Subtypes Of Frontotemporal Dementia Research Articles

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 behavioral variant FTD (bvFTD) and 35 semantic variant progressive primary aphasia (svPPA)] and 58 healthy controls (HCs) 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 HCs from 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 HCs. 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 HCs in Dataset 1; 50 bvFTD, 32 svPPA, 30 nfvPPA and 110 HCs in Dataset 2) and symptom-specific networks [combined dataset 1 and 2, apathy without depression Vs non-apathy without depression (80:26), disinhibition Vs 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.

Differential diagnosis of frontotemporal dementia subtypes with explainable deep learning on structural MRI.

Frontotemporal dementia (FTD) represents a collection of neurobehavioral and neurocognitive syndromes that are associated with a significant degree of clinical, pathological, and genetic heterogeneity. Such heterogeneity hinders the identification of effective biomarkers, preventing effective targeted recruitment of participants in clinical trials for developing potential interventions and treatments. In the present study, we aim to automatically differentiate patients with three clinical phenotypes of FTD, behavioral-variant FTD (bvFTD), semantic variant PPA (svPPA), and nonfluent variant PPA (nfvPPA), based on their structural MRI by training a deep neural network (DNN). Data from 277 FTD patients (173 bvFTD, 63 nfvPPA, and 41 svPPA) recruited from two multi-site neuroimaging datasets: the Frontotemporal Lobar Degeneration Neuroimaging Initiative and the ARTFL-LEFFTDS Longitudinal Frontotemporal Lobar Degeneration databases. Raw T1-weighted MRI data were preprocessed and parcellated into patch-based ROIs, with cortical thickness and volume features extracted and harmonized to control the confounding effects of sex, age, total intracranial volume, cohort, and scanner difference. A multi-type parallel feature embedding framework was trained to classify three FTD subtypes with a weighted cross-entropy loss function used to account for unbalanced sample sizes. Feature visualization was achieved through post-hoc analysis using an integrated gradient approach. The proposed differential diagnosis framework achieved a mean balanced accuracy of 0.80 for bvFTD, 0.82 for nfvPPA, 0.89 for svPPA, and an overall balanced accuracy of 0.84. Feature importance maps showed more localized differential patterns among different FTD subtypes compared to groupwise statistical mapping. In this study, we demonstrated the efficiency and effectiveness of using explainable deep-learning-based parallel feature embedding and visualization framework on MRI-derived multi-type structural patterns to differentiate three clinically defined subphenotypes of FTD: bvFTD, nfvPPA, and svPPA, which could help with the identification of at-risk populations for early and precise diagnosis for intervention planning.

Strategies for translating proteomics discoveries into drug discovery for dementia.

Tauopathies, diseases characterized by neuropathological aggregates of tau including Alzheimer's disease and subtypes of frontotemporal dementia, make up the vast majority of dementia cases. Although there have been recent developments in tauopathy biomarkers and disease-modifying treatments, ongoing progress is required to ensure these are effective, economical, and accessible for the globally ageing population. As such, continued identification of new potential drug targets and biomarkers is critical. "Big data" studies, such as proteomics, can generate information on thousands of possible new targets for dementia diagnostics and therapeutics, but currently remain underutilized due to the lack of a clear process by which targets are selected for future drug development. In this review, we discuss current tauopathy biomarkers and therapeutics, and highlight areas in need of improvement, particularly when addressing the needs of frail, comorbid and cognitively impaired populations. We highlight biomarkers which have been developed from proteomic data, and outline possible future directions in this field. We propose new criteria by which potential targets in proteomics studies can be objectively ranked as favorable for drug development, and demonstrate its application to our group's recent tau interactome dataset as an example.

Development of a Speech-based Composite Score for Remotely Quantifying Language Changes in Frontotemporal Dementia.

