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In this paper, the image motion introduced by the staring action itself during optical remote sensing satellites staring imaging with area-array detectors is studied. The image motion is decomposed into the angle-rotation image motion caused by the change of observation angle, the size-scaling image motion caused by the change of observation distance, and the Earth-rotation image motion caused by the rotation of the ground object with the Earth. The theoretical derivation of the angle-rotation image motion and size-scaling image motion is conducted, and the numerical analysis of the Earth-rotation image motion is carried out. Based on the comparison among the characteristics of the three types of image motions, the conclusion is drawn that, for general staring imaging scenes, the angle-rotation image motion is dominant, followed by the size-scaling image motion and the ignorable Earth-rotation image motion. On the condition that the image motion does not exceed 1 pixel, the allowed maximum exposure time for area-array staring imaging is analyzed. It is found that the large-array satellite is not suitable for long-exposure imaging, as its allowed exposure time decreases rapidly with the increase of roll angle. A satellite with a 12k×12k area-array detector and 500 km orbit is taken as an example. The allowed exposure time is 0.88 s when roll angle of the satellite is 0°; it decreases to 0.02 s when the roll angle increases to 28°.
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Fragile X syndrome (FXS) is a monogenic form of intellectual disability and autism spectrum disorder caused by the absence of the fragile X mental retardation protein (FMRP). In biological models for the disease, this leads to upregulated mRNA translation and as a consequence, deficits in synaptic architecture and plasticity. Preclinical studies revealed that pharmacological interventions restore those deficits, which are thought to mediate the FXS cognitive and behavioral symptoms. Here, we characterized the de novo rate of protein synthesis in patients with FXS and their relationship with clinical severity. We measured the rate of protein synthesis in fibroblasts derived from 32 individuals with FXS and from 17 controls as well as in fibroblasts and primary neurons of 27 Fmr1 KO mice and 20 controls. Here, we show that levels of protein synthesis are increased in fibroblasts of individuals with FXS and Fmr1 KO mice. However, this cellular phenotype displays a broad distribution and a proportion of fragile X individuals and Fmr1 KO mice do not show increased levels of protein synthesis, having measures in the normal range. Because the same Fmr1 KO animal measures in fibroblasts predict those in neurons we suggest the validity of this peripheral biomarker. Our study offers a potential explanation for the comprehensive drug development program undertaken thus far yielding negative results and suggests that a significant proportion, but not all individuals with FXS, may benefit from the reduction of excessive levels of protein synthesis.
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Transtorno do Espectro Autista/genética , Proteína do X Frágil da Deficiência Intelectual/genética , Síndrome do Cromossomo X Frágil/genética , Adolescente , Adulto , Idoso , Animais , Transtorno do Espectro Autista/fisiopatologia , Criança , Modelos Animais de Doenças , Feminino , Fibroblastos/metabolismo , Fibroblastos/patologia , Proteína do X Frágil da Deficiência Intelectual/biossíntese , Síndrome do Cromossomo X Frágil/fisiopatologia , Hipocampo/metabolismo , Hipocampo/fisiopatologia , Humanos , Masculino , Camundongos , Camundongos Knockout , Pessoa de Meia-Idade , Neurônios/metabolismo , Neurônios/patologia , Adulto JovemRESUMO
PURPOSE: The purpose of this study was to evaluate the pharmacogenomics of response to topical ocular tumor necrosis factor α (TNFα) inhibitor licaminlimab in patients with DED. METHODS: Three single-nucleotide polymorphisms (SNPs) associated with Sjögren syndrome, 3 in the TNFα gene and 1 in the TNF receptor 1 (TNFR1) gene, were assessed for association with response to licaminlimab in participants from a randomized, vehicle-controlled, Phase 2 study in which adults with DED and severe ocular discomfort persisting despite treatment with artificial tears received licaminlimab or vehicle for 6 weeks. Response was assessed for change from baseline in Global Ocular Discomfort score at Day 29 of treatment. The pharmacogenomic analysis was a prospectively specified exploratory objective of the study. mRNA expression for TNFα, interleukin (IL) 1ß, and IL8 in conjunctival epithelium cells was determined. The relationship between SNPs and response to licaminlimab was assessed using a mixed model repeated measures analysis. RESULTS: SNP rs1800693 in the TNFR1 gene showed a significant effect on response to licaminlimab (P < 0.0001, initial association test); no effect was seen for any of the other SNPs tested. The CC genotype of rs1800693 was associated with much greater response to licaminlimab than the CT or TT genotypes: LS mean changes from baseline to Day 29 in Global Ocular Discomfort score were -29.5, -0.09, and -3.90, in patients with the CC, CT, and TT genotypes, respectively (P < 0.0001). No significant effect was observed in vehicle-treated patients. Improvements from baseline were seen in 3/4 licaminlimab-treated participants with the CC genotype. Conjunctival epithelium cell levels of mRNA for TNFα, IL1ß, and IL8 decreased from baseline in participants with the CC genotype, but not with the CT or TT genotypes. Between-genotype differences in mRNA levels were not observed in participants receiving vehicle. CONCLUSIONS: The CC genotype of rs1800693, relatively common in patients with DED, was strongly associated with response to licaminlimab and decreased inflammatory cytokine gene expression in ocular surface cells during treatment. This study is one of the first to our knowledge to investigate pharmacogenomics in the treatment of DED.
