Population-based blood screening for preclinical Alzheimer's disease in a British birth cohort at age 70.
- 作者列表："Keshavan A","Pannee J","Karikari TK","Rodriguez JL","Ashton NJ","Nicholas JM","Cash DM","Coath W","Lane CA","Parker TD","Lu K","Buchanan SM","Keuss SE","James SN","Murray-Smith H","Wong A","Barnes A","Dickson JC","Heslegrave A","Portelius E","Richards M","Fox NC","Zetterberg H","Blennow K","Schott JM
:Alzheimer's disease has a preclinical stage when cerebral amyloid-β deposition occurs before symptoms emerge, and when amyloid-β-targeted therapies may have maximum benefits. Existing amyloid-β status measurement techniques, including amyloid PET and CSF testing, are difficult to deploy at scale, so blood biomarkers are increasingly considered for screening. We compared three different blood-based techniques-liquid chromatography-mass spectrometry measures of plasma amyloid-β, and single molecule array (Simoa) measures of plasma amyloid-β and phospho-tau181-to detect cortical 18F-florbetapir amyloid PET positivity (defined as a standardized uptake value ratio of >0.61 between a predefined cortical region of interest and eroded subcortical white matter) in dementia-free members of Insight 46, a substudy of the population-based British 1946 birth cohort. We used logistic regression models with blood biomarkers as predictors of amyloid PET status, with or without age, sex and APOE ε4 carrier status as covariates. We generated receiver operating characteristics curves and quantified areas under the curves to compare the concordance of the different blood tests with amyloid PET. We determined blood test cut-off points using Youden's index, then estimated numbers needed to screen to obtain 100 amyloid PET-positive individuals. Of the 502 individuals assessed, 441 dementia-free individuals with complete data were included; 82 (18.6%) were amyloid PET-positive. The area under the curve for amyloid PET status using a base model comprising age, sex and APOE ε4 carrier status was 0.695 (95% confidence interval: 0.628-0.762). The two best-performing Simoa plasma biomarkers were amyloid-β42/40 (0.620; 0.548-0.691) and phospho-tau181 (0.707; 0.646-0.768), but neither outperformed the base model. Mass spectrometry plasma measures performed significantly better than any other measure (amyloid-β1-42/1-40: 0.817; 0.770-0.864 and amyloid-β composite: 0.820; 0.775-0.866). At a cut-off point of 0.095, mass spectrometry measures of amyloid-β1-42/1-40 detected amyloid PET positivity with 86.6% sensitivity and 71.9% specificity. Without screening, to obtain 100 PET-positive individuals from a population with similar amyloid PET positivity prevalence to Insight 46, 543 PET scans would need to be performed. Screening using age, sex and APOE ε4 status would require 940 individuals, of whom 266 would proceed to scan. Using mass spectrometry amyloid-β1-42/1-40 alone would reduce these numbers to 623 individuals and 243 individuals, respectively. Across a theoretical range of amyloid PET positivity prevalence of 10-50%, mass spectrometry measures of amyloid-β1-42/1-40 would consistently reduce the numbers proceeding to scans, with greater cost savings demonstrated at lower prevalence.
: 阿尔茨海默病有一个临床前阶段，即在症状出现之前发生大脑淀粉样蛋白-β 沉积，以及淀粉样蛋白-β 靶向治疗可能具有最大益处。现有的淀粉样蛋白-β 状态测量技术，包括淀粉样蛋白PET和CSF测试，难以大规模部署，因此血液生物标志物越来越多地被考虑用于筛查。我们比较了三种不同的基于血液的技术-血浆淀粉样蛋白-β 和单分子阵列 (Simoa) 的液相色谱-质谱测量测量血浆淀粉样蛋白-β 和phospho-tau181-to检测皮质18F-florbetapir淀粉样蛋白PET阳性 (定义为预定的皮质感兴趣区域和侵蚀的皮质下白质之间的标准化摄取值比> 0.61)在Insight 46的无痴呆成员中，基于人群的英国1946出生队列的子研究。我们使用逻辑回归模型，以血液生物标志物作为淀粉样蛋白PET状态的预测因子，以年龄、性别和APOE ε4携带者状态作为协变量。我们生成了受试者工作特征曲线和定量曲线下面积，以比较不同血液测试与淀粉样蛋白PET的一致性。我们使用Youden指数确定了血液检测的截止点，然后估计需要筛选以获得100个淀粉样蛋白PET阳性个体的数字。在评估的502名个体中，包括441名具有完整数据的无痴呆个体; 82名 (18.6%) 为淀粉样蛋白PET阳性。使用包含年龄、性别和apoe4 4携带者状态的基础模型的淀粉样蛋白PET状态的曲线下面积为0.695 (95% 置信区间: 0.628-0.762)。两种表现最好的Simoa血浆生物标志物是淀粉样蛋白-β42/40 (0.620; 0.548-0.691) 和phospho-tau181 (0.707; 0.646-0.768)，但两者都没有优于基础模型。质谱血浆测量的表现显著优于任何其他测量 (淀粉样蛋白-β1-42/1-40: 0.817; 0.770-0.864和淀粉样蛋白-β 复合物: 0.820; 0.775-0.866)。在0.095的截止点处，质谱测量淀粉样蛋白-β1-42/1-40以86.6% 的灵敏度和71.9% 的特异性检测到淀粉样蛋白PET阳性。如果不进行筛查，要从淀粉样蛋白PET阳性患病率与Insight 46相似的人群中获得100个PET阳性个体，需要进行543次PET扫描。使用年龄、性别和APOE ε4状态进行筛查需要940人，其中266人将进行扫描。单独使用质谱分析淀粉样蛋白-β1-42/1-40将分别将这些数目减少至623个个体和243个个体。在淀粉样蛋白PET阳性患病率为10-50% 的理论范围内，淀粉样蛋白-β1-42/1-40的质谱测量将持续减少进行扫描的数量，在较低患病率下显示出更大的成本节约。