Changes to speech and language are common symptoms across different subtypes of frontotemporal dementia (FTD). These changes affect the ability to communicate, impacting everyday functions. Accurately assessing these changes may help clinicians to track disease progression and detect response to treatment. To determine which aspects of speech show significant change over time and to develop a novel composite score for tracking speech and language decline in individuals with FTD. We recruited individuals with FTD to complete remote digital speech assessments based on a picture description task. Speech samples were analyzed to derive acoustic and linguistic measures of speech and language, which were tested for longitudinal change over the course of the study and were used to compute a novel composite score. Thirty-six (16 F, 20 M; M age = 61.3 years) individuals were enrolled in the study, with 27 completing a follow-up assessment 12 months later. We identified eight variables reflecting different aspects of language that showed longitudinal decline in the FTD clinical syndrome subtypes and developed a novel composite score based on these variables. The resulting composite score demonstrated a significant effect of change over time, high test-retest reliability, and a correlation with standard scores on various other speech tasks. Remote digital speech assessments have the potential to characterize speech and language abilities in individuals with FTD, reducing the burden of clinical assessments while providing a novel measure of speech and language abilities that is sensitive to disease and relevant to everyday function.

A multi-omics dataset for the analysis of frontotemporal dementia genetic subtypes

Understanding the molecular mechanisms underlying frontotemporal dementia (FTD) is essential for the development of successful therapies. Systematic studies on human post-mortem brain tissue of patients with genetic subtypes of FTD are currently lacking. The Risk and Modyfing Factors of Frontotemporal Dementia (RiMod-FTD) consortium therefore has generated a multi-omics dataset for genetic subtypes of FTD to identify common and distinct molecular mechanisms disturbed in disease. Here, we present multi-omics datasets generated from the frontal lobe of post-mortem human brain tissue from patients with mutations in MAPT, GRN and C9orf72 and healthy controls. This data resource consists of four datasets generated with different technologies to capture the transcriptome by RNA-seq, small RNA-seq, CAGE-seq, and methylation profiling. We show concrete examples on how to use the resulting data and confirm current knowledge about FTD and identify new processes for further investigation. This extensive multi-omics dataset holds great value to reveal new research avenues for this devastating disease.

A - 44 Social Cognition and its Neuroanatomic Correlates in Frontotemporal Dementia.

Frontotemporal dementia (FTD) often presents with impaired social cognition in both the behavioral and language variants. Establishing reliable measures and neural correlates of social cognition may aid in staging and monitoring FTD subtypes. Here, we examined group differences in social cognitive measures between FTD subtypes and cortical thickness correlates of social cognition across groups. Participants with behavioral variant FTD (n = 53; bvFTD), semantic variant primary progressive aphasia (n = 32; svPPA) and non-fluent variant PPA (n = 32; nfPPA) were enrolled in the Frontotemporal Lobar Degeneration Neuroimaging Initiative (NIFD). In first-visit data, we examined group differences in social cognition measures [Interpersonal Reactivity Index (IRI), Revised Social-Monitoring Scale (RSMS), and Behavioral Inhibition/Activation (BIS/BAS) Scales]. We used multivariate regression adjusted for age, total intracranial volume, and CDR global score to explore associations between social cognition and cortical thickness in pre-specified regions. Reduced perspective-taking and sensitivity to socio-emotional expressiveness was observed in early-stage bvFTD and svPPA groups compared to the nfPPA group. Across FTD cohorts, increased perspective-taking was associated with reduced cortical thickness of regions within the salience and default mode networks. Increased empathic concern was associated with increased left inferior parietal cortical thickness. Increased behavioral inhibition was associated with reduced right posterior cingulate cortical thickness. Increased behavioral activation was associated with reduced right pars triangularis cortical thickness. Social cognition is affected in early-stage bvFTD and svPPA to a greater extent than nfPPA. Neural correlates of social cognition are varied and warrant additional study as our findings contrast with previous literature that has typically linked lower perspective-taking with atrophy.

A Systematic Review of the Genetics and Pathology of Psychosis in Frontotemporal Dementia.

