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1.
Brain ; 140(12): 3081-3104, 2017 Dec 01.
Artigo em Inglês | MEDLINE | ID: mdl-29053785

RESUMO

Progranulin, a secreted glycoprotein, is encoded in humans by the single GRN gene. Progranulin consists of seven and a half, tandemly repeated, non-identical copies of the 12 cysteine granulin motif. Many cellular processes and diseases are associated with this unique pleiotropic factor that include, but are not limited to, embryogenesis, tumorigenesis, inflammation, wound repair, neurodegeneration and lysosome function. Haploinsufficiency caused by autosomal dominant mutations within the GRN gene leads to frontotemporal lobar degeneration, a progressive neuronal atrophy that presents in patients as frontotemporal dementia. Frontotemporal dementia is an early onset form of dementia, distinct from Alzheimer's disease. The GRN-related form of frontotemporal lobar dementia is a proteinopathy characterized by the appearance of neuronal inclusions containing ubiquitinated and fragmented TDP-43 (encoded by TARDBP). The neurotrophic and neuro-immunomodulatory properties of progranulin have recently been reported but are still not well understood. Gene delivery of GRN in experimental models of Alzheimer's- and Parkinson's-like diseases inhibits phenotype progression. Here we review what is currently known concerning the molecular function and mechanism of action of progranulin in normal physiological and pathophysiological conditions in both in vitro and in vivo models. The potential therapeutic applications of progranulin in treating neurodegenerative diseases are highlighted.


Assuntos
Degeneração Lobar Frontotemporal/genética , Peptídeos e Proteínas de Sinalização Intercelular/genética , Animais , Demência Frontotemporal/tratamento farmacológico , Demência Frontotemporal/genética , Demência Frontotemporal/metabolismo , Degeneração Lobar Frontotemporal/tratamento farmacológico , Degeneração Lobar Frontotemporal/metabolismo , Haploinsuficiência , Humanos , Técnicas In Vitro , Peptídeos e Proteínas de Sinalização Intercelular/metabolismo , Camundongos , Modelos Neurológicos , Terapia de Alvo Molecular , Mutação , Progranulinas , Proteinopatias TDP-43/tratamento farmacológico , Proteinopatias TDP-43/genética , Proteinopatias TDP-43/metabolismo
2.
Eur J Pharmacol ; 817: 2-6, 2017 Dec 15.
Artigo em Inglês | MEDLINE | ID: mdl-29031901

RESUMO

Amyotrophic lateral sclerosis (ALS) and frontotemporal lobar degeneration (FTLD) are neurodegenerative disorders, related by signs of deteriorating motor and cognitive functions, and short survival. The causes are still largely unknown and no effective treatment currently exists. It has been shown that FTLD may coexist with ALS. The overlap between ALS and frontotemporal dementia (FTD), the clinical syndrome associated with FTLD, occurs at clinical, genetic, and pathological levels. The hallmark proteins of the pathognomonic inclusions are SOD-1, TDP-43 or FUS, rarely the disease is caused by mutations in the respective genes. Frontotemporal lobar degenerations (FTLD) is genetically, neuropathologically and clinically heterogeneous and may present with behavioural, language and occasionally motor disorder, respectively. Almost all cases of ALS, as well as tau-negative FTLD share a common neuropathology, neuronal and glial inclusion bodies containing abnormal TDP-43 protein, collectively called TDP-43 proteinopathy. Recent discoveries in genetics (e.g. C9orf72 hexanucleotide expansion) and the subsequent neuropathological characterization have revealed remarkable overlap between ALS and FTLD-TDP indicating common pathways in pathogenesis. For ALS, an anti-glutamate agent riluzole may be offered to slow disease progression (Level A), and a promising molecule, arimoclomol, is currently in clinical trials. Other compounds, however, are being trailed and some have shown encouraging results. As new therapeutic approaches continue to emerge by targeting SOD1, TDP-43, or GRN, we present some advances that are being made in our understanding of the molecular mechanisms of these diseases, which together with gene and stem cell therapies may translate into new treatment options.


