Bringing the Spotlight to Tau and TDP-43 in Frontotemporal Dementia: A Review of Promising Chemical Compounds.

There is a wide variety of neurodegenerative diseases, among which frontotemporal dementia stands out. These are the second most frequent cause of dementia in the world and demand the search for an effective treatment. This disease is linked to the abnormal behavior of proteins, which group together to form insoluble aggregates. It has been shown that the tau protein and TDP-43 are the main proteins involved in these pathologies. This article details 11 compounds already used in different neuropathologies, which may serve as potential drugs against these proteins. The mechanism of how most of these molecules inhibited the tau and TDP-43 aggregation process was highlighted. Importantly, Curcumin, Proanthocyanidin B2, Oleocanthal, Oleuropein Aglycone, Thionine, and Resveratrol had been reported as direct inhibitors of tau. While 4-aminoquinoline, Dimethoxycurcumin, and Auranofin directly inhibited TDP-43. Epigallocatechin- 3- gallate and Methylene Blue were described as tau and TDP-43 inhibitors. In this review, it is proposed that future research could elucidate the detailed inhibition mechanisms of these compounds to obtain relevant data to advance in treatments search for these coexisting proteins in frontotemporal dementia.

A case of developmental pedophilia unmasked by frontotemporal dementia.

A 65-year-old right-handed man gradually became socially indifferent and less active. Four years later, he was indicted for molesting children on multiple occasions. Psychomotor slowness and executive impairment contrasted with sparing of language, semantic memory, visuospatial perception, construction praxis, and right-left orientation. Neuroimaging showed asymmetric atrophy of dorsomedial frontal and anterior temporal lobes, and hypoperfusion of medial prefrontal cortex consistent with a diagnosis of behavioral variant of frontotemporal dementia. Further information revealed that the patient exhibited pedophilic behavior several years prior to symptom onset. We conclude that preexisting developmental pedophilia was "unmasked" by the underlying progressive frontotemporal degeneration.

Behavioral variant frontotemporal dementia in patients with previous severe mental illness: a systematic and critical review.

OBJECTIVES: To explore the relationship between severe/serious mental illness (SMI) and the behavioral variant of frontotemporal dementia (bvFTD), as the patterns of symptoms and cognitive performance that characterize both disorders share similarities. METHODS: We performed a systematic review investigating what has already been published regarding the relationship between bvFTD and SMI. Studies were selected from PubMed and LILACS databases, including those published up to February 12, 2018. The search strategy included the following terms: "frontotemporal dementia" plus "bipolar", OR "frontotemporal dementia" plus "schizophrenia", OR "frontotemporal dementia" plus "schizoaffective". Publications without abstracts, case reports with absent genetic or histopathological confirmation, reviews and non-English language papers were excluded across the search process. RESULTS: The search on PubMed retrieved 186 articles, of which 42 met eligibility criteria. On the LILACS database, none met the requirements. Generally, three major research aims were identified: 1) to look for frontotemporal lobar degeneration-associated genetic abnormalities in patients with prior SMI; 2) to compare the cognitive profile between patients affected by neurodegenerative disorders and schizophrenic patients; 3) to highlight the association between bvFTD and preceding psychiatric conditions and/or distinguish them both. The investigated mutations were found infrequently in the studied SMI samples. Cross-sectional studies comparing cognitive performance between bvFTD and psychiatric disorders mostly found no remarkable differences. There were only a few case reports identifying definite frontotemporal lobar degeneration in patients with previous psychiatric diagnoses. CONCLUSIONS: The available evidence demonstrates how fragile the current understanding is regarding the association between bvFTD and prior SMI.

Behavioral variant frontotemporal dementia in patients with previous severe mental illness: a systematic and critical review / Demência frontotemporal variante comportamental em pacientes com transtorno mental grave prévio: revisão sistemática e crítica