Frontotemporal dementia (FTD) patients frequently present with psychosis, which complicates diagnosis and management. In this study, we aim to examine the relationship between psychosis and the most common genetic mutations predisposing to FTD, and in the different pathological subtypes of FTD. We conducted a systematic review, searching the literature up to December 2022, and reviewed 50 articles that met our inclusion criteria. From the reviewed articles, we extracted and summarized data regarding the frequency of psychosis and patient characteristics in each major genetic and pathological subtype of FTD. Among FTD patients with confirmed genetic mutations or pathological diagnosss, the frequency of psychosis was 24.2%. Among the genetic mutation carriers, C9orf72 mutation carriers had the highest frequency of psychosis (31.4%), whereas GRN (15.0%) and MAPT (9.2%) mutation carriers had lower frequencies of psychosis. MAPT mutation carriers notably developed psychosis at a younger age compared to other genetic groups. The most common psychotic symptoms were delusions among C9orf72 carriers and visual hallucinations among GRN mutation carriers. Among the pathological subtypes, 30% of patients with FUS pathology, 25.3% of patients with TDP-43 pathology, and 16.4% of patients with tau pathology developed psychosis. In the TDP-43 group, subtype B pathology was the most common subtype reported in association with psychosis. Our systematic review suggests a high frequency of psychosis in specific subgroups of FTD patients. Further studies are required to understand the structural and biological underpinnings of psychosis in FTD.

A Scoping Review of Ethical and Legal Issues in Behavioural Variant Frontotemporal Dementia

Behavioural variant frontotemporal dementia (bvFTD) is a subtype of frontotemporal dementia characterized by changes in personality, social behaviour, and cognition. Although neural abnormalities cause bvFTD patients to struggle with inhibiting problematic behaviour, they are generally considered fully autonomous individuals. Subsequently, bvFTD patients demonstrate understanding of right and wrong but are unable to act in accordance with moral norms. To investigate the ethical, legal, and social issues associated with bvFTD, we conducted a scoping review of academic literature with inclusion & exclusion criteria and codes derived from our prior work. Among our final sample of fifty-six articles, four mentioned bvFTD patient-offenders as unfit to stand trial by insanity, and sixteen mentioned the use of dementia evidence in a court of law to better understand the autonomy of bvFTD patients. Additional emergent issues that were discovered include: training police officers to handle situations involving bvFTD patients and educating healthcare providers on how to help caregivers navigate bvFTD. The current literature highlights the inadequacy of traditional applications of medico-legal categories such as autonomy, capacity and competence, in informing cognitive capacity assessments in clinical and legal settings and deserves consideration by neuroethicists.

Changes in motor activity level in individuals with frontotemporal dementia.

Changes in motor activity are common in individuals with Frontotemporal dementia (FTD). Yet, it remains unclear why some individuals become motorically hyperactive, while others hypoactive even in early stages of the disease. This study aimed to examine the relationship between motor activity level and (1) FTD clinical subtype, and (2) cortical thickness and subcortical volumes. Eighty-two charts were retrospectively reviewed from patients meeting consensus criteria for one of the three main clinical subtypes of FTD: probable bvFTD, semantic variant Primary Progressive Aphasia (PPA), or non-fluent variant PPA. Participants were assigned to one of three groups: (1) hyperactive, (2) hypoactive, or (3) no record of change. Hyperactivity was prevalent among bvFTD (58.5%) and semantic PPA (68.8%) subtypes while hypoactivity was less common in both subtypes (29.3% and 18.8%, respectively). The majority of patients with non-fluent PPA showed no record of change in motor activity (66.7%). The analysis of cortical thickness and subcortical volumes did not identify significant associations with motor activity levels. In conclusion, increased motor activity is highly prevalent among individuals with FTD, especially bvFTD and svPPA subtypes. These findings may inform prognosis and prediction of changes in motor activity, and allow planning for appropriate environmental and behavioural interventions. Future studies with prospective, standardized longitudinal collection of information regarding the type and level of change in motor activity, including wearable measures of actigraphy, may help to further delineate the onset and progression of abnormal motor behaviours and determine neuroanatomic associations in FTD.

Communication-related experiences of individuals in the early phase of semantic dementia and their families: an interview study.

Semantic dementia (SD), a subtype of frontotemporal dementia, manifests as verbal symptoms, including social and behavioural deficits, associated with focal atrophy of the frontotemporal lobes. This study aimed to clarify the experiences of individuals with early-onset SD receiving speech and language rehabilitation (hereafter referred to as 'rehabilitation'), with the intent of making it routine, as well as the experiences of their families. Individual interviews were conducted with nine families with members who had adopted rehabilitation. Verbatim transcripts were used as data, and analyzed inductively according to the content analysis process. The family members realised the changes in the personality and behaviour of the individual with SD early, to the extent that they thought the individual with SD was different from before and were distressed by the loss of verbal communication. Nevertheless, the family members found a way to communicate by maintaining residual functions through rehabilitation and utilising their unique relationship with the individual with SD. It is important to carefully explain the characteristics of the disease and the long-term significance of rehabilitation to individuals with SD and their families in the early stages of the disease.

