Social cognition deficits and biometric signatures in the behavioural variant of Alzheimer's disease.

The behavioural variant of Alzheimer's disease (bvAD) is characterized by early predominant behavioural changes, mimicking the behavioural variant of frontotemporal dementia (bvFTD), which is characterized by social cognition deficits and altered biometric responses to socioemotional cues. These functions remain understudied in bvAD. We investigated multiple social cognition components (i.e. emotion recognition, empathy, social norms and moral reasoning), using the Ekman 60 faces test, Interpersonal Reactivity Index, empathy eliciting videos, Social Norms Questionnaire and moral dilemmas, while measuring eye movements and galvanic skin response. We compared 12 patients with bvAD with patients with bvFTD (n = 14), typical Alzheimer's disease (tAD, n = 13) and individuals with subjective cognitive decline (SCD, n = 13), using ANCOVAs and age- and sex-adjusted post hoc testing. Patients with bvAD (40.1 ± 8.6) showed lower scores on the Ekman 60 faces test compared to individuals with SCD (49.7 ± 5.0, P < 0.001), and patients with tAD (46.2 ± 5.3, P = 0.05) and higher scores compared to patients with bvFTD (32.4 ± 7.3, P = 0.002). Eye-tracking during the Ekman 60 faces test revealed no differences in dwell time on the eyes (all P > 0.05), but patients with bvAD (18.7 ± 9.5%) and bvFTD (19.4 ± 14.3%) spent significantly less dwell time on the mouth than individuals with SCD (30.7 ± 11.6%, P < 0.01) and patients with tAD (32.7 ± 12.1%, P < 0.01). Patients with bvAD (11.3 ± 4.6) exhibited lower scores on the Interpersonal Reactivity Index compared with individuals with SCD (15.6 ± 3.1, P = 0.05) and similar scores to patients with bvFTD (8.7 ± 5.6, P = 0.19) and tAD (13.0 ± 3.2, P = 0.43). The galvanic skin response to empathy eliciting videos did not differ between groups (all P > 0.05). Patients with bvAD (16.0 ± 1.6) and bvFTD (15.2 ± 2.2) showed lower scores on the Social Norms Questionnaire than patients with tAD (17.8 ± 2.1, P < 0.05) and individuals with SCD (18.3 ± 1.4, P < 0.05). No group differences were observed in scores on moral dilemmas (all P > 0.05), while only patients with bvFTD (0.9 ± 1.1) showed a lower galvanic skin response during personal dilemmas compared with SCD (3.4 ± 3.3 peaks per min, P = 0.01). Concluding, patients with bvAD showed a similar although milder social cognition profile and a similar eye-tracking signature to patients with bvFTD and greater social cognition impairments and divergent eye movement patterns compared with patients with tAD. Our results suggest reduced attention to salient facial features in these phenotypes, potentially contributing to their emotion recognition deficits.

Decreased emotion recognition and reduced focus on facial hallmarks in behavioral variant frontotemporal dementia compared to primary psychiatric disorders and controls.

BACKGROUND AND PURPOSE: Early diagnosis of behavioral variant frontotemporal dementia (bvFTD) is challenging due to symptomatic overlap with primary psychiatric disorders (PPD). As emotion recognition deficits are early and key features of bvFTD, the aim was to explore processes driving social cognition deficits that may aid in the differentiation between bvFTD and PPD. METHODS: The total sample (N = 51) included 18 patients with bvFTD, 11 patients with PPD (mood, autism spectrum and psychotic disorders) and 22 controls from the Alzheimer Center Amsterdam of the Amsterdam UMC. Emotion recognition was assessed with the Ekman 60 Faces test, during which eye tracking metrics were collected in the first 5 s a face was presented. Group differences in dwell time on the total image as well as the circumscribed eyes area and mouth area were analysed using ANOVA, with post hoc comparisons. RESULTS: Patients with bvFTD scored lowest, patients with PPD scored intermediate and controls scored highest on emotion recognition. During facial processing, patients with bvFTD spent less dwell time on the total image than controls (mean difference 11.3%, F(2, 48) = 6.095, p = 0.004; bvFTD-controls p = 0.001, 95% confidence interval [CI] -892.64, -239.70). Dwell time on the eyes area did not differ between diagnostic groups, whilst patients with bvFTD spent less dwell time on the mouth area than PPD patients (mean difference 10.7%; F(2, 48) = 3.423, p = 0.041; bvFTD-PPD p = 0.022, 95% CI -986.38, -79.47) and controls (mean difference 7.8%; bvFTD-controls p = 0.043, 95% CI -765.91, -12.76). CONCLUSIONS: In bvFTD, decreased emotion recognition may be related to reduced focus on facial hallmarks. These findings suggest a valuable role for biometrics in social cognition assessment and the differentiation between bvFTD and PPD.

