BACKGROUND & AIMS: :Apigenin, belonging to a less toxic and non-mutagenic flavone subclass of flavonoids, has been reported to possess numerous biological activities beneficial to health. Although evidence has shown apigenin might exert its protective effects by reducing the toxicity induced by amyloid-β peptides (Aβ), the precise mechanism is unclear. In the present study, we investigated the in vitro neuroprotective activity of apigenin interrelated with amyloid toxicity and mental homeostasis in an Alzheimer's disease (AD) cell model and explored its potential signal transduction. Our results showed that apigenin protected neurons against Aβ-mediated toxicity induced by copper, which was characterized by increasing neuronal viability and relieving mitochondrial membrane dissipation and neuronal nuclear condensation. Further, we demonstrated that apigenin did not provide sufficient effect on decreasing β-amyloid precursor protein (AβPP) expression and lowering Aβ(1-42) secretion, but conserved redox balance by increasing intracellular glutathione levels and enhancing cellular superoxide dismutase and glutathione peroxidase activities, reduced intracellular reactive oxygen species (ROS) generation, blocked ROS-induced p38 mitogen-activated protein kinases (p38 MAPK)- MAPKAP kinase-2 (MK2)-heat shock protein 27 (Hsp27) and stress-activated protein kinase (SAPK)/c-Jun N-terminal kinase (JNK)-c-Jun signaling pathways, preserved mitochondrial function, and then regulated apoptotic pathways. In conclusion, apigenin could exert neuroprotection against Aβ-induced toxicity in the presence of copper mainly through the mechanisms that regulate redox imbalance, preserve mitochondrial function, inhibit MAPK pathways, and depress neuronal apoptosis.

背景与目标： 芹菜素属于黄酮类中毒性较低且非致突变的黄酮类，据报道具有多种有益于健康的生物活性。尽管有证据表明芹菜素可能通过降低淀粉样 β 肽 (a β) 诱导的毒性发挥其保护作用，但确切的机制尚不清楚。在本研究中，我们在阿尔茨海默氏病 (AD) 细胞模型中研究了芹菜素与淀粉样蛋白毒性和精神稳态相关的体外神经保护活性，并探索了其潜在的信号转导。我们的结果表明，芹菜素保护神经元免受铜诱导的a β 介导的毒性，其特征是增加神经元活力，减轻线粒体膜耗散和神经元核浓缩。此外，我们证明芹菜素对降低 β-淀粉样蛋白前体蛋白 (a β pp) 表达和降低a β(1-42) 分泌没有足够的作用，但通过增加细胞内谷胱甘肽水平和增强细胞超氧化物歧化酶和谷胱甘肽过氧化物酶活性来保持氧化还原平衡，细胞内活性氧 (ROS) 生成减少，阻断ROS诱导的p38丝裂原活化蛋白激酶 (p38 MAPK)- MAPKAP激酶-2 (MK2)-热休克蛋白27 (Hsp27) 和应激活化蛋白激酶 (SAPK)/c-6月N端激酶 (JNK)-c-6月信号通路，保留线粒体功能，进而调控凋亡途径。总之，芹菜素可以通过调节氧化还原失衡，保留线粒体功能，抑制MAPK途径和抑制神经元凋亡的机制，在铜存在下对a β 诱导的毒性发挥神经保护作用。

BACKGROUND & AIMS: :Charing Cross Hospital provides facilities for the study of handicapped children in a normal nursery which forms part of its Child Development Centre. The period of assessment varies from one day to three weeks; the advantages of prolonged assessment are discussed. Parental involvement and support, and the teaching of medical students are emphasized. A study of the Centre's first 385 patients is presented.

背景与目标： : 查令十字医院为在普通托儿所中研究残疾儿童提供设施，该托儿所是其儿童发展中心的一部分。评估期从一天到三周不等; 讨论了长期评估的优势。强调父母的参与和支持，以及医学生的教学。介绍了该中心第385名患者的研究。