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Retrospective data are presented to support a spectrum of early Alzheimer's disease (AD) along a continuum defined by gender and genotype. The putative neurodegenerative mechanisms driving distinct phenotypes at each end of the spectrum are glial hypoactivity associated with early failure of synaptic cholinergic neurotransmission and glial overactivation associated with loss of neural network connectivity due to accelerated age-related breakdown of myelin. In early AD, male butyrylcholinesterase K-variant carriers with one or two apolipoprotein É4 alleles have prominent medial temporal atrophy, synaptic failure, cognitive decline, and accumulation of aggregated beta-amyloid peptide. Increasing synaptic acetylcholine in damaged but still functional cholinergic synapses improves cognitive symptoms, whereas increasing the ability of glia to support synapses and to clear beta-amyloid peptide might be disease-modifying. Conversely, chronic glial overactivation can also drive degenerative processes and in butyrylcholinesterase K-variant negative females generalized glial overactivation may be the main driver from mild cognitive impairment to AD. Females are more likely than males to have accelerated age-related myelin breakdown, more widespread white matter loss, loss of neural network connectivity, whole brain atrophy, and functional decline. Increasing extracellular acetylcholine levels blocks glial activation, reduces myelin loss and damage to neural network connectivity, and is disease-modifying. Between extremes characterized by gender, genotype, and age, pathophysiology may be mixed and this spectrum may explain much of the heterogeneity of amnestic mild cognitive impairment. Preservation of the functional integrity of the neural network may be an important component of strengthening cognitive reserve and significantly delaying the onset and progression of dementia, particularly in females. Prospective confirmation of these hypotheses is required. Implications for future research and therapeutic opportunities are discussed.
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Doença de Alzheimer/genética , Butirilcolinesterase/genética , Predisposição Genética para Doença/genética , Doença de Alzheimer/patologia , Feminino , Genótipo , Humanos , Masculino , Caracteres SexuaisRESUMO
Purpose: To assess the progression in functional and structural measures over a five-year period in patients with retinal dystrophy caused by RLBP1 gene mutation. Methods: This prospective, noninterventional study included patients with biallelic RLBP1 mutations from two clinical sites in Sweden and Canada. Key assessments included ocular examinations, visual functional measures (best-corrected visual acuity [BCVA], contrast sensitivity [CS], dark-adaptation [DA] kinetics up to six hours for two wavelengths [450 and 632 nm], Humphrey visual fields [HVF], full-field flicker electroretinograms), and structural ocular assessments. Results: Of the 45 patients enrolled, 38 completed the full five years of follow-up. At baseline, patients had BCVA ranging from -0.2 to 1.3 logMAR, poor CS, HVF defects, and prominent thinning in central foveal thickness. All patients had extremely prolonged DA rod recovery of approximately six hours at both wavelengths. The test-retest repeatability was high across all anatomic and functional endpoints. Cross-sectionally, poorer VA was associated with older age (right eye, correlation coefficient [CC]: 0.606; left eye, CC: -0.578; P < 0.001) and HVF MD values decreased with age (right eye, CC: -0.672, left eye, CC: -0.654; P < 0.001). However, no major changes in functional or structural measures were noted longitudinally over the five-year period. Conclusions: This natural history study, which is the first study to monitor patients with RLBP1 RD for five years, showed that severely delayed DA sensitivity recovery, a characteristic feature of this disease, was observed in all patients across all age groups (17-69 years), making it a potentially suitable efficacy assessment for gene therapy treatment in this patient population.