ABSTRACT Objectives: To explore the relationship between severe/serious mental illness (SMI) and the behavioral variant of frontotemporal dementia (bvFTD), as the patterns of symptoms and cognitive performance that characterize both disorders share similarities. Methods: We performed a systematic review investigating what has already been published regarding the relationship between bvFTD and SMI. Studies were selected from PubMed and LILACS databases, including those published up to February 12, 2018. The search strategy included the following terms: "frontotemporal dementia" plus "bipolar", OR "frontotemporal dementia" plus "schizophrenia", OR "frontotemporal dementia" plus "schizoaffective". Publications without abstracts, case reports with absent genetic or histopathological confirmation, reviews and non-English language papers were excluded across the search process. Results: The search on PubMed retrieved 186 articles, of which 42 met eligibility criteria. On the LILACS database, none met the requirements. Generally, three major research aims were identified: 1) to look for frontotemporal lobar degeneration-associated genetic abnormalities in patients with prior SMI; 2) to compare the cognitive profile between patients affected by neurodegenerative disorders and schizophrenic patients; 3) to highlight the association between bvFTD and preceding psychiatric conditions and/or distinguish them both. The investigated mutations were found infrequently in the studied SMI samples. Cross-sectional studies comparing cognitive performance between bvFTD and psychiatric disorders mostly found no remarkable differences. There were only a few case reports identifying definite frontotemporal lobar degeneration in patients with previous psychiatric diagnoses. Conclusions: The available evidence demonstrates how fragile the current understanding is regarding the association between bvFTD and prior SMI.

RESUMO Objetivos: Explorar a relação entre doença mental grave (DMG) e a variante comportamental da demência frontotemporal (DFTvc), uma vez que os padrões de sintomas e de desempenho cognitivo que caracterizam ambos os transtornos compartilham semelhanças. Métodos: Revisão sistemática investigando estudos publicados sobre a relação entre DFTvc e DMG. Os estudos foram selecionados nas bases de dados PubMed e LILACS, incluindo aqueles publicados até 12 de fevereiro de 2018. A estratégia de busca incluiu os seguintes termos: "demência frontotemporal" e "bipolar", OU "demência frontotemporal" e "esquizofrenia" OU "demência frontotemporal" e "esquizoafetivo". Publicações sem resumos, relatos de casos sem confirmação genética ou histopatológica, revisões e artigos escritos em idiomas que não fossem o inglês não foram selecionados na busca sistemática. Resultados: A pesquisa no PubMed encontrou 186 artigos, dos quais 42 alcançaram critérios de elegibilidade. Na base de dados LILACS, nenhum dos nove artigos identificados atendeu aos requisitos. Foram identificados três objetivos de pesquisa principais: buscar anormalidades genéticas associadas à degeneração lobar frontotemporal (DLFT) em pacientes com SMI prévia; comparar o perfil cognitivo entre pacientes acometidos por doenças neurodegenerativos e esquizofrênicos; destacar a associação entre DFTvc e condições psiquiátricas precedentes e/ou distinguir ambos. As mutações investigadas foram encontradas infrequentemente nas amostras estudadas. Os estudos transversais comparando o desempenho cognitivo entre DFTvc e os transtornos psiquiátricos não encontraram diferença, e houve apenas relatos de casos confirmando de DLFT em pacientes com diagnósticos psiquiátricos prévios. Conclusões: A evidência disponível demonstra quão frágil é o entendimento atual sobre a associação entre DFTvc e DMG.

Long-Term Severe Mental Disorders Preceding Behavioral Variant Frontotemporal Dementia: Frequency and Clinical Correlates in an Outpatient Sample.

BACKGROUND: The behavioral variant frontotemporal dementia (bvFTD) shares some clinical features with severe mental disorders, such as bipolar affective disorder (BAD), schizophrenia (SCZ), and schizoaffective disorder (SZA), and at least for a small subgroup of patients, these conditions may share similar pathological genetic mutations. OBJECTIVES: To investigate the frequency of a past medical history satisfying diagnostic criteria for BAD, SCZ, and SZA in a bvFTD outpatient sample, and to compare the clinical profile of patients with and without a positive history. METHODS: Cross-sectional study in which participants were consecutively selected after receiving a diagnosis of probable bvFTD and had a caregiver interviewed with SCID-I. The sample was categorized into two groups: with (bvFTD+) or without (bvFTD-) prior medical history satisfying diagnostic criteria for BAD/SCZ/SZA. Subjects went through cognitive, functional, and neuropsychiatric evaluations. RESULTS: Overall, 46 bvFTD patients were included; bvFTD+ patients accounted for 36.9% of the sample. The main nosology fulfilling criteria was BAD (76.5%). The groups differed in Neuropsychiatric Inventory scores (p = 0.01), use of antipsychotics (p = 0.01), family history of psychosis (p = 0.01), presence of primitive reflexes (p = 0.04), Frontal Assessment Battery performance (p = 0.01), Ekman's facial emotion recognition test (p = 0.03), frequency of apathy (p = 0.03), and stereotyped behavior (p = 0.01). All these parameters were more frequent/worse in the bvFTD+ group. CONCLUSIONS: A prior medical history compatible with BAD/SCZ/SZA was found in more than 1/3 of this sample of bvFTD patients and was associated with subtle distinctive clinical features.