BACKGROUND & AIMS: INTRODUCTION:MAPT H1 haplotype is implicated as a risk factor for neurodegenerative diseases including Alzheimer's disease (AD). METHODS:Using Alzheimer's Disease Genetics Consortium (ADGC) genome-wide association study (GWAS) data (n = 18,841), we conducted a MAPT H1/H2 haplotype-stratified association to discover MAPT haplotype-specific AD risk loci. RESULTS:We identified 11 loci-5 in H2-non-carriers and 6 in H2-carriers-although none of the MAPT haplotype-specific associations achieved genome-wide significance. The most significant H2 non-carrier-specific association was with a NECTIN2 intronic (P = 1.33E-07) variant, and that for H2 carriers was near NKX6-1 (P = 1.99E-06). The GABRG2 locus had the strongest epistasis with MAPT H1/H2 variant rs8070723 (P = 3.91E-06). Eight of the 12 genes at these loci had transcriptome-wide significant differential expression in AD versus control temporal cortex (q < 0.05). Six genes were members of the brain transcriptional co-expression network implicated in "synaptic transmission" (P = 9.85E-59), which is also enriched for neuronal genes (P = 1.0E-164), including MAPT. DISCUSSION:This stratified GWAS identified loci that may confer AD risk in a MAPT haplotype-specific manner. This approach may preferentially enrich for neuronal genes implicated in synaptic transmission.

背景与目标：

BACKGROUND & AIMS: :Basic fibroblast growth factor (bFGF) has been demonstrated to correlate with glioma grade and clinical outcome and has established its possible usefulness as a target for glioma therapy. Vpr has been described as an antitumor agent and displays a potent antitumor nature. Here, we try to investigate whether a combined treatment with bFGF-siRNA and Vpr gene would have a enhanced effectiveness on glioma in vitro and in vivo.After treatments with only Ad-bFGF-siRNA, only Ad-Vpr, and a combination of both, we assessed the changes in cell proliferation, cell cycle, and apoptosis in vitro by the methods of MTT, PI and FITC-AnnexinV double staining, respectively. In addition, we also evaluated the combined effect of bFGF-siRNA and Vpr gene therapy on glioma in vivo using xenograft glioma models in nude mice. Combined Ad-bFGF-siRNA and Ad-Vpr treatment was more better successful in inhibiting cell proliferation in comparison with treatments of either Ad-bFGF-siRNA or Ad-Vpr alone. Treatment of Ad-Vpr alone or a treatment of a combination of Ad-bFGF-siRNA and Ad-Vpr induced the G2/M cell cycle arrest and apoptosis; however, combined treatment was more effective than the Ad-Vpr treatment alone. Although each single treatment can slow the growth of xenograft glioma, the combined treatment with Ad-bFGF-siRNA and Ad-Vpr was better than either the Ad-bFGF-siRNA or Ad-Vpr treatment alone. Our results suggest that the combination therapy with bFGF-siRNA and Vpr gene can achieve a enhanced activity of anti-glioma, supporting the idea that the combination of these two antitumor agents could open new perspectives in glioma therapy.

背景与目标： : 碱性成纤维细胞生长因子 (bFGF) 已被证明与神经胶质瘤分级和临床结果相关，并已确定其作为神经胶质瘤治疗靶标的可能用途。Vpr已被描述为抗肿瘤剂，并具有有效的抗肿瘤性质。在这里，我们试图研究用bFGF-siRNA和Vpr基因联合治疗是否能在体外和体内增强对神经胶质瘤的疗效。在仅用Ad-bFGF-siRNA，仅用Ad-Vpr和两者结合治疗后，我们评估了细胞增殖的变化，分别通过MTT，PI和FITC-AnnexinV双重染色的方法进行细胞周期和体外凋亡。此外，我们还使用裸鼠异种移植瘤神经胶质瘤模型评估了bFGF-siRNA和Vpr基因治疗对神经胶质瘤的联合作用。与单独使用Ad-bFGF-siRNA或Ad-Vpr治疗相比，Ad-bFGF-siRNA和Ad-Vpr联合治疗在抑制细胞增殖方面更成功。单独治疗Ad-Vpr或联合治疗Ad-bFGF-siRNA和Ad-Vpr可诱导G2/M细胞周期停滞和凋亡; 然而，联合治疗比单独的Ad-Vpr治疗更有效。尽管每种单一治疗都可以减缓异种移植神经胶质瘤的生长，但Ad-bFGF-siRNA和Ad-Vpr的联合治疗优于单独的Ad-bFGF-siRNA或Ad-Vpr治疗。我们的结果表明，bFGF-siRNA和Vpr基因的联合治疗可以增强抗神经胶质瘤的活性，这支持了这两种抗肿瘤药物的结合可以为神经胶质瘤治疗开辟新的前景的想法。

