Behavioral Frontotemporal Dementia Research Articles

Clinical heterogeneity within the ALS-FTD spectrum in a family with a homozygous optineurin mutation.

Mutations in the gene encoding for optineurin (OPTN) have been reported in the context of different neurodegenerative diseases including the amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) spectrum. Based on single case reports, neuropathological data in OPTN mutation carriers have revealed transactive response DNA-binding protein 43 kDa (TDP-43) pathology, in addition to accumulations of tau and alpha-synuclein. Herein, we present two siblings from a consanguineous family with a homozygous frameshift mutation in the OPTN gene and different clinical presentations. Both affected siblings underwent (i) clinical, (ii) neurophysiological, (iii) neuropsychological, (iv) radiological, and (v) laboratory examinations, and (vi) whole-exome sequencing (WES). Postmortem histopathological examination was conducted in the index patient, who deceased at the age of 41. The index patient developed rapidly progressing clinical features of upper and lower motor neuron dysfunction as well as apathy and cognitive deterioration at the age of 41. Autopsy revealed an ALS-FTLD pattern associated with prominent neuronal and oligodendroglial TDP-43 pathology, and an atypical limbic 4-repeat tau pathology reminiscent of argyrophilic grain disease. The brother of the index patient exhibited behavioral changes and mnestic deficits at the age of 38 and was diagnosed with behavioral FTD 5 years later, without any evidence of motor neuron dysfunction. WES revealed a homozygous frameshift mutation in the OPTN gene in both siblings (NM_001008212.2: c.1078_1079del; p.Lys360ValfsTer18). OPTN mutations can be associated with extensive TDP-43 pathology and limbic-predominant tauopathy and present with a heterogeneous clinical phenotype within the ALS-FTD spectrum within the same family.

Data-driven analysis of regional brain metabolism in behavioral frontotemporal dementia and late-onset primary psychiatric diseases with frontal lobe syndrome: A PET/MRI study

Late-onset primary psychiatric disease (PPD) and behavioral frontotemporal dementia (bvFTD) present with a similar frontal lobe syndrome. We compare brain glucose metabolism in bvFTD and late-onset PPD and investigate the metabolic correlates of cognitive and behavioral disturbances through FDG-PET/MRI. We studied 37 bvFTD and 20 late-onset PPD with a mean clinical follow-up of three years. At baseline evaluation, metabolism of the dorsolateral, ventrolateral, orbitofrontal regions and caudate could classify the patients with a diagnostic accuracy of 91% (95% CI: 0.81–0.98%). 45% of PPD showed low-grade hypometabolism in the anterior cingulate and/or parietal regions. Frontal lobe metabolism was normal in 32% of genetic bvFTD and bvFTD with motor neuron signs. Hypometabolism of the frontal and caudate regions could help in distinguishing bvFTD from PPD, except in cases with motor neuron signs and/or genetic bvFTD for which brain metabolism may be less informative.

Sporadic behavioral phenotype of Right Temporal Variant of Frontotemporal Dementia: a case report

AbstractBackgroundThere are two subtypes of the right Temporal Variant of Frontotemporal Dementia (rtv‐FTD). Semantic dementia (SMD) phenotype is defined by negative familiar history, word‐finding, anomia, comprehension difficulties, prosopagnosia, and topographagnosia. The behavioral frontotemporal dementia (bvFTD) phenotype is defined by personality changes, inappropriate behaviors, positive family history, and relatively poor performance on neurobehavioral testing with better performance on confrontational naming tests. (1) We present a rare interesting case.MethodWe describe the clinical and imaging features of a man who presented a sporadic behavioral phenotype of rtv‐FTD, showing negative genetic results.ResultA 62‐year‐old man with 8 years of progressive behavioral impairment. He showed personality changes, and compulsive‐like / ritualistic behaviors such as excessive unpurposed accumulation of items, washing hands repeatedly every five minutes, and walking and wandering repeatedly in circles. He also had hiperorality, cravings for sweet foods, social cognition impairment, associated with loss of empathy, and inappropriate social behavior (hypersexuality, verbal aggressivity to unrelated people, and talking bad words to neighbors with no reason). After years he followed with mild to moderate apathy. The neuropsychological evaluation showed impairment of executive functioning, episodic memory impairment, and MMSE 19/30. The neurological exam was unremarkable, and the familiar history was negative. Brain MRI revealed frontotemporal atrophy with a marked asymmetry in the right temporal lobe. The genetic testing was negative, illustrating and sporadic case.ConclusionTheoretically, rtv‐FTD is considered a right variant of semantic phenotype, and the general assumption is that is also a sporadic disorder. Although the behavioral phenotype of rtv‐FTD normally has a genetic basis, showing positive family history, It can be presented as a sporadic disorder with non‐familial variants of FTD, as in this case. (2)