Recalling feature bindings differentiates Alzheimer's disease from frontotemporal dementia.

It has been challenging to identify clinical cognitive markers that can differentiate patients with Alzheimer's disease (AD) from those with behavioral variant frontotemporal dementia (bvFTD). The short-term memory binding (STMB) test assesses the ability to integrate colors and shapes into unified representations and to hold them temporarily during online performance. The objective of this study is to investigate whether free recall deficits during short-term memory binding (STMB) test can differentiate patients with AD from those with bvFTD and controls. Participants were 32 cognitively intact adults, 35 individuals with AD and 18 with bvFTD. All patients were in the mild dementia stage. Receiver-operating characteristic (ROC) analyses were used to examine the diagnostic accuracy of the STMB. The results showed that AD patients performed significantly worse than controls and bvFTD patients in the STMB test, while the latter groups showed equivalent performance. The bound condition of the STMB test showed an AUC of 0.853, with 84.4% of sensitivity and 80% of specificity to discriminate AD from controls and an AUC of 0.794, with 72.2% of sensitivity and 80% of specificity to differentiate AD from bvFTD. Binding deficits seem specific to AD. The free recall version of the STMB test can be used for clinical purposes and may aid in the differential diagnosis of AD. Findings support the view that the STMB may be a suitable cognitive marker for AD.

[Pathological gambling and epilepsy in patients with frontotemporal dementia: Two case reports]. / Ludopatía y epilepsia en demencia frontotemporal: Reporte de dos casos.

Frontotemporal dementia is a neurodegenerative disorder of which the behavioral variant is most common. This condition is currently considered the most common cause of dementia in people younger than 60 years. Here, we present two unrelated cases in which the typical symptoms were cognitive and behavioral progressive deterioration and psychiatric disorders such as disinhibition, impulsive acts, apathy, lack of empathy, stereotypies, and changes in eating habits. The first case exhibited pathological gambling as the initial symptom and resided in a psychiatric facility for a year. Notably, this was the second such case in Latin America and one of only a few such cases reported worldwide. The second case presented with epileptic seizures during evolution. In both cases, brain magnetic resonance revealed left-predominant frontotemporal atrophy, and alterations in executive function were evident during neuropsychological assessments.

Your perspective and my benefit: multiple lesion models of self-other integration strategies during social bargaining.

Recursive social decision-making requires the use of flexible, context-sensitive long-term strategies for negotiation. To succeed in social bargaining, participants' own perspectives must be dynamically integrated with those of interactors to maximize self-benefits and adapt to the other's preferences, respectively. This is a prerequisite to develop a successful long-term self-other integration strategy. While such form of strategic interaction is critical to social decision-making, little is known about its neurocognitive correlates. To bridge this gap, we analysed social bargaining behaviour in relation to its structural neural correlates, ongoing brain dynamics (oscillations and related source space), and functional connectivity signatures in healthy subjects and patients offering contrastive lesion models of neurodegeneration and focal stroke: behavioural variant frontotemporal dementia, Alzheimer's disease, and frontal lesions. All groups showed preserved basic bargaining indexes. However, impaired self-other integration strategy was found in patients with behavioural variant frontotemporal dementia and frontal lesions, suggesting that social bargaining critically depends on the integrity of prefrontal regions. Also, associations between behavioural performance and data from voxel-based morphometry and voxel-based lesion-symptom mapping revealed a critical role of prefrontal regions in value integration and strategic decisions for self-other integration strategy. Furthermore, as shown by measures of brain dynamics and related sources during the task, the self-other integration strategy was predicted by brain anticipatory activity (alpha/beta oscillations with sources in frontotemporal regions) associated with expectations about others' decisions. This pattern was reduced in all clinical groups, with greater impairments in behavioural variant frontotemporal dementia and frontal lesions than Alzheimer's disease. Finally, connectivity analysis from functional magnetic resonance imaging evidenced a fronto-temporo-parietal network involved in successful self-other integration strategy, with selective compromise of long-distance connections in frontal disorders. In sum, this work provides unprecedented evidence of convergent behavioural and neurocognitive signatures of strategic social bargaining in different lesion models. Our findings offer new insights into the critical roles of prefrontal hubs and associated temporo-parietal networks for strategic social negotiation.