BACKGROUND & AIMS: :Shenzhiling oral liquid (SZL) is a Traditional Chinese Medicine (TCM) compound to be approved by the China Food and Drug Administration (CFDA) (Z20120010) for the treatment of mild-to-moderate Alzheimer's disease (AD). However, its mechanism in early AD is not clear. We studied its mechanism in protecting myelin. Three-month-old APPswe/PS1dE9double transgenic mice were used as AD model and wild-type C57BL/6 mice were used as control. After 3-month intervention, the Morris water maze was used to detect behavioural changes. Myelin mTOR pathway (PI3K, p-PI3K, Akt, p-Akt, mTOR, p-mTOR), myelin basic protein (MBP) and postsynaptic density protein 95 (PSD95) were detected by immunohistochemistry and western blot and reverse transcriptase polymerase chain reaction (RT-PCR). After 3 months of SZL treatment, compared with the model group (M), SZL medium-dose (SM) and SZL low-dose groups (SL) exhibited increased staying and crossing results in Morris water maze (P < 0.05). Compared with M, PI3K-positive cells in SM and SL groups were increased (P < 0.01), p-PI3K expression increased in the Donepezil group (D), SZL high-dose group (SH) and SM (P < 0.05); number of Akt-positive cells and Akt expression in D, SM and SL were increased (P < 0.01, P < 0.05); number of p-Akt- and mTOR-positive cells and mTOR expression in all drug-treated groups were significantly increased (P < 0.01); p-Akt and p-mTOR expression increased in all drug-treated groups (P < 0.05, P < 0.01); MBP expression in D and SH increased (P < 0.05), while in SM and SL it increased more significantly (P < 0.01); and PSD95 expression in D, SM and SL was increased (P < 0.05). RT-PCR results showed that compared with M, PI3K mRNA and Akt mRNA expression in all drug-treated groups increased, but there was no statistical difference (P > 0.05), mTOR mRNA expression in all the drug-treated groups increased significantly (P < 0.01) and MBP mRNA and PSD95 mRNA expression in D and SH increased (P < 0.05). SZL oral liquid could play a role in myelin protection in early AD.

背景与目标： : 参之灵口服液 (SZL) 是经中国食品药品监督管理局 (CFDA) (Z20120010) 批准用于治疗轻中度阿尔茨海默氏病 (AD) 的中药 (TCM) 化合物。然而，它在公元早期的机制并不清楚。我们研究了其保护髓磷脂的机制。3个月大的APPswe/ps1de9双转基因小鼠作为AD模型，野生型C57BL/6小鼠作为对照。干预3个月后，使用Morris水迷宫检测行为变化。免疫组织化学、western blot和逆转录酶聚合酶链反应 (rt-pcr) 检测髓鞘mTOR通路 (PI3K、p-PI3K、Akt、p-Akt、mTOR、p-mTOR) 、髓鞘碱性蛋白 (MBP) 和突触后密度蛋白95 (PSD95)。SZL治疗3个月后，与模型组 (M) 相比，SZL中剂量组 (SM) 和SZL低剂量组 (SL) 在Morris水迷宫中的停留和交叉结果增加 (p  <  0.05)。与M组相比，SM组和SL组PI3K-positive细胞增加 (p  <  0.01)，多奈哌齐组 (D) 、SZL高剂量组 (SH) 和SM组 (p  <  0.05) p-PI3K表达增加; D组Akt阳性细胞数和Akt表达增加，SM和SL升高 (p  <  0.01，p  <  0.05); 所有药物治疗组p-Akt和mTOR阳性细胞数和mTOR表达均显着增加 (p  <  0.01); p-Akt和p-mTOR在所有药物治疗组中表达增加 (p  <  0.05，p  <  0.01); MBP在D和SH中的表达增加 (p  <  0.05)，而在SM和SL中的表达增加更明显 (p  <  0.01); PSD95在D、SM和SL中的表达增加 (p  <  0.05)。Rt-pcr结果显示，与M相比，所有药物治疗组PI3K mRNA和Akt mRNA的表达均增加，但无统计学差异 (p  >  0.05)。所有药物处理组mTOR mRNA表达均显着增加 (p  <  0.01)，D和SH MBP mRNA和PSD95 mRNA表达增加 (p  <  0.05)。SZL口服液可在AD早期发挥髓鞘保护作用。