Assuntos
Esclerose Amiotrófica Lateral , Degeneração Lobar Frontotemporal , Esclerose Amiotrófica Lateral/tratamento farmacológico , Esclerose Amiotrófica Lateral/genética , Esclerose Amiotrófica Lateral/patologia , Animais , Degeneração Lobar Frontotemporal/tratamento farmacológico , Degeneração Lobar Frontotemporal/genética , Degeneração Lobar Frontotemporal/patologia , Humanos
3.
Alzheimers Dement ; 12(10): 1051-1065, 2016 10.
Artigo em Inglês | MEDLINE | ID: mdl-27751442

RESUMO

A group of neurodegenerative diseases referred to as tauopathies are characterized by the presence of brain cells harboring inclusions of pathological species of the tau protein. These disorders include Alzheimer's disease and frontotemporal lobar degeneration due to tau pathology, including progressive supranuclear palsy, corticobasal degeneration, and Pick's disease. Tau is normally a microtubule (MT)-associated protein that appears to play an important role in ensuring proper axonal transport, but in tauopathies tau becomes hyperphosphorylated and disengages from MTs, with consequent misfolding and deposition into inclusions that mainly affect neurons but also glia. A body of experimental evidence suggests that the development of tau inclusions leads to the neurodegeneration observed in tauopathies, and there is a growing interest in developing tau-directed therapeutic agents. The following review provides a summary of strategies under investigation for the potential treatment of tauopathies, highlighting both the promises and challenges associated with these various therapeutic approaches.


Assuntos
Doença de Alzheimer/tratamento farmacológico , Degeneração Lobar Frontotemporal/tratamento farmacológico , Tauopatias/tratamento farmacológico , Doença de Alzheimer/patologia , Encéfalo/patologia , Degeneração Lobar Frontotemporal/patologia , Humanos , Proteínas tau/metabolismo
4.
Hum Mol Genet ; 24(6): 1682-90, 2015 Mar 15.
Artigo em Inglês | MEDLINE | ID: mdl-25410659

RESUMO

Mutations in SQSTM1, encoding for the protein SQSTM1/p62, have been recently reported in 1-3.5% of patients with amyotrophic lateral sclerosis and frontotemporal lobar degeneration (ALS/FTLD). Inclusions positive for SQSTM1/p62 have been detected in patients with neurodegenerative disorders, including ALS/FTLD. In order to investigate the pathogenic mechanisms induced by SQSTM1 mutations in ALS/FTLD, we developed a zebrafish model. Knock-down of the sqstm1 zebrafish ortholog, as well as impairment of its splicing, led to a specific phenotype, consisting of behavioral and axonal anomalies. Here, we report swimming deficits associated with shorter motor neuronal axons that could be rescued by the overexpression of wild-type human SQSTM1. Interestingly, no rescue of the loss-of-function phenotype was observed when overexpressing human SQSTM1 constructs carrying ALS/FTLD-related mutations. Consistent with its role in autophagy regulation, we found increased mTOR levels upon knock-down of sqstm1. Furthermore, treatment of zebrafish embryos with rapamycin, a known inhibitor of the mTOR pathway, yielded an amelioration of the locomotor phenotype in the sqstm1 knock-down model. Our results suggest that loss-of-function of SQSTM1 causes phenotypic features characterized by locomotor deficits and motor neuron axonal defects that are associated with a misregulation of autophagic processes.


Assuntos
Proteínas Adaptadoras de Transdução de Sinal/genética , Esclerose Amiotrófica Lateral/genética , Degeneração Lobar Frontotemporal/genética , Locomoção/genética , Sirolimo/farmacologia , Proteínas de Peixe-Zebra/genética , Esclerose Amiotrófica Lateral/tratamento farmacológico , Animais , Modelos Animais de Doenças , Degeneração Lobar Frontotemporal/tratamento farmacológico , Técnicas de Silenciamento de Genes , Locomoção/efeitos dos fármacos , Fenótipo , Proteína Sequestossoma-1 , Serina-Treonina Quinases TOR/metabolismo , Peixe-Zebra/genética , Proteínas de Peixe-Zebra/metabolismo
5.
Drug Dev Res ; 75(6): 366-71, 2014 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-25195580

RESUMO

Frontotemporal lobar degeneration (FTLD) encompasses a spectrum of neurodegenerative disorders characterized by behavioral, executive and language impairment, with a common overlap with parkinsonism and motor-neuron disease. Despite an increased understanding of its genetic background and molecular pathophysiology, FTLD is still an orphan disorder and there are currently no effective therapies available. In this brief overview we report the results obtained by several high-throughput and bioinformatic studies aimed at discovering impairment in the transcriptional profiles in brain and peripheral tissues from FTLD patients and in animal models. Taken together, all these results provide an interesting but still fragmentary list of genes and miRNAs whose role in FTLD should be thoroughly investigated.


