Journal Article

MRI free water mediates the association between diffusion tensor image analysis along the perivascular space and executive function in four independent middle to aged cohorts

Jann, Kay, DeCarli, Charles S., Kramer, Joel H., Singh, Herpreet, Maillard, Pauline, Lu, Hanzhang, Seshadri, Sudha, Wang, Danny J. J., Caprihan, Arvind, Greenberg, Steven M., Stables, Lara, Satizabal, Claudia L., Beiser, Alexa S., Cen, Steven, Helmer, Karl G., Habes, Mohamad, Barisano, Giuseppe, Shao, Xingfeng, Arfanakis, Konstantinos, Liu, Xiaodan, Ringman, John M., Gold, Brian T.

2025

Overview

INTRODUCTION 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). METHODS 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. RESULTS 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. DISCUSSION 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. Highlights 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.

• Publisher: John Wiley & Sons, Inc,John Wiley and Sons Inc
• Subject: Aged / Biological markers / Biomarkers / Brain research / cerebral small vessel disease (cSVD) / Cerebral Small Vessel Diseases - diagnostic imaging / Clinical research / Clinical trials / Cognition / Cognition & reasoning / Cognitive ability / Cognitive Dysfunction - diagnostic imaging / Cognitive functioning / Cognitive impairment / Cohort Studies / Dementia / Dementia, Vascular - diagnostic imaging / Demography / diffusion tensor image analysis along the perivascular space index (DTI‐ALPS) / Diffusion Tensor Imaging / Disease / Drainage / Executive function / Executive Function - physiology / Female / free water (FW) / Function / glymphatic system (GS) / Glymphatic System - diagnostic imaging / Humans / Indexes / Magnetic Resonance Imaging / Male / Mediation / Memory / Middle Aged / Nervous system / Observational studies / Older people / Risk factors / vascular cognitive impairment and dementia (VCID) / Water / Water supply / White Matter - diagnostic imaging