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Distrofias Retinianas , Retinose Pigmentar , Humanos , Adolescente , Adulto Jovem , Adulto , Pessoa de Meia-Idade , Idoso , Estudos Prospectivos , Campos Visuais , Acuidade Visual , Retinose Pigmentar/diagnóstico , Retinose Pigmentar/genéticaRESUMO
PURPOSE: We evaluated the association between ambient particulate matter (PM) exposure and eosinophilic chronic rhinosinusitis with nasal polyps (CRSwNP), and predicted the CRSwNP recurrence risk using machine learning algorithms. METHODS: In total, 1,086 patients with CRSwNP were recruited from nine hospitals in China during 2014-2019. The average annual concentrations of ambient PMs before surgery were assessed using satellite-based daily concentrations of PM2.5 and PM10 for a 1 × 1-km2 area. Linear regression and logistic regression models were used to evaluate the associations of PM exposure with eosinophilia and risks of eosinophilic CRSwNPs. In addition, mediation effect analysis was used to validate the interrelationships of the aforementioned factors. Finally, machine learning algorithms were used to predict the recurrence risks of CRSwNPs. RESULTS: There was a significantly increased risk of eosinophilic CRSwNPs with each 10 µg/m3 increase in PMs, with odds ratios (ORs) of 1.039 (95% confidence interval [CI] = 1.007-1.073) for PM10 and 1.058 (95% CI = 1.007- 1.112) for PM2.5. Eosinophils had a significant mediation effect, which accounted for 52% and 35% of the relationships of CRSwNP recurrence with PM10 and PM2.5, respectively. Finally, we developed a naïve Bayesian model to predict the risk of CRSwNP recurrence based on PM exposure, inflammatory data, and patients' demographic factors. CONCLUSIONS: Increased PM exposure is associated with an increased risk of eosinophilic CRSwNP in China. Therefore, patients with eosinophilic CRSwNP should reduce PM exposure to mitigate its harmful impacts.
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Eosinofilia , Pólipos Nasais , Rinite , Sinusite , Humanos , Pólipos Nasais/epidemiologia , Pólipos Nasais/complicações , Pólipos Nasais/cirurgia , Rinite/epidemiologia , Teorema de Bayes , Eosinófilos , Eosinofilia/complicações , Eosinofilia/cirurgia , Sinusite/epidemiologia , Sinusite/complicações , Sinusite/cirurgia , Doença CrônicaRESUMO
The Kaposi's sarcoma herpesvirus (KSHV) has been identified as the etiologic agent of Kaposi's sarcoma (KS), but initial events leading to KS development remain unclear. Characterization of the KSHV genome reveals the presence of numerous potential oncogenes. To address their contribution to the initiation of the endothelial cell-derived KS tumor, we developed a novel transgenic mouse that enabled endothelial cell-specific infection in vivo using virus expressing candidate KSHV oncogenes. Here we show that transduction of one gene, vGPCR, was sufficient to induce angioproliferative tumors that strikingly resembled human KS. Endothelial cells expressing vGPCR were further able to promote tumor formation by cells expressing KSHV latent genes, suggestive of a cooperative role among viral genes in the promotion of Kaposi's sarcomagenesis.
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Transformação Celular Neoplásica , Herpesvirus Humano 8/genética , Proteínas Proto-Oncogênicas , Receptores de Quimiocinas/metabolismo , Sarcoma de Kaposi/virologia , Proteínas Virais/metabolismo , Animais , Vírus da Leucose Aviária/genética , Células Cultivadas , Endotélio Vascular/fisiologia , Endotélio Vascular/ultraestrutura , Endotélio Vascular/virologia , Engenharia Genética/métodos , Imuno-Histoquímica , Camundongos , Camundongos Transgênicos , Microscopia Eletrônica , Proteínas de Neoplasias/genética , Regiões Promotoras Genéticas , Sarcoma de Kaposi/genética , Sarcoma de Kaposi/ultraestrutura , Transdução GenéticaRESUMO
Importance: Clonal hematopoiesis of indeterminate potential (CHIP) is associated with increased risk of atherosclerotic cardiovascular disease, and mouse experiments suggest that CHIP related to Tet2 loss of function in myeloid cells accelerates atherosclerosis via augmented interleukin (IL) 1ß signaling. Objective: To assess whether individuals with CHIP have greater cardiovascular event reduction in response to IL-1ß neutralization in the Canankinumab Anti-inflammatory Thrombosis Outcomes Trial (CANTOS). Design, Setting, and Participants: This randomized clinical trial took place from April 2011 to June 2017 at more than 1000 clinical sites in 39 countries. Targeted deep sequencing of genes previously associated with CHIP in a subset of trial participants using genomic DNA prepared from baseline peripheral blood samples were analyzed. All participants had prior myocardial infarction and elevated high-sensitivity C-reactive protein level above 0.20 mg/dL. Analysis took place between June 2017 and December 2021. Interventions: Canakinumab, an anti-IL-1ß antibody, given at doses of 50, 150, and 300 mg once every 3 months. Main Outcomes and Measures: Major adverse cardiovascular events (MACE). Results: A total of 338 patients (8.6%) were identified in this subset with evidence for clonal hematopoiesis. As expected, the incidence of CHIP increased with age; the mean (SD) age of patients with CHIP was 66.3 (9.2) years and 61.5 (9.6) years in patients without CHIP. Unlike other populations that were not preselected for elevated C-reactive protein, in the CANTOS population variants in TET2 were more common than DNMT3A (119 variants in 103 patients vs 86 variants in 85 patients). Placebo-treated patients with CHIP showed a nonsignificant increase in the rate of MACE compared with patients without CHIP using a Cox proportional hazard model (hazard ratio, 1.32 [95% CI, 0.86-2.04]; P = .21). Exploratory analyses of placebo-treated patients with a somatic variant in either TET2 or DNMT3A (n = 58) showed an equivocal risk for MACE (hazard ratio, 1.65 [95% CI, 0.97-2.80]; P = .06). Patients with CHIP due to somatic variants in TET2 also had reduced risk for MACE while taking canakinumab (hazard ratio, 0.38 [95% CI, 0.15-0.96]) with equivocal difference compared with others (P for interaction = .14). Conclusions and Relevance: These results are consistent with observations of increased risk for cardiovascular events in patients with CHIP and raise the possibility that those with TET2 variants may respond better to canakinumab than those without CHIP. Future studies are required to further substantiate this hypothesis. Trial Registration: ClinicalTrials.gov Identifier: NCT01327846.