Ultraversatile Fluorescent Sensors Based on Two CoII/NiII Coordination Polymers for Identifying Various Antibiotics via the Turn-On/Off Effect and Detecting pH.

Because the accurate and rapid detection of antibiotics and pH plays an important role in biological systems and environmental fields, developing suitable and efficient sensors that can simultaneously detect antibiotics and pH has become important. In this work, we successfully designed and synthesized two new one-dimensional coordination polymers based on the mixed ligands L [N,N'-bis(4-methylpyridin-4-yl)-2,6-naphthalene dicarboxylamide] and H2CPG [3-(4-chlorophenyl)glutaric acid], [M(L)(HCPG)2(H2O)2] (M = Co for CP 1, and M = Ni for CP 2), which were structurally characterized by single-crystal X-ray diffraction, infrared spectroscopy, powder X-ray diffraction, and thermogravimetric analysis. CP 1 and CP 2 can be used as ultraversatile fluorescent sensors, which can sense erythromycin (ERY) and oxacillin (OXC) by turn-on fluorescent enhancement and detect furaltadone (FTD) via the turn-off fluorescent quenching effect, separately. The concentration ranges of different analytes sensed by CPs 1 and 2 were 0-0.046 and 0-0.069 mM for ERY, 0-0.04 and 0-0.028 mM for OXC, and 0-0.155 and 0-0.019 mM for FTD, respectively. Moreover, CP 2 can effectively sense pH, in both a wide pH range and the fine physiological range. The sensors have a rapid luminescence response, good recyclability, and excellent fluorescence stability. More importantly, they not only represent the first example of detecting ERY or OXC based on fluorescent CPs but also are the very rare ultraversatile fluorescent sensors. The fluorescent sensing mechanism for antibiotics and pH was discussed in detail.

High-Resolution Profiling of the Functional Heterogeneity of Technical Lignins.

In technical lignins, functionality is strongly related to molar mass. Hence, any technical lignin exhibits concurrent functionality-type distribution (FTD) along its molar mass distribution (MMD). This study combined preparative size-exclusion chromatography with offline characterizations to acquire highly resolved profiles of the functional heterogeneity of technical lignins, which represent crucial information for their material use. The shape of these profiles showed considerable dissimilarity between different technical lignins and followed sigmoid trends. Determining the dispersity in functionality (DF) of lignins via their FTD revealed a rather homogeneous distribution of their functionalities (DF of 1.00-1.21). The high resolution of the acquired profiles of functional heterogeneity facilitated the development of a robust calculation method for the estimation of functional group contents of lignin fractions based simply on their MMD, an invaluable tool to simulate the effects of intended purification processes. Moreover, a more thorough evaluation of separations based on functionality becomes accessible.

Cannabidiol in the management of bruxism in behavioral variant of frontotemporal degeneration.

Awake bruxism is an understudied feature of behavioral variant of frontotemporal dementia (bvFTD). We present the case of aman who presented with psychiatric, behavioral, cognitive changes, and teeth clenching that resulted in significant changes in his teeth alignment including an underbite. He received multiple treatments with partial response. He then started using acannabidiol (CBD) capsule, and the grinding was almost completely relieved after this intervention. There is still no standardized pharmacology treatment for bruxism in patients with bvFTD. As aconsequence, acase-by-case approach is suggested. CBD can be helpful as an adjunct therapeutic agent for awake bruxism.Not StartedCompletedRejected.

Clinical spectrum of valosin containing protein (VCP)-opathy.

