Abstract

A deeper understanding of the spatial relationships of β-amyloid (Aβ), tau, and neurodegeneration in Alzheimer’s disease (AD) could provide insight into pathogenesis and clinical trial design. We included 81 amyloid-positive patients (age 64.4 ± 9.5) diagnosed with AD dementia or mild cognitive impairment due to AD and available ¹¹C-PiB (PIB), ¹⁸F-Flortaucipir (FTP),¹⁸F-FDG-PET, and 3T-MRI, and 31 amyloid-positive, cognitively normal participants (age 77.3 ± 6.5, no FDG-PET). W-score voxel-wise deviation maps were created and binarized for each imaging-modality (W > 1.64, P < 0.05) adjusting for age, sex, and total intracranial volume (sMRI-only) using amyloid-negative cognitively normal adults. For symptomatic patients, FDG-PET and atrophy W-maps were combined into neurodegeneration maps (ND). Aβ-pathology showed the greatest proportion of cortical gray matter suprathreshold voxels (spatial extent) for both symptomatic and asymptomatic participants (median 94–55%, respectively), followed by tau (79–11%) and neurodegeneration (41–3%). Amyloid > tau > neurodegeneration was the most frequent hierarchy for both groups (79–77%, respectively), followed by tau > amyloid > neurodegeneration (13–10%) and amyloid > neurodegeneration > tau (6–13%). For symptomatic participants, most abnormal voxels were PIB+/FTP+/ND− (median 35%), and the great majority of ND+ voxels (91%) colocalized with molecular pathology. Amyloid spatially exceeded tau and neurodegeneration, with individual heterogeneities. Molecular pathology and neurodegeneration showed a progressive overlap along AD course, indicating shared vulnerabilities or synergistic toxic mechanisms.

中文翻译：

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阿尔茨海默病连续体中分子病理学与神经变性之间的空间关系。

摘要

深入了解阿尔茨海默病 (AD) 中 β-淀粉样蛋白 (Aβ)、tau 和神经变性的空间关系，可以深入了解发病机制和临床试验设计。我们纳入了 81 名被诊断患有 AD 痴呆或轻度认知障碍的淀粉样蛋白阳性患者（年龄 64.4 ± 9.5）和可用的¹¹ C-PiB (PIB)、¹⁸ F-Flortaucipir (FTP)、¹⁸ F-FDG-PET 和3T-MRI 和 31 名淀粉样蛋白阳性、认知正常的参与者（年龄 77.3 ± 6.5，无 FDG-PET）。为每个成像模态创建 W 分数体素偏差图并进行二值化 ( W  > 1.64, P < 0.05) 使用淀粉样蛋白阴性认知正常的成年人调整年龄、性别和颅内总体积（仅 sMRI）。对于有症状的患者，将 FDG-PET 和萎缩 W-maps 组合成神经退行性疾病图 (ND)。Aβ 病理显示有症状和无症状参与者的皮质灰质阈上体素（空间范围）的比例最大（中位数分别为 94-55%），其次是 tau（79-11%）和神经变性（41-3%） . 淀粉样蛋白 > tau > 神经变性是两组最常见的层次结构（分别为 79-77%），其次是 tau > 淀粉样蛋白 > 神经变性（13-10%）和淀粉样蛋白 > 神经变性 > tau（6-13%）。对于有症状的参与者，大多数异常体素是 PIB+/FTP+/ND-（中位数 35%），并且绝大多数 ND+ 体素 (91%) 与分子病理学共定位。淀粉样蛋白在空间上超过 tau 和神经变性，具有个体异质性。分子病理学和神经变性在 AD 病程中逐渐重叠，表明存在共同的弱点或协同毒性机制。