BACKGROUND & AIMS: UNLABELLED:The availability of new PET ligands offers the potential to measure fibrillar β-amyloid in the brain. Nevertheless, physiologic information in the form of perfusion or metabolism may still be useful in differentiating causes of dementia during life. In this study, we investigated whether early (11)C-Pittsburgh compound B ((11)C-PIB) PET frames (perfusion (11)C-PIB [pPIB]) could provide information equivalent to blood flow and metabolism. First, we assessed the similarity of pPIB and (18)F-FDG PET images in a test cohort with various clinical diagnoses (n = 10), and then we validated the results in a cohort of patients with Alzheimer disease (AD) (n = 42; mean age ± SD, 66.6 ± 10.6 y; mean Mini-Mental State Examination [MMSE] score ± SD, 22.2 ± 6.0) or frontotemporal lobar degeneration (FTLD) (n = 31; age ± SD, 63.9 ± 7.1 y, mean MMSE score ± SD, 23.8 ± 6.7). METHODS:To identify the (11)C-PIB frames best representing perfusion, we ran on a test cohort an iterative algorithm, including generating normalized (cerebellar reference) perfusion pPIB images across variable frame ranges and calculating Pearson R values of the sum of these pPIB frames with the sum of all (18)F-FDG frames (cerebellar normalized) for all brain tissue voxels. Once this perfusion frame range was determined on the test cohort, it was then validated on an extended cohort and the power of pPIB in differential diagnosis was compared with (18)F-FDG by performing a logistic regression of regions-of-interest tracer measure (pPIB or (18)F-FDG) versus diagnosis. RESULTS:A 7-min window, corresponding to minutes 1-8 (frames 5-15), produced the highest voxelwise correlation between (18)F-FDG and pPIB (R = 0.78 ± 0.05). This pPIB frame range was further validated on the extended AD and FTLD cohort across 12 regions of interest (R = 0.91 ± 0.09). A logistic model using pPIB was able to classify 90.5% of the AD and 83.9% of the FTLD patients correctly. Using (18)F-FDG, we correctly classified 88.1% of AD and 83.9% of FTLD patients. The temporal pole and temporal neocortex were significant discriminators (P < 0.05) in both models, whereas in the model with pPIB the frontal region was also significant. CONCLUSION:The high correlation between pPIB and (18)F-FDG measures and their comparable performance in differential diagnosis are promising in providing functional information using (11)C-PIB PET data. This approach could be useful, obviating (18)F-FDG scans when longer-lived amyloid imaging agents become available.

背景与目标：

BACKGROUND & AIMS: BACKGROUND:Although high protein diets have been tested in controlled environments for applications to weight management, it is not understood if adding high protein foods to the diet would impact ad libitum energy balance in the absence of other lifestyle changes. METHODS:This double-blinded randomized crossover trial compared the effects of a protein shake (PS) to a carbohydrate shake (CS), consumed prior to each major meal to equate to 20% of total energy needs over the course of the day, on energy balance over two 5-day treatment periods in healthy adults with BMI 20-30 kg/m2. Tri-axial accelerometers estimated physical activity energy expenditure. Ad libitum energy intake was measured in a laboratory kitchen. RESULTS:Energy balance was positive during both treatment periods but was not different between periods. There were no interactions between treatment and preload caloric dose or treatment and BMI status on energy balance. Satiety ratings did not differ for any pairwise comparisons between treatment and caloric dose. Controlling for gender and basal metabolic rate, thermic effect of food was greater for PS than CS. CONCLUSIONS:Preload periods significantly altered the macronutrient composition of the overall diet. This study found limited evidence that carbohydrate or protein preloads have differential effects on energy balance in short-term ad libitum settings. TRIAL REGISTRATION:This trial was pre-registered on clinicaltrials.gov as NCT02613065 on 11/30/2015.

背景与目标：

BACKGROUND & AIMS: :Increasing evidence suggests that intestinal dysfunctions may represent early events in Alzheimer's disease and contribute to brain pathology. This study examined the relationship between onset of cognitive impairment and colonic dysfunctions in a spontaneous AD model before the full development of brain pathology. SAMP8 mice underwent Morris water maze and assessment of faecal output at four, six and eight months of age. In vitro colonic motility was examined. Faecal and colonic Aβ, tau proteins, α-synuclein and IL-1β were assessed by ELISA. Colonic citrate synthase activity was assessed by spectrophotometry. Colonic NLRP3, caspase-1 and ASC expression were evaluated by Western blotting. Colonic eosinophil density and claudin-1 expression were evaluated by immunohistochemistry. The effect of Aβ on NLRP3 signalling and mitochondrial function was tested in cultured cells. Cognitive impairment and decreased faecal output occurred in SAMP8 mice from six months. When compared with SAMR1, SAMP8 animals displayed: (1) impaired in vitro colonic contractions; (2) increased enteric AD-related proteins, IL-1β, active-caspase-1 expression and eosinophil density; and (3) decreased citrate synthase activity and claudin-1 expression. In THP-1 cells, Aβ promoted IL-1β release, which was abrogated upon incubation with caspase-1 inhibitor or in ASC-/- cells. Aβ decreased mitochondrial function in THP-1 cells. In SAMP8, enteric AD-related proteins deposition, inflammation and impaired colonic excitatory neurotransmission, occurring before the full brain pathology development, could contribute to bowel dysmotility and represent prodromal events in AD.