The cognitive consequences of the COVID-19 infection and behavioral variant frontotemporal dementia: Is there a link?

IntroductionFrontotemporal dementia behavioral variant (bvFTD) is the most common subtype of frontotemporal dementia, characterized by early and often severely disabling alterations in personality and social conduct that carry a huge impact on the patient, family, and society.ObjectivesThe aim of the study was to correlate the clinical data collected from our patient with relevant literature and discuss the diagnosis of bvFTD in the context of the COVID-19 pandemic.MethodsCase report and a systematic review of the literature.ResultsThe middle-aged female patient we examined presented an array of psychiatric symptoms, including cognitive, behavioral, and personality changes that emerged in two months after a mild form of SARS-CoV-2 infection. Objectively, a cranial CT scan displayed frontal and anterior temporal lobe atrophy. The rapid and severe decline of the patient’s mental faculties throughout the last year, along with the circumstances in which the pathology developed, raised a question about the etiological factors that contributed to this early-onset dementia.ConclusionsAlthough diagnostic criteria are useful, frontotemporal dementia may be difficult to differentiate from other conditions because there are no disease-specific biomarkers. Correlations between the COVID-19 infection and the fulminant bvFTD symptoms remain unclear and require further investigations.Disclosure of InterestNone Declared

The ScreeLing: Detecting Semantic, Phonological, and Syntactic Deficits in the Clinical Subtypes of Frontotemporal and Alzheimer's Dementia.

The ScreeLing is a screening instrument developed to assess post-stroke aphasia, via the linguistic levels Syntax, Phonology, and Semantics. It could also be a useful test for the clinical subtypes of frontotemporal dementia (FTD) and Alzheimer's dementia (AD), as specific and often selective disorders are expected. Its ability to differentiate between the clinical subtypes of FTD and AD is, however, still unknown. We investigated differences in ScreeLing total and subscores, linguistic-level disorders' relationship with disease severity, and classification abilities, in patients with behavioral variant FTD (bvFTD; n = 46), patients with primary progressive aphasia (PPA; n = 105) (semantic variant primary progressive aphasia [svPPA], non-fluent variant primary progressive aphasia [nfvPPA], and logopenic variant primary progressive aphasia [lvPPA], AD [n = 20] and controls [n = 35]). We examined group differences in ScreeLing total and subscores, and one-, two- or three-level linguistic disorders using one-way analyses of covariance (ANCOVAs) or Quade's rank ANCOVA. We used frequency analyses to obtain the occurrence of the linguistic-level disorders. We determined sensitivity and specificity by the area under the curve by receiver-operating characteristics analyses to investigate classification abilities. The total score was lower in patients (bvFTD: 63.8 ± 8.5, svPPA: 58.8 ± 11.3, nfvPPA: 63.5 ± 8.4, lvPPA: 61.7 ± 6.6, AD: 63.8 ± 5.5) than controls (71.3 ± 1.0) (p < .001). Syntax subscores were lower in svPPA (19.4 ± 4.6; p < .001) and lvPPA (20.3 ± 3.2; p = .002) than controls (23.8 ± 0.4). Phonology subscores were lower in lvPPA (19.8 ± 2.6) than bvFTD (21.7 ± 2.8) (p = .010). Semantics subscores were lowest in svPPA (17.8 ± 5.0; p < .002). A selective phonological disorder was most prevalent in lvPPA (34.9%). The higher the disease severity, the more linguistic-level disorders. The optimal cutoff for the total score was 70, and 23 for all three subscores. Good classification abilities were found for the Semantics (svPPA vs. bvFTD), Phonology (lvPPA vs. svPPA), and Syntax (nfvPPA vs. lvPPA) subscores. This easy to administer test gives information about language processing with the potential to improve differential diagnosis in memory clinics and in the future potentially also clinical trial planning.

Brain regions show different metabolic and protein arginine methylation phenotypes in frontotemporal dementias and Alzheimer's disease.