Assuntos
Degeneração Lobar Frontotemporal/genética , Perfilação da Expressão Gênica/métodos , MicroRNAs/genética , Análise de Sequência com Séries de Oligonucleotídeos/métodos , Animais , Descoberta de Drogas/métodos , Degeneração Lobar Frontotemporal/tratamento farmacológico , Degeneração Lobar Frontotemporal/patologia , Regulação da Expressão Gênica , Estudo de Associação Genômica Ampla , Humanos
6.
Neurobiol Aging ; 35(4): 886-98, 2014 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-24139281

RESUMO

Loss-of-function progranulin (PGRN) mutations have been identified as the major cause of frontotemporal lobar degeneration with TDP-43 protein inclusions (FTLD-TDP). Previously, we reported cell cycle-related alterations in lymphoblasts from FTLD-TDP patients, carrying the c.709-1G>A null PGRN mutation, suggesting aberrant cell cycle activation in affected neurons. Here we report that PGRN haploinsufficiency activates the extracellular signal-regulated protein kinases 1 and 2 pathway in a Ca(2+), protein kinase C-dependent, and pertussis toxin-sensitive manner. Addition of exogenous PGRN or conditioned medium from control cells normalized the response of PGRN-deficient lymphoblasts to serum activation. Our data indicated that noncanonical Wnt5a signaling might be overactivated by PGRN deficiency. We detected increased cellular and secreted levels of Wnt5a in PGRN-deficient lymphoblasts associated with enhanced phosphorylated calmodulin kinase II. Moreover, treatment of control cells with exogenous Wingless-type 5a (Wnt5a)-activated Ca(2+)/calmodulin kinase II (CaMKII), increased extracellular signal-regulated protein kinases 1 and 2 activity and cell proliferation up to the levels found in c.709-1G>A carrier cells. PGRN knockdown SH-SY5Y neuroblastoma cells also show enhanced Wnt5a content and signaling. Taken together, our results revealed an important role of Wnt signaling in FTLD-TDP pathology and suggest a novel target for therapeutic intervention.


Assuntos
Degeneração Lobar Frontotemporal/genética , Heterozigoto , Peptídeos e Proteínas de Sinalização Intercelular/genética , Mutação , Proteínas Proto-Oncogênicas , Proteínas Wnt , Via de Sinalização Wnt/fisiologia , Proteína Quinase Tipo 2 Dependente de Cálcio-Calmodulina/metabolismo , Proliferação de Células , Células Cultivadas , Proteínas de Ligação a DNA , Degeneração Lobar Frontotemporal/tratamento farmacológico , Degeneração Lobar Frontotemporal/patologia , Humanos , Peptídeos e Proteínas de Sinalização Intercelular/deficiência , Linfócitos/patologia , Proteína Quinase 1 Ativada por Mitógeno/metabolismo , Proteína Quinase 3 Ativada por Mitógeno/metabolismo , Terapia de Alvo Molecular , Neurônios/patologia , Toxina Pertussis , Progranulinas , Via de Sinalização Wnt/genética , Proteína Wnt-5a
8.
Proc Natl Acad Sci U S A ; 110(47): E4530-9, 2013 Nov 19.
Artigo em Inglês | MEDLINE | ID: mdl-24170860

RESUMO

Expanded hexanucleotide repeats in the chromosome 9 open reading frame 72 (C9orf72) gene are the most common genetic cause of ALS and frontotemporal degeneration (FTD). Here, we identify nuclear RNA foci containing the hexanucleotide expansion (GGGGCC) in patient cells, including white blood cells, fibroblasts, glia, and multiple neuronal cell types (spinal motor, cortical, hippocampal, and cerebellar neurons). RNA foci are not present in sporadic ALS, familial ALS/FTD caused by other mutations (SOD1, TDP-43, or tau), Parkinson disease, or nonneurological controls. Antisense oligonucleotides (ASOs) are identified that reduce GGGGCC-containing nuclear foci without altering overall C9orf72 RNA levels. By contrast, siRNAs fail to reduce nuclear RNA foci despite marked reduction in overall C9orf72 RNAs. Sustained ASO-mediated lowering of C9orf72 RNAs throughout the CNS of mice is demonstrated to be well tolerated, producing no behavioral or pathological features characteristic of ALS/FTD and only limited RNA expression alterations. Genome-wide RNA profiling identifies an RNA signature in fibroblasts from patients with C9orf72 expansion. ASOs targeting sense strand repeat-containing RNAs do not correct this signature, a failure that may be explained, at least in part, by discovery of abundant RNA foci with C9orf72 repeats transcribed in the antisense (GGCCCC) direction, which are not affected by sense strand-targeting ASOs. Taken together, these findings support a therapeutic approach by ASO administration to reduce hexanucleotide repeat-containing RNAs and raise the potential importance of targeting expanded RNAs transcribed in both directions.


