provide initial validation for a simplified anterior-posterior index (API) from NR in distinguishing FTD and AD in a clinical cohort. MATERIAL AND METHODS: A retrospective chart review was completed. We derived a simplified API: API = (logVA/VP-µ)/σ where VA is weighted volume of frontal and temporal lobes and VP of parietal and occipital lobes. µ and σ are the mean and standard deviation of logVA/VP computed for AD participants. Receiver operating characteristic (ROC) curves and regression analyses assessed the efficacy of the API versus brain areas in predicting diagnosis of AD versus FTD. RESULTS: A total of 39 participants with FTD and 78 participants with AD were included. The API had an excellent performance in distinguishing AD from FTD with an area under the ROC curve of 0.82 and a positive association with diagnostic classification on logistic regression analysis (B = 1.491, P < 0.001). CONCLUSION: The API successfully distinguished AD and FTD with excellent performance. The results provide preliminary validation of the API in a clinical setting.