与阿尔茨海默病和认知能力下降相关的突触前丧失。

Association of Presynaptic Loss with Alzheimer's Disease and Cognitive Decline.

机构信息

Institute of Biomedical Engineering, Shenzhen Bay Laboratory, Shenzhen, China.

Tsinghua Shenzhen International Graduate School (SIGS), Tsinghua University, Shenzhen, China.

出版信息

Ann Neurol. 2022 Dec;92(6):1001-1015. doi: 10.1002/ana.26492. Epub 2022 Sep 15.

DOI:10.1002/ana.26492

PMID:36056679

Abstract

OBJECTIVE

Increased presynaptic dysfunction measured by cerebrospinal fluid (CSF) growth-associated protein-43 (GAP43) may be observed in Alzheimer's disease (AD), but how CSF GAP43 increases relate to AD-core pathologies, neurodegeneration, and cognitive decline in AD requires further investigation.

METHODS

We analyzed 731 older adults with baseline β-amyloid (Aβ) positron emission tomography (PET), CSF GAP43, CSF phosphorylated tau181 (p-Tau ), and F-fluorodeoxyglucose PET, and longitudinal residual hippocampal volume and cognitive assessments. Among them, 377 individuals had longitudinal F-fluorodeoxyglucose PET, and 326 individuals had simultaneous longitudinal CSF GAP43, Aβ PET, and CSF p-Tau data. We compared baseline and slopes of CSF GAP43 among different stages of AD, as well as their associations with Aβ PET, CSF p-Tau , residual hippocampal volume, F-fluorodeoxyglucose PET, and cognition cross-sectionally and longitudinally.

RESULTS

Regardless of Aβ positivity and clinical diagnosis, CSF p-Tau -positive individuals showed higher CSF GAP43 concentrations (p < 0.001) and faster rates of CSF GAP43 increases (p < 0.001) compared with the CSF p-Tau -negative individuals. Moreover, higher CSF GAP43 concentrations and faster rates of CSF GAP43 increases were strongly related to CSF p-Tau independent of Aβ PET. They were related to more rapid hippocampal atrophy, hypometabolism, and cognitive decline (p < 0.001), and predicted the progression from MCI to dementia (area under the curve for baseline 0.704; area under the curve for slope 0.717) over a median 4 years of follow up.

INTERPRETATION

Tau aggregations rather than Aβ plaques primarily drive presynaptic dysfunction measured by CSF GAP43, which may lead to sequential neurodegeneration and cognitive impairment in AD or neurodegenerative diseases. ANN NEUROL 2022;92:1001-1015.

摘要

目的

通过测量脑脊液（CSF）中的生长相关蛋白-43（GAP43）来评估突触前功能障碍，在阿尔茨海默病（AD）患者中可能会观察到这种情况，但 CSF GAP43 增加与 AD 核心病理学、神经退行性变以及 AD 认知能力下降的关系仍需进一步研究。

方法

我们分析了 731 名基线时进行β-淀粉样蛋白（Aβ）正电子发射断层扫描（PET）、CSF GAP43、CSF 磷酸化 tau181（p-Tau）和 F-氟脱氧葡萄糖 PET 检查、纵向残留海马体积和认知评估的老年人。其中 377 名患者进行了纵向 F-氟脱氧葡萄糖 PET 检查，326 名患者同时进行了纵向 CSF GAP43、Aβ PET 和 CSF p-Tau 数据检查。我们比较了 AD 不同阶段的 CSF GAP43 的基线和斜率，并比较了它们与 Aβ PET、CSF p-Tau、残留海马体积、F-氟脱氧葡萄糖 PET 和认知的横断面和纵向关联。

结果

无论 Aβ 阳性与否以及临床诊断如何，与 CSF p-Tau 阴性患者相比，CSF p-Tau 阳性患者的 CSF GAP43 浓度更高（p<0.001），CSF GAP43 增加的速度更快（p<0.001）。此外，较高的 CSF GAP43 浓度和更快的 CSF GAP43 增加速度与 Aβ PET 无关，与 CSF p-Tau 密切相关。它们与更快的海马萎缩、低代谢和认知能力下降相关（p<0.001），并在中位数为 4 年的随访期间预测了从 MCI 向痴呆的进展（基线时的曲线下面积为 0.704，斜率时的曲线下面积为 0.717）。