Ludopatía y epilepsia en demencia frontotemporal: Reporte de dos casos / Pathological gambling and epilepsy in patients with frontotemporal dementia: Two case reports

RESUMEN La demencia frontotemporal es un trastorno neurodegenerativo cuyo subtipo más común es la variante conductual. Es considerada la causa de demencia más frecuente en menores de 60 años. Se presentan dos casos no emparentados cuyos síntomas típicos fueron: deterioro progresivo de la cognición, del comportamiento, alteraciones psiquiátricas como desinhibición, actos impulsivos, apatía, falta de empatía, estereotipias y cambios en los hábitos de alimentación. La resonancia magnética cerebral, en ambos casos, mostró atrofia frontotemporal a predominio izquierdo; en la evaluación neuropsicológica se evidenció alteraciones de las funciones ejecutivas. El primer caso cursó con ludopatía como síntoma inicial, motivo por el cual permaneció por un año en un centro psiquiátrico, siendo el segundo en Latinoamérica y uno de los pocos casos reportados en el mundo. El segundo caso presentó crisis epilépticas en su evolución.

ABSTRACT Frontotemporal dementia is a neurodegenerative disorder of which the behavioral variant is most common. This condition is currently considered the most common cause of dementia in people younger than 60 years. Here, we present two unrelated cases in which the typical symptoms were cognitive and behavioral progressive deterioration and psychiatric disorders such as disinhibition, impulsive acts, apathy, lack of empathy, stereotypies, and changes in eating habits. The first case exhibited pathological gambling as the initial symptom and resided in a psychiatric facility for a year. Notably, this was the second such case in Latin America and one of only a few such cases reported worldwide. The second case presented with epileptic seizures during evolution. In both cases, brain magnetic resonance revealed left-predominant frontotemporal atrophy, and alterations in executive function were evident during neuropsychological assessments.

Brain Network Organization and Social Executive Performance in Frontotemporal Dementia.

OBJECTIVES: Behavioral variant frontotemporal dementia (bvFTD) is characterized by early atrophy in the frontotemporoinsular regions. These regions overlap with networks that are engaged in social cognition-executive functions, two hallmarks deficits of bvFTD. We examine (i) whether Network Centrality (a graph theory metric that measures how important a node is in a brain network) in the frontotemporoinsular network is disrupted in bvFTD, and (ii) the level of involvement of this network in social-executive performance. METHODS: Patients with probable bvFTD, healthy controls, and frontoinsular stroke patients underwent functional MRI resting-state recordings and completed social-executive behavioral measures. RESULTS: Relative to the controls and the stroke group, the bvFTD patients presented decreased Network Centrality. In addition, this measure was associated with social cognition and executive functions. To test the specificity of these results for the Network Centrality of the frontotemporoinsular network, we assessed the main areas from six resting-state networks. No group differences or behavioral associations were found in these networks. Finally, Network Centrality and behavior distinguished bvFTD patients from the other groups with a high classification rate. CONCLUSIONS: bvFTD selectively affects Network Centrality in the frontotemporoinsular network, which is associated with high-level social and executive profile.

[Mental simulation in frontotemporal dementia]. / Simulación mental en Demencia Frontotemporal.

There is a common network for perception and execution of actions necessary for the acquisition of Theory of Mind, and the mirror neuron system could be the neural substrate. OBJECTIVE: To study the presence of apraxia and their relationship to Theory of Mind in patients with behavioral variant of Frontotemporal Dementia. METHODS: 24 patients were assessed, and the cognitive praxis assessment battery and theory of mind were administered. RESULTS: All the tasks of the cognitive praxis assessment battery showed a significant correlation with the first order False Believe task, while Faces Test showed correlations with all the battery tasks except Auditory verbal income. Significant correlations were also found between Reading the Mind in the Eyes and Income of visual objects and Imitation of familiar gestures, and between Faux Pas and Use of tools, Gestural decision and Naming by function. DISCUSSION: These findings reinforce the hypothesis that the processes of Theory of Mind are based, according to mental simulation theory, in a matching execution/observation of actions system, whose neural substrate may correspond to the mirror neuron system.

