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Analytical and Clinical Performance of Amyloid-Beta Peptides Measurements in CSF of ADNIGO/2 Participants by an LC-MS/MS Reference Method.

通过 LC-MS/MS 参考方法对 ADNIGO/2 参与者 CSF 中淀粉样 β 肽测量的分析和临床性能。

  • 影响因子:3.34
  • DOI:10.1093/clinchem/hvaa012
  • 作者列表:"Korecka M","Figurski MJ","Landau SM","Brylska M","Alexander J","Blennow K","Zetterberg H","Jagust WJ","Trojanowski JQ","Shaw LM","Alzheimer’s Disease Neuroimaging Initiative.
  • 发表时间:2020-02-22

BACKGROUND:Cerebrospinal fluid (CSF) amyloid-β1-42 (Aβ42) reliably detects brain amyloidosis based on its high concordance with plaque burden at autopsy and with amyloid positron emission tomography (PET) ligand retention observed in several studies. Low CSF Aβ42 concentrations in normal aging and dementia are associated with the presence of fibrillary Aβ across brain regions detected by amyloid PET imaging. METHODS:An LC-MS/MS reference method for Aβ42, modified by adding Aβ40 and Aβ38 peptides to calibrators, was used to analyze 1445 CSF samples from ADNIGO/2 participants. Seventy runs were completed using 2 different lots of calibrators. For preparation of Aβ42 calibrators and controls spiking solution, reference Aβ42 standard with certified concentration was obtained from EC-JRC-IRMM (Belgium). Aβ40 and Aβ38 standards were purchased from rPeptide. Aβ42 calibrators' accuracy was established using CSF-based Aβ42 Certified Reference Materials (CRM). RESULTS:CRM-adjusted Aβ42 calibrator concentrations were calculated using the regression equation Y (CRM-adjusted) = 0.89X (calibrators) + 32.6. Control samples and CSF pools yielded imprecision ranging from 6.5 to 10.2% (Aβ42) and 2.2 to 7.0% (Aβ40). None of the CSF pools showed statistically significant differences in Aβ42 concentrations across 2 different calibrator lots. Comparison of Aβ42 with Aβ42/Aβ40 showed that the ratio improved concordance with concurrent [18F]-florbetapir PET as a measure of fibrillar Aβ (n = 766) from 81 to 88%. CONCLUSIONS:Long-term performance assessment substantiates our modified LC-MS/MS reference method for 3 Aβ peptides. The improved diagnostic performance of the CSF ratio Aβ42/Aβ40 suggests that Aβ42 and Aβ40 should be measured together and supports the need for an Aβ40 CRM.


背景: 脑脊液 (CSF) 淀粉样蛋白-β 1-42 (a β 42) 可靠地检测脑淀粉样变,基于其与尸检时斑块负荷和淀粉样正电子发射断层扫描 (PET) 的高度一致性在几项研究中观察到配体保留。正常衰老和痴呆中 CSF a β 42 浓度低与淀粉样蛋白 PET 成像检测到的跨脑区存在纤维 a β 相关。 方法: 采用 a β 42 的 LC-MS/MS 参考方法,通过在校准品中加入 a β 40 和 a β 38 肽进行改良,对 ADNIGO/2 名参与者的 1445 份 CSF 样本进行分析。使用 2 批不同的校准器完成了 70 次运行。对于 a β 42 校准品和对照加标溶液的制备,从 EC-JRC-IRMM (比利时) 获得认证浓度的参考 a β 42 标准品。A β 40 和 a β 38 标准品购自 rPeptide。使用基于 CSF 的 a β 42 认证标准物质 (CRM) 建立 a β 42 校准品的准确性。 结果: 使用回归方程 Y (CRM-adjusted) = 0.89X (calibrators) + 32.6 计算 CRM 调整的 a β 42 校准物浓度。对照样本和 CSF 池产生的不精密度范围为 6.5-10.2% (a β 42) 和 2.2-7.0% (a β 40)。在 2 个不同的校准品批次中,CSF 池的 a β 42 浓度均未显示统计学显著差异。A β 42 与 a β 42/a β 40 的比较表明,该比值与同时 [18F]-florbetapir PET 作为纤维性 a β 的指标 (n = 766) 的一致性从 81 提高到 88%。 结论: 长期性能评估证实了我们对 3 a β 肽的改良 LC-MS/MS 参考方法。CSF 比值 a β 42/a β 40 诊断性能的提高提示 a β 42 和 a β 40 应该一起测量,并支持 a β 40 CRM 的需要。



作者列表:["Galm, Brandon P.","Buckless, Colleen","Swearingen, Brooke","Torriani, Martin","Klibanski, Anne","Bredella, Miriam A.","Tritos, Nicholas A."]