Assuntos
Esclerose Amiotrófica Lateral/tratamento farmacológico , Expansão das Repetições de DNA/genética , Degeneração Lobar Frontotemporal/tratamento farmacológico , Terapia Genética/métodos , Oligonucleotídeos Antissenso/farmacologia , Proteínas/genética , Esclerose Amiotrófica Lateral/genética , Animais , Southern Blotting , Proteína C9orf72 , Sistema Nervoso Central/citologia , Sistema Nervoso Central/metabolismo , Primers do DNA/genética , Fibroblastos/metabolismo , Degeneração Lobar Frontotemporal/genética , Genótipo , Hibridização in Situ Fluorescente , Camundongos , Oligonucleotídeos Antissenso/administração & dosagem , Oligonucleotídeos Antissenso/genética , Oligonucleotídeos Antissenso/uso terapêutico , Reação em Cadeia da Polimerase em Tempo Real , Análise de Sequência de RNA
9.
Lancet Neurol ; 12(2): 149-56, 2013 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-23290598

RESUMO

BACKGROUND: Memantine has been used off-label to treat frontotemporal lobar degeneration (FTD). A previous 26-week open-label study suggested a transient, modest benefit on neuropsychiatric symptoms as measured by the neuropsychiatric inventory (NPI). We aimed to determine whether memantine is an effective treatment for FTD. METHODS: We did a randomised, parallel group, double-blind, placebo-controlled trial of 20 mg memantine taken orally daily for 26 weeks in patients with FTD. Participants met Neary criteria for behavioural variant FTD (bvFTD) or semantic dementia and had characteristic brain atrophy. Use of acetylcholinesterase inhibitors was prohibited. Individuals were randomly assigned to receive either memantine or matched placebo tablets (1:1) in blocks of two and four patients. All patients and study personnel were masked to treatment assignment. Primary endpoints were the change in total NPI score and clinical global impression of change (CGIC) score after 26 weeks and were analysed by intention to treat. This study is registered with Clinicaltrials.gov, number NCT00545974. FINDINGS: Of 100 patients screened, 81 were randomly assigned to receive memantine (39 patients) or placebo (42 patients). Five (6%) patients discontinued, and 76 completed the 26-week treatment. Enrolment numbers were lower than planned because of many patients' preference to take memantine or cholinesterase inhibitors off-label rather than participate in a clinical trial. Memantine treatment had no effect on either the NPI (mean difference 2·2, 95% CI -3·9 to 8·3, p=0·47) or CGIC (mean difference 0·0, -0·4 to 0·4, p=0·90) after 26 weeks of treatment. Memantine was generally well tolerated; however, patients in the memantine group had more frequent cognitive adverse events (six patients) than those in the placebo group (one). INTERPRETATION: Memantine treatment showed no benefit in patients with FTD. These data do not support memantine use in FTD. FUNDING: Forest Research Institute.


Assuntos
Antagonistas de Aminoácidos Excitatórios/uso terapêutico , Degeneração Lobar Frontotemporal/tratamento farmacológico , Memantina/uso terapêutico , Idoso , Distribuição de Qui-Quadrado , Método Duplo-Cego , Feminino , Seguimentos , Humanos , Masculino , Pessoa de Meia-Idade , Testes Neuropsicológicos , Escalas de Graduação Psiquiátrica , Estudos Retrospectivos , Resultado do Tratamento
10.
J Clin Neurosci ; 20(4): 611-3, 2013 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-23313527

RESUMO

Encephalitis associated with antibodies against N-methyl-d-aspartic acid (NMDA) receptor is characterized by severe memory deficits, decreased consciousness, epileptic seizures and movement disorders and occurs most commonly in young women. Recovery is mostly good but little is known about the disease course in patients whose treatment has been delayed severely. We present a 16-year-old girl with a 36-month follow-up. A single course of methylprednisolone attenuated some symptoms but severe and incapacitating frontotemporal syndrome remained. Second-line treatment with rituximab was initiated 12months after the onset of symptoms. A surprising recovery occurred 18months after treatment and 30months after onset. Recovery in NMDA receptor antibody-associated encephalitis can be severely delayed and does not have to be linear. Whether delayed therapy contributed to recovery in this patient cannot be answered with certainty. Spontaneous recovery independent of therapy is possible, as it has been observed previously as late as 3years after onset. Although serum antibodies disappeared with recovery in this patient, previous cases have shown serum antibodies to be unreliable markers of disease activity. Second-line treatment, especially with substances as well tolerated as rituximab, should at least be considered in NMDA receptor encephalitis with persistent neuropsychiatric syndromes after first-line therapy.