INTRODUCTION: Valosin containing protein (VCP) mutations cause a rare disorder characterized by hereditary inclusion body myopathy, Paget disease of bone (PDB), and frontotemporal dementia (FTD) with variable penetrance. VCP mutations have also been linked to amyotrophic lateral sclerosis and Charcot-Marie-Tooth disease type 2. METHODS: Review of clinical, serological, electrophysiological, and myopathological findings of 6 VCP-opathy patients from 4 unrelated families. RESULTS: Patients manifested muscle weakness between ages 40 and 53 years and developed predominant asymmetric limb girdle weakness. One patient had distal weakness at onset and co-existing peripheral neuropathy. Another patient had PDB, 1 had mild cognitive deficits, and 1 had FTD. All patients had myopathic and neurogenic electromyographic findings with predominant neurogenic changes in 2. Rimmed vacuoles were infrequent, while neurogenic changes were prominent in muscle biopsies. CONCLUSIONS: VCP-opathy is a multifaceted disorder in which myopathy and peripheral neuropathy can coexist. The electrophysiological and pathological neurogenic changes raise the possibility of coexisting motor neuron involvement. Muscle Nerve, 2015 Muscle Nerve 54: 94-99, 2016 Muscle Nerve 54: 94-99, 2016.

Fatal Complication of Mouthguard Used to Treat Awake Bruxism in Patient with Frontotemporal Dementia.

Awake bruxism is an understudied manifestation of frontotemporal dementia, yet awake bruxism can have fatal consequences in the aging population. This report presents a patient suffering from awake bruxism associated with frontotemporal dementia being treated with a mouthguard, which ultimately becomes lodged in her posterior oropharynx leading to asphyxiation. The case highlights the need for investigation into the occurrence and treatment of awake bruxism among patients with dementia, and the unique risk-benefit analysis that must be performed to develop proper treatment plans for patients with dementia.

Functional outcomes and complications of total glossectomy with laryngeal preservation and flap reconstruction: A systematic review and meta-analysis.

OBJECTIVE: To analyze the functional outcomes and complications of total glossectomy with laryngeal preservation and reconstruction with free or pedicled flaps. METHODS: A search was conducted using Pubmed/MEDLINE, Cochrane Library, Scopus, and Google Scholar databases. A single arm meta-analysis was performed for feeding tube dependence (FTD), tracheostomy dependence (TD), and speech intelligibility (SI) rates. Peri-operative sequels and complications were evaluated as secondary outcomes. RESULTS: A total number of 642 patients (median age: 54.2 years; 95% CI 52.1-58) were included. Functional assessment was performed after a median of 12 months (n = 623/642; 95% CI 10.6-12). Overall, the cumulative FTD rate was 22.9% (n = 188/627; 95% CI 10.2-38.7), the TD rate was 7.3% (n = 95/549; 95% CI 1.9-15.8), and the SI was 91.1% (n = 314/409; 95% CI 80.7%-97.8). The cumulative complication rate was 33.1% (n = 592/642). Eighteen patients (n = 18/592; 3.0%) experienced a major fistula, while aspiration pneumonia occurred in 17 cases (n = 17/592; 2.8%). CONCLUSIONS: Total glossectomy with laryngeal preservation and pedicled/free flaps reconstruction may guarantee good functional results and an acceptable quality of life. Further prospective studies are advised to define clinical guidelines about proper patients' and flaps' selection.

Expanding the spectrum of KIF5A mutations-case report of a large kindred with familial ALS and overlapping syndrome.

OBJECTIVES: This paper presents the first report of amyotrophic lateral sclerosis (ALS) kindred due to the KIF5A p.Arg1007Lys, a splice-altering variant. METHODS: An index case was a 54-year-old male who developed progressive gait difficulty and imbalance followed by mild parkinsonism, spasticity, neuropathy, ataxia, and cognitive impairment with predominant subcortical frontal involvement. Brain MRI showed marked bilateral parietal lobes atrophy. Electromyography demonstrated chronic diffuse neurogenic changes. Due to the positive history of similar symptoms in his father and the diagnosis of ALS in 10 other family members, extensive genetic testing was pursued. RESULTS: Genetic screening for GRN, C9orf72, TARDBP, SOD1, FUS, MAPT mutations, and hereditary ataxia panel, was unremarkable. Whole-exome sequencing revealed c.3020G > A (p.Arg1007Lys) mutation in the KIF5A gene, later confirmed in two affected relatives. DISCUSSION: Similar to previous reports on KIF5A-related ALS, our index case, had a mild disease course with prolonged survival. However, as the rate of progression and survival time differed even among the same family members, other factors were probably at play. Additionally, our index case and his father displayed features overlapping ALS, spastic paraplegia, Charcot-Marie-Tooth disease type 2, and frontotemporal dementia. Therefore, we suggest considering KIF5A mutations in the differential diagnosis, particularly in the presence of overlapping features of spasticity, neuropathy, cerebellar ataxia, and dementia.