背景与目标： 越来越多的证据表明，肠道功能障碍可能代表阿尔茨海默病的早期事件，并导致大脑病理。这项研究在脑病理全面发展之前，研究了自发性AD模型中认知障碍的发作与结肠功能障碍之间的关系。SAMP8小鼠在四个，六个月和八个月大时接受了Morris水迷宫并评估了粪便输出量。检查了体外结肠运动。通过ELISA评估粪便和结肠a β，tau蛋白，α-突触核蛋白和IL-1β。通过分光光度法评估结肠柠檬酸合酶活性。通过蛋白质印迹法评估结肠NLRP3、caspase-1和ASC表达。通过免疫组织化学评估结肠嗜酸性粒细胞密度和claudin-1表达。在培养的细胞中测试了a β 对NLRP3信号传导和线粒体功能的影响。从六个月开始，SAMP8小鼠发生了认知障碍和粪便输出量减少。与SAMR1相比，SAMP8动物显示 :( 1) 体外结肠收缩受损; (2) 肠道AD相关蛋白，IL-1β，active-caspase-1表达和嗜酸性粒细胞密度增加; (3) 柠檬酸合酶活性和claudin-1表达降低。在THP-1细胞中，a β 促进IL-1β 释放，其在与caspase-1抑制剂或ASC-/-细胞孵育后被消除。A β 降低了THP-1细胞的线粒体功能。在SAMP8中，在整个大脑病理发展之前发生的肠道AD相关蛋白沉积，炎症和结肠兴奋性神经传递受损，可能会导致肠动力障碍并代表AD的前驱事件。

BACKGROUND & AIMS: OBJECTIVES:To explore the atrophy rate of entorhinal cortex (ERC) in AD and normal aging and assess the value of rate measurement of ERC atrophy for classifying subjects with AD from cognitively normal (CN) control subjects. METHODS:Twenty-one AD patients and 23 CN subjects had MRI scans and clinical evaluations twice within 1.8 +/- 0.6 years. ERC volumes were manually measured on volumetric T1-weighted MR images. RESULTS:Patients with AD had a greater annual percentage volume change of ERC than CN subjects on both sides (left: 6.8 +/- 4.3%/year for AD vs 1.4 +/- 2.5%/year for CN [F(1,42) = 25.6, p < 0.001]; right: 6.3 +/- 3.3%/year for AD vs 1.4 +/- 2.3%/year for CN [F(1,42) = 25.6, p < 0.001]). Furthermore, increased ERC atrophy rate was correlated (r = -0.56, p = 0.01) with decreased memory performance in AD. CN subjects had on average annual ERC atrophy rates greater than zero (p < 0.01). Baseline volume of ERC predicted atrophy rate of ERC (left: r = -0.53, p < 0.01; right: r = -0.42, p < 0.05) in CN subjects but not in AD subjects. Using ERC baseline volumes alone resulted in 77% overall correct classification (p < 0.01) between AD and CN subjects, with 76% sensitivity and 78% specificity and an area under receiver operator characteristic (ROC) curve of 0.83. Adding annual atrophy rate of ERC to the model accounted for most of the variance (p < 0.01), diminishing contributions from baseline volume and yielding 82% overall classification, with 76% sensitivity and 86% specificity and an area under the ROC curve of 0.93. CONCLUSION:ERC volume loss over time may be a better indicator for AD than cross-sectional measurements.

背景与目标：

BACKGROUND & AIMS: :Alzheimer's disease is a chronic neurological ailment that seriously threatens human health and imposes a huge burden on families and the society at large. Emerging evidence suggests that neuroinflammation is an important pathological manifestation of neurodegenerative diseases, and currently considered a new research target. We previously found that artemisinin B from Artemisia annua Linn. has strong anti-inflammatory and immunological activities. In the present study, we assessed the anti-neuroinflammatory effects of artemisinin B in vitro and in vivo, exploring the underlying mechanisms. The results demonstrated that artemisinin B inhibited NO secretion from LPS-induced BV2 cells and significantly reduced the expression levels of the inflammatory cytokines IL-1β, IL-6 and TNF-α. This was accompanied by reduced gene expression levels of MyD88 and NF-κB as well as TLR4 and MyD88 protein levels. These inhibitory effects were further confirmed in AD model mice. This study also showed that artemisinin B improved spatial memory in dementia mice in the water maze and step-through tests, and altered the pathological features and the levels of inflammatory cytokines in the hippocampus and the cortex. These results suggested that artemisinin B might inhibit neuroinflammation and exert neuroprotective effects on cognitive functions by modulating the TLR4-MyD88-NF-κB signaling pathway. This study provides direct evidence for the potential application of artemisinin B in the treatment of neuroinflammatory diseases.