Assuntos
Doenças Autoimunes/tratamento farmacológico , Doenças Autoimunes/imunologia , Encefalite/tratamento farmacológico , Encefalite/imunologia , Degeneração Lobar Frontotemporal/tratamento farmacológico , Degeneração Lobar Frontotemporal/imunologia , Receptores de N-Metil-D-Aspartato/imunologia , Adolescente , Anticorpos Monoclonais Murinos/uso terapêutico , Autoanticorpos/análise , Encéfalo/patologia , Feminino , Técnica Indireta de Fluorescência para Anticorpo , Degeneração Lobar Frontotemporal/psicologia , Humanos , Imunoglobulina G/análise , Imagem por Ressonância Magnética , Recuperação de Função Fisiológica , Rituximab
12.
Int J Geriatr Psychiatry ; 28(3): 319-25, 2013 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-22674572

RESUMO

OBJECTIVES: To follow up on the increases we reported in normalized metabolic activity in salience network hubs from a 2-month open-label study of memantine in frontotemporal dementia (FTD). METHODS: We repeated fluorodeoxyglucose positron emission tomography (FDG-PET) after 6 months of drug use and subjected the data to Statistical Parametrical Mapping (SPM) analysis to reveal clusters of significant change from baseline. We also sought correlations between changes in behavioral disturbances on the Frontal Behavioral Inventory (FBI) and the PET signal. RESULTS: Recruitment of one progressive nonfluent aphasia and one behavioral variant FTD precluded statistical analysis for any FTD subtype other than semantic dementia (SD). The baseline-to-6-month interval showed increased normalized metabolic activity in the left orbitofrontal cortex (p < 0.002) for five participants with SD. The 2-6-month interval revealed a late increase in normalized metabolic activity in the left insula (p < 0.013), right insula (p < 0.009), and left anterior cingulate (p < 0.005). The right anterior cingulate showed both an initial increase and a delayed further increase (2-6 months, p < 0.016). FBI scores worsened by 43.3%. One participant with SD opted not to continue memantine beyond 2 months yet showed similar FDG-PET increases. CONCLUSIONS: Increases in normalized cortical metabolic activity in salience network hubs were sustained in SD over a 6-month period. Because one participant without medication also showed these changes, further investigation is recommended through a double-blind, placebo-controlled study with FDG-PET as an outcome measure.


Assuntos
Antiparkinsonianos/uso terapêutico , Fluordesoxiglucose F18/farmacocinética , Degeneração Lobar Frontotemporal/tratamento farmacológico , Degeneração Lobar Frontotemporal/metabolismo , Memantina/uso terapêutico , Tomografia por Emissão de Pósitrons/métodos , Compostos Radiofarmacêuticos/farmacocinética , Degeneração Lobar Frontotemporal/diagnóstico por imagem , Humanos , Projetos Piloto , Fatores de Tempo
13.
Alzheimers Dement ; 9(2): 176-88, 2013 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-23043900

RESUMO

Frontotemporal degeneration (FTD) is a common cause of dementia for which there are currently no approved therapies. Over the past decade, there has been an explosion of knowledge about the biology and clinical features of FTD that has identified a number of promising therapeutic targets as well as animal models in which to develop drugs. The close association of some forms of FTD with neuropathological accumulation of tau protein or increased neuroinflammation due to progranulin protein deficiency suggests that a drug's success in treating FTD may predict efficacy in more common diseases such as Alzheimer's disease. A variety of regulatory incentives, clinical features of FTD such as rapid disease progression, and relatively pure molecular pathology suggest that there are advantages to developing drugs for FTD as compared with other more common neurodegenerative diseases such as Alzheimer's disease. In March 2011, the Frontotemporal Degeneration Treatment Study Group sponsored a conference entitled "FTD, the Next Therapeutic Frontier," which focused on preclinical aspects of FTD drug development. The goal of the meeting was to promote collaborations between academic researchers and biotechnology and pharmaceutical researchers to accelerate the development of new treatments for FTD. Here we report the key findings from the conference, including the rationale for FTD drug development; epidemiological, genetic, and neuropathological features of FTD; FTD animal models and how best to use them; and examples of successful drug development collaborations in other neurodegenerative diseases.


Assuntos
Modelos Animais de Doenças , Descoberta de Drogas , Degeneração Lobar Frontotemporal/tratamento farmacológico , Fármacos Neuroprotetores/uso terapêutico , Animais , Humanos
14.
Alzheimers Dement ; 9(2): 189-98, 2013 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-23062850