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Anticorpos Monoclonais Humanizados , Aterosclerose , Hematopoiese Clonal , Dioxigenases , Anticorpos Monoclonais Humanizados/uso terapêutico , Aterosclerose/tratamento farmacológico , Proteína C-Reativa/análise , Proteínas de Ligação a DNA/genética , Dioxigenases/genética , HumanosRESUMO
Apolipoprotein E (APOE) epsilon4 and butyrylcholinesterase-K (BuChE-K) are associated with an increased risk for Alzheimer's disease. The primary objective was to evaluate frequencies of these alleles in dementia with Lewy bodies (DLB) and Parkinson's disease dementia (PDD). A secondary objective was to evaluate influences on rate of cognitive decline. This analysis used data from participants consenting to pharmacogenetic testing in placebo-controlled rivastigmine studies. Allele frequencies in DLB and PDD were compared using logistic regression. Within the PDD placebo sample, associations with cognitive decline were evaluated (the DLB sample was too small for these evaluations). Fifty-seven DLB and 323 PDD subjects provided APOE and BuChE data. Allelic frequencies were higher in DLB, relative to PDD subjects, for BuChE-K (P = 0.06), APOE epsilon4 (P < 0.001), or both alleles together (P < 0.001). More rapid cognitive decline was seen in PDD patients carrying both alleles, compared with other genotypes. Subjects with hyperhomocysteinemia were associated with more rapid decline in the presence of BuChE-K, with or without APOE epsilon4. These results suggest that genetic and biochemical risk factors for AD and PDD pathology may be important in dementia onset and progression in these Lewy body disorders.
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Apolipoproteína E4/genética , Butirilcolinesterase/genética , Transtornos Cognitivos/epidemiologia , Genótipo , Hiper-Homocisteinemia/epidemiologia , Doença por Corpos de Lewy/epidemiologia , Doença por Corpos de Lewy/genética , Idoso , Transtornos Cognitivos/diagnóstico , Feminino , Frequência do Gene , Humanos , Doença por Corpos de Lewy/tratamento farmacológico , Masculino , Fármacos Neuroprotetores/uso terapêutico , Testes Neuropsicológicos , Fenilcarbamatos/uso terapêutico , Transtornos Psicomotores/diagnóstico , Transtornos Psicomotores/epidemiologia , Ensaios Clínicos Controlados Aleatórios como Assunto , Rivastigmina , Índice de Gravidade de DoençaRESUMO
PURPOSE: To assess the clinical safety, tolerability, and efficacy of topically administered MGV354, a soluble guanylate cyclase (sGC) activator, in patients with ocular hypertension (OH) or glaucoma. DESIGN: Double-masked, randomized, and vehicle-controlled study. METHODS: Parts 1 and 2 evaluated safety and tolerability to identify the maximum tolerated dose (MTD) of once-daily MGV354 in 32 healthy volunteers (Part 1) and 16 patients with OH or glaucoma (Part 2) at a single clinical site. Part 3 was a multisite trial that evaluated intraocular pressure (IOP)-lowering efficacy of the MTD administered nightly for 1 week in 50 patients with minimum IOP of 24 mm Hg at 8 AM, with a main outcome measure of mean diurnal IOP at day 8 compared to baseline (ClinicalTrials.govNCT02743780). RESULTS: There was no difference in favor of MGV354 for IOP lowering; change from baseline to day 8 in mean diurnal IOP was -0.6 mm Hg for MGV354-treated patients and -1.1 mm Hg for vehicle-treated patients in Part 3, with a confidence interval of -0.7 to 1.7. The most common adverse events reported after MGV354 administration were conjunctival and ocular hyperemia. CONCLUSIONS: Overall, MGV354 0.1% demonstrated no statistically significant effect compared to vehicle in lowering IOP based on the study's main outcome measure. MGV354 produced ocular hyperemia consistent with its pharmacology.