背景与目标： 阿尔茨海默病是一种慢性神经系统疾病，严重威胁人类健康，给家庭和整个社会带来巨大负担。新兴证据表明，神经炎症是神经退行性疾病的重要病理表现，目前被认为是一个新的研究目标。我们以前发现青蒿中的青蒿素B。具有很强的抗炎和免疫活性。在本研究中，我们评估了青蒿素B在体外和体内的抗神经炎症作用，并探索了潜在的机制。结果表明，青蒿素B可抑制LPS诱导的BV2细胞的NO分泌，并显着降低炎性细胞因子IL-1β，IL-6和TNF-α 的表达水平。伴随着MyD88和NF-κ b的基因表达水平以及TLR4和MyD88蛋白水平降低。这些抑制作用在AD模型小鼠中得到进一步证实。这项研究还表明，青蒿素B在水迷宫和步进测试中改善了痴呆小鼠的空间记忆，并改变了海马和皮质的病理特征和炎性细胞因子的水平。这些结果表明，青蒿素B可能通过调节TLR4-MyD88-NF-κB信号通路来抑制神经炎症并对认知功能发挥神经保护作用。这项研究为青蒿素B在治疗神经炎性疾病中的潜在应用提供了直接证据。

BACKGROUND & AIMS: BACKGROUND:The selective attention of children with attention deficit/hyperactivity disorder (AD/HD) to briefly exposed delay-related cues was examined in two experiments using a dot-probe conditioning paradigm. METHOD:Colour cues were paired with negatively (i.e., imposition of delay) and positively valenced cues (i.e., escape from or avoidance of delay) during a conditioning phase. These cues were presented alongside neutral cues in a subsequent dot-probe detection phase. RESULTS:In experiment 1 teacher-identified children with AD/HD (N = 12), but not controls (N = 12), displayed an attentional bias towards both positively and negatively valenced cues. In experiment 2 children with a diagnosis of hyperkinetic disorder (N = 15), but not controls (N = 15), displayed a bias towards delay-related cues. However, this effect was largely carried by the response to positively valenced cues. CONCLUSIONS:These results confirm the dot-probe conditioning paradigm as a useful test of motivational influence on attention. They provide the first evidence of qualitative differences in the attentional style of children with AD/HD and give further support to those theories that highlight the motivational significance of delay in AD/HD.

背景与目标：

BACKGROUND & AIMS: OBJECTIVE:MRI-based measurements of hippocampal atrophy are a sensitive indicator of the early pathologic degeneration of the medial temporal lobe in AD. However, AD pathology appears first in the transentorhinal/entorhinal cortex, not the hippocampus. The authors tested the hypothesis that MRI-based measurements of the entorhinal cortex are more sensitive than measurements of hippocampal volume in discriminating among three clinical groups; controls, patients with a mild cognitive impairment (MCI), and patients with mild probable AD.

METHODS:The authors studied 30 controls, 30 patients with MCI, and 30 patients with AD who were matched among clinical groups on age, gender, and education. All underwent a standardized MRI protocol from which the authors made measurements of hippocampal volume, entorhinal cortex volume, and the cumulative length of the medial border of the entorhinal cortex.

RESULTS:Pairwise intergroup differences (p < 0.01) were found for all MRI measurements with the exception of the cumulative length of the entorhinal cortex, which did not differentiate controls from MCI patients. Whereas the hippocampal and entorhinal cortex volume measurements provided slightly better intergroup discrimination than the entorhinal distance measurement, overall differences in discriminating ability among the three MRI measurements were minor.

CONCLUSIONS:Despite the theoretical rationale for the superiority of entorhinal measurements in early AD, the authors found MRI measurements of the hippocampus and entorhinal cortex were approximately equivalent at intergroup discrimination. Measurements of the hippocampus may be preferable because MRI depiction of the boundaries of the entorhinal cortex can be obscured by anatomic ambiguity, image artifact, or both.