FDG-PET-based neural correlates of Addenbrooke's cognitive examination III scores in Alzheimer's disease and frontotemporal degeneration.

The Addenbrooke's Cognitive Examination III (ACE-III) is a brief test useful for neuropsychological assessment. Several studies have validated the test for the diagnosis of Alzheimer's disease (AD) and frontotemporal dementia (FTD). In this study, we aimed to examine the metabolic correlates associated with the performance of ACE-III in AD and behavioral variant FTD. We enrolled 300 participants in a cross-sectional study, including 180 patients with AD, 60 with behavioral FTD (bvFTD), and 60 controls. An 18F-Fluorodeoxyglucose positron emission tomography study was performed in all cases. Correlation between the ACE-III and its domains (attention, memory, fluency, language, and visuospatial) with the brain metabolism was estimated. The ACE-III showed distinct neural correlates in bvFTD and AD, effectively capturing the most relevant regions involved in these disorders. Neural correlates differed for each domain, especially in the case of bvFTD. Lower ACE-III scores were associated with more advanced stages in both disorders. The ACE-III exhibited high discrimination between bvFTD vs. HC, and between AD vs. HC. Additionally, it was sensitive to detect hypometabolism in brain regions associated with bvFTD and AD. Our study contributes to the knowledge of the brain regions associated with ACE-III, thereby facilitating its interpretation, and highlighting its suitability for screening and monitoring. This study provides further validation of ACE-III in the context of AD and FTD.

Parkinson-ALS with a novel MAPT variant

The mutations on microtubule associated protein tau (MAPT) gene manifest clinically with behavioural frontotemporal dementia (FTD), parkinsonism, such as progressive supranuclear palsy and corticobasal degeneration, and rarely with amyotrophic lateral sclerosis (ALS). FTD-parkinsonism and FTD-ALS are clinical overlaps included in the spectrum of MAPT mutation’s phenotypes. The mutations on MAPT gene cause the dysfunction of tau protein determining its accumulation in neurofibrillary tangles. Recent data describe frequently the co-occurrence of the aggregation of tau protein and α-synuclein in patients with parkinsonism and Parkinson disease (PD), suggesting an interaction of the two proteins in determining neurodegenerative process. The sporadic description of PD-ALS clinical complex, known as Brait–Fahn–Schwarz disease, supports the hypothesis of common neuropathological pathways between different disorders. Here we report the case of a 54-year-old Italian woman with idiopathic PD later complicated by ALS carrying a novel MAPT variant (Pro494Leu). The variant is characterized by an amino acid substitution and is classified as damaging for MAPT functions. The case supports the hypothesis of tau dysfunction as the basis of multiple neurodegenerative disorders.

IgG4 Disease-Related Ataxia.

We describe a male patient presenting with cerebellar ataxia and behavioural frontotemporal dementia in whom imaging showed cerebellar atrophy. He had significantly low N-acetyl aspartate to creatine (NAA/Cr) area ratio on MR spectroscopy of the cerebellum, primarily affecting the vermis. CT body scan showed extensive abnormal tissue within the mesentery, the retroperitoneum and perinephric areas. PET-CT showed increased tracer uptake within the wall of the aorta suggestive of an aortitis and within the perinephric tissue bilaterally. Biopsy of the perinephric tissue confirmed IgG4 disease. Treatment with steroids and mycophenolate improved his clinical state, but he developed symptoms attributed to pericardiac effusion that necessitated treatment initially with drainage and subsequently with pericardial window. After a course of rituximab, he had an episode of sepsis that did not respond to appropriate treatment and died as a result. Both the imaging findings and neurological presentation with cerebellar ataxia and behavioural frontotemporal dementia are novel in the context of IgG4 disease.