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Ativadores de Enzimas/uso terapêutico , Glaucoma de Ângulo Aberto/tratamento farmacológico , Guanilato Ciclase/metabolismo , Pressão Intraocular/efeitos dos fármacos , Piperidinas/uso terapêutico , Pirazóis/uso terapêutico , Piridinas/uso terapêutico , Administração Oftálmica , Adolescente , Adulto , Idoso , Método Duplo-Cego , Ativadores de Enzimas/efeitos adversos , Feminino , Glaucoma de Ângulo Aberto/fisiopatologia , Humanos , Pressão Intraocular/fisiologia , Masculino , Dose Máxima Tolerável , Pessoa de Meia-Idade , Nível de Efeito Adverso não Observado , Hipertensão Ocular/tratamento farmacológico , Hipertensão Ocular/fisiopatologia , Soluções Oftálmicas , Piperidinas/efeitos adversos , Pirazóis/efeitos adversos , Piridinas/efeitos adversos , Tonometria Ocular , Resultado do Tratamento , Acuidade Visual/fisiologia , Adulto JovemRESUMO
OBJECTIVE: To assess the effect of rivastigmine in patients with mild cognitive impairment (MCI) on the time to clinical diagnosis of Alzheimer's disease (AD) and the rate of cognitive decline. METHODS: The study was a double-blind, randomised, placebo-controlled trial of up to 48 months. All patients had MCI operationally defined by having cognitive symptoms, a global clinical dementia rating stage of 0.5, a score of less than 9 on the New York University delayed paragraph recall test, and by not meeting the diagnostic criteria for AD. Primary efficacy variables were time to clinical diagnosis of AD, and change in performance on a cognitive test battery. This study is registered with the US National Institutes of Health clinical trials database (ClinicalTrials.gov), number NCT00000174. FINDINGS: Of 1018 study patients enrolled, 508 were randomly assigned to rivastigmine and 510 to placebo; 17.3% of patients on rivastigmine and 21.4% on placebo progressed to AD (hazard ratio 0.85 [95% CI 0.64-1.12]; p=0.225). There was no significant difference between the rivastigmine and placebo groups on the standardised Z score for the cognitive test battery measured as mean change from baseline to endpoint (-0.10 [95% CI -0.63 to 0.44], p=0.726). Serious adverse events were reported by 141 (27.9%) rivastigmine-treated patients and 155 (30.5%) patients on placebo; adverse events of all types were reported by 483 (95.6%) rivastigmine-treated patients and 472 (92.7%) placebo-treated patients. The predominant adverse events were cholinergic: the frequencies of nausea, vomiting, diarrhoea, and dizziness were two to four times higher in the rivastigmine group than in the placebo group. INTERPRETATION: There was no significant benefit of rivastigmine on the progression rate to AD or on cognitive function over 4 years. The overall rate of progression from MCI to AD in this randomised clinical trial was much lower than predicted. Rivastigmine treatment was not associated with any significant safety concerns.
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Doença de Alzheimer/tratamento farmacológico , Inibidores da Colinesterase/uso terapêutico , Transtornos Cognitivos/tratamento farmacológico , Fenilcarbamatos/uso terapêutico , Idoso , Idoso de 80 Anos ou mais , Doença de Alzheimer/complicações , Doença de Alzheimer/diagnóstico , Análise de Variância , Inibidores da Colinesterase/efeitos adversos , Transtornos Cognitivos/etiologia , Progressão da Doença , Método Duplo-Cego , Feminino , Seguimentos , Humanos , Masculino , Pessoa de Meia-Idade , Testes Neuropsicológicos , Fenilcarbamatos/efeitos adversos , Rivastigmina , Tremor/induzido quimicamente , Vômito/induzido quimicamenteRESUMO
BACKGROUND: Younger Alzheimer's disease (AD) patients appear to differ genetically and neuropathologically from older AD patients, and may experience a more aggressive disease course compared with older patients. A randomised trial investigated the efficacy and tolerability of rivastigmine, an inhibitor of acetylcholinesterase (AChE) and butyrylcholinesterase (BuChE), and donepezil, an AChE-selective inhibitor, in patients with AD over a 2-year period. This retrospective analysis investigated whether younger and older patients showed differential tolerability and efficacy responses to cholinesterase inhibitor treatment. METHODS: For the current analysis, patients were divided according to age at baseline: those aged < 75 years and those aged >or= 75 years. Efficacy measures were the Severe Impairment Battery (SIB), Neuropsychiatric Inventory (NPI), Global Deterioration Scale (GDS), Mini-Mental State Examination (MMSE) and the AD Cooperative Study Activities of Daily Living scale (ADCS-ADL). Changes in efficacy parameters and adverse event frequencies were calculated for rivastigmine and donepezil-treated patients in both age groups. Exploratory analyses were also conducted on SIB, ADCS-ADL and NPI in patients who consented to pharmacogenetic testing at baseline. Genotyping of the apolipoprotein E (APOE) epsilon4 allele and the BuChE K-variant was conducted using the TaqMan assay. Main efficacy analyses were based on an intent-to-treat last observation carried forward (ITT-LOCF) population. RESULTS: Of the 994 patients who received the study drug, 362 (36.4%) were younger than 75 years and 632 (63.6%) were aged 75 years or over. Rivastigmine provided significant benefits in younger patients compared with donepezil on the NPI-10, NPI-12, NPI-D, GDS and ADCS-ADL (all p < 0.05, ITT-LOCF). With the exception of the NPI-D in favour of donepezil (p < 0.05, ITT-LOCF), no significant treatment differences were observed in older patients. Younger patients with two wild-type BuChE alleles had a significantly greater response to rivastigmine than donepezil on the ADCS-ADL (p < 0.01, ITT-LOCF) and SIB (p < 0.05, ITT-LOCF). The most common adverse events were nausea and vomiting and these were more frequent in rivastigmine-treated patients. CONCLUSION: In this sub group analysis, patients younger than 75 years of age showed greater treatment responses to rivastigmine than donepezil. Analysis of response by BuChE genotype suggests that this differential effect may be due to the inhibition of BuChE, in addition to AChE, by rivastigmine.