Frontotemporal dementia (FTD) is a heterogeneous neurodegenerative disease with multiple histopathological subtypes. FTD patients share similar symptoms with Alzheimer's disease (AD). Hence, FTD patients are commonly misdiagnosed as AD, despite the consensus clinical diagnostic criteria. It is therefore of great clinical need to identify a biomarker that can distinguish FTD from AD and control individuals, and potentially further differentiate between FTD pathological subtypes. We conducted a metabolomic analysis on post-mortem human brain tissue from three regions: cerebellum, frontal cortex and occipital cortex from control, FTLD-TDP type A, type A-C9, type C and AD. Our results indicate that the brain subdivisions responsible for different functions show different metabolic patterns. We further explored the region-specific metabolic characteristics of different FTD subtypes and AD patients. Different FTD subtypes and AD share similar metabolic phenotypes in the cerebellum, but AD exhibited distinct metabolic patterns in the frontal and occipital regions compared to FTD. The identified brain region-specific metabolite biomarkers could provide a tool for distinguishing different FTD subtypes and AD and provide the first insights into the metabolic changes of FTLD-TDP type A, type A-C9, type C and AD in different regions of the brain. The importance of protein arginine methylation in neurodegenerative disease has come to light, so we investigated whether the arginine methylation level contributes to disease pathogenesis. Our findings provide new insights into the relationship between arginine methylation and metabolic changes in FTD subtypes and AD that could be further explored, to study the molecular mechanism of pathogenesis.

Thalamic pathology in frontotemporal dementia: Predilection for specific nuclei, phenotype-specific signatures, clinical correlates, and practical relevance.

Frontotemporal dementia (FTD) phenotypes are classically associated with distinctive cortical atrophy patterns and regional hypometabolism. However, the spectrum of cognitive and behavioral manifestations in FTD arises from multisynaptic network dysfunction. The thalamus is a key hub of several corticobasal and corticocortical circuits. The main circuits relayed via the thalamic nuclei include the dorsolateral prefrontal circuit, the anterior cingulate circuit, and the orbitofrontal circuit. In this paper, we have reviewed evidence for thalamic pathology in FTD based on radiological and postmortem studies. Original research papers were systematically reviewed for preferential involvement of specific thalamic regions, for phenotype-associated thalamic disease burden patterns, characteristic longitudinal changes, and genotype-associated thalamic signatures. Moreover, evidence for presymptomatic thalamic pathology was also reviewed. Identified papers were systematically scrutinized for imaging methods, cohort sizes, clinical profiles, clinicoradiological associations, and main anatomical findings. The findings of individual research papers were amalgamated for consensus observations and their study designs further evaluated for stereotyped shortcomings. Based on the limitations of existing studies and conflicting reports in low-incidence FTD variants, we sought to outline future research directions and pressing research priorities. FTD is associated with focal thalamic degeneration. Phenotype-specific thalamic traits mirror established cortical vulnerability patterns. Thalamic nuclei mediating behavioral and language functions are preferentially involved. Given the compelling evidence for considerable thalamic disease burden early in the course of most FTD subtypes, we also reflect on the practical relevance, diagnostic role, prognostic significance, and monitoring potential of thalamic metrics in FTD. Cardinal manifestations of FTD phenotypes are likely to stem from thalamocortical circuitry dysfunction and are not exclusively driven by focal cortical changes.

Incongruences Between Facial Expression and Self-Reported Emotional Reactivity in Frontotemporal Dementia and Related Disorders.

Emotional reactivity normally involves a synchronized coordination of subjective experience and facial expression. These aspects of emotional reactivity can be uncoupled by neurological illness and produce adverse consequences for patient and caregiver quality of life because of misunderstandings regarding the patient's presumed internal state. Frontotemporal dementia (FTD) is often associated with altered social and emotional functioning. FTD is a heterogeneous disease, and socioemotional changes in patients could result from altered internal experience, altered facial expressive ability, altered language skills, or other factors. The authors investigated how individuals with FTD subtypes differ from a healthy control group regarding the extent to which their facial expressivity aligns with their self-reported emotional experience. Using a compound measure of emotional reactivity to assess reactions to three emotionally provocative videos, the authors explored potential explanations for differences in alignment of facial expressivity with emotional experience, including parkinsonism, physiological reactivity, and nontarget verbal responses. Participants with the three main subtypes of FTD all tended to express less emotion on their faces than they did through self-report. Exploratory analyses suggest that reasons for this incongruence likely differ not only between but also within diagnostic subgroups.