Episodic Memory in Amnestic Behavioral Frontotemporal Dementia and Alzheimer's Disease.

Behavioral frontotemporal dementia (bvFTD) may present with episodic memory deficits. In 38 patients with bvFTD and 61 with Alzheimer's disease (AD) specific measures of verbal memory (learning curves and serial position effects) were studied through the Rey Auditory Verbal Learning test. Forty-two percent of bvFTD showed deficits of delayed recall memory similar to that found in AD including the serial position effects. Amnestic bvFTD had more severe atrophy in the left mesial temporal lobe than non-amnestic bvFTD. AD-like memory deficits are not infrequent in bvFTD and may be in part related to mesial temporal lobe atrophy.

The contribution of thalamic pathology to the clinical manifestations of frontotemporal dementia phenotypes (P5-12.004)

<h3>Objective:</h3> To systematically characterise thalamus pathology in frontotemporal dementia (FTD) phenotypes <h3>Background:</h3> FTD is classically associated with distinctive cortical atrophy patterns. However, the spectrum of cognitive and behavioural manifestations in FTD arise from multi-synaptic 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. <h3>Design/Methods:</h3> Thalamus pathology was quantitatively evaluated at a nuclear, vertex and morphometric level in a prospective, multimodal imaging study using a standardised neuroimaging protocol. 10 patients with behavioural FTD (bvFTD), 15 patients with non-fluent variant primary progressive aphasia (nfvPPA) and 5 patients with semantic variant PPA (svPPA) were evaluated with reference to 100 healthy controls. All patients underwent detailed clinical and neuropsychological profiling and whole-genome sequencing. <h3>Results:</h3> Volumetric analyses revealed widespread bilateral thalamic nuclear volume loss in bvFTD; selective bilateral with left-sided predominant thalamic degeneration was captured in nfvPPA; and more focal, left-lateralised thalamic volume loss identified in svPPA. Vertex analyses showed diffuse thalamic surface changes in bvFTD and nfvPPA, but not svPPA. Morphometric analyses demonstrated extensive symmetric intra-thalamic changes in nfvPPA, and mostly right-sided changes in both bvFTD and svPPA. <h3>Conclusions:</h3> FTD is associated with considerable focal thalamic degeneration. Phenotype-specific thalamic traits mirror established cortical vulnerability patterns. Thalamic nuclei associated with behaviour and language functions are preferentially involved. FTD is not solely associated with cortical atrophy. The manifestations of FTD are likely to stem from cortico-subcortical circuitry dysfunction and not exclusively driven by focal cortical changes. <b>Disclosure:</b> Dr. McKenna has nothing to disclose. Dr. Hutchinson has received personal compensation in the range of $0-$499 for serving on a Scientific Advisory or Data Safety Monitoring board for Novartis. Dr. Hutchinson has received personal compensation in the range of $0-$499 for serving on a Scientific Advisory or Data Safety Monitoring board for Teva. Dr. Hutchinson has received personal compensation in the range of $0-$499 for serving on a Speakers Bureau for Teva. Dr. Bede has nothing to disclose.

Moral emotions in neuropsychiatry : testing FTD and Schizophrenia patients with the MEA scale.