[Frontotemporal dementia with cortico-basal syndrome]. / Lobno-visochnaya dementsiya s kortikobazal'nym sindromom.

FTD is a group of neurodegenerative diseases with progressive deterioration of behavioral and speech disorders, morphologically associated with pathology of the frontal or temporal lobes. International clinical trials have made it possible to define modern diagnostic criteria for various subtypes of clinically «possible/probable¼ FTD. Our article is devoted to one of the rare subtypes of frontotemporal dementia (FTD), corticobasal syndrome (CBD), in which we presented a review of current data with a demonstration of clinical observation. A clinical case of a patient with a patient with speech disorders and memory impairment is presented. A 60-year-old man at the time of the outpatient visit had been complaining of speech impairment for two years, a slight decrease in memory for current events. Neurological and neuropsychological studies revealed two leading clinical syndromes in the patient: «frontal¼ syndrome with impaired higher cortical functions in the form of efferent motor aphasia, impaired writing and reading with visual-spatial agnosia and dysgraphia, «frontal¼ signs (positive «palm-mouth «and¼ grasping «reflexes); «Corticobasal syndrome¼ with pronounced dynamic, optic-kinesthetic dyspraxia, dermolexia, apraxia of closing the eyes, «alien¼ hand syndrome with symptoms of levitation and intermanual conflict. MRI diagnostics revealed changes characteristic of neurodegeneration of the frontotemporal type (atrophy of the frontal and temporal lobes prevails). Taking into account complaints, anamnesis of the disease, identified clinical syndromes and structural changes according to MRI data, the patient was diagnosed with a clinically «probable¼ FTD. Determination and accurate diagnosis of FTD subtypes will help the neurologist in managing these patients with the appointment of the correct pharmacologic treatment. In FTD, in contrast to AD patients, the administration of cholinesterase inhibitors does not lead to a positive therapeutic effect a positive therapeutic effect and, therefore, is not advisable. The standards of patient therapy should include recommendations for antipsychotic therapy, the use of antidepressants (SSRIs) and anxiolytics with nootropic effects for the correction of affective and behavioral disorders.

Mutations linked to neurological disease enhance self-association of low-complexity protein sequences.

Protein domains of low sequence complexity do not fold into stable, three-dimensional structures. Nevertheless, proteins with these sequences assist in many aspects of cell organization, including assembly of nuclear and cytoplasmic structures not surrounded by membranes. The dynamic nature of these cellular assemblies is caused by the ability of low-complexity domains (LCDs) to transiently self-associate through labile, cross-ß structures. Mechanistic studies useful for the study of LCD self-association have evolved over the past decade in the form of simple assays of phase separation. Here, we have used such assays to demonstrate that the interactions responsible for LCD self-association can be dictated by labile protein structures poised close to equilibrium between the folded and unfolded states. Furthermore, missense mutations causing Charcot-Marie-Tooth disease, frontotemporal dementia, and Alzheimer's disease manifest their pathophysiology in vitro and in cultured cell systems by enhancing the stability of otherwise labile molecular structures formed upon LCD self-association.

The spectrum of neurodevelopmental, neuromuscular and neurodegenerative disorders due to defective autophagy.

