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

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

doi:10.1002/alz.14453

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

Alzheimers Dement. 2024 Dec 30. doi: 10.1002/alz.14453. Online ahead of print.

Authors

Xiaodan Liu^{1

2}, Pauline Maillard³, Giuseppe Barisano⁴, Arvind Caprihan⁵, Steven Cen⁶, Xingfeng Shao¹, Kay Jann¹, John M Ringman⁶, Hanzhang Lu⁷, Konstantinos Arfanakis^{8

9}, Charles S DeCarli³, Brian T Gold¹⁰, Sudha Seshadri¹¹, Claudia L Satizabal¹¹, Alexa S Beiser¹², Mohamad Habes¹³, Joel H Kramer¹⁴, Lara Stables¹⁴, Herpreet Singh¹⁵, Karl G Helmer^{16

17

18}, Steven M Greenberg¹⁵, Danny J J Wang^{1

6}; MarkVCID Consortium

Affiliations

¹ Laboratory of FMRI Technology (LOFT), Mark & Mary Stevens Neuroimaging and Informatics Institute, University of Southern California, Los Angeles, California, USA.
² Department of Radiology and Biomedical Imaging, University of California, San Francisco, California, USA.
³ Department of Neurology, University of California, Davis, Sacramento, California, USA.
⁴ Department of Neurosurgery, Stanford University, Stanford, California, USA.
⁵ The Mind Research Network, Albuquerque, New Mexico, USA.
⁶ Department of Neurology, Keck School of Medicine, University of Southern California, Los Angeles, California, USA.
⁷ Department of Radiology, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA.
⁸ Department of Biomedical Engineering, Illinois Institute of Technology, Chicago, Illinois, USA.
⁹ Rush Alzheimer's Disease Center, Rush University Medical Center, Chicago, Illinois, USA.
¹⁰ Department of Neuroscience, University of Kentucky, Lexington, Kentucky, USA.
¹¹ Population Health Sciences and Glenn Biggs Institute for Neurodegenerative Diseases, University of Texas Health Science Center at San Antonio, San Antonio, Texas, USA.
¹² Department of Biostatistics, School of Public Health, Boston University, Boston, Massachusetts, USA.
¹³ Neuroimage Analytics Laboratory and Glenn Biggs Institute Neuroimaging Core, Glenn Biggs Institute for Neurodegenerative Diseases, University of Texas Health Science Center at San Antonio, San Antonio, Texas, USA.
¹⁴ Department of Neurology, University of California, San Francisco, California, USA.
¹⁵ Department of Neurology, Massachusetts General Hospital, Boston, Massachusetts, USA.
¹⁶ Department of Radiology, Harvard Medical School, Boston, Massachusetts, USA.
¹⁷ Athinoula A. Martinos Center for Biomedical Imaging, Massachusetts General Hospital, Charlestown, Massachusetts, USA.
¹⁸ Department of Computer Science and AI Lab, Massachusetts Institute of Technology, Cambridge, Massachusetts, USA.

PMID: 39740225
DOI: 10.1002/alz.14453

Abstract

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.

Keywords: cerebral small vessel disease (cSVD); diffusion tensor image analysis along the perivascular space index (DTI‐ALPS); free water (FW); glymphatic system (GS); vascular cognitive impairment and dementia (VCID).

Abstract

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