AbstractBackgroundMoral emotions have a key role in human prosocial behaviors. Impaired moral emotion processing can lead to disrupted decision‐making and behavioral adaptation.Better knowledge about moral emotion processing in neuropsychiatric diseases is necessary to facilitate diagnosis and patient care.The aim of this study was to investigate and to compare moral emotion processing in patients with neurodegenerative diseases ‐behavioral fronto temporal dementia (FTD) and Alzheimer’s disease (AD)‐ and patients with schizophrenia.MethodWe investigated 22 FTD, 15 AD, 30 schizophrenia patients and a control group with validated task, the Moral Emotions Assessment (MEA). This tool consisted in 42 scenarios exploring positive and negative moral emotions such as admiration, gratitude, shame or anger. Subjects had to choose between several emotions the most appropriate to the context of the scenario. To control for moral specificity, we contrasted the 42 moral scenarios with 18 extra‐moral scenarios eliciting the emotions without involving any inter‐human moral context.ResultFTD patients and Schizophrenia patients were significantly impaired in moral emotion processing, when compared to healthy controls, whereas AD patients were not impaired. There was a specific impairment of moral emotions in FTD, (73.1% of correct answers VS 95.1% in control group p&lt;0,001) and the most impaired emotion was guilt. AD patients didn’t show impairment in moral emotion processing compared to healthy controls. In Schizophrenia patients, moral emotion processing was significantly impaired (85,8% of correct answers VS 95,9% in control group, p&lt;0,001), and the most impaired emotions were anger and shame.ConclusionMoral emotions processing seemed significantly impaired in FTD patients and schizophrenia patients, with different patterns of deficits, whereas AD patients seemed to have preserved moral cognition. These results provide a better understanding of the behavioral changes observed in FTD and schizophrenia patients.

Editors' Note: Timing and Impact of Psychiatric, Cognitive, and Motor Abnormalities in Huntington Disease

Dr. McAllister and colleagues retrospectively analyzed the prevalence, timing, and functional impact of psychiatric, cognitive, and motor abnormalities in Huntington disease (HD) gene carriers in 6,316 individuals in the European HD Network (REGISTRY). They found that psychiatric and cognitive symptoms were common and functionally debilitating in HD gene carriers, with 42.4% of patients with HD reporting at least 1 psychiatric or cognitive symptom before motor symptoms, most commonly depression. However, the initial manifestation of HD was increasingly likely to be motor and less likely to be psychiatric as the age at presentation increased. The authors concluded that nonmotor symptoms should not be used to make a clinical diagnosis of HD because it was impossible to distinguish confidently between nonmotor symptoms arising from HD vs primary psychiatric disorders, particularly in younger premanifest patients. In response, Dr. Bird et al. argue that such a conclusion is too broad and negative, while agreeing that caution is needed and depression should not be used as a diagnostic factor. They argue that psychiatric, behavioral, and cognitive symptoms can be diagnostically meaningful in the setting of a positive genetic test, noting examples like the onset of auditory hallucinations, paranoid delusions, a sustained personality change, or decreased work performance with impaired cognition. They note that such symptoms are part of the diagnostic process for genetic forms of behavioral frontotemporal dementia, which is phenotypically similar to HD, and that earlier diagnosis can help connect patients and families to critical services. Responding to these comments, the authors note that clinical onset of HD is typically diagnosed using the emergence of specific extrapyramidal motor features. They agree that certain neuropsychiatric symptoms like apathy and increased aggression are more strongly suggestive of HD pathology. However, they caution that other commonly reported symptoms may reflect environmental sequelae or those related to the knowledge of their genetic status and should not be used on their own to make an HD diagnosis. This exchange highlights the clinical challenges of defining the onset of a complex neuropsychiatric disease like HD when one already knows the patient's genetic status. Nonetheless, the early diagnosis of HD in the appropriate clinical and genetic setting may allow for deployment of important patient resources. Dr. McAllister and colleagues retrospectively analyzed the prevalence, timing, and functional impact of psychiatric, cognitive, and motor abnormalities in Huntington disease (HD) gene carriers in 6,316 individuals in the European HD Network (REGISTRY). They found that psychiatric and cognitive symptoms were common and functionally debilitating in HD gene carriers, with 42.4% of patients with HD reporting at least 1 psychiatric or cognitive symptom before motor symptoms, most commonly depression. However, the initial manifestation of HD was increasingly likely to be motor and less likely to be psychiatric as the age at presentation increased. The authors concluded that nonmotor symptoms should not be used to make a clinical diagnosis of HD because it was impossible to distinguish confidently between nonmotor symptoms arising from HD vs primary psychiatric disorders, particularly in younger premanifest patients. In response, Dr. Bird et al. argue that such a conclusion is too broad and negative, while agreeing that caution is needed and depression should not be used as a diagnostic factor. They argue that psychiatric, behavioral, and cognitive symptoms can be diagnostically meaningful in the setting of a positive genetic test, noting examples like the onset of auditory hallucinations, paranoid delusions, a sustained personality change, or decreased work performance with impaired cognition. They note that such symptoms are part of the diagnostic process for genetic forms of behavioral frontotemporal dementia, which is phenotypically similar to HD, and that earlier diagnosis can help connect patients and families to critical services. Responding to these comments, the authors note that clinical onset of HD is typically diagnosed using the emergence of specific extrapyramidal motor features. They agree that certain neuropsychiatric symptoms like apathy and increased aggression are more strongly suggestive of HD pathology. However, they caution that other commonly reported symptoms may reflect environmental sequelae or those related to the knowledge of their genetic status and should not be used on their own to make an HD diagnosis. This exchange highlights the clinical challenges of defining the onset of a complex neuropsychiatric disease like HD when one already knows the patient's genetic status. Nonetheless, the early diagnosis of HD in the appropriate clinical and genetic setting may allow for deployment of important patient resources.