RESUMO

Frontotemporal degeneration (FTD) encompasses a spectrum of related neurodegenerative disorders with behavioral, language, and motor phenotypes for which there are currently no effective therapies. This is the second of two articles that summarize the presentations and discussions that occurred at two symposia in 2011 sponsored by the Frontotemporal Degeneration Treatment Study Group, a collaborative group of academic and industry researchers that is devoted to developing treatments for FTD. This article discusses the current status of FTD clinical research that is relevant to the conduct of clinical trials, and why FTD research may be an attractive pathway for developing therapies for neurodegenerative disorders. The clinical and molecular features of FTD, including rapid disease progression and relatively pure molecular pathology, suggest that there are advantages to developing drugs for FTD as compared with other dementias. FTD qualifies as orphan indication, providing additional advantages for drug development. Two recent sets of consensus diagnostic criteria will facilitate the identification of patients with FTD, and a variety of neuropsychological, functional, and behavioral scales have been shown to be sensitive to disease progression. Moreover, quantitative neuroimaging measurements demonstrate progressive brain atrophy in FTD at rates that may surpass Alzheimer's disease. Finally, the similarities between FTD and other neurodegenerative diseases with drug development efforts already underway suggest that FTD researchers will be able to draw on this experience to create a road map for FTD drug development. We conclude that FTD research has reached sufficient maturity to pursue clinical development of specific FTD therapies.


Assuntos
Modelos Animais de Doenças , Descoberta de Drogas , Degeneração Lobar Frontotemporal/tratamento farmacológico , Fármacos Neuroprotetores/uso terapêutico , Animais , Humanos
15.
Am J Alzheimers Dis Other Demen ; 27(4): 260-6, 2012 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-22605780

RESUMO

INTRODUCTION: Clinical evidence indicates that acetylcholinesterase inhibitors (AChEIs) are not efficacious to treat frontotemporal lobar degeneration (FTLD). The British Association for Psychopharmacology recommends avoiding the use of AChEI and memantine in patients with FTLD. METHODS: Cross-sectional design using 1092 cases with Alzheimer's disease (AD) and 64 cases with FTLD registered by the Registry of Dementias of Girona. Bivariate analyses were performed, and binary logistic regressions were used to detect variables associated with antidementia drugs consumption. RESULTS: The AChEIs were consumed by 57.6% and 42.2% of the patients with AD and FTLD, respectively. Memantine was used by 17.2% and 10.9% of patients with AD and FTLD, respectively. Binary logistic regressions yielded no associations with antidementia drugs consumption. CONCLUSIONS: There is a discrepancy regarding clinical practice and the recommendations based upon clinical evidence. The increased central nervous system drug use detected in FTLD requires multicentric studies aiming at finding the best means to treat these patients.


Assuntos
Doença de Alzheimer/tratamento farmacológico , Inibidores da Colinesterase/uso terapêutico , Degeneração Lobar Frontotemporal/tratamento farmacológico , Memantina/uso terapêutico , Idoso , Idoso de 80 Anos ou mais , Estudos Transversais , Feminino , Humanos , Masculino , Sistema de Registros , Análise de Regressão
16.
Brain Res ; 1462: 118-28, 2012 Jun 26.
Artigo em Inglês | MEDLINE | ID: mdl-22338605

RESUMO

Frontotemporal lobar degeneration (FTLD), a neurodegenerative disease primarily affecting the frontal and temporal lobes, is one of the most common types of dementia. While the majority of FTLD cases are sporadic, approximately 10-40% of patients have an inherited form of FTLD. Mutations in the progranulin gene (GRN) have recently been identified as a major cause of FTLD with ubiquitin positive inclusions (FTLD-U). Because over 70 disease-linked GRN mutations cause abnormal deficiencies in the production of PGRN, a protein that plays a crucial role in embryogenesis, cell growth and survival, wound repair and inflammation, researchers now aim to design therapies that would increase PGRN levels in affected individuals, thereby alleviating the symptoms associated with disease. Several compounds and genetic factors, as well as PGRN receptors, have recently been identified because of their ability to regulate PGRN levels. Strict quality control measures are needed given that extreme PGRN levels at either end of the spectrum - too low or too high - can lead to neurodegeneration or cancer, respectively. The aim of this review is to highlight what is known regarding PGRN biology; to improve understanding of the mechanisms involved in regulating PGRN levels and highlight studies that are laying the groundwork for the development of effective therapeutic modulators of PGRN. This article is part of a Special Issue entitled RNA-Binding Proteins.


Assuntos
Degeneração Lobar Frontotemporal/genética , Peptídeos e Proteínas de Sinalização Intercelular/genética , Animais , Modelos Animais de Doenças , Degeneração Lobar Frontotemporal/tratamento farmacológico , Humanos , Inflamação/genética , Inflamação/patologia , Peptídeos e Proteínas de Sinalização Intercelular/deficiência , Peptídeos e Proteínas de Sinalização Intercelular/fisiologia , Camundongos , Mutação , Fatores de Crescimento Neural/fisiologia , Progranulinas , Transdução de Sinais/fisiologia , Cicatrização/fisiologia
17.
Curr Med Chem ; 19(7): 1008-20, 2012.
Artigo em Inglês | MEDLINE | ID: mdl-22257060

