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Background Alzheimer’s disease (AD) and behavioral variant frontotemporal dementia (bvFTD) cause distinct atrophy and functional disruptions within two major intrinsic brain networks, namely the default network and the salience network, respectively. It remains unclear if inter-network relationships and whole-brain network topology are also altered and underpin cognitive and social–emotional functional deficits. Methods In total, 111 participants (50 AD, 14 bvFTD, and 47 age- and gender-matched healthy controls) underwent resting-state functional magnetic resonance imaging (fMRI) and neuropsychological assessments. Functional connectivity was derived among 144 brain regions of interest. Graph theoretical analysis was applied to characterize network integration, segregation, and module distinctiveness (degree centrality, nodal efficiency, within-module degree, and participation coefficient) in AD, bvFTD, and healthy participants. Group differences in graph theoretical measures and empirically derived network community structures, as well as the associations between these indices and cognitive performance and neuropsychiatric symptoms, were subject to general linear models, with age, gender, education, motion, and scanner type controlled. Results Our results suggested that AD had lower integration in the default and control networks, while bvFTD exhibited disrupted integration in the salience network. Interestingly, AD and bvFTD had the highest and lowest degree of integration in the thalamus, respectively. Such divergence in topological aberration was recapitulated in network segregation and module distinctiveness loss, with AD showing poorer modular structure between the default and control networks, and bvFTD having more fragmented modules in the salience network and subcortical regions. Importantly, aberrations in network topology were related to worse attention deficits and greater severity in neuropsychiatric symptoms across syndromes. Conclusions Our findings underscore the reciprocal relationships between the default, control, and salience networks that may account for the cognitive decline and neuropsychiatric symptoms in dementia.

INTRODUCTION Imaging biomarkers are fundamental in diagnosing neurodegenerative diseases, but their use in FTD remains limited. This study examines PET biomarkers in Argentine bvFTD patients. METHODS We studied a cohort of bvFTD patients (n = 20) and controls (n = 21) with three different PET radiotracers (18F‐FDG, 11C‐PiB, and 18F‐AV1451). RESULTS In bvFTD patients, 18F‐FDG PET showed significant hypometabolism in frontotemporal regions, along with hypermetabolism in the precentral gyrus, compared to normal controls. 11C‐PIB did not reveal a pattern typical of Alzheimer's disease, yet increased uptake was notably observed in the precentral region. We found 18F‐AV1451 uptake in frontal lobe, parietal, precuneus, cuneus, posterior cingulum, highly significant in bvFTD with respect to NCs. DISCUSSION PET biomarkers are a crucial tool in diverse real‐world clinical scenarios. However, their utility in revealing questions about the underlying pathology in FTD is still limited. Highlights First bvFTD study using 18F‐FDG, 11C‐PIB, and 18F‐AV1451 PET in a Latin American cohort. Frontotemporal hypometabolism with compensatory precentral hypermetabolism due to amyloid. Amyloid deposits observed in the precentral gyrus without an Alzheimer's‐like pattern. 18F‐AV1451 shows limitations in specificity for bvFTD pathology. Study provides new insights into PET biomarker utility for bvFTD clinical assessment.