Evaluation of the effect of transcranial direct current stimulation on language impairments in the behavioural variant of frontotemporal dementia

The behavioural variant of frontotemporal dementia is a neurodegenerative disease characterized by bilateral atrophy of the prefrontal cortex, gradual deterioration of behavioural and executive capacities, a breakdown of language initiation and impaired search mechanisms in the lexicon. To date, only a few studies have analysed the modulation of language deficits in the behavioural variant of frontotemporal dementia patients with transcranial direct current stimulation, yet with inconsistent results. Our goal was to assess the impact on language performance of a single session of transcranial direct current stimulation on patients with the behavioural variant of frontotemporal dementia. Using a sham-controlled double-blind crossover design in a cohort of behavioural frontotemporal dementia patients (n = 12), we explored the impact on language performance of a single transcranial direct current stimulation session delivering anodal or cathodal transcranial direct current stimulation, over the left and right dorsolateral prefrontal cortex, compared with sham stimulation. A Letter fluency and a Picture naming task were performed prior and following transcranial direct current stimulation, to assess modulatory effects on language. Behavioural frontotemporal dementia patients were impaired in all evaluation tasks at baseline compared with healthy controls. Computational finite element method (FEM) models of cortical field distribution corroborated expected impacts of left-anodal and right-cathodal transcranial direct current stimulation over the dorsolateral prefrontal cortex and showed lower radial field strength in case of atrophy. However, none of the two tasks showed statistically significant evidence of language improvement caused by active transcranial direct current stimulation compared with sham. Our findings do not argue in favour of pre-therapeutic effects and suggest that stimulation strategies evaluating the modulatory role of transcranial direct current stimulation in the behavioural variant of frontotemporal dementia must carefully weigh the influence of symptom severity and cortical atrophy affecting prefrontal regions to ensure clinical success.

Multidimensional Clinical Assessment in Frontotemporal Dementia and Its Spectrum in Latin America and the Caribbean: A Narrative Review and a Glance at Future Challenges.

