Life Molecular Imaging GmbH, Tegeler Str. 6-7, 13353, Berlin, Germany.
Fundació ACE Institut Català de Neurociències Aplicades, Research Center and Memory Unit - Universitat Internacional de Catalunya (UIC), Barcelona, Spain.
Alzheimers Res Ther. 2021 Mar 27;13(1):67. doi: 10.1186/s13195-021-00807-6.
A low amount and extent of Aβ deposition at early stages of Alzheimer's disease (AD) may limit the use of previously developed pathology-proven composite SUVR cutoffs. This study aims to characterize the population with earliest abnormal Aβ accumulation using F-florbetaben PET. Quantitative thresholds for the early (SUVR) and established (SUVR) Aβ deposition were developed, and the topography of early Aβ deposition was assessed. Subsequently, Aβ accumulation over time, progression from mild cognitive impairment (MCI) to AD dementia, and tau deposition were assessed in subjects with early and established Aβ deposition.
The study population consisted of 686 subjects (n = 287 (cognitively normal healthy controls), n = 166 (subjects with subjective cognitive decline (SCD)), n = 129 (subjects with MCI), and n = 101 (subjects with AD dementia)). Three categories in the Aβ-deposition continuum were defined based on the developed SUVR cutoffs: Aβ-negative subjects, subjects with early Aβ deposition ("gray zone"), and subjects with established Aβ pathology.
SUVR using the whole cerebellum as the reference region and centiloid (CL) cutoffs for early and established amyloid pathology were 1.10 (13.5 CL) and 1.24 (35.7 CL), respectively. Cingulate cortices and precuneus, frontal, and inferior lateral temporal cortices were the regions showing the initial pathological tracer retention. Subjects in the "gray zone" or with established Aβ pathology accumulated more amyloid over time than Aβ-negative subjects. After a 4-year clinical follow-up, none of the Aβ-negative or the gray zone subjects progressed to AD dementia while 91% of the MCI subjects with established Aβ pathology progressed. Tau deposition was infrequent in those subjects without established Aβ pathology.
This study supports the utility of using two cutoffs for amyloid PET abnormality defining a "gray zone": a lower cutoff of 13.5 CL indicating emerging Aβ pathology and a higher cutoff of 35.7 CL where amyloid burden levels correspond to established neuropathology findings. These cutoffs define a subset of subjects characterized by pre-AD dementia levels of amyloid burden that precede other biomarkers such as tau deposition or clinical symptoms and accelerated amyloid accumulation. The determination of different amyloid loads, particularly low amyloid levels, is useful in determining who will eventually progress to dementia. Quantitation of amyloid provides a sensitive measure in these low-load cases and may help to identify a group of subjects most likely to benefit from intervention.
Data used in this manuscript belong to clinical trials registered in ClinicalTrials.gov ( NCT00928304 , NCT00750282 , NCT01138111 , NCT02854033 ) and EudraCT (2014-000798-38).
在阿尔茨海默病（AD）的早期阶段，Aβ 沉积的数量和程度较低，可能会限制以前开发的基于病理的复合 SUVR 截止值的使用。本研究旨在使用 F-氟比苯酮 PET 来描述最早出现异常 Aβ 积累的人群。为早期（SUV R）和已建立的（SUV R）Aβ 沉积开发了定量阈值，并评估了早期 Aβ 沉积的分布。随后，在具有早期和已建立的 Aβ 沉积的受试者中评估了 Aβ 的随时间积累、从轻度认知障碍（MCI）到 AD 痴呆的进展以及 tau 沉积。
研究人群包括 686 名受试者（n=287（认知正常的健康对照），n=166（有主观认知下降（SCD）的受试者），n=129（有 MCI 的受试者），n=101（有 AD 痴呆的受试者））。基于开发的 SUV R 截止值，将 Aβ 沉积连续体分为三个类别：Aβ 阴性受试者、早期 Aβ 沉积（“灰色地带”）受试者和已建立 Aβ 病理学的受试者。
使用全脑作为参考区域和百分位数（CL）的 SUV R 截止值分别为 1.10（13.5 CL）和 1.24（35.7 CL）。扣带回皮质和楔前叶、额叶和下外侧颞叶皮质是最初显示病理性示踪剂保留的区域。处于“灰色地带”或有已建立的 Aβ 病理学的受试者随时间积累的淀粉样蛋白比 Aβ 阴性的受试者更多。在 4 年的临床随访后，没有 Aβ 阴性或灰色区域的受试者进展为 AD 痴呆，而 91%的有已建立 Aβ 病理学的 MCI 受试者进展为 AD 痴呆。在没有已建立的 Aβ 病理学的受试者中，tau 沉积很少见。
本研究支持使用两种 Aβ PET 异常截止值来定义“灰色地带”：较低的截止值为 13.5 CL，表明出现 Aβ 病理学，较高的截止值为 35.7 CL，此时淀粉样蛋白负荷水平与已建立的神经病理学发现相对应。这些截止值定义了一组以 AD 痴呆前淀粉样蛋白负荷水平为特征的受试者，该水平先于其他生物标志物（如 tau 沉积或临床症状）出现，并加速了淀粉样蛋白的积累。确定不同的淀粉样蛋白负荷，特别是低淀粉样蛋白水平，对于确定哪些患者最终会进展为痴呆症很有用。淀粉样蛋白的定量提供了一种在这些低负荷情况下敏感的测量方法，并且可能有助于识别最有可能受益于干预的受试者群体。
本文使用的数据属于 ClinicalTrials.gov（NCT00928304、NCT00750282、NCT01138111、NCT02854033）和 EudraCT（2014-000798-38）注册的临床试验。