Demencia frontotemporal y esclerosis lateral amiotrófica: presentación de un caso clínico / Frontotemporal dementia and amyotrophic lateral sclerosis: a case report

For a long time amyotrophic lateral sclerosis was seen as an exclusively motor disease, however, a lot of investigations have proved the existence of cognitive symptoms similar to frontotemporal dementia that could precede, coexist or appear after the motor symptoms. We report the case of a 69 years old hispanic man who consults about progressive swallowing impairments. In the speech languagepathologist assessment, we detected cognitive impairments that made necessary to complete the workout with specific test. The results of the assessment, shown disturbance in swallowing with suggestive symptomatology of motor neuron disease, besides cognitive impairments in executive functions, visuospatial abilities, memory, language and behaviors and conductual abnormalities. A few months after speech language pathologist assessment, the diagnosis of amyotrophic lateral sclerosis was given. This case emphasize in the importance of a exhaustive anamnesis and clinical assessment, as well as early diagnosis focused on opportune interventions. Additionally, it’s important to note the need for professionals with update knowledge in neuropsychology, to support interventions.

Durante mucho tiempo se pensó que la esclerosis lateral amiotrófica era una enfermedad exclusivamente motora, sin embargo, diversos estudios han mostrado la existencia de síntomas cognitivos que pueden manifestarse antes, durante o después de los síntomas motores y que serían compatibles con una demencia frontotemporal. Se presenta un caso de un hombre de 69 años que consulta por dificultades de deglución de carácter progresivo. En la evaluación fonoaudiológica se pesquisan dificultades cognitivas, por lo cual se decide aplicar diversas pruebas con el objetivo de aclarar estas alteraciones. Los resultados de la evaluación revelan alteraciones a nivel de deglución, con sintomatologia sugerente de enfermedad de motoneurona, además de alteraciones cognitivas a nivel de funciones ejecutivas, habilidades visuoespaciales, memoria, lenguaje y alteraciones en conducta y comportamiento. En el transcurso de unos meses, posterior a la evaluación fonoaudiológica, se realiza el diagnóstico de esclerosis lateral amiotrófica. Se enfatiza en la importancia de la anamnesis y evaluación clínica, el diagnóstico precoz enfocado en la intervención oportuna y la relevancia de contar con profesionales competentes y capaces, con conocimientos sobre neuropsicología que puedan ser de apoyo para la intervención.

[Spontaneous speech prosody and discourse analysis in schizophrenia and Fronto Temporal Dementia (FTD) patients]. / Valoración de prosodia espontánea afectiva y análisis de discurso en pacientes con esquizofrenia y demencia frontotemporal (DFT) variante lingüística.

UNLABELLED: Patients with schizophrenia and Frontotemporal Dementia (FTD) in their linguistic variants share some language characteristics such as the lexical access difficulties, disordered speech with disruptions, many pauses, interruptions and reformulations. For the schizophrenia patients it reflects a difficulty of affect expression, while for the FTD patients it reflects a linguistic issue. METHODS: This study, through an analysis of a series of cases assessed Clinic both in memory and on the Mental Health Unit of HUSI-PUJ (Hospital Universitario San Ignacio), with additional language assessment (analysis speech and acoustic analysis), present distinctive features of the DFT in its linguistic variants and schizophrenia that will guide the specialist in finding early markers of a differential diagnosis. RESULTS: In patients with FTD language variants, in 100% of cases there is a difficulty understanding linguistic structure of complex type; and important speech fluency problems. In patients with schizophrenia, there are significant alterations in the expression of the suprasegmental elements of speech, as well as disruptions in discourse. CONCLUSIONS: We present how depth language assessment allows to reassess some of the rules for the speech and prosody analysis of patients with dementia and schizophrenia; we suggest how elements of speech are useful in guiding the diagnosis and correlate functional compromise in everyday psychiatrist's practice.