Introduction Early‐Onset Dementia (EOD), including Frontotemporal Dementia (FTD), behavioral variant FTD (bvFTD), and Early‐Onset Alzheimer’s Disease (EOAD), presents significant diagnostic and therapeutic challenges due to heterogeneous clinical features and rapid progression. EOD involves distinct patterns of brain network disruption, measurable through graph‐theoretical analysis. Methods We reviewed 23 studies applying graph theory to electroencephalography (EEG), functional MRI (fMRI), diffusion tensor imaging (DTI), and fluorodeoxyglucose positron emission tomography (FDG‐PET) in EOD populations. Metrics included global and local efficiency, small‐world properties, modularity, hub connectivity, and rich‐club organization. Results EOD demonstrates widespread topological disruption, including reduced global and local efficiency, hub vulnerability, and modular fragmentation. Subtype‐specific patterns include compensatory efficiency increases and parietal‐to‐frontal hub shifts in FTD; disruption of hub connectivity and modular integrity within the salience network in bvFTD; and pronounced deterioration of the default‐mode network in EOAD. Small‐world properties are generally preserved in early stages, reflecting initial compensatory reorganization that precedes system‐wide collapse. Conclusion Graph‐theoretical analysis reveals characteristic topological disruptions in EOD. However, most studies rely on static measures, limiting insight into dynamic network vulnerability. Incorporating network resilience based computational models, longitudinal designs, and standardized analytical pipelines could clarify network failure mechanisms, uncover latent fragilities, and guide targeted interventions. Graphical This review discusses findings from 23 neuroimaging studies using Electroencephalography (EEG), resting‐state Functional Magnetic Resonance Imaging (rs‐fMRI), Diffusion Tensor Imaging (DTI), and Positron Emission Tomography (PET) to examine brain network topology in Early‐Onset Dementia (EOD), including Frontotemporal Dementia (FTD), behavioral variant Frontotemporal Dementia (bvFTD), and Early‐Onset Alzheimer's Disease (EOAD). Findings indicate heterogeneous alterations in global efficiency, modularity, and hub organization, with small‐worldness often preserved. Current gaps involve the lack of network resilience modeling and limited understanding of cognitive reserve mechanisms. Future directions emphasize resilience‐based frameworks to capture dynamic network reconfiguration and individual variability in disease progression.

Patients with progressive apraxia of speech (PAOS) often develop atypical parkinsonian features suggestive of corticobasal syndrome (CBS) or progressive supranuclear palsy (PSP), and typically have an underlying 4-repeat tauopathy at autopsy. We describe three cases of PAOS with underlying Pick’s disease, a 3-repeat tauopathy, who lacked CBS or PSP features during life. We reviewed patients enrolled in the Neurodegenerative Research Group’s ongoing studies on speech and language disorders and identified those with PAOS who had autopsy-confirmed Pick’s disease. All patients had comprehensive neurologic, speech-language, and neuropsychological assessments, as well as multimodal neuroimaging, during life. Three female patients presented with phonetic PAOS without parkinsonism. Patient 1 had speech onset at age 54, later developed behavioral variant frontotemporal dementia (bvFTD), and died at 64. Patient 2 had speech onset at 47, early bvFTD features, prominent frontal and temporal involvement, and died at 53. Patient 3 had speech onset at 58, minimal behavioral changes, primarily frontal involvement on imaging, and died at 63. Our findings highlight that Pick's disease can present with PAOS and may be distinguished from 4R-tau PAOS by an absence of motoric CBS/PSP features and, in some cases, by prominent temporal hypometabolism with bvFTD development. These atypical features may prove useful in the antemortem identification of Pick's disease as a cause of PAOS. •Progressive apraxia of speech typically shares features with 4R tauopathies.•We report three autopsy-confirmed cases of PAOS with underlying 3R tau.•Early behavioral changes and lack of parkinsonism may be clinical clues to 3R tau.•Prominent temporal involvement on imaging may be a marker of 3R tau.

Fractal dimension (FD) is a quantitative parameter that can characterizes the complexity of human brain tissue. Extensive grey matter (GM) pathology has been previously identified in Frontotemporal dementia (FTD) and its variants. The aim of the present study was to investigate the GM morphometric abnormalities in the behavioral variant FTD (bvFTD) and primary progressive aphasia (PPA) using FD analysis. Twenty-seven bvFTD, 12 PPA and 20 controls were studied. SPM8 was used to segment the brain into GM tissue. Then the FD values were estimated for the GM skeleton, surface and general structure in patients and controls using our previously published algorithm. We found that patients with bvFTD had significant reduction in FD values of skeleton and general structure when compared to controls. In PPA, more significant decrease in FD was noted in the whole brain and left hemisphere skeleton along with left hemisphere general structure. Only the right hemisphere skeleton had a significant correlation with total score of Frontal Systems Behavior Scale (FrSBe). The results showed that the variants of FTD are associated with disease specific morphometric complexity patterns. These results indicate that FD can be used as a biomarker for the structural changes associated with neurodegenerative diseases.