Primary dysfunction of autophagy due to Mendelian defects affecting core components of the autophagy machinery or closely related proteins have recently emerged as an important cause of genetic disease. This novel group of human disorders may present throughout life and comprises severe early-onset neurodevelopmental and more common adult-onset neurodegenerative disorders. Early-onset (or congenital) disorders of autophagy often share a recognizable "clinical signature," including variable combinations of neurological, neuromuscular and multisystem manifestations. Structural CNS abnormalities, cerebellar involvement, spasticity and peripheral nerve pathology are prominent neurological features, indicating a specific vulnerability of certain neuronal populations to autophagic disturbance. A typically biphasic disease course of late-onset neurodegeneration occurring on the background of a neurodevelopmental disorder further supports a role of autophagy in both neuronal development and maintenance. Additionally, an associated myopathy has been characterized in several conditions. The differential diagnosis comprises a wide range of other multisystem disorders, including mitochondrial, glycogen and lysosomal storage disorders, as well as ciliopathies, glycosylation and vesicular trafficking defects. The clinical overlap between the congenital disorders of autophagy and these conditions reflects the multiple roles of the proteins and/or emerging molecular connections between the pathways implicated and suggests an exciting area for future research. Therapy development for congenital disorders of autophagy is still in its infancy but may result in the identification of molecules that target autophagy more specifically than currently available compounds. The close connection with adult-onset neurodegenerative disorders highlights the relevance of research into rare early-onset neurodevelopmental conditions for much more common, age-related human diseases.Abbreviations: AC: anterior commissure; AD: Alzheimer disease; ALR: autophagic lysosomal reformation; ALS: amyotrophic lateral sclerosis; AMBRA1: autophagy and beclin 1 regulator 1; AMPK: AMP-activated protein kinase; ASD: autism spectrum disorder; ATG: autophagy related; BIN1: bridging integrator 1; BPAN: beta-propeller protein associated neurodegeneration; CC: corpus callosum; CHMP2B: charged multivesicular body protein 2B; CHS: Chediak-Higashi syndrome; CMA: chaperone-mediated autophagy; CMT: Charcot-Marie-Tooth disease; CNM: centronuclear myopathy; CNS: central nervous system; DNM2: dynamin 2; DPR: dipeptide repeat protein; DVL3: disheveled segment polarity protein 3; EPG5: ectopic P-granules autophagy protein 5 homolog; ER: endoplasmic reticulum; ESCRT: homotypic fusion and protein sorting complex; FIG4: FIG4 phosphoinositide 5-phosphatase; FTD: frontotemporal dementia; GBA: glucocerebrosidase; GD: Gaucher disease; GRN: progranulin; GSD: glycogen storage disorder; HC: hippocampal commissure; HD: Huntington disease; HOPS: homotypic fusion and protein sorting complex; HSPP: hereditary spastic paraparesis; LAMP2A: lysosomal associated membrane protein 2A; MEAX: X-linked myopathy with excessive autophagy; mHTT: mutant huntingtin; MSS: Marinesco-Sjoegren syndrome; MTM1: myotubularin 1; MTOR: mechanistic target of rapamycin kinase; NBIA: neurodegeneration with brain iron accumulation; NCL: neuronal ceroid lipofuscinosis; NPC1: Niemann-Pick disease type 1; PD: Parkinson disease; PtdIns3P: phosphatidylinositol-3-phosphate; RAB3GAP1: RAB3 GTPase activating protein catalytic subunit 1; RAB3GAP2: RAB3 GTPase activating non-catalytic protein subunit 2; RB1: RB1-inducible coiled-coil protein 1; RHEB: ras homolog, mTORC1 binding; SCAR20: SNX14-related ataxia; SENDA: static encephalopathy of childhood with neurodegeneration in adulthood; SNX14: sorting nexin 14; SPG11: SPG11 vesicle trafficking associated, spatacsin; SQSTM1: sequestosome 1; TBC1D20: TBC1 domain family member 20; TECPR2: tectonin beta-propeller repeat containing 2; TSC1: TSC complex subunit 1; TSC2: TSC complex subunit 2; UBQLN2: ubiquilin 2; VCP: valosin-containing protein; VMA21: vacuolar ATPase assembly factor VMA21; WDFY3/ALFY: WD repeat and FYVE domain containing protein 3; WDR45: WD repeat domain 45; WDR47: WD repeat domain 47; WMS: Warburg Micro syndrome; XLMTM: X-linked myotubular myopathy; ZFYVE26: zinc finger FYVE-type containing 26.

UBQLN2-HSP70 axis reduces poly-Gly-Ala aggregates and alleviates behavioral defects in the C9ORF72 animal model.