背景与目标： 目的 : 基于MRI的海马萎缩测量是AD内侧颞叶早期病理性变性的敏感指标。然而，AD病理首先出现在经耳嗅/内嗅皮层，而不是海马。作者检验了以下假设: 在区分三个临床组时，基于MRI的内嗅皮层测量比海马体积测量更敏感; 对照组，轻度认知障碍 (MCI) 患者，以及可能患有轻度AD的患者。
方法 : 作者研究了30名对照者，30名MCI患者和30名AD患者，这些患者在年龄，性别和教育程度。所有这些都经过了标准化的MRI协议，作者从中测量了海马体积，内嗅皮层体积以及内嗅皮层内侧边界的累积长度。
结果 : 除内嗅皮层的累积长度外，所有MRI测量结果均存在成对的组间差异 (p <0.01)，这并未将对照组与MCI患者区分开。海马和内嗅皮层体积测量比内嗅距离测量提供了更好的组间辨别能力，而三种MRI测量之间的辨别能力总体差异很小。
结论 : 尽管在早期AD中，内嗅测量具有优越性的理论依据，但作者发现，在组间歧视中，海马和内嗅皮层的MRI测量大致相同。海马的测量可能是可取的，因为MRI对内嗅皮层边界的描述可能会被解剖模糊，图像伪影或两者兼而有之。

BACKGROUND & AIMS: :The objective was to study the association between cerebrospinal fluid (CSF) levels of amyloid-β (Aβ)(1-42), t-tau, and p-tau and cognitive performance along the Alzheimer's disease (AD) continuum from healthy subjects to AD patients and, specifically, among patients in the pre-dementia stage of the disease. A total of 101 subjects were studied: 19 healthy controls (CTR), 17 subjects with subjective memory complaints (SMC), 47 with mild cognitive impairment (MCI), and 18 AD patients. Only memory performance significantly correlated with CSF levels of Aβ(1-42), t-tau, and p-tau along the AD continuum. Subgroup analyses revealed that in SMC patients Aβ(1-42) levels positively correlated with the total recall score of the Free and Cued Selective Reminding Test (FCRST) (r = 0.666; p < 0.005), Digit Span (r = 0.752; p < 0.005), and CERAD world list learning (r = 0.697; p < 0.005). In MCI patients, a significant inverse correlation was found between the word list recall score from the CERAD and t-tau (r = -0.483; p < 0.005) and p-tau levels (r = -0.495; p < 0.005), as well as between the total recall subtest score from the FCRST and both t-tau (r = -0.420; p < 0.005) and p-tau levels (r = -0.422; p < 0.005). No significant correlations were found between other aspects of cognition and CSF levels in CTR or AD patients. These results indicate that memory performance is related to Aβ(1-42) levels in SMC, while it is associated with tau in the prodromal stage of the disease. This suggests that in the continuum from healthy aging to AD, memory performance is first related with Aβ(1-42) levels and then with t-tau or p-tau, before becoming independent of biomarker levels in the dementia stage.

背景与目标： : 目的是研究淀粉样蛋白 β (a β)(1-42)，t-tau和p-tau的脑脊液 (CSF) 水平与从健康受试者到AD患者的阿尔茨海默氏病 (AD) 连续体的认知表现之间的关系，特别是，在痴呆症前期的患者中。共研究了101名受试者: 19名健康对照 (CTR)，17名主观记忆抱怨 (SMC)，47名轻度认知障碍 (MCI) 和18名AD患者。沿AD连续体，只有记忆表现与CSF的a β(1-42)，t-tau和p-tau水平显着相关。亚组分析显示，在SMC患者中，a β(1-42) 水平与自由和提示选择性提醒测试 (FCRST) 的总回忆得分呈正相关 (r = 0.666; p <0.005)，数字跨度 (r = 0.752; p <0.005)，和CERAD世界列表学习 (r = 0.697; p <0.005)。在MCI患者中，CERAD和t-tau的单词列表回忆得分 (r = -0.483; p < 0.005) 与p-tau水平 (r = -0.495; p < 0.005) 之间存在显着的负相关，以及来自FCRST的总回忆子测试分数与t-tau (r = -0.420; p < 0.005) 和p-tau水平 (r = -0.422; p < 0.005) 之间。在CTR或AD患者中，认知的其他方面与CSF水平之间没有发现显着相关性。这些结果表明，记忆性能与SMC中的a β(1-42) 水平有关，而与疾病前驱期的tau有关。这表明，在从健康衰老到AD的连续过程中，记忆性能首先与a β(1-42) 水平相关，然后与t-tau或p-tau相关，然后在痴呆阶段变得独立于生物标志物水平。