RESUMO

Frontotemporal Lobar Degeneration (FTLD) is characterized by behavioral changes, executive dysfunctions, and language impairment, sustained by different neuropathological patterns. The collective efforts of clinical, pathological and genetic studies have recently opened new insights into the underpinnings of pathological mechanisms of this complex disorder. Different types of inclusions define the new conceptual framework for FTLD classification. Up to now, Tau (FTLDTau-positive), TAR DNA-binding protein (TDP43, FTLD Tau-negative TDP43-positive) have been recognized as the most frequent neuropathological hallmarks of FTLD. In some clinical cases, monogenic forms are identified, mainly due to Microtubule Associated Protein (MAPT) or Granulin (GRN) mutations. No treatments for FTLD are available yet, and off-label medications studies testing potential modifying treatments on the basis of neuropathological positive, inhibitors of Tau kinases or manipulation of Tau-processing haploinsuffciency associated with GRN mutations, has been counteracted into pathological processing of TDP-43 and other key-molecules involved and their consequent translocation from nucleus to cytoplasm, and growing number of potential therapeutic targets. In this continuously new findings on molecular targets and modifying therapies in FTLD.


Assuntos
Degeneração Lobar Frontotemporal/tratamento farmacológico , Fármacos Neuroprotetores/uso terapêutico , Adenosina Trifosfatases/metabolismo , Proteínas de Ciclo Celular/metabolismo , Ensaios Clínicos como Assunto , Sistemas de Liberação de Medicamentos , Desenho de Drogas , Complexos Endossomais de Distribuição Requeridos para Transporte/metabolismo , Degeneração Lobar Frontotemporal/fisiopatologia , Humanos , Proteína com Valosina
18.
Braz J Psychiatr ; 33(1): 81-90, 2011 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-21537725

RESUMO

OBJECTIVE: To identify the therapeutic options available for treatment of cognitive and behavioral symptoms in frontotemporal lobar degeneration. METHOD: Systematic review using the descriptors "frontotemporal lobar degeneration" OR "frontotemporal dementia" OR "fronto-temporal dementia" OR "fronto-temporal degeneration" OR "Pick's disease" OR "Pick's atrophy" OR "semantic dementia" OR "progressive aphasia" AND "pharmacotherapy" OR "treatment" OR "efficacy" OR "effects" OR "management" was performed in the Medline and Lilacs databases. SELECTION CRITERIA: Quality A - randomized clinical trials. Quality B - open studies or reports of six or more cases. Quality C - reports of five or fewer cases. Two reviewers independently assessed the clinical studies. Information collected included diagnostic criteria used, sample size, duration, efficacy and tolerability measures used and results obtained. RESULTS: From the 532 studies found, 29 complied with the inclusion criteria. All studies worked with a small sample, had short duration of treatment and used non-uniform measures in evaluating efficacy and tolerability. Studies showed disparate results with respect to behavior and cognition. CONCLUSION: There is still little, and poor, evidence available for treatment of frontotemporal lobar degeneration and studies with better methodological background are needed.


Assuntos
Degeneração Lobar Frontotemporal/tratamento farmacológico , Demência Frontotemporal/tratamento farmacológico , Humanos , Doença de Pick/tratamento farmacológico , Ensaios Clínicos Controlados Aleatórios como Assunto , Resultado do Tratamento
19.
Rev. bras. psiquiatr ; 33(1): 81-90, Mar. 2011. tab
Artigo em Inglês | LILACS | ID: lil-584109

RESUMO

OBJECTIVE: To identify the therapeutic options available for treatment of cognitive and behavioral symptoms in frontotemporal lobar degeneration. METHOD: Systematic review using the descriptors "frontotemporal lobar degeneration" OR "frontotemporal dementia" OR "fronto-temporal dementia" OR "fronto-temporal degeneration" OR "Pick's disease" OR "Pick's atrophy" OR "semantic dementia" OR "progressive aphasia" AND "pharmacotherapy" OR "treatment" OR "efficacy" OR "effects" OR "management" was performed in the Medline and Lilacs databases. Selection criteria: Quality A - randomized clinical trials. Quality B - open studies or reports of six or more cases. Quality C - reports of five or fewer cases. Two reviewers independently assessed the clinical studies. Information collected included diagnostic criteria used, sample size, duration, efficacy and tolerability measures used and results obtained. RESULTS: From the 532 studies found, 29 complied with the inclusion criteria. All studies worked with a small sample, had short duration of treatment and used non-uniform measures in evaluating efficacy and tolerability. Studies showed disparate results with respect to behavior and cognition. CONCLUSION: There is still little, and poor, evidence available for treatment of frontotemporal lobar degeneration and studies with better methodological background are needed.


