Longitudinal β-Amyloid Deposition and Hippocampal Volume in Preclinical Alzheimer Disease and Suspected Non-Alzheimer Disease Pathophysiology.
Longitudinal β-Amyloid Deposition and Hippocampal Volume in Preclinical Alzheimer Disease and Suspected Non-Alzheimer Disease Pathophysiology.
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DOI：
10.1001/jamaneurol.2016.2642
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发表时间：
2016-10-01
期刊：
影响因子：
29
通讯作者：
Benzinger TL
中科院分区：
文献类型：
--
作者：
Gordon BA;Blazey T;Su Y;Fagan AM;Holtzman DM;Morris JC;Benzinger TL
临床前阿尔茨海默病 (AD) 可以使用 2 因素模型进行分期，该模型表示是否存在 β-淀粉样蛋白 (Aβ+/-) 和神经变性 (ND+/-)。这些阶段与纵向生物标志物结果的关联尚不清楚。根据初始临床前分期检查纵向 Aβ 积累和海马萎缩是否存在差异。这项基于人群的纵向队列研究使用了密苏里州圣路易斯华盛顿大学奈特阿尔茨海默病研究中心从 2006 年 12 月 1 日至 2015 年 6 月 31 日期间收集的数据。认知正常的老年人 (n = 174) 是从奈特阿尔茨海默病研究中心的纵向成年儿童研究以及健康老龄化和老年痴呆研究中招募的。在基线时，所有参与者均进行了磁共振成像 (MRI) 扫描、使用碳 11 标记的匹兹堡化合物 B (PiB) 进行的正电子发射断层扫描 (PET) 扫描，以及 12 个月内获得的 tau 蛋白和磷酸化 tau 蛋白 (ptau) 的脑脊液检测结果。使用基线生物标志物，将个体分为临床前阶段 0 (Aβ−/ND−)、1 (Aβ+/ND−) 或 2+ (Aβ+/ND+) 或疑似非 AD 病理生理学阶段 (SNAP；Aβ−/ND+)。随后用 PiB PET 评估 Aβ 的纵向积累，并用 MRI 评估每组海马体积的损失。在 174 名参与者（81 名男性 [46.6%]；93 名女性 [53.4%]；平均 [SD] 年龄，65.7 [8.9] 岁）中，一部分 (14%-17%) 患有单纯神经退行性变 (SNAP) 的个体后来表现出 Aβ+。 SNAP 个体的 Aβ 积累率和海马体积损失率与基线时没有任何病理特征的个体没有区别（对于 Aβ 积累：当使用海马体积定义 ND 时，t = 0.00 [P > .99]；当使用 tau 和 ptau 定义 ND 时，t = -0.02 [P = .98]；对于海马体积损失：当使用海马体积定义 ND，t = -1.34 [P = .18]；使用 tau 和 ptau 定义 ND 时，t = 0.84 [P = .40]）。后来的临床前阶段（阶段 1 和阶段 2+）Aβ 积累升高。使用海马体积来定义 ND，阶段 1 的个体相对于阶段 0 (t = 11.06; P < .001)、阶段 2+ (t = 2.10; P = .04) 和 SNAP (t = 9.32; P < .001) 加速了 Aβ 积累，阶段 2+ 的个体相对于阶段 0 加速了 Aβ 积累 (t = 4.38; P < .001)。 .001) 和 SNAP (t = 4.08; P < .001)。当使用 tau 和 ptau 定义 ND 时，2+ 阶段的个体相对于阶段 0 (t = 4.96) 和 SNAP (t = 4.06) 加速了 Aβ 积累，而阶段 1 的个体相对于阶段 0 (t = 8.44) 和 SNAP (t = 6.61) 加速了 Aβ 积累（所有比较 P < .001）。当使用脑脊液生物标志物定义 ND 时，2+ 阶段的个体相对于 0 阶段（t = -3.41；P < .001）、1 阶段（t = -2.48；P = .03）和 SNAP（t = -2.26；P = .03），海马萎缩加速。 AD 临床前阶段越晚期，纵向 Aβ 积累就越多。 SNAP 似乎最有可能捕获大脑结构中固有的个体差异或代表共病病理特征，而不是早期出现的 AD。单独的海马体积低或 tau 或 ptau 水平升高可能无法准确代表正在进行的神经退行性过程。
Preclinical Alzheimer disease (AD) can be staged using a 2-factor model denoting the presence or absence of β-amyloid (Aβ+/−) and neurodegeneration (ND+/−). The association of these stages with longitudinal biomarker outcomes is unknown. To examine whether longitudinal Aβ accumulation and hippocampal atrophy differ based on initial preclinical staging. This longitudinal population-based cohort study used data collected at the Knight Alzheimer Disease Research Center, Washington University, St Louis, Missouri, from December 1, 2006, to June 31, 2015. Cognitively normal older adults (n = 174) were recruited from the longitudinal Adult Children Study and Healthy Aging and Senile Dementia Study at the Knight Alzheimer Disease Research Center. At baseline, all participants had magnetic resonance imaging (MRI) scans, positron emission tomography (PET) scans with carbon 11-labeled Pittsburgh Compound B (PiB), and cerebrospinal fluid assays of tau and phosphorylated tau (ptau) acquired within 12 months. Using the baseline biomarkers, individuals were classified into preclinical stage 0 (Aβ−/ND−), 1 (Aβ+/ND−), or 2+ (Aβ+/ND+) or suspected non-AD pathophysiology (SNAP; Aβ−/ND+). Subsequent longitudinal accumulation of Aβ assessed with PiB PET and loss of hippocampal volume assessed with MRI in each group. Among the 174 participants (81 men [46.6%]; 93 women [53.4%]; mean [SD] age, 65.7 [8.9] years), a proportion (14%-17%) of individuals with neurodegeneration alone (SNAP) later demonstrated Aβ+. The rates of Aβ accumulation and loss of hippocampal volume in individuals with SNAP were indistinguishable from those without any pathologic features at baseline (for Aβ accumulation: when hippocampal volume was used to define ND, t = 0.00 [P > .99]; when tau and ptau were used to define ND, t = −0.02 [P = .98]; for loss of hippocampal volume: when hippocampal volume was used to define ND, t = −1.34 [P = .18]; when tau and ptau were used to define ND, t = 0.84 [P = .40]). Later preclinical stages (stages 1 and 2+) had elevated Aβ accumulation. Using hippocampal volume to define ND, individuals with stage 1 had accelerated Aβ accumulation relative to stage 0 (t = 11.06; P < .001), stage 2+ (t = 2.10; P = .04), and SNAP (t = 9.32; P < .001), and those with stage 2+ had accelerated Aβ accumulation relative to stage 0 (t = 4.38; P < .001) and SNAP (t = 4.08; P < .001). When ND was defined using tau and ptau, individuals with stage 2+had accelerated Aβ accumulation relative to stage 0 (t = 4.96) and SNAP (t = 4.06), and those with stage 1 had accelerated Aβ accumulation relative to stage 0 (t = 8.44) and SNAP (t = 6.61) (P < .001 for all comparisons). When ND was defined using cerebrospinal fluid biomarkers, individuals with stage 2+ had accelerated hippocampal atrophy relative to stage 0 (t = −3.41; P < .001), stage 1 (t = −2.48; P = .03), and SNAP (t = −2.26; P = .03). More advanced preclinical stages of AD have greater longitudinal Aβ accumulation. SNAP appears most likely to capture inherent individual variability in brain structure or to represent comorbid pathologic features rather than early emerging AD. Low hippocampal volumes or elevated levels of tau or ptau in isolation may not accurately represent ongoing neurodegenerative processes.