Mark and Mary Stevens Neuroimaging and Informatics Institute, Keck School of Medicine of the University of Southern California, Los Angeles, CA 90033, United States.
Department of Physiology and Neuroscience and the Zilkha Neurogenetic Institute, Keck School of Medicine of the University of Southern California, Los Angeles, CA 90033, United States.
Brain Behav Immun. 2021 May;94:299-307. doi: 10.1016/j.bbi.2021.01.010. Epub 2021 Jan 22.
CNS inflammation is a key factor in Alzheimer's Disease (AD), but its relation to pathological Aβ, tau, and APOE4 is poorly understood, particularly prior to the onset of cognitive symptoms. To better characterize early relationships between inflammation, APOE4, and AD pathology, we assessed correlations between cerebrospinal fluid (CSF) inflammatory markers and brain levels of Aβ and tau in cognitively normal older adults. Each participant received a lumbar puncture to collect and quantify CSF levels of TNFα, IL-6, IL-8, and IL-10, a T1-weighted MRI, and PET scanning with [F]flortaucipir (FTP; n = 57), which binds to tau tangles and/or [F]florbetapir (FBP; n = 58), which binds to Aβ. Parallel voxelwise regressions assessed relationships between each CSF inflammatory marker and FTP and FBP SUVR, as well as APOE4*CSF inflammation interactions. Unexpectedly, we detected significant negative associations between regional Aβ and tau PET uptake and CSF inflammatory markers. For Aβ PET, we detected negative associations with CSF IL-6 and IL-8 in regions known to show early accumulation of Aβ (i.e. lateral and medial frontal lobes). For tau PET, negative relationships were observed with CSF TNFα and IL-8, predominantly in regions known to exhibit early tau accumulation (i.e. medial temporal lobe). In subsequent analyses, significant interactions between APOE4 status and IL-8 on Aβ and tau PET levels were observed in spatially distinct regions from those showing CSF-Aβ/tau relationships. Results from the current cross-sectional study support previous findings that neuroinflammation may be protective against AD pathology at a given stage of the disease, and extend these findings to a cognitively normal aging population. This study provides new insight into a dynamic relationship between neuroinflammation and AD pathology and may have implications for whom and when neuroinflammatory therapies may be appropriate.
中枢神经系统炎症是阿尔茨海默病（AD）的一个关键因素，但人们对其与病理性 Aβ、tau 和 APOE4 的关系知之甚少，尤其是在认知症状出现之前。为了更好地描述炎症、APOE4 和 AD 病理学之间的早期关系，我们评估了认知正常的老年人脑脊液（CSF）炎症标志物与脑内 Aβ 和 tau 水平之间的相关性。每位参与者都接受了腰椎穿刺，以收集和定量 CSF 中的 TNFα、IL-6、IL-8 和 IL-10 水平，进行 T1 加权 MRI 和 [F]flortaucipir（FTP；n=57）的 PET 扫描，该物质与 tau 缠结结合，或 [F]florbetapir（FBP；n=58），与 Aβ 结合。平行体素回归评估了每个 CSF 炎症标志物与 FTP 和 FBP SUVR 之间的关系，以及 APOE4*CSF 炎症相互作用。出乎意料的是，我们在区域 Aβ 和 tau PET 摄取与 CSF 炎症标志物之间检测到了显著的负相关。对于 Aβ PET，我们在 Aβ 早期积累的区域（即外侧和内侧额叶）检测到与 CSF IL-6 和 IL-8 的负相关。对于 tau PET，我们观察到 CSF TNFα 和 IL-8 与 tau PET 水平呈负相关，主要在 tau 早期积累的区域（即内侧颞叶）。在后续分析中，在与 CSF-Aβ/tau 关系不同的空间区域，观察到 APOE4 状态和 IL-8 对 Aβ 和 tau PET 水平的显著相互作用。本横断面研究的结果支持了先前的研究结果，即神经炎症在疾病的某个阶段可能对 AD 病理学具有保护作用，并将这些发现扩展到认知正常的老年人群。本研究提供了神经炎症与 AD 病理学之间动态关系的新见解，并可能对何时以及针对哪些人群使用神经炎症治疗具有重要意义。