Distinct cell type-specific protein signatures in GRN and MAPT genetic subtypes of frontotemporal dementia

Frontotemporal dementia is characterized by progressive atrophy of frontal and/or temporal cortices at an early age of onset. The disorder shows considerable clinical, pathological, and genetic heterogeneity. Here we investigated the proteomic signatures of frontal and temporal cortex from brains with frontotemporal dementia due to GRN and MAPT mutations to identify the key cell types and molecular pathways in their pathophysiology. We compared patients with mutations in the GRN gene (n = 9) or with mutations in the MAPT gene (n = 13) with non-demented controls (n = 11). Using quantitative proteomic analysis on laser-dissected tissues we identified brain region-specific protein signatures for both genetic subtypes. Using published single cell RNA expression data resources we deduced the involvement of major brain cell types in driving these different protein signatures. Subsequent gene ontology analysis identified distinct genetic subtype- and cell type-specific biological processes. For the GRN subtype, we observed a distinct role for immune processes related to endothelial cells and for mitochondrial dysregulation in neurons. For the MAPT subtype, we observed distinct involvement of dysregulated RNA processing, oligodendrocyte dysfunction, and axonal impairments. Comparison with an in-house protein signature of Alzheimer’s disease brains indicated that the observed alterations in RNA processing and oligodendrocyte function are distinct for the frontotemporal dementia MAPT subtype. Taken together, our results indicate the involvement of different brain cell types and biological mechanisms in genetic subtypes of frontotemporal dementia. Furthermore, we demonstrate that comparison of proteomic profiles of different disease entities can separate general neurodegenerative processes from disease-specific pathways, which may aid the development of disease subtype-specific treatment strategies.

The Role of Graph Theory in Evaluating Brain Network Alterations in Frontotemporal Dementia.

Frontotemporal dementia (FTD) is a spectrum of clinical syndromes that affects personality, behavior, language, and cognition. The current diagnostic criteria recognize three main clinical subtypes: the behavioral variant of FTD (bvFTD), the semantic variant of primary progressive aphasia (svPPA), and the non-fluent/agrammatic variant of PPA (nfvPPA). Patients with FTD display heterogeneous clinical and neuropsychological features that highly overlap with those presented by psychiatric syndromes and other types of dementia. Moreover, up to now there are no reliable disease biomarkers, which makes the diagnosis of FTD particularly challenging. To overcome this issue, different studies have adopted metrics derived from magnetic resonance imaging (MRI) to characterize structural and functional brain abnormalities. Within this field, a growing body of scientific literature has shown that graph theory analysis applied to MRI data displays unique potentialities in unveiling brain network abnormalities of FTD subtypes. Here, we provide a critical overview of studies that adopted graph theory to examine the topological changes of large-scale brain networks in FTD. Moreover, we also discuss the possible role of information arising from brain network organization in the diagnostic algorithm of FTD-spectrum disorders and in investigating the neural correlates of clinical symptoms and cognitive deficits experienced by patients.

Radiomics Model for Frontotemporal Dementia Diagnosis Using T1-Weighted MRI.

Radiomics has been proposed as a useful approach to extrapolate novel morphological and textural information from brain Magnetic resonance images (MRI). Radiomics analysis has shown unique potential in the diagnostic work-up and in the follow-up of patients suffering from neurodegenerative diseases. However, the potentiality of this technique in distinguishing frontotemporal dementia (FTD) subtypes has so far not been investigated. In this study, we explored the usefulness of radiomic features in differentiating FTD subtypes, namely, the behavioral variant of FTD (bvFTD), the non-fluent and/or agrammatic (PNFA) and semantic (svPPA) variants of a primary progressive aphasia (PPA). Classification analyses were performed on 3 Tesla T1-weighted images obtained from the Frontotemporal Lobar Degeneration Neuroimaging Initiative. We included 49 patients with bvFTD, 25 patients with PNFA, 34 patients with svPPA, and 60 healthy controls. Texture analyses were conducted to define the first-order statistic and textural features in cortical and subcortical brain regions. Recursive feature elimination was used to select the radiomics signature for each pairwise comparison followed by a classification framework based on a support vector machine. Finally, 10-fold cross-validation was used to assess classification performances. The radiomics-based approach successfully identified the brain regions typically involved in each FTD subtype, achieving a mean accuracy of more than 80% in distinguishing between patient groups. Note mentioning is that radiomics features extracted in the left temporal regions allowed achieving an accuracy of 91 and 94% in distinguishing patients with svPPA from those with PNFA and bvFTD, respectively. Radiomics features show excellent classification performances in distinguishing FTD subtypes, supporting the clinical usefulness of this approach in the diagnostic work-up of FTD.