Valoración de prosodia espontánea afectiva y análisis de discurso en pacientes con esquizofrenia y demencia frontotemporal (DFT) variante lingüística / Spontaneous speech prosody and discourse analysis in schizophrenia and Fronto Temporal Dementia (FTD) patients

La esquizofrenia y la demencia frontotemporal (DFT) variante lingüística comparten características de lenguaje tales como la dificultad para acceder al léxico, la desorganización del discurso con múltiples interrupciones, reformulaciones, pausas y retractaciones. En el caso de los pacientes esquizofrénicos, estas dificultades revelan fallas para expresar el afecto, mientras que en los pacientes con DFT variante lingüística refleja un problema lingüístico. Métodos: El presente estudio, a través de un análisis de una serie de casos valorados tanto en la Clínica de memoria como en la Unidad de Salud Mental del HUSI-PUJ (Hospital Universitario de San Ignacio), con evaluación lingüística adicional (análisis de discurso y análisis acústico), presenta características distintivas de la DFT en sus variantes lingüísticas y la esquizofrenia que permiten guiar al especialista en la búsqueda de marcadores tempranos de un diagnóstico diferencial. Resultados: En el 100%de los pacientes con DFT variante lingüística, hay dificultades para comprender estructuras lingüísticas de tipo complejo e importantes problemas de fluidez del discurso. En los pacientes con esquizofrenia se encuentran importantes alteraciones en la expresión de los elementos suprasegmentales del habla e interrupciones en el discurso. Conclusiones: Se presenta como una evaluación lingüística en profundidad permite revaluar algunas de las modalidades de valoración del discurso y la prosodia de los pacientes con demencia y esquizofrenia; indica que algunos elementos del discurso son útiles para orientar el diagnóstico y correlacionar el deterioro funcional en la cotidianidad de la práctica del psiquiatra.

Patients with schizophrenia and Frontotemporal Dementia (FTD) in their linguistic variants share some language characteristics such as the lexical access difficulties, disordered speech with disruptions, many pauses, interruptions and reformulations. For the schizophrenia patients it reflects a difficulty of affect expression, while for the FTD patients it reflects a linguistic issue. Methods: This study, through an analysis of a series of cases assessed Clinic both in memory and on the Mental Health Unit of HUSI-PUJ (Hospital Universitario San Ignacio), with additional language assessment (analysis speech and acoustic analysis), present distinctive features of the DFT in its linguistic variants and schizophrenia that will guide the specialist in finding early markers of a differential diagnosis. Results: In patients with FTD language variants, in 100% of cases there is a difficulty understanding linguistic structure of complex type; and important speech fluency problems. In patients with schizophrenia, there are significant alterations in the expression of the suprasegmental elements of speech, as well as disruptions in discourse. Conclusions: We present how depth language assessment allows to reassess some of the rules for the speech and prosody analysis of patients with dementia and schizophrenia; we suggest how elements of speech are useful in guiding the diagnosis and correlate functional compromise in everyday psychiatrist's practice.

Reversible behavioral phenotypes in a conditional mouse model of TDP-43 proteinopathies.

Transactive response DNA-binding protein 43 (TDP-43) mislocalization and aggregation are hallmark features of amyotrophic lateral sclerosis and frontotemporal dementia (FTD). We have previously shown in mice that inducible overexpression of a cytoplasmically localized form of TDP-43 (TDP-43-ΔNLS) in forebrain neurons evokes neuropathological changes that recapitulate several features of TDP-43 proteinopathies. Detailed behavioral phenotyping could provide further validation for its usage as a model for FTD. In the present study, we performed a battery of behavioral tests to evaluate motor, cognitive, and social phenotypes in this model. We found that transgene (Tg) induction by doxycycline removal at weaning led to motor abnormalities including hyperlocomotion in the open field test, impaired coordination and balance in the rotarod test, and increased spasticity as shown by a clasping phenotype. Cognitive assessment demonstrated impaired recognition and spatial memory, measured by novel object recognition and Y-maze tests. Remarkably, TDP-43-ΔNLS mice displayed deficits in social behavior, mimicking a key aspect of FTD. To determine whether these symptoms were reversible, we suppressed Tg expression for 14 d in 1.5-month-old mice showing an established behavioral phenotype but modest neurodegeneration and found that motor and cognitive deficits were ameliorated; however, social performance remained altered. When Tg expression was suppressed in 6.5-month-old mice showing overt neurodegeneration, motor deficits were irreversible. These results indicate that TDP-43-ΔNLS mice display several core behavioral features of FTD with motor neuron disease, possibly due to functional changes in surviving neurons, and might serve as a valuable tool to unveil the underlying mechanisms of this and other TDP-43 proteinopathies.