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Doença de Alzheimer/tratamento farmacológico , Indanos/uso terapêutico , Fármacos Neuroprotetores/uso terapêutico , Nootrópicos/uso terapêutico , Fenilcarbamatos/uso terapêutico , Piperidinas/uso terapêutico , Fatores Etários , Idoso , Idoso de 80 Anos ou mais , Análise de Variância , Donepezila , Feminino , Humanos , Indanos/efeitos adversos , Masculino , Pessoa de Meia-Idade , Fármacos Neuroprotetores/efeitos adversos , Nootrópicos/efeitos adversos , Fenilcarbamatos/efeitos adversos , Piperidinas/efeitos adversos , Estudos Retrospectivos , Rivastigmina , Índice de Gravidade de Doença , Resultado do TratamentoRESUMO
BACKGROUND: Fragile X syndrome (FXS) is the most common form of inherited intellectual disability, resulting from the loss of function of the fragile X mental retardation 1 (FMR1) gene. The molecular pathways associated with FMR1 epigenetic silencing are still elusive, and their characterization may enhance the discovery of novel therapeutic targets as well as the development of novel clinical biomarkers for disease status. RESULTS: We have deployed customized epigenomic profiling assays to comprehensively map the FMR1 locus chromatin landscape in peripheral mononuclear blood cells (PBMCs) from eight FXS patients and in fibroblast cell lines derived from three FXS patient. Deoxyribonucleic acid (DNA) methylation (5-methylcytosine (5mC)) and hydroxymethylation (5-hydroxymethylcytosine (5hmC)) profiling using methylated DNA immunoprecipitation (MeDIP) combined with a custom FMR1 microarray identifies novel regions of DNA (hydroxy)methylation changes within the FMR1 gene body as well as in proximal flanking regions. At the region surrounding the FMR1 transcriptional start sites, increased levels of 5mC were associated to reciprocal changes in 5hmC, representing a novel molecular feature of FXS disease. Locus-specific validation of FMR1 5mC and 5hmC changes highlighted inter-individual differences that may account for the expected DNA methylation mosaicism observed at the FMR1 locus in FXS patients. Chromatin immunoprecipitation (ChIP) profiling of FMR1 histone modifications, together with 5mC/5hmC and gene expression analyses, support a functional relationship between 5hmC levels and FMR1 transcriptional activation and reveal cell-type specific differences in FMR1 epigenetic regulation. Furthermore, whilst 5mC FMR1 levels positively correlated with FXS disease severity (clinical scores of aberrant behavior), our data reveal for the first time an inverse correlation between 5hmC FMR1 levels and FXS disease severity. CONCLUSIONS: We identify novel, cell-type specific, regions of FMR1 epigenetic changes in FXS patient cells, providing new insights into the molecular mechanisms of FXS. We propose that the combined measurement of 5mC and 5hmC at selected regions of the FMR1 locus may significantly enhance FXS clinical diagnostics and patient stratification.