Frontotemporal dementia (FTD) is the third most common form of dementia across all age groups and is a leading cause of early-onset dementia. The Frontotemporal dementia (FTD) includes a spectrum of diseases that are classified according to their clinical presentation and patterns of neurodegeneration. There are two main types of FTD: behavioral FTD variant (bvFTD), characterized by a deterioration in social function, behavior, and personality; and primary progressive aphasias (PPA), characterized by a deficit in language skills. There are other types of FTD-related disorders that present motor impairment and/or parkinsonism, including FTD with motor neuron disease (FTD-MND), progressive supranuclear palsy (PSP), and corticobasal syndrome (CBS). The FTD and its associated disorders present great clinical heterogeneity. The diagnosis of FTD is based on the identification through clinical assessments of a specific clinical phenotype of impairments in different domains, complemented by an evaluation through instruments, i.e., tests and questionnaires, validated for the population under study, thus, achieving timely detection and treatment. While the prevalence of dementia in Latin America and the Caribbean (LAC) is increasing rapidly, there is still a lack of standardized instruments and consensus for FTD diagnosis. In this context, it is important to review the published tests and questionnaires adapted and/or validated in LAC for the assessment of cognition, behavior, functionality, and gait in FTD and its spectrum. Therefore, our paper has three main goals. First, to present a narrative review of the main tests and questionnaires published in LAC for the assessment of FTD and its spectrum in six dimensions: (i) Cognitive screening; (ii) Neuropsychological assessment divided by cognitive domain; (iii) Gait assessment; (iv) Behavioral and neuropsychiatric symptoms; (v) Functional assessment; and (vi) Global Rating Scale. Second, to propose a multidimensional clinical assessment of FTD in LAC identifying the main gaps. Lastly, it is proposed to create a LAC consortium that will discuss strategies to address the current challenges in the field.

Genetic Algorithms for Optimized Diagnosis of Alzheimer's Disease and Frontotemporal Dementia Using Fluorodeoxyglucose Positron Emission Tomography Imaging.

Genetic algorithms have a proven capability to explore a large space of solutions, and deal with very large numbers of input features. We hypothesized that the application of these algorithms to 18F-Fluorodeoxyglucose Positron Emission Tomography (FDG-PET) may help in diagnosis of Alzheimer’s disease (AD) and Frontotemporal Dementia (FTD) by selecting the most meaningful features and automating diagnosis. We aimed to develop algorithms for the three main issues in the diagnosis: discrimination between patients with AD or FTD and healthy controls (HC), differential diagnosis between behavioral FTD (bvFTD) and AD, and differential diagnosis between primary progressive aphasia (PPA) variants. Genetic algorithms, customized with K-Nearest Neighbor and BayesNet Naives as the fitness function, were developed and compared with Principal Component Analysis (PCA). K-fold cross validation within the same sample and external validation with ADNI-3 samples were performed. External validation was performed for the algorithms distinguishing AD and HC. Our study supports the use of FDG-PET imaging, which allowed a very high accuracy rate for the diagnosis of AD, FTD, and related disorders. Genetic algorithms identified the most meaningful features with the minimum set of features, which may be relevant for automated assessment of brain FDG-PET images. Overall, our study contributes to the development of an automated, and optimized diagnosis of neurodegenerative disorders using brain metabolism.

Diagnosis of Alzheimer’s disease and frontotemporal dementia using FDG‐PET: Application of genetic algorithms

AbstractBackgroundGenetic algorithms are methods used in machine learning, which have a proven capability to explore a large space of solutions, deal with very large numbers of input features, and avoid local minima. Diagnosis of Alzheimer’s Disease (AD) and Frontotemporal dementia (FTD) is often challenging, and thorough costly assessments are often needed. We hypothesised that the application of machine learning, and specifically genetic algorithms, to 18F‐Fluorodeoxyglucose Positron Emission Tomography (FDG‐PET) may help in diagnosis by selecting the most meaningful features and automating diagnosis. In this study, we aimed to develop algorithms for three common situations: discrimination between patients with AD or FTD and healthy controls (HC), differential diagnosis between behavioural FTD (bvFTD) and AD, and differential diagnosis between primary progressive aphasia (PPA) variants.MethodEighty‐one patients with bvFTD, 88 patients with AD, 68 patients with PPA, and 39 HC were enrolled. Patients underwent a comprehensive clinical and neuropsychological protocol, and FDG‐PET imaging. Genetic algorithms, customised with K‐Nearest Neighbor and BayesNet Naives as the fitness function, were developed applied to the PET imaging and compared with Principal Component Analysis. The highest accuracy rate and most relevant features were identified. K‐fold cross validation within the same sample and external validation with ADNI samples were performed.ResultDiscrimination accuracy of FDG‐PET was 92‐95% for AD vs HCs, 95‐96% for bvFTD vs HCs, 89‐90% for AD vs bvFTD, and 90‐91% for classification of PPA subtypes. A reduced number of features was achieved, with cutting rates from 62% to 95.69% regarding the total number of variables, and several key brain regions were selected. External validation with ADNI obtained an accuracy of 82.93% for BayesNet Naives algorithm for the differentiation between AD and HC.ConclusionGenetic algorithms identified the most meaningful features with the minimum set of features, which may be relevant for automated assessment of brain FDG‐PET images. Overall, our study contributes to the development of an automated, and optimised diagnosis of neurodegenerative disorders using brain metabolism.