METHODS::The ATP binding-cassette superfamily corresponds the mostly transmembrane transporters family found in humans. These proteins actively transport endogenous and exogenous substrates through biological membranes in body tissues, so they have an important role in the regulation of many physiological functions necessary for human homeostasis, as well as in response regulation to several pharmacological substrates. The development of multidrug resistance has become one of the main troubles in conventional chemotherapy in different illnesses including cancer, being the increased efflux of antineoplastic drugs the main reason for this multidrug resistance, with a key role of the ABC superfamily. Likely, the interindividual variability in the pharmacological response among patients is well known, and may be due to intrinsically factors of the disease, genetic and environmental ones. Thus, the understanding of this variability, especially the genetic variability associated with the efficacy and toxicity of drugs, can provide a safer and more effective pharmacological treatment, so ABC genes are considered as important regulators due to their relationship with the reduction in pharmacological response. In this review, updated information about transporters belonging to this superfamily was collected, the possible role of these transporters in cancer, the role of genetic variability in their genes, as well as some therapeutic tools that have been tried to raise against main transporters associated with chemoresistance in cancer.
METHODS:BACKGROUND:Cholinergic neurotransmission regulates neuroinflammation in Parkinson disease (PD). RESEARCH DESIGN AND METHODS:The authors conducted a delayed-start study of donepezil for cognitive decline in non-demented PD patients. The study consisted of a 96-week randomized placebo-controlled double-blind phase 1, followed by a 24-week donepezil extension phase 2. The primary outcome measure was a change in the Mini-Mental State Examination (MMSE) at week 120. RESULTS:A total of 98 patients were randomly allocated to the early-start (donepezil-to-donepezil) and delayed-start (placebo-to-donepezil) groups. Mean (SD) of the baseline MMSE was 27.6 (2.0) and 28.0 (2.1), respectively. MMSE change at week 120 was better in the early-start group than in the delayed-start group, but the difference was not significant. The MMSE declined in apolipoprotein ε4 carriers, but not in non-carriers, and the factor interaction (intervention × ε4 genotype) was highly significant (P < 0.001). Analyzed with the interaction, the difference was significant (group difference 1.95 [0.33 to 3.57], P = 0.018). The MMSE decline slope in phase 1 was significantly better in the early-start group than in the delayed-start group (P = 0.048). CONCLUSIONS:Cognitive function deteriorated in ε4 carriers, but not in non-carriers, and early-start donepezil may postpone cognitive decline in the former.
METHODS::Since the discovery of dental pulp stem cells, a lot of teams have expressed an interest in dental pulp regeneration. Many approaches, experimental models and biological explorations have been developed, each including the use of stem cells and scaffolds with the final goal being clinical application in humans. In this review, the authors' objective was to compare the experimental models and strategies used for the development of biomaterials for tissue engineering of dental pulp with stem cells. Electronic queries were conducted on PubMed using the following terms: pulp regeneration, scaffold, stem cells, tissue engineering and biomaterial. The extracted data included the following information: the strategy envisaged, the type of stem cells, the experimental models, the exploration or analysis methods, the cytotoxicity or viability or proliferation cellular tests, the tests of scaffold antibacterial properties and take into account the vascularization of the regenerated dental pulp. From the 71 selected articles, 59% focused on the "cell-transplantation" strategy, 82% used in vitro experimentation, 58% in vivo animal models and only one described an in vivo in situ human clinical study. 87% used dental pulp stem cells. A majority of the studies reported histology (75%) and immunohistochemistry explorations (66%). 73% mentioned the use of cytotoxicity, proliferation or viability tests. 48% took vascularization into account but only 6% studied the antibacterial properties of the scaffolds. This article gives an overview of the methods used to regenerate dental pulp from stem cells and should help researchers create the best development strategies for research in this field.