OBJETIVO: Identificar as opções terapêuticas disponíveis para tratamento dos sintomas cognitivos e comportamentais da degeneração lobar frontotemporal. MÉTODO: Revisão sistemática utilizando os descritores "frontotemporal lobar degeneration OR frontotemporal dementia OR fronto-temporal dementia OR fronto-temporal degeneration OR Pick's disease OR Pick's atrophy OR semantic dementia OR progressive aphasia AND pharmacotherapy OR treatment OR efficacy OR effects OR management" nas bases Medline e Lilacs. Critérios de seleção: Qualidade A - Estudos clínicos randomizados. Qualidade B - Estudos abertos ou relatos de seis ou mais casos. Qualidade C - Relatos de cinco ou menos casos. Dois revisores avaliaram independentemente os estudos clínicos. As informações coletadas incluíram critérios de diagnóstico utilizados, número da amostra, duração, medidas de eficácia e tolerabilidade utilizadas e os resultados obtidos. RESULTADOS: Encontraram-se 532 estudos e 29 preenchiam os critérios. Todos os estudos incluíam uma amostra pequena, com curta duração de tratamento, com utilização de medidas não uniformes na avaliação da eficácia e da tolerabilidade. O comportamento e a cognição apresentaram resultados díspares entre os estudos. CONCLUSÃO: São poucas as evidências disponíveis para tratamento da degeneração lobar frontotemporal e de qualidade insatisfatória, sendo necessários estudos com maior rigor metodológico.


Assuntos
Humanos , Degeneração Lobar Frontotemporal/tratamento farmacológico , Demência Frontotemporal/tratamento farmacológico , Doença de Pick/tratamento farmacológico , Ensaios Clínicos Controlados Aleatórios como Assunto , Resultado do Tratamento
20.
J Neurosci ; 31(5): 1885-94, 2011 Feb 02.
Artigo em Inglês | MEDLINE | ID: mdl-21289198

RESUMO

Numerous loss-of-function mutations in the progranulin (GRN) gene cause frontotemporal lobar degeneration with ubiquitin and TAR-DNA binding protein 43-positive inclusions by reduced production and secretion of GRN. Consistent with the observation that GRN has neurotrophic properties, pharmacological stimulation of GRN production is a promising approach to rescue GRN haploinsufficiency and prevent disease progression. We therefore searched for compounds capable of selectively increasing GRN levels. Here, we demonstrate that four independent and highly selective inhibitors of vacuolar ATPase (bafilomycin A1, concanamycin A, archazolid B, and apicularen A) significantly elevate intracellular and secreted GRN. Furthermore, clinically used alkalizing drugs, including chloroquine, bepridil, and amiodarone, similarly stimulate GRN production. Elevation of GRN levels occurs via a translational mechanism independent of lysosomal degradation, autophagy, or endocytosis. Importantly, alkalizing reagents rescue GRN deficiency in organotypic cortical slice cultures from a mouse model for GRN deficiency and in primary cells derived from human patients with GRN loss-of-function mutations. Thus, alkalizing reagents, specifically those already used in humans for other applications, and vacuolar ATPase inhibitors may be therapeutically used to prevent GRN-dependent neurodegeneration.


Assuntos
Álcalis/farmacologia , Córtex Cerebral/metabolismo , Fibroblastos/metabolismo , Degeneração Lobar Frontotemporal/metabolismo , Peptídeos e Proteínas de Sinalização Intercelular/metabolismo , Neurônios/metabolismo , ATPases Vacuolares Próton-Translocadoras/antagonistas & inibidores , Amiodarona/farmacologia , Animais , Animais Recém-Nascidos , Proteína 5 Relacionada à Autofagia , Bepridil/farmacologia , Northern Blotting , Compostos Bicíclicos Heterocíclicos com Pontes/farmacologia , Células Cultivadas , Córtex Cerebral/efeitos dos fármacos , Cloroquina/farmacologia , Ensaio de Imunoadsorção Enzimática , Feminino , Fibroblastos/efeitos dos fármacos , Degeneração Lobar Frontotemporal/tratamento farmacológico , Degeneração Lobar Frontotemporal/genética , Células HEK293 , Células HeLa , Humanos , Peptídeos e Proteínas de Sinalização Intercelular/deficiência , Peptídeos e Proteínas de Sinalização Intercelular/genética , Macrolídeos/farmacologia , Masculino , Camundongos , Proteínas Associadas aos Microtúbulos/deficiência , Proteínas Associadas aos Microtúbulos/genética , Mutação , Neurônios/efeitos dos fármacos , RNA Mensageiro/efeitos dos fármacos , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Tiazóis/farmacologia
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