Behavioural variant frontotemporal dementia (bvFTD) is a form of frontotemporal degeneration characterized by early changes in personality, emotional blunting, and/or loss of empathy. Recent research has highlighted that these features may be at least partially explained by impairments in the theory of mind (ToM; i.e., the ability to understand and predict other people’s behaviour by attributing independent mental states to them). The aim of this randomized, double-blind, placebo-controlled study was to test the hypothesis that transcranial direct current stimulation (tDCS) over the medial frontal cortex (MFC) selectively enhances communicative intention processing, a specific ToM ability. Using a single-session online design, we administered a ToM task that measures the ability to represent other people’s private and communicative intentions during active or sham tDCS to 16 bvFTD patients. To assess the impact of dementia on performance on the ToM task, we included 16 age-matched healthy volunteers who were asked to perform the entire experimental ToM task. BvFTD is characterized by an impairment in the comprehension of both communicative and private intentions relative to a healthy control group and by a disproportional impairment in communicative intention compared with private intention processing. Significant and selective accuracy improvement in the comprehension of communicative intentions after active stimulation was observed in patients with bvFTD. This is the first study that analyses ToM ability in patients with bvFTD using tDCS stimulation. Our findings could potentially contribute to the development of an effective, noninvasive brain stimulation treatment of ToM impairments in patients with bvFTD.

Introduction Sodium selenate increases tau dephosphorylation through protein phosphatase 2 activation. Here we report an open‐label Phase 1b study of sodium selenate as a disease‐modifying treatment for behavioral variant frontotemporal dementia (bvFTD). Methods Twelve participants with bvFTD received sodium selenate (15 mg, three times a day) for 52 weeks. Safety assessments were carried out throughout the trial. Primary outcomes were frequency of adverse events (AEs), serious adverse events (SAEs), and discontinuations. Secondary outcomes of potential efficacy included cognitive and behavioral assessments, magnetic resonance imaging (MRI) whole brain volume, and cerebrospinal fluid (CSF) and blood total tau (t‐tau), phosphorylated tau (p‐tau), and neurofilament light (NfL) levels, which were measured at baseline and at week 52. Results Sodium selenate was safe and well tolerated. All participants completed the study, and the majority (64.7%) of reported AEs were mild. One SAE occurred, which was not treatment related. Small declines in MRI and cognitive and behavioral measures were observed over the treatment period. There was no evidence for change in CSF protein levels (t‐tau, p‐tau, or NfL). Further analysis showed two distinct groups when measuring disease progression markers over the course of the study—one (n = 4) with substantial brain atrophy (2.5% to 6.5% reduction) and cognitive and behavioral decline over the 12‐month treatment period, and the second group (n = 7) with no detectable change in cognitive and behavioral measures and less brain atrophy (0.3% to 1.7% reduction). Conclusion Sodium selenate is safe and well tolerated in patients with bvFTD. Randomized‐controlled trials are warranted to investigate potential efficacy.

