Liu Xiaodan, Maillard Pauline, Barisano Giuseppe, Caprihan Arvind, Cen Steven, Shao Xingfeng, Jann Kay, Ringman John M, Lu Hanzhang, Arfanakis Konstantinos, DeCarli Charles S, Gold Brian T, Seshadri Sudha, Satizabal Claudia L, Beiser Alexa S, Habes Mohamad, Kramer Joel H, Stables Lara, Singh Herpreet, Helmer Karl G, Greenberg Steven M, Wang Danny J J
Laboratory of FMRI Technology (LOFT), Mark & Mary Stevens Neuroimaging and Informatics Institute, University of Southern California, Los Angeles, California, USA.
Department of Radiology and Biomedical Imaging, University of California, San Francisco, California, USA.
Alzheimers Dement. 2025 Feb;21(2):e14453. doi: 10.1002/alz.14453. Epub 2024 Dec 30.
Diffusion tensor image analysis along the perivascular space (DTI-ALPS) index was proposed for assessing glymphatic clearance function. This study evaluated DTI-ALPS as a biomarker for cerebral small vessel disease (cSVD) related vascular cognitive impairment and dementia (VCID).
Four independent cohorts were examined. A composite score of executive function (UDS3-EF) was used to evaluate EF status. The association between the ALPS index and UDS3-EF scores and the mediator effect of free water in white matter (WM-FW) on such association was analyzed.
The ALPS index was significantly associated with UDS3-EF scores in all cohorts. Additionally, WM-FW mediates the relationship between the ALPS index and UDS3-EF scores.
Lower ALPS index may be a surrogate marker of glymphatic dysfunction, which is associated with impaired EF, and this association is mediated by the interstitial fluid (ISF) drainage ISF in WM, providing a clinical rationale for using ALPS index as a biomarker for cSVD-related VCID.
This is the first study to investigate the mediation role of interstitial FW fraction (WM-FW) on the relationship between glymphatic clearance (ALPS index) and EF (UDS3-EF scores) in four independent middle to aged cohorts at risk for cSVD. This study identified that ALPS index was independently associated with UDS3-EF scores after adjusting for demographics, VRFs, and WM hyperintensity burden and that WM-FW mediated this association in all middle to aged cohorts. Our findings suggest that in middle to aged individuals, glymphatic dysfunction (reflected by ALPS index) is strongly associated with EF and that this association is mediated by the ISF drainage in WM. This study provides a strong clinical rationale for the use of the ALPS index as a marker of cognitive function in multi-site observational studies and clinical trials to monitor and prevent VCID.
沿血管周围间隙的扩散张量成像分析（DTI-ALPS）指数被提出用于评估类淋巴系统清除功能。本研究评估DTI-ALPS作为脑小血管疾病（cSVD）相关血管性认知障碍和痴呆（VCID）的生物标志物。
对四个独立队列进行了检查。使用执行功能综合评分（UDS3-EF）来评估执行功能状态。分析了ALPS指数与UDS3-EF评分之间的关联以及白质自由水（WM-FW）在此关联中的中介作用。
在所有队列中，ALPS指数均与UDS3-EF评分显著相关。此外，WM-FW介导了ALPS指数与UDS3-EF评分之间的关系。
较低的ALPS指数可能是类淋巴系统功能障碍的替代标志物，其与执行功能受损相关，且这种关联由白质中的组织间液（ISF）引流介导，这为将ALPS指数用作cSVD相关VCID的生物标志物提供了临床依据。
这是第一项在四个有cSVD风险的独立中老年队列中研究组织间自由水分数（WM-FW）在类淋巴系统清除功能（ALPS指数）与执行功能（UDS3-EF评分）之间关系的中介作用的研究。本研究发现，在调整人口统计学、血管危险因素和白质高信号负荷后，ALPS指数与UDS3-EF评分独立相关，且WM-FW在所有中老年队列中介导了这种关联。我们的研究结果表明，在中老年个体中，类淋巴系统功能障碍（由ALPS指数反映）与执行功能密切相关，且这种关联由白质中的组织间液引流介导。本研究为在多中心观察性研究和临床试验中使用ALPS指数作为认知功能标志物以监测和预防VCID提供了有力的临床依据。