BACKGROUND & AIMS: :Here we investigated the effect of the rivastigmine patch alone on depression in 50 mild Alzheimer's disease (AD) patients with comorbid major depressive episode (MDE). First diagnosis acetyl-cholinesterase inhibitor and psychoactive drug-free outpatients (n=50) were recruited in memory clinics and reassessed after 3 and 6 months. Global cognitive functioning, depressive symptoms and MDE frequency were evaluated with the Mini Mental State Examination, the CERAD Dysphoria scale and the modified DSM-IV criteria for MDE in AD. MDE frequency reduced significantly from the first diagnostic visit (100%) to the 6-month follow-up (62%). We also found a significant reduction in CERAD Dysphoria scores that decreased from 6.2±3.9 mean±standard deviation to 4.9±4.5 at the 6-month follow-up. In AD patients with MDE rivastigmine alone can have a positive impact on depressive phenomena. Thus, future controlled study are justified to definitively verify if rivastigmine alone may improve depression in AD.

背景与目标： : 在这里，我们研究了单独使用rivastigmine贴片对50例合并重度抑郁发作 (MDE) 的轻度阿尔茨海默氏病 (AD) 患者的抑郁症的影响。首次诊断乙酰胆碱酯酶抑制剂和无精神药物门诊患者 (n = 50) 在记忆诊所招募，并在3和6个月后重新评估。通过迷你精神状态检查，CERAD烦躁量表和改良的dsm-iv AD MDE标准评估了整体认知功能，抑郁症状和MDE频率。从首次诊断访问 (100%) 到6个月的随访 (62%)，MDE频率显着降低。我们还发现CERAD烦躁评分显着降低，在6个月的随访中从6.2 ± 3.9平均值 ± 标准差降至4.9 ± 4.5。在AD患者中，单独使用MDE利伐斯的明可以对抑郁现象产生积极影响。因此，将来的对照研究有理由明确验证单独使用利伐斯的明是否可以改善AD的抑郁症。

BACKGROUND & AIMS: :Despite being able to make accurate predictions, most existing prognostic models lack a proper indication about the uncertainty of each prediction, that is, the risk of prediction error for individual patients. This hampers their translation to primary care settings through decision support systems. To address this problem, we studied different methods for transforming classifiers into probabilistic/confidence-based predictors (here called uncertainty methods), where predictions are complemented with probability estimates/confidence regions reflecting their uncertainty (uncertainty estimates). We tested several uncertainty methods: two well-known calibration methods (Platt Scaling and Isotonic Regression), Conformal Predictors, and Venn-ABERS predictors. We evaluated whether these methods produce valid predictions, where uncertainty estimates reflect the ground truth probabilities. Furthermore, we assessed the proportion of valid predictions made at high-certainty thresholds (predictions with uncertainty measures above a given threshold) since this impacts their usefulness in clinical decisions. Finally, we proposed an ensemble-based approach where predictions from multiple pairs of (classifier, uncertainty method) are combined to predict whether a given MCI patient will convert to AD. This ensemble should putatively provide predictions for a larger number of patients while releasing users from deciding which pair of (classifier, uncertainty method) is more appropriate for data under study. The analysis was performed with a Portuguese cohort (CCC) of around 400 patients and validated in the publicly available ADNI cohort. Despite our focus on MCI to AD prognosis, the proposed approach can be applied to other diseases and prognostic problems.

背景与目标： : 尽管能够做出准确的预测，但大多数现有的预后模型都缺乏关于每个预测的不确定性的适当指示，即单个患者的预测错误风险。这妨碍了他们通过决策支持系统转化为初级保健环境。为了解决这个问题，我们研究了将分类器转换为基于概率/置信的预测变量的不同方法 (这里称为不确定性方法)，其中预测与反映其不确定性 (不确定性估计) 的概率估计/置信区域互补。我们测试了几种不确定度方法: 两种著名的校准方法 (普氏定标和等渗回归)，共形预测器和Venn-abeers预测器。我们评估了这些方法是否产生有效的预测，其中不确定性估计反映了地面真实概率。此外，我们评估了在高确定性阈值 (不确定性度量高于给定阈值的预测) 下做出的有效预测的比例，因为这会影响其在临床决策中的有用性。最后，我们提出了一种基于集合的方法，其中将来自多对 (分类器，不确定性方法) 的预测组合在一起，以预测给定的MCI患者是否会转换为AD。这个集合应该可以为更多的患者提供预测，同时让用户决定哪对 (分类器，不确定性方法) 更适合研究中的数据。该分析是对约400名患者的葡萄牙队列 (CCC) 进行的，并在公开可用的ADNI队列中进行了验证。尽管我们关注MCI对AD预后的影响，但所提出的方法仍可应用于其他疾病和预后问题。