Expansion of a hexanucleotide repeat GGGGCC (G4C2) in the intron of the C9ORF72 gene is the most common cause of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) (C9-ALS/FTD). Transcripts carrying G4C2 repeat expansions generate neurotoxic dipeptide repeat (DPR) proteins, including poly-Gly-Ala (poly-GA), which tends to form protein aggregates. Here, we demonstrate that UBQLN2, another ALS/FTD risk factor, is recruited to reduce poly-GA aggregates and alleviate poly-GA-induced neurotoxicity. UBQLN2 could recognize HSP70 ubiquitination, which facilitates the UBQLN2-HSP70-GA complex formation and promotes poly-GA degradation. ALS/FTD-related UBQLN2 mutants fail to bind HSP70 and clear poly-GA aggregates. Disruption of the interaction between UBQLN2 and HSP70 inhibits poly-GA aggregation in C9-ALS/FTD iPSC-derived neurons. Finally, enhancing HSP70 by the chemical compound 17AAG at the adult stage mitigates behavioral defects in poly-GA animals. Our findings suggest a critical role of the UBQLN2-HSP70 axis in protein aggregate clearance in C9-ALS/FTD.

Proline/arginine dipeptide repeat polymers derail protein folding in amyotrophic lateral sclerosis.

Amyotrophic lateral sclerosis and frontotemporal dementia are two neurodegenerative diseases with overlapping clinical features and the pathological hallmark of cytoplasmic deposits of misfolded proteins. The most frequent cause of familial forms of these diseases is a hexanucleotide repeat expansion in the non-coding region of the C9ORF72 gene that is translated into dipeptide repeat polymers. Here we show that proline/arginine repeat polymers derail protein folding by sequestering molecular chaperones. We demonstrate that proline/arginine repeat polymers inhibit the folding catalyst activity of PPIA, an abundant molecular chaperone and prolyl isomerase in the brain that is altered in amyotrophic lateral sclerosis. NMR spectroscopy reveals that proline/arginine repeat polymers bind to the active site of PPIA. X-ray crystallography determines the atomic structure of a proline/arginine repeat polymer in complex with the prolyl isomerase and defines the molecular basis for the specificity of disease-associated proline/arginine polymer interactions. The combined data establish a toxic mechanism that is specific for proline/arginine dipeptide repeat polymers and leads to derailed protein homeostasis in C9orf72-associated neurodegenerative diseases.

Soluble and insoluble dipeptide repeat protein measurements in C9orf72-frontotemporal dementia brains show regional differential solubility and correlation of poly-GR with clinical severity.

A C9orf72 repeat expansion is the most common genetic cause of frontotemporal dementia (FTD) and amyotrophic lateral sclerosis. One of the suggested pathomechanisms is toxicity from dipeptide repeat proteins (DPRs), which are generated via unconventional translation of sense and antisense repeat transcripts with poly-GA, poly-GP and poly-GR being the most abundant dipeptide proteins. Animal and cellular studies highlight a neurotoxic role of poly-GR and poly-PR and to a lesser degree of poly-GA. Human post-mortem studies in contrast have been much less clear on a potential role of DPR toxicity but have largely focused on immunohistochemical methods to detect aggregated DPR inclusions. This study uses protein fractionation and sensitive immunoassays to quantify not only insoluble but also soluble poly-GA, poly-GP and poly-GR concentrations in brain homogenates of FTD patients with C9orf72 mutation across four brain regions. We show that soluble DPRs are less abundant in clinically affected areas (i.e. frontal and temporal cortices). In contrast, the cerebellum not only shows the largest DPR load but also the highest relative DPR solubility. Finally, poly-GR levels and poly-GP solubility correlate with clinical severity. These findings provide the first cross-comparison of soluble and insoluble forms of all sense DPRs and shed light on the distribution and role of soluble DPRs in the etiopathogenesis of human C9orf72-FTD.

