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

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

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4 Scopus citations

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.

Original language	English
Article number	e14453
Journal	Alzheimer's and Dementia
Volume	21
Issue number	2
DOIs	https://doi.org/10.1002/alz.14453
State	Published - Feb 2025

Bibliographical note

Publisher Copyright:
© 2024 The Author(s). Alzheimer's & Dementia published by Wiley Periodicals LLC on behalf of Alzheimer's Association.

Funding

We thank all the participants and their care partners and family, collaborators and staff from different sites, and the entire study team members for their contribution to this study. Specifically, X.L., P.M., and D.J.J.W. contributed to the conception and design of the study. X.L. drafted the manuscript. X.L., P.M., G.B., S.C. conducted the data processing and statistical analysis. All authors interpreted the data, reviewed and provided critical revisions, and approved the final version for publication. Data used in the preparation of this article were obtained from the MarkVCID consortium. A complete listing of MarkVCID investigators can be found at\u00A0https://markvcid.partners.org/acknowledgements. Data collection and sharing for this project was funded by NINDS/NIA as part of the MarkVCID Consortium (U24NS100591, UH3NS100599, UH3NS100605, UH3NS100588, UH3NS100608, UH3NS100606, UH3NS100598, UH3NS100614). We thank all the participants and their care partners and family, collaborators and staff from different sites, and the entire study team members for their contribution to this study. Specifically, X.L., P.M., and D.J.J.W. contributed to the conception and design of the study. X.L. drafted the manuscript. X.L., P.M., G.B., S.C. conducted the data processing and statistical analysis. All authors interpreted the data, reviewed and provided critical revisions, and approved the final version for publication. Data used in the preparation of this article were obtained from the MarkVCID consortium. A complete listing of MarkVCID investigators can be found at https://markvcid.partners.org/acknowledgements . Data collection and sharing for this project was funded by NINDS/NIA as part of the MarkVCID Consortium (U24NS100591, UH3NS100599, UH3NS100605, UH3NS100588, UH3NS100608, UH3NS100606, UH3NS100598, UH3NS100614).

Funders	Funder number
National Institute on Aging
Institute of Neurological Disorders and Stroke National Advisory Neurological Disorders and Stroke Council
MarkVCID Consortium	UH3NS100608, UH3NS100606, UH3NS100598, UH3NS100588, UH3NS100599, UH3NS100605, UH3NS100614, U24NS100591

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)

ASJC Scopus subject areas

Epidemiology
Health Policy
Developmental Neuroscience
Clinical Neurology
Geriatrics and Gerontology
Cellular and Molecular Neuroscience
Psychiatry and Mental health

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

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10.1002/alz.14453

Cite this

@article{0c504b4678bd4cf7a1e09f0bac99e15f,

title = "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",

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)",

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

note = "Publisher Copyright: {\textcopyright} 2024 The Author(s). Alzheimer's \& Dementia published by Wiley Periodicals LLC on behalf of Alzheimer's Association.",

year = "2025",

month = feb,

doi = "10.1002/alz.14453",

language = "English",

volume = "21",

number = "2",

}

TY - JOUR

T1 - 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

AU - Liu, Xiaodan

AU - Maillard, Pauline

AU - Barisano, Giuseppe

AU - Caprihan, Arvind

AU - Cen, Steven

AU - Shao, Xingfeng

AU - Jann, Kay

AU - Ringman, John M.

AU - Lu, Hanzhang

AU - Arfanakis, Konstantinos

AU - DeCarli, Charles S.

AU - Gold, Brian T.

AU - Seshadri, Sudha

AU - Satizabal, Claudia L.

AU - Beiser, Alexa S.

AU - Habes, Mohamad

AU - Kramer, Joel H.

AU - Stables, Lara

AU - Singh, Herpreet

AU - Helmer, Karl G.

AU - Greenberg, Steven M.

AU - Wang, Danny J.J.

PY - 2025/2

Y1 - 2025/2

N2 - 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.

AB - 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.

KW - cerebral small vessel disease (cSVD)

KW - diffusion tensor image analysis along the perivascular space index (DTI-ALPS)

KW - free water (FW)

KW - glymphatic system (GS)

KW - vascular cognitive impairment and dementia (VCID)

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SN - 1552-5260

VL - 21

JO - Alzheimer's and Dementia

JF - Alzheimer's and Dementia

IS - 2

M1 - e14453

ER -

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

Abstract

Bibliographical note

Funding

Keywords

ASJC Scopus subject areas

UN SDGs

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