脑小血管病负担可预测前驱期阿尔茨海默病的神经退行性变和临床进展。

Cerebral Small Vessel Disease Burden Predicts Neurodegeneration and Clinical Progression in Prodromal Alzheimer's Disease.

机构信息

Department of Neurology, Qingdao Municipal Hospital, Qingdao University, Qingdao, China.

Department of Neurology and Institute of Neurology, Huashan Hospital, State Key Laboratory of Medical Neurobiology and MOE Frontiers Center for Brain Science, Shanghai Medical College, Fudan University, Shanghai, China.

出版信息

J Alzheimers Dis. 2023;93(1):283-294. doi: 10.3233/JAD-221207.

DOI:10.3233/JAD-221207

PMID:36970905

Abstract

BACKGROUND

Cerebral small vessel disease (CSVD) has been suggested to contribute to the pathogenesis of Alzheimer's disease (AD).

OBJECTIVE

This study aimed to comprehensively investigated the associations of CSVD burden with cognition and AD pathologies.

METHODS

A total of 546 non-demented participants (mean age, 72.1 years, range, 55-89; 47.4% female) were included. The longitudinal neuropathological and clinical correlates of CSVD burden were assessed using linear mixed-effects and Cox proportional-hazard models. Partial least squares structural equation model (PLS-SEM) was used to assess the direct and indirect effects of CSVD burden on cognition.

RESULTS

We found that higher CSVD burden was associated with worse cognition (MMSE, β= -0.239, p = 0.006; MoCA, β= -0.493, p = 0.013), lower cerebrospinal fluid (CSF) Aβ level (β= -0.276, p < 0.001) and increased amyloid burden (β= 0.048, p = 0.002). In longitudinal, CSVD burden contributed to accelerated rates of hippocampus atrophy, cognitive decline, and higher risk of AD dementia. Furthermore, as the results of PLS-SEM, we observed both significant direct and indirect impact of advanced age (direct, β= -0.206, p < 0.001; indirect, β= -0.002, p = 0.043) and CSVD burden (direct, β= -0.096, p = 0.018; indirect, β= -0.005, p = 0.040) on cognition by Aβ-p-tau-tau pathway.

CONCLUSION

CSVD burden could be a prodromal predictor for clinical and pathological progression. Simultaneously, we found that the effects were mediated by the one-direction-only sequence of pathological biomarker changes starting with Aβ, through abnormal p-tau, and neurodegeneration.

摘要

背景

脑小血管病（CSVD）被认为是阿尔茨海默病（AD）发病机制的一个因素。

目的

本研究旨在全面探讨 CSVD 负荷与认知和 AD 病理学之间的关系。

方法

共纳入 546 名非痴呆参与者（平均年龄 72.1 岁，范围为 55-89 岁；47.4%为女性）。采用线性混合效应和 Cox 比例风险模型评估 CSVD 负荷的纵向神经病理学和临床相关性。偏最小二乘结构方程模型（PLS-SEM）用于评估 CSVD 负荷对认知的直接和间接影响。

结果

我们发现 CSVD 负荷越高，认知越差（MMSE，β=-0.239，p=0.006；MoCA，β=-0.493，p=0.013），脑脊液（CSF）Aβ水平越低（β=-0.276，p<0.001），淀粉样蛋白负荷越高（β=0.048，p=0.002）。在纵向研究中，CSVD 负荷与海马萎缩加速、认知下降和 AD 痴呆风险增加有关。此外，作为 PLS-SEM 的结果，我们观察到高龄（直接，β=-0.206，p<0.001；间接，β=-0.002，p=0.043）和 CSVD 负荷（直接，β=-0.096，p=0.018；间接，β=-0.005，p=0.040）对认知的直接和间接影响均通过 Aβ-p-tau-tau 通路。