Demência frontotemporal em paciente feminina de 56 anos: relato de caso / Frontotemporal Dementia (FTD) in a fifty-six-years-old female patient: case report / Demencia Frontotemporal (DFT) en una paciente de cincuenta y seis años: informe de un caso

A demência é uma das mais importantes causas de morbimortalidade entre os idosos e se caracteriza pelo declínio progressivo em múltiplos domínios cognitivos. Paciente do sexo feminino, 56 anos, iniciou quadro há 3 anos, caracterizado por apatia, anedonia e isolamento social. Procurou atendimento com médico que atribuiu sintomas a depressão. Contudo, não houve melhora. Há dois anos evoluiu com delírios persecutórios, confabulações, alucinação visual. Acompanhante notou que a paciente tinha dificuldades em se expressar e na compreensão. Devido à refratariedade ao tratamento foi solicitada avaliação de neurologista. À consulta inicial, paciente apresentava-se orientada no tempo, espaço. Mini exame do estado mental 26/30 pontos. Fluência verbal semântica. Após 6 meses, evoluiu com empobrecimento do vocabulário. À época estava dependente de familiares para realização de atividades de vida diária. Na ressonância magnética encefálica apresentou atrofia cortical difusa, com predomínio em regiões frontais e temporais à esquerda. Atualmente está em uso de risperidona e memantina. A atrofia cerebral dos lobos frontais e temporais ou demência fronto temporal (DFT) afeta predominantemente o lobo frontal do cérebro, podendo se estender para o temporal. A patologia caracteriza-se por significativa alteração da personalidade e do comportamento, com relativa preservação das funções mnésticas e visuoespaciais. A linguagem é progressivamente afetada. A memória encontra-se preservada no início da doença e as alterações comportamentais e da personalidade são bastante significativas. A variante comportamental é a mais comum. Ela apresenta uma deterioração gradual da função executiva e da personalidade, enquanto a capacidade visuoespacial é afetada apenas em estádios avançados(AU)

Dementia is one of the most important causes of morbimortality among elderly people and is characterized by progressive decline in multiple cognitive domains. A fifty-six-years-old female patient started a medical condition three years ago, characterized by apathy, anhedonia and social isolation. She sought healthcare with a medical who assigned symptoms to depression. However, there was no improvement. Two years ago, she evolved with persecutory delirium, confabulations, visual hallucination. Due to the refractoriness of the treatment, a neurologist evaluation was requested. At the initial consultation, the patient was oriented in time and space. The Mini­Mental State Examination (MMSE) test was 26/30 points. Regarding to Semantic verbal fluency, after 6 months, she evolved with impoverishment of vocabulary. At the time she was dependent on family members for daily activities. In brain magnetic resonance, she showed having diffuse cortical atrophy, with predominance in frontal and temporal regions on the left. Currently, she's using risperidone and memantine. Cerebral atrophy of the frontal and temporal lobes or Front-Temporal Dementia (FTD) affects, predominantly the frontal lobe of the brain, and may extend to the temporal. The pathology is characterized by significant personality and behavioral changes, with relative preservation of the mnestic and visuospatial functions. The language is progressively affected. Memory is preserved at the onset of the disease and the behavioral and personality changes are quite significant. The behavioral variant is the most common. It presents a gradual deterioration of executive function and personality, while visuospatial capacity is affected only in advanced stages(AU)

La demencia es una de las causas más importantes de morbimortalidad entre personas mayores y se caracteriza por una disminución progresiva en múltiples dominios cognitivos. Una paciente de cincuenta y seis años de edad comenzó una condición médica hace tres años, caracterizada por apatía, anedonia y aislamiento social. Ella buscó atención médica y asignaron sus síntomas a depresión. Hace dos años, ella evolucionó con delirio persecutorio, confabulaciones, alucinación visual. Debido a la refractariedad del tratamiento, se solicitó una evaluación neurológica. En la consulta, el paciente estaba orientado con respecto a tiempo y espacio. En el Examen de Estado Mini-Mental (EEMM) obtuvo 26/30 puntos. Con respecto a la fluidez verbal semántica, después de 6 meses, evolucionó poco en su vocabulario. En ese momento ella dependía de los miembros de la familia para las actividades diarias. En la resonancia magnética cerebral, mostró una atrofia cortical difusa, con predominio en las regiones frontal y temporal de la izquierda. Actualmente, ella está usando risperidona y memantina. La atrofia cerebral de los lóbulos frontal y temporal afecta predominantemente el lóbulo frontal del cerebro, y puede extenderse al temporal. La patología se caracteriza por cambios significativos en la personalidad y el comportamiento, con una preservación relativa de las funciones mnisticas y visuoespaciales. El lenguaje se ve progresivamente afectado. La memoria se preserva al inicio de la enfermedad con variaciones constantes en la personalidad. La función ejecutiva se deteriora paulatinamente, mientras que la capacidad visuoespacial se ve afectada en etapas avanzadas(AU)

Poly-dipeptides encoded by the C9orf72 repeats bind nucleoli, impede RNA biogenesis, and kill cells.