Slowly progressive behavioral frontotemporal dementia syndrome in a family co-segregating the C9orf72 expansion and a Synaptophysin mutation.

Synaptophysin, already related to X-linked intellectual disability, is expressed mainly in the central nervous system. Studies in humans indicate that the downregulation of synaptophysin could be involved in the development of dementia. Our study presents the first familial case of behavioral variant frontotemporal dementia associated with the co-occurrence of the repeat expansion in C9orf72 and a pathogenic variant in the SYP gene. Exome sequencing and repeat-primed PCR for C9orf72 were performed for two siblings with clinical and imaging findings suggestive of slowly progressive behavioral frontotemporal dementia. We found that both siblings have the hexanucleotide expansion in C9orf72 and a null variant in the SYP gene. The most affected sibling presents the putative variant in a hemizygous state. With milder symptoms, his sister has the same pathogenic variant in heterozygosis, compatible with X-linked inheritance. Our results strengthened previous suggestive evidence that the phenotypes associated with C9orf72 repeat expansion are variable and probably influenced by additional genetic modifiers. We hypothesized that the pathogenic variant in the SYP gene might have modified the typical phenotype associated with the C9orf72 mutation.

Neurofilaments as Emerging Biomarkers of Neuroaxonal Damage to Differentiate Behavioral Frontotemporal Dementia from Primary Psychiatric Disorders: A Systematic Review.

The behavioral variant of frontotemporal dementia (bvFTD) is a clinical syndrome resulting from various causes of neuronal demises associated with frontotemporal lobar degeneration. Symptoms include behavioral and personality changes, social cognitive impairment, and executive function deficits. There is a significant clinical overlap between this syndrome and various primary psychiatric disorders (PPD). Structural and functional neuroimaging are considered helpful to support the diagnosis of bvFTD, but their sensitivity and specificity remain imperfect. There is growing evidence concerning the potential of neurofilaments as biomarkers reflecting axonal and neuronal lesions. Ultrasensitive analytic platforms have recently enabled neurofilament light chains’ (NfL) detection not only from cerebrospinal fluid but also from peripheral blood samples in FTD patients. In this short review, we present recent advances and perspectives for the use of NfL assessments as biomarkers of neuroaxonal damage to differentiate bvFTD from primary psychiatric disorders.

Catatonia as Presenting Manifestation of Behavioral Frontotemporal Dementia: Insight From a PET/MRI Study.

Catatonia as Presenting Manifestation of Behavioral Frontotemporal Dementia: Insight From a PET/MRI Study.

Exploring dementia and neuronal ceroid lipofuscinosis genes in 100 FTD-like patients from 6 towns and rural villages on the Adriatic Sea cost of Apulia