Neuropathology of Dementia Disorders.

This article provides an overview of the neuropathology of common age-related dementing disorders, focusing on the pathologies that underlie Alzheimer disease (AD) and related dementias, including Lewy body dementias, frontotemporal dementia, vascular dementia, limbic-predominant age-related transactive response DNA-binding protein 43 (TDP-43) encephalopathy (LATE), and mixed-etiology dementias. This article also discusses the underlying proteinopathies of neurodegenerative diseases (eg, amyloid-β, paired helical filament tau, α-synuclein, and TDP-43 pathology) and vascular pathologies, including tissue injury (eg, infarcts, hemorrhages) with or without vessel disease. New criteria for AD pathologic diagnosis highlight amyloid-β as the sine qua non of AD; they require molecular markers of amyloid and establish a minimum threshold of Braak neurofibrillary tangle stage 3. Pathologic diagnosis is separated from clinical disease (ie, pathologic diagnosis no longer requires dementia). TDP-43 pathology, a major pathology in a frontotemporal dementia subtype, was found as a central pathology in LATE, a newly named amnestic disorder. Multiple pathologies (often co-occurring with AD) contribute to dementia and add complexity to the clinical picture. Conversely, Lewy body, LATE, and vascular dementias often have accompanying AD pathology. Pathology and biomarker studies highlight subclinical pathologies in older people without cognitive impairment. This resilience to brain pathology is common and is known as cognitive reserve. The pathologies of dementia in aging are most commonly amyloid, tangles, Lewy bodies, TDP-43, hippocampal sclerosis, and vascular pathologies. These pathologies often co-occur (mixed pathologies), which may make specific clinical diagnoses difficult. In addition, dementia-related pathologies are often subclinical, suggesting varying levels of resilience in older people.

Differential linguistic features of verbal fluency in behavioral variant frontotemporal dementia and primary progressive aphasia

Frontotemporal dementia (FTD) is an early-onset neurodegenerative disorder with a heterogeneous clinical presentation. Verbal fluency is regularly used as a sensitive measure of language ability, semantic memory, and executive functioning, but qualitative changes in verbal fluency in FTD are currently overlooked. This retrospective study examined qualitative, linguistic features of verbal fluency in 137 patients with behavioral variant (bv)FTD (n = 50), or primary progressive aphasia (PPA) [25 non-fluent variant (nfvPPA), 27 semantic variant (svPPA), and 34 logopenic variant (lvPPA)] and 25 control participants. Between-group differences in clustering, switching, lexical frequency (LF), age of acquisition (AoA), neighborhood density (ND), and word length (WL) were examined in the category and letter fluency with analysis of variance adjusted for age, sex, and the total number of words. Associations with other cognitive functions were explored with linear regression analysis. The results showed that the verbal fluency performance of patients with svPPA could be distinguished from controls and other patient groups by fewer and smaller clusters, more switches, higher LF, and lower AoA (all p < 0.05). Patients with lvPPA specifically produced words with higher ND than the other patient groups (p < 0.05). Patients with bvFTD produced longer words than the PPA groups (p < 0.05). Clustering, switching, LF, AoA, and ND—but not WL—were differentially predicted by measures of language, memory, and executive functioning (range standardized regression coefficient 0.25–0.41). In addition to the total number of words, qualitative linguistic features differ between subtypes of FTD. These features provide additional information on lexical processing and semantic memory that may aid the differential diagnosis of FTD.