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Metilação de DNA , Epigênese Genética , Proteína do X Frágil da Deficiência Intelectual/genética , Síndrome do Cromossomo X Frágil/genética , Inativação Gênica , Adolescente , Adulto , Criança , Imunoprecipitação da Cromatina , Epigênese Genética/genética , Epigenômica , Proteína do X Frágil da Deficiência Intelectual/fisiologia , Marcadores Genéticos , Humanos , Masculino , Pessoa de Meia-Idade , Interferência de RNA , Adulto JovemRESUMO
OBJECTIVES: Randomised controlled trials that directly compare cholinesterase inhibitors for the treatment of Alzheimer's disease have been characterised by significant methodological limitations. As a consequence, they have failed to establish whether there are differences between agents in this class. To help address this question, a double-blind, randomised, controlled, multicentre trial was designed to evaluate the efficacy and tolerability of cholinesterase inhibitor treatment in patients with moderate to moderately-severe Alzheimer's disease over a 2-year period. METHODS: Patients were randomly assigned to rivastigmine 3-12 mg/day or donepezil 5-10 mg/day. Efficacy measures comprised assessments of cognition, activities of daily living, global functioning and behavioural symptoms. Safety and tolerability assessments included adverse events and measurement of vital signs. RESULTS: In total, 994 patients received cholinesterase inhibitor treatment (rivastigmine, n = 495; donepezil, n = 499), and 57.9% of patients completed the study. The most frequent reason for premature discontinuation in both treatment groups was adverse events, primarily gastrointestinal. Adverse events were more frequent in the rivastigmine group during the titration phase, but similar in the maintenance phase. Serious adverse events were reported by 31.7% of rivastigmine- and 32.5% of donepezil-treated patients, respectively. Rivastigmine and donepezil had similar effects on measures of cognition and behaviour, but rivastigmine showed a statistically significant advantage on measures of activities of daily living and global functioning in the ITT-LOCF population. However, this was not maintained in the non-ITT-LOCF populations. In secondary subgroup analyses, AD patients who had genotypes that encoded for full expression of the butyrylcholinesterase enzyme (BuChE wt/wt; n = 226/340), who were < 75 years of age (n = 362/994) or who had symptoms suggestive of concomitant Lewy body disease (n = 49/994) showed significantly greater benefits from rivastigmine treatment. CONCLUSIONS: Cholinesterase inhibitor treatment may offer continued therapeutic benefit for up to 2 years in patients with moderate AD. Although both drugs performed similarly on cognition and behaviour, rivastigmine may provide greater benefit in activities of daily living and global functioning.
Assuntos
Doença de Alzheimer/tratamento farmacológico , Inibidores da Colinesterase/uso terapêutico , Indanos/uso terapêutico , Fenilcarbamatos/uso terapêutico , Piperidinas/uso terapêutico , Idoso , Idoso de 80 Anos ou mais , Inibidores da Colinesterase/farmacologia , Donepezila , Método Duplo-Cego , Feminino , Humanos , Indanos/farmacologia , Masculino , Pessoa de Meia-Idade , Fenilcarbamatos/farmacologia , Piperidinas/farmacologia , Rivastigmina , Fatores de Tempo , Resultado do TratamentoRESUMO
Fragile X syndrome (FXS) is an X-linked condition associated with intellectual disability and behavioral problems. It is caused by expansion of a CGG repeat in the 5' untranslated region of the fragile X mental retardation 1 (FMR1) gene. This mutation is associated with hypermethylation at the FMR1 promoter and resultant transcriptional silencing. FMR1 silencing has many consequences, including up-regulation of metabotropic glutamate receptor 5 (mGluR5)-mediated signaling. mGluR5 receptor antagonists have shown promise in preclinical FXS models and in one small open-label study of FXS. We examined whether a receptor subtype-selective inhibitor of mGluR5, AFQ056, improves the behavioral symptoms of FXS in a randomized, double-blind, two-treatment, two-period, crossover study of 30 male FXS patients aged 18 to 35 years. We detected no significant effects of treatment on the primary outcome measure, the Aberrant Behavior Checklist-Community Edition (ABC-C) score, at day 19 or 20 of treatment. In an exploratory analysis, however, seven patients with full FMR1 promoter methylation and no detectable FMR1 messenger RNA improved, as measured with the ABC-C, significantly more after AFQ056 treatment than with placebo (P < 0.001). We detected no response in 18 patients with partial promoter methylation. Twenty-four patients experienced an adverse event, which was mostly mild to moderately severe fatigue or headache. If confirmed in larger and longer-term studies, these results suggest that blockade of the mGluR5 receptor in patients with full methylation at the FMR1 promoter may show improvement in the behavioral attributes of FXS.
Assuntos
Epigênese Genética/genética , Proteína do X Frágil da Deficiência Intelectual/genética , Síndrome do Cromossomo X Frágil/genética , Receptores de Glutamato Metabotrópico/antagonistas & inibidores , Adulto , Metilação de DNA/genética , Síndrome do Cromossomo X Frágil/tratamento farmacológico , Humanos , Masculino , Pessoa de Meia-Idade , Regiões Promotoras Genéticas/genética , Receptor de Glutamato Metabotrópico 5 , Adulto JovemRESUMO
Non-enzymatic functions of butyrylcholinesterase (BuChE) include prevention of the aggregation of amyloid-beta peptide (A beta) in a concentration-dependent manner. This is mediated by the C-terminus of the protein, distal from the enzymatic site. The BuChE-K variant polymorphism lowers expression of BuChE protein and/or alters C-terminal activity. In combination with factors that increase production or reduce elimination of A beta, and/or increase susceptibility to A beta toxicity - such as the apolipoprotein E (APOE) epsilon 4 allele and/or hyperhomocysteinemia - BuChE-K may accelerate cholinergic synaptic and neuronal damage and cognitive decline. A beta-mediated damage to ascending cholinergic pathways may be further accentuated by Lewy body and/or cerebrovascular disease. As the disease advances and functioning cholinergic synapses disappear, both the rapid cognitive decline and response to cholinesterase inhibitor therapy in individuals with these factors may diminish. Non-enzymatic functions of the BuChE protein, APOE epsilon 4 status and hyperhomocysteinemia influence the progression of pathology, symptom expression, and response to cholinesterase inhibition in a stage-specific manner in neurodegenerative disorders associated with Alzheimer, Lewy body and vascular pathology.