METHODS:Purpose Given the paucity of reliable predictors of tumor recurrence, progression, or response to somatostatin receptor ligand (SRL) therapy in acromegaly, we attempted to determine whether preoperative MR image texture was predictive of these clinical outcomes. We also determined whether image texture could differentiate somatotroph adenomas from non-functioning pituitary adenomas (NFPAs). Methods We performed a retrospective study of patients with acromegaly due to a macroadenoma who underwent transsphenoidal surgery at our institution between 2007 and 2015. Clinical data were extracted from electronic medical records. MRI texture analysis was performed on preoperative non-enhanced T1-weighted images using ImageJ (NIH). Logistic and Cox models were used to determine if image texture parameters predicted outcomes. Results Eighty-nine patients had texture parameters measured, which were compared to that of NFPAs, while 64 of these patients had follow-up and were included in the remainder of analyses. Minimum pixel intensity, skewness, and kurtosis were significantly different in somatotroph adenomas versus NFPAs (area under the receiver operating characteristic curve, 0.7771, for kurtosis). Furthermore, those with a maximum pixel intensity above the median had an increased odds of IGF-I normalization on SRL therapy (OR 5.96, 95% CI 1.33–26.66), which persisted after adjusting for several potential predictors of response. Image texture did not predict tumor recurrence or progression. Conclusion Our data suggest that MRI texture analysis can distinguish NFPAs from somatotroph macroadenomas with good diagnostic accuracy and can predict normalization of IGF-I with SRL therapy.

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翻译标题与摘要 下载文献
作者列表:["Xiong Y","Tang Y","Fan F","Zeng Y","Li C","Zhou G","Hu Z","Zhang L","Liu Z"]

METHODS::Growth hormone-secreting pituitary adenoma (GHPA), a benign endocrine tumor located in the base of the skull, results in acromegaly. In addition to the mass effect of the tumor itself in the sellar region, GHPA can lead to the overgrowth of almost every organ. Previous findings indicated that the processes underlying acromegaly were partly attributable to hyperactivity of the growth hormone/insulin-like growth factor-1 (GH/IGF-1) axis. However, the mechanisms driving this syndrome remains largely unknown. Additionally, the roles of GHPA-derived exosomes, which contain functional microRNAs and proteins that manipulate target cell proliferation and differentiation in distal extremities, are also unknown. In this study, we demonstrated that GHPA exosomes promote bone formation in vitro and trabecula number in vivo. The mechanism of increased trabecula formation may be attributable to GHPA exosome-induced osteoblast proliferation via increased cell viability and DNA replication. We further discovered that exosomal hsa-miR-21-5p plays a distinct role from the GH/IGF-1 axis in these processes. Accordingly, the results of this study provide a novel mechanism whereby GHPA influences distal extremities and a new perspective for treating GHPA.

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翻译标题与摘要 下载文献
作者列表:["Arlien-Søborg MC","Grøndahl C","Bæk A","Dal J","Madsen M","Høgild ML","Pedersen SB","Bjerre M","Jørgensen JOL"]

METHODS:BACKGROUND:Fibroblast growth factor 21 (FGF21) is a circulating hormone with pleiotropic metabolic effects, which is inactivated by fibroblast activation protein (FAP). Data regarding interaction between FGF21, FAP, and growth hormone (GH) are limited, but it is noteworthy that collagens are also FAP substrates, since GH potently stimulates collagen turnover. AIM:To measure circulating FGF21 components, including FAP, in patients with acromegaly before and after disease control. METHODS:Eighteen patients with active acromegaly were studied at the time of diagnosis and ≥ 6 months after disease control by either surgery or medical treatment. Serum levels of total and active FGF21, β-klotho, FAP, and collagen turnover markers were measured by immunoassays. Expression of putative FGF21-dependent genes were measured in adipose tissue by reverse transcriptase-polymerase chain reaction, body composition assessed by dual-energy x-ray absorptiometry scan, and insulin sensitivity estimated with homeostatic model assessment of insulin resistance (HOMA-IR). RESULTS:Total FGF21, active FGF21 and β-klotho remained unchanged. Insulin sensitivity and body fat mass increased after disease control but neither correlated with active FGF21. Expression of FGF21-dependent genes did not change after treatment. FAP levels (µg/L) were markedly reduced after treatment [105.6 ± 29.4 vs 62.2 ± 32.4, P < 0.000]. Collagen turnover markers also declined significantly after treatment and ΔFAP correlated positively with ΔProcollagen Type I (P < 0.000) and Type III (P < 0.000). CONCLUSION:1) Circulating FGF21 and β-klotho do not change in response to acromegaly treatment, 2) FAP concentrations in serum decrease after disease control and correlate positively with collagen turnover markers, and 3) FAP is a hitherto unrecognized GH target linked to collagen turnover. CLINICAL TRIALS REGISTRATION:NCT00647179.