Many RNA regulatory proteins controlling pre-messenger RNA splicing contain serine:arginine (SR) repeats. Here, we found that these SR domains bound hydrogel droplets composed of fibrous polymers of the low-complexity domain of heterogeneous ribonucleoprotein A2 (hnRNPA2). Hydrogel binding was reversed upon phosphorylation of the SR domain by CDC2-like kinases 1 and 2 (CLK1/2). Mutated variants of the SR domains changing serine to glycine (SR-to-GR variants) also bound to hnRNPA2 hydrogels but were not affected by CLK1/2. When expressed in mammalian cells, these variants bound nucleoli. The translation products of the sense and antisense transcripts of the expansion repeats associated with the C9orf72 gene altered in neurodegenerative disease encode GRn and PRn repeat polypeptides. Both peptides bound to hnRNPA2 hydrogels independent of CLK1/2 activity. When applied to cultured cells, both peptides entered cells, migrated to the nucleus, bound nucleoli, and poisoned RNA biogenesis, which caused cell death.

Expression of frontotemporal dementia with parkinsonism associated to chromosome 17 tau induces specific degeneration of the ventral dentate gyrus and depressive-like behavior in mice.

When bearing certain frontotemporal dementia with parkinsonism (FTDP) mutations, overexpression of human tau resulted in a decrease of the dentate gyrus ventral blade, apparently due to a reduction in the proliferation of neuronal precursors and an increase in neuronal cell death. This degenerative process was accompanied by a dramatic increase in behavioral despair, as evident in the Porsolt swim test. Interestingly, we observed an increase in GABAergic innervation in the molecular layer of the dorsal dentate gyrus but not in the ventral domain. We suggest that this increase in GABAergic innervation reflects a compensatory neuroprotective response to the overexpression of toxic tau, which may prevent or delay degeneration in the dorsal blade of the dental gyrus. Finally, we suggest that this transgenic mouse, which overexpresses human FTPD tau, may serve as a useful model to study specific functions of the ventral dentate gyrus.

Associated conditions and clinical significance of awake bruxism.

BACKGROUND: Awake bruxism is defined as an oral parafunctional activity that includes clenching and grinding of teeth during wakefulness. Confirming the possible related anatomy and the clinical significance of awake bruxism in geriatric hospitals is the aim of this study. METHODS: We analyzed the medical records of 503 patients who were admitted to hospital from April to June 2008. After the recognition of bruxism, the clinical, brain imaging studies and statistical parametric mapping (SPM) of brain single photon emission computed tomography were performed. RESULTS: In each disease group, five of 125 Alzheimer's disease (AD) patients (4.0%), three of 11 frontotemporal dementia (FTD) patients (27.3%), seven of 230 stroke patients (including two patients related to citalopram, 3.0%), one of 45 Parkinson's disease patients (2.2%) and four of 17 hydrocephalus patients (23.5%) had bruxism. Even though awake bruxism occurred early after stroke onset, it occurred late after AD and FTD onset. This occurred in a far advanced stage of AD, while it occurred in a moderately advanced stage of FTD. SPM analysis in AD and FTD patients with awake bruxism revealed significant hypoperfusion in frontotemporal and other subcortical structures. Surface electromyography recordings from the masseter muscle showed rhythmic regular motor activity at a rate of 1-2/s. CONCLUSION: This study suggests that awake bruxism is encountered not infrequently in various diseases in geriatric hospitals. It is frequently observed in FTD and normal pressure hydrocephalus, which characteristically shows frontal lobe dysfunction. These facts and SPM analysis show that awake bruxism can be regarded as a frontal neurological sign of various neurological disorders.