Background Neuropsychological testing is considered crucial for differential diagnosis of Alzheimer’s disease (AD) and behavioural variant frontotemporal dementia (bvFTD). In-depth neuropsychological assessment revealed specific dysfunctions in the two dementia syndromes. However, a significant overlap of cognitive impairments exists in early disease stages. We questioned whether a standard neuropsychological assessment at initial clinical presentation can delineate patients with AD versus bvFTD. Methods In a retrospective approach, we evaluated and compared how cognitive profiles assessed at initial clinical presentation predicted the diagnosis of later verified AD ( n  = 43) and bvFTD ( n  = 26). Additionally, the neuropsychological standard domains memory, language, visuospatial skills, executive functions, praxis and social cognition were subjected to stepwise discriminant analysis to compare their differential contribution to diagnosis. Results Regardless of diagnosis, a percentage of patients presented with major deterioration in a wide range of cognitive domains when compared with age-matched normative data. Only few significant differences were detected on the group level: Patients with AD were relatively more impaired in the verbal recall , verbal recognition , figure copy , and surprisingly in the executive subdomains, set shifting and processing speed whereas bvFTD was characterised by more deficits in imitation of face postures . A combination of tests for verbal recall , imitation of limb and face postures , and figure copy showed the greatest discriminatory power. Conclusions Our results imply that the contribution of a standard neuropsychological assessment is limited for differential diagnosis of AD and bvFTD at initial presentation. In contrast to current clinical guidelines, executive functions are neither particularly nor exclusively impaired in patients with bvFTD when assessed within a standard clinical neuropsychological test battery. The significant overlap of bvFTD and AD concerning the profile of cognitive impairments questions current neuropsychological diagnostic criteria and calls for revision, regarding both the degree and the profile of cognitive deficits.

Purpose To evaluate the diagnostic value of combined semiquantitative and quantitative assessment of brain atrophy in the diagnostic workup of the behavioural-variant of frontotemporal dementia (bvFTD). Methods Three neuroradiologists defined brain atrophy grading and identified atrophy pattern suggestive of bvFTD on 3D-T1 brain MRI of 112 subjects using a semiquantitative rating scale (Kipps’). A quantitative atrophy assessment was performed using two different automated software (Quantib® ND and Icometrix®). A combined semiquantitative and quantitative assessment of brain atrophy was made to evaluate the improvement in brain atrophy grading to identify probable bvFTD patients. Results Observers’ performances in the diagnosis of bvFTD were very good for Observer 1 ( k value = 0.881) and 2 ( k value = 0.867), substantial for Observer 3 ( k value = 0.741). Semiquantitative atrophy grading of all the observers showed a moderate and a poor correlation with the volume values calculated by Icometrix® and by Quantib® ND, respectively. For the definition of neuroradiological signs presumptive of bvFTD, the use of Icometrix® software improved the diagnostic accuracy for Observer 1 resulting in an AUC of 0.974, and for Observer 3 resulting in a AUC of 0.971 ( p -value < 0.001). The use of Quantib® ND software improved the diagnostic accuracy for Observer 1 resulting in an AUC of 0.974, and for Observer 3 resulting in a AUC of 0.977 ( p -value < 0.001). No improvement was observed for Observer 2. Conclusion Combining semiquantitative and quantitative brain imaging evaluation allows to reduce discrepancies in the neuroradiological diagnostic workup of bvFTD by different readers.

Alzheimer's disease (AD) and the behavioral variant of frontotemporal dementia (bvFTD) are the most common causes of dementia; however, their overlapping clinical syndromes and involved brain regions make a differential diagnosis difficult. We aimed to identify the differences in the cognition and motor cortex excitability between AD and bvFTD patients. Twenty-seven AD patients and 30 bvFTD patients were included in the study. Each participant received a neurological evaluation. Cognitive event-related potentials (P300) were recorded during an auditory oddball task. Next, the excitability of the motor cortex, including the resting, facilitated motor threshold (RMT and FMT) and cortical silent period (CSP), were assessed during transcranial magnetic stimulation (TMS). The bvFTD patients exhibited significantly longer P300 latencies compared with AD patients. There was a significant negative correlation between cognition and P300 latency in the bvFTD group. The AD patients showed significantly reduced RMT and FMT values compared to the bvFTD group; however, no significant correlation was found between AD severity and the excitability of the motor cortex. Cognition and motor cortical functions are different between AD and bvFTD patients. Noninvasive electrophysiological examinations have the potential to identify unique pathophysiological features that can be used to differentially diagnose AD and bvFTD patients.