Frontotemporal dementia (FTD) refers to a complex spectrum of clinically and genetically heterogeneous disorders. Although fully penetrant mutations in several genes have been identified and can explain the pathogenic mechanisms underlying a great portion of the Mendelian forms of the disease, still a significant number of families and sporadic cases remains genetically unsolved. We performed whole exome sequencing in 100 patients with a late-onset and heterogeneous FTD-like clinical phenotype from Apulia and screened mendelian dementia and neuronal ceroid lipofuscinosis genes. We identified a nonsense mutation in SORL1 VPS domain (p.R744X), in 2 siblings displaying AD with severe language problems and primary progressive aphasia and a near splice-site mutation in CLCN6 (p.S116P) segregating with an heterogeneous phenotype, ranging from behavioural FTD to FTD with memory onset and to the logopenic variant of primary progressive aphasia in one family. Moreover 2 sporadic cases with behavioural FTD carried heterozygous mutations in the CSF1R Tyrosin kinase flanking regions (p.E573K and p.R549H). By contrast, only a minority of patients carried pathogenic C9orf72 repeat expansions (1%) and likely moderately pathogenic variants in GRN (p.C105Y, p.C389fs and p.C139R) (3%). In concert with recent studies, our findings support a common pathogenic mechanisms between FTD and neuronal ceroid lipofuscinosis and suggests that neuronal ceroid lipofuscinosis genes should be investigated also in dementia patients with predominant frontal symptoms and language impairments.

Atypical Presentations of Alzheimer’s Disease: Beyond Amnestic Dementia

Neuropathological and biomarker-based studies indicate that Alzheimer’s disease may sometimes present not with the typical amnestic dementia syndrome of the hippocampal type but with atypical clinical pictures. Atypical presentations include frontal dementia sometimes with additional behavioural component mimicking frontotemporal dementia, logopenic primary progressive aphasia and posterior cortical atrophy, while mixed presentations include patients with additional vascular or Lewy body pathology. More atypical presentations include non-logopenic (semantic, non-fluent agrammatic and unclassifiable) primary progressive aphasia, corticobasal syndrome and cases mixed with normal pressure hydrocephalus. Atypical clinical presentations of Alzheimer’s disease may be more common than previously thought. Cerebrospinal fluid levels of biomarkers such as amyloid beta peptide, hyperphosphorylated tau protein and total tau protein, may offer a useful tool for correct ante mortem identification of such patients, which is likely to affect therapeutic decisions.

A longitudinal study of automated analysis of acoustic speech markers in FTD and PPA

AbstractBackgroundSpeech is a complex activity requiring proper function and connectivity of multiple brain networks and as such is sensitive to focal neurodegeneration. We have previously reported on acoustic markers of dysprosody in speech samples of speakers with frontotemporal dementia (FTD) phenotypes. In the current study we explore the longitudinal changes in acoustic‐prosodic markers in FTD.MethodWe analyzed 102 speech samples of picture descriptions from 46 participants with FTD (Table 1): 8 with non‐fluent/agrammatic primary progressive aphasia (naPPA), 14 with semantic variant PPA (svPPA), 10 with logopenic aphasia (lvPPA) and 14 with behavioral FTD (bvFTD). We automatically segmented the acoustic signal into segments of continuous speech or silence, measured their durations, and derived other measures. We used linear mixed effects (lme) models to test changes over time for each acoustic measure, controlling for sex, education, and random intercepts. We also examined any interaction between phenotypes and disease duration.ResultbvFTD speakers increased their pause duration by 0.27 seconds per year and their pause rate by 3.9 pauses per minute (ppm) each year. Their speech segment duration shortened by 0.1 seconds per year (p=0.041), decreasing their total speech time by 6.6 seconds (p=0.003) per year. Thus, bvFTD patients reduced the proportion of speech in their samples by 5.16 percent per year (p=0.008). svPPA speakers increased their pause rate similarly, but in contrast, their pause duration decreased by 0.097 seconds per year and they increased their speech segment frequency by 8.32 per minute each year (p=0.054). naPPA and lvPPA speakers increased their pause rate over time and spent less total time (speech + pause) describing the picture (by 5.6 seconds per year; p=0.018). They did not differ from bvFTD and svPPA in these two acoustic measures.ConclusionIn our study all FTD speakers became more dysfluent and produced shorter descriptions with time, however, only bvFTD speakers actually exhibited reduced speech production. In contrast, svPPA speech had more frequent pauses and speech segments over time, rendering it “fragmented” and inefficient. These findings support the role of automated acoustic analysis in characterizing speech longitudinally in neurodegeneration.