Contextual social cognition and the behavioral variant of frontotemporal dementia.

The significance of social situations is commonly context-embedded. Although the role of context has been extensively studied in basic sensory processing or simple stimulus-response settings, its relevance for social cognition is unknown. We propose the social context network model (SCNM), a fronto-insular-temporal network responsible for processing social contextual effects. The SCNM may 1) update the context and use it to make predictions, 2) coordinate internal and external milieus, and 3) consolidate context-target associative learning. We suggest the behavioral variant of frontotemporal dementia (bvFTD) as a specific disorder in which the reported deficits in social cognition (e.g., facial recognition, empathy, decision-making, figurative language, theory of mind) can be described as context impairments due to deficits in the SCNM. Disruption of orbitofrontal-amygdala circuit, as well as the frontal, temporal, and insular atrophy in bVFTD, suggests a relationship between context-sensitive social cognition and SCNM. In considering context as an intrinsic part of social cognition, we highlight the need for a situated cognition approach in social cognition research as opposed to an abstract, universal, and decontextualized approach. The assessment of context-dependent social cognition paradigms, the SCNM, and their possible application to neuropsychiatric disorders may provide new insight into bvFTD and other related frontal disorders.

Comparing the clinical usefulness of the Institute of Cognitive Neurology (INECO) Frontal Screening (IFS) and the Frontal Assessment Battery (FAB) in frontotemporal dementia.

We compared the utility of two executive-function brief screening tools, the Institute of Cognitive Neurology (INECO) Frontal Screening (IFS) and the Frontal Assessment Battery (FAB), in their ability to detect executive dysfunction in a group of behavioral variant frontotemporal dementia (bv-FTD, n = 25) and Alzheimer's disease (AD, n = 25) patients in the early stages of their disease and in comparison to a group of age-, gender-, and education-matched controls (n = 26). Relative to the FAB, the IFS showed (a) better capability to differentiate between types of dementia; (b) higher sensitivity and specificity for the detection of executive dysfunction; (c) stronger correlations with standard executive tasks. We conclude that while both tools are brief and specific for the detection of early executive dysfunction in dementia, the IFS is more sensitive and specific in differentiating bvFTD from AD, and its use in everyday clinical practice can contribute to the differential diagnosis between types of dementia.

Postural instability, frontotemporal dementia, and ophthalmoplegia: clinicopathological case.

A 56-year-old man presented with gait disturbance, personality change, and behavioral disturbances. He subsequently developed falls, postural instability, and axial rigidity. The cognitive problems progressed and he developed aphasia and later eye movement abnormalities. He died after 9 years of disease. Experts discuss the syndromal diagnosis and predict the underlying pathology. The pathological diagnosis is given and clinical learning points are considered.

A Brazilian family with hereditary inclusion body myopathy associated with Paget disease of bone and frontotemporal dementia

Inclusion body myopathy associated with Paget disease and frontotemporal dementia (IBMPFD) is a progressive and usually misdiagnosed autosomal dominant disorder. It is clinically characterized by a triad of features: proximal and distal myopathy, early onset Paget disease of bone (PDB), and frontotemporal dementia (FTD). It is caused by missense mutations in the valosin-containing protein (VCP) gene. We describe here the clinical and molecular findings of the first Brazilian family identified with IBMPFD. Progressive myopathy affecting the limb girdles was detected by clinical examination followed by muscle biopsy and creatine kinase measurement. PDB was suggested after anatomopathological bone examination and FTD was diagnosed by clinical, neuropsychological and language evaluations. Brain magnetic resonance revealed severe atrophy of the anterior temporal lobes, including the hippocampi. A R93C mutation in VCP was detected by direct sequencing screening in subject W (age 62) and in his mother. Four more individuals diagnosed with "dementia" were reported in this family. We also present a comprehensive genotype-phenotype correlation analysis of mutations in VCP in 182 patients from 29 families described in the literature and show that while IBM is a conspicuously penetrant symptom, PDB has a lower penetrance when associated with mutations in the AAAD1 domain and FTD has a lower penetrance when associated with mutations in the Junction (L1-D1) domain. Furthermore, the R93C mutation is likely to be associated with the penetrance of all the clinical symptoms of the triad.