Assuntos
Apolipoproteína E4/genética , Butirilcolinesterase/genética , Demência/complicações , Hiper-Homocisteinemia/complicações , Transtornos Cognitivos/complicações , Demência/enzimologia , Demência/genética , Humanos , Hiper-Homocisteinemia/enzimologia , Hiper-Homocisteinemia/genéticaRESUMO
OBJECTIVE: To evaluate the synergistic effects of the apolipoprotein E (APOE) epsilon4 and butyrylcholinesterase K-variant (BCHE-K) alleles on progression to Alzheimer's disease (AD) in individuals with mild cognitive impairment (MCI). METHODS: This was a post-hoc exploratory analysis from a 3-4-year, randomized, placebo-controlled study of rivastigmine in participants with MCI (InDDEx study). Participants who consented to genetic testing were included in the current analyses. The incidence of progression to AD, cognitive decline and changes in MRI brain volumes were investigated in participants from the placebo arm of the InDDEx study. RESULTS: Of the 1018 participants in the overall study, 464 were successfully genotyped for both APOE and butyrylcholinesterase. Of these, 68 (14.7%) carried > or =1 APOE epsilon4 and > or =1 BCHE-K allele. The presence of APOE epsilon4 was associated with a significantly higher incidence of progression to AD whereas the presence of BCHE-K had no independent effect on progression. A synergistic effect of the combined presence of APOE epsilon4 and BCHE-K on the time to clinical diagnosis of AD and on MRI brain volumes was seen. Progression to AD and hippocampal volumetric loss was greatest in participants who carried both APOE epsilon4 and BCHE-K alleles and lowest in BCHE-K carriers without the APOE epsilon4 allele. CONCLUSION: In MCI, the risk of cognitive decline, hippocampal volumetric loss and progression to AD seems to be the greatest in individuals who carry at least one copy of both the BCHE-K and APOE epsilon4 alleles.
Assuntos
Doença de Alzheimer/genética , Apolipoproteína E4/genética , Butirilcolinesterase/genética , Transtornos Cognitivos/genética , Idoso , Doença de Alzheimer/patologia , Transtornos Cognitivos/patologia , Progressão da Doença , Feminino , Testes Genéticos , Genótipo , Hipocampo/patologia , Humanos , Imageamento por Ressonância Magnética , Masculino , Testes NeuropsicológicosRESUMO
A randomized double-blind trial evaluated the efficacy and tolerability of rivastigmine, an inhibitor of acetylcholinesterase (AChE) and butyrylcholinesterase (BuChE), and donepezil, an AChE-selective inhibitor, in patients with Alzheimer's disease over a 2-year period. A retrospective analysis showed differential responses to cholinesterase inhibitors (ChE-Is) in patients younger than 75 years. This analysis investigated the effect of BuChE genotype on response to ChE-I therapy in these patients. In a retrospective analysis, patients younger than 75 who had consented to pharmacogenetic analysis were divided into groups according to BuChE genotype. Efficacy measures were the Severe Impairment Battery (SIB), Neuropsychiatric Inventory (NPI), Global Deterioration Scale (GDS), Mini-Mental State Examination (MMSE) and the Alzheimer's Disease Cooperative Study-Activities of Daily Living Scale (ADCS-ADL). Changes on efficacy parameters were calculated for rivastigmine-treated and donepezil-treated patients in both groups. Of 114 (34.1%) patients younger than 75 who were successfully assessed for BuChE genotype, 76 (66.7%) were homozygous for wild-type BuChE, and 38 (33.3%) carried at least one BuChE K-variant allele. Wild-type BuChE carriers showed significantly greater responses to rivastigmine than to donepezil on the SIB, ADCS-ADL, GDS and NPI. No significant between-treatment differences in efficacy were observed in BuChE K-variant carriers, although adverse events were more frequent in rivastigmine-treated patients. In this retrospective analysis, Alzheimer's disease patients younger than 75 with wild-type BuChE exhibited differential efficacy to rivastigmine, while BuChE K-variant carriers experienced similar long-term treatment effects with both agents. These differences may reflect rivastigmine's ability to inhibit BuChE and AChE.