Centiloid cut-off values for optimal agreement between PET and CSF core AD biomarkers
Centiloid cut-off values for optimal agreement between PET and CSF core AD biomarkers
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DOI：
10.1186/s13195-019-0478-z
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发表时间：
2019-03-21
影响因子：
9
通讯作者：
Vilor-Tejedor, Natalia
中科院分区：
文献类型：
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作者：
Salvado, Gemma;Luis Molinuevo, Jose;Vilor-Tejedor, Natalia
研究背景：目前已发展出标准化淀粉样蛋白PET成像测量的Centiloid量表。这种连续测量的参考截止值使多中心研究和临床试验决策的一致操作化成为可能。在这项研究中，我们的目的是在两个大的独立cohols.MethodsA的ALFA+研究（N=205）和ADNI（N=311）共516名参与者进行淀粉样蛋白PET成像，以获得参考Centiloid阈值，最大限度地对核心阿尔茨海默病（AD）脑脊液（CSF）生物标志物的协议（分别为[F-18] flutemetaline和[F-18]florbetapir）和使用Elecsys（R）测试的核心AD CSF生物标志物测定。示踪剂摄取以厘沲单位（CL）定量。使用预先确定的参考截止值，寻求最佳的Centiloid截止值，其基于A（42）、tTau、pTau的CSF水平及其比率，最大化PET和二分测定之间的一致性。为此，接收器工作特性分析（ROC）进行，和Centiloid截止计算为那些最大化的约登J指数或整体百分比agreement recorded.ResultsAll的Centiloid截止落在25-35的范围内，除了CSF A（42），呈现最佳截止值为12 CL。正如预期，tau/A（42）比值的一致性高于CSF A（42）。即使建立在一个独立的队列和对CSF cut-offs.ConclusionsA截止的变化，Centiloid截止的鲁棒性得到了证实，12 CL匹配先前报道的值对AD神经病理学的尸检措施。与这些先前的发现一起，我们的结果标记了两个相关的拐点，它们将作为淀粉样蛋白病理学不同阶段的边界：一个在12 CL左右，标志着从不存在病理学到轻微病理学的转变，另一个在30 CL左右，表明存在已建立的病理学。核心AD生物标志物的稳健和可推广的截止值的推导需要具有中间水平的充分代表性的队列。试验注册ALFA+研究，NCT 02485730 ALFA PET子研究，NCT 02685969
BackgroundThe Centiloid scale has been developed to standardize measurements of amyloid PET imaging. Reference cut-off values of this continuous measurement enable the consistent operationalization of decision-making for multicentre research studies and clinical trials. In this study, we aimed at deriving reference Centiloid thresholds that maximize the agreement against core Alzheimer's disease (AD) cerebrospinal fluid (CSF) biomarkers in two large independent cohorts.MethodsA total of 516 participants of the ALFA+ Study (N=205) and ADNI (N=311) underwent amyloid PET imaging ([F-18]flutemetamol and [F-18]florbetapir, respectively) and core AD CSF biomarker determination using Elecsys (R) tests. Tracer uptake was quantified in Centiloid units (CL). Optimal Centiloid cut-offs were sought that maximize the agreement between PET and dichotomous determinations based on CSF levels of A(42), tTau, pTau, and their ratios, using pre-established reference cut-off values. To this end, a receiver operating characteristic analysis (ROC) was conducted, and Centiloid cut-offs were calculated as those that maximized the Youden's J Index or the overall percentage agreement recorded.ResultsAll Centiloid cut-offs fell within the range of 25-35, except for CSF A(42) that rendered an optimal cut-off value of 12 CL. As expected, the agreement of tau/A(42) ratios was higher than that of CSF A(42). Centiloid cut-off robustness was confirmed even when established in an independent cohort and against variations of CSF cut-offs.ConclusionsA cut-off of 12 CL matches previously reported values derived against postmortem measures of AD neuropathology. Together with these previous findings, our results flag two relevant inflection points that would serve as boundary of different stages of amyloid pathology: one around 12 CL that marks the transition from the absence of pathology to subtle pathology and another one around 30 CL indicating the presence of established pathology. The derivation of robust and generalizable cut-offs for core AD biomarkers requires cohorts with adequate representation of intermediate levels.Trial registrationALFA+ Study, NCT02485730ALFA PET Sub-study, NCT02685969