- 作者列表："Moscoso A","Grothe MJ","Ashton NJ","Karikari TK","Rodriguez JL","Snellman A","Suárez-Calvet M","Zetterberg H","Blennow K","Schöll M","Alzheimer’s Disease Neuroimaging Initiative.
:Tau phosphorylated at threonine 181 (p-tau181) measured in blood plasma has recently been proposed as an accessible, scalable, and highly specific biomarker for Alzheimer's disease. Longitudinal studies, however, investigating the temporal dynamics of this novel biomarker are lacking. It is therefore unclear when in the disease process plasma p-tau181 increases above physiological levels and how it relates to the spatiotemporal progression of Alzheimer's disease characteristic pathologies. We aimed to establish the natural time course of plasma p-tau181 across the sporadic Alzheimer's disease spectrum in comparison to those of established imaging and fluid-derived biomarkers of Alzheimer's disease. We examined longitudinal data from a large prospective cohort of elderly individuals enrolled in the Alzheimer's Disease Neuroimaging Initiative (ADNI) (n = 1067) covering a wide clinical spectrum from normal cognition to dementia, and with measures of plasma p-tau181 and an 18F-florbetapir amyloid-β PET scan at baseline. A subset of participants (n = 864) also had measures of amyloid-β1-42 and p-tau181 levels in CSF, and another subset (n = 298) had undergone an 18F-flortaucipir tau PET scan 6 years later. We performed brain-wide analyses to investigate the associations of plasma p-tau181 baseline levels and longitudinal change with progression of regional amyloid-β pathology and tau burden 6 years later, and estimated the time course of changes in plasma p-tau181 and other Alzheimer's disease biomarkers using a previously developed method for the construction of long-term biomarker temporal trajectories using shorter-term longitudinal data. Smoothing splines demonstrated that earliest plasma p-tau181 changes occurred even before amyloid-β markers reached abnormal levels, with greater rates of change correlating with increased amyloid-β pathology. Voxel-wise PET analyses yielded relatively weak, yet significant, associations of plasma p-tau181 with amyloid-β pathology in early accumulating brain regions in cognitively healthy individuals, while the strongest associations with amyloid-β were observed in late accumulating regions in patients with mild cognitive impairment. Cross-sectional and particularly longitudinal measures of plasma p-tau181 were associated with widespread cortical tau aggregation 6 years later, covering temporoparietal regions typical for neurofibrillary tangle distribution in Alzheimer's disease. Finally, we estimated that plasma p-tau181 reaches abnormal levels ∼6.5 and 5.7 years after CSF and PET measures of amyloid-β, respectively, following similar dynamics as CSF p-tau181. Our findings suggest that plasma p-tau181 increases are associated with the presence of widespread cortical amyloid-β pathology and with prospective Alzheimer's disease typical tau aggregation, providing clear implications for the use of this novel blood biomarker as a diagnostic and screening tool for Alzheimer's disease.
在血浆中测量的苏氨酸181 (p-tau181) 磷酸化的Tau最近被提出作为阿尔茨海默病的可获得的、可扩展的和高度特异性的生物标志物。然而，缺乏研究这种新型生物标志物的时间动态的纵向研究。因此，不清楚在疾病过程中血浆p-tau181何时增加到高于生理水平，以及它如何与阿尔茨海默病特征性病理的时空进展相关。我们旨在与已建立的阿尔茨海默病成像和流体衍生生物标志物相比，建立散发性阿尔茨海默病谱系血浆p-tau181的自然时程。我们检查了阿尔茨海默病神经影像学倡议 (ADNI) (n = 1067) 中招募的老年人的大型前瞻性队列的纵向数据，涵盖从正常认知到痴呆的广泛临床范围，并在基线时测量血浆p-tau181和18f-florbetapir-β 淀粉样蛋白PET扫描。一部分参与者 (n = 864) 也测量了脑脊液中淀粉样蛋白-β1-42和p-tau181水平，另一部分参与者 (n = 298) 在6年后接受了18F-flortaucipir tau PET扫描。我们进行了全脑分析，以研究血浆p-tau181基线水平和纵向变化与6年后区域淀粉样蛋白-β 病理进展和tau负荷的相关性。并且使用先前开发的用于构建长期生物标志物时间轨迹的方法使用短期纵向数据来估计血浆p-tau181和其他阿尔茨海默病生物标志物的变化的时间过程。平滑样条表明，最早的血浆p-tau181变化甚至发生在淀粉样蛋白-β 标记物达到异常水平之前，具有与增加的淀粉样蛋白-β 病理学相关的更大的变化率。在认知健康的个体中，体素相关的PET分析产生了相对弱但显著的血浆p-tau181与淀粉样蛋白-β 病理学的关联，而在轻度认知障碍患者的晚期累积区域中观察到与淀粉样蛋白-β 最强烈的关联。6年后，血浆p-tau181的横截面和特别是纵向测量与广泛的皮质tau聚集相关，覆盖了阿尔茨海默病中典型的神经原纤维缠结分布的颞顶区。最后，我们估计血浆p-tau181在CSF和PET测量淀粉样蛋白-β 后分别达到异常水平 ~ 6.5年和5.7年，遵循与CSF p-tau181相似的动力学。我们的研究结果表明，血浆p-tau181的增加与广泛存在的皮质淀粉样蛋白-β 病理和前瞻性阿尔茨海默病典型的tau蛋白聚集有关，这为使用这种新型血液生物标志物作为阿尔茨海默病的诊断和筛查工具提供了明确的意义.
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.