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Abstract

Background and Objectives

Previous studies have linked the MRI measures of perivascular spaces (PVSs), diffusivity along the perivascular spaces (DTI-ALPS), and free water (FW) to cerebral small vessel disease (SVD) and SVD-related cognitive impairments. However, studies on the longitudinal associations between the three MRI measures, SVD progression, and cognitive decline are lacking. This study aimed to explore how PVS, DTI-ALPS, and FW contribute to SVD progression and cognitive decline.

Methods

This is a cohort study that included participants with SVD who underwent neuroimaging and cognitive assessment, specifically measuring Mini-Mental State Examination (MMSE), cognitive index, and processing speed, at 2 time points. Three MRI measures were quantified: PVS in basal ganglia (BG-PVS) volumes, FW fraction, and DTI-ALPS. We performed a latent change score model to test inter-relations between the 3 MRI measures and linear regression mixed models to test their longitudinal associations with the changes of other SVD MRI markers and cognitive performances.

Results

In baseline assessment, we included 289 participants with SVD, characterized by a median age of 67.0 years and 42.9% women. Of which, 220 participants underwent the follow-up assessment, with a median follow-up time of 3.4 years. Baseline DTI-ALPS was associated with changes in BG-PVS volumes (β = −0.09, p = 0.030), but not vice versa (β = −0.08, p = 0.110). Baseline BG-PVS volumes were associated with changes in white matter hyperintensity (WMH) volumes (β = 0.33, p-corrected < 0.001) and lacune numbers (β = 0.28, p-corrected < 0.001); FW fraction was associated with changes in WMH volumes (β = 0.30, p-corrected < 0.001), lacune numbers (β = 0.28, p-corrected < 0.001), and brain volumes (β = −0.45, p-corrected < 0.001); DTI-ALPS was associated with changes in WMH volumes (β = −0.20, p-corrected = 0.002) and brain volumes (β = 0.23, p-corrected < 0.001). Furthermore, baseline FW fraction was associated with decline in MMSE score (β = −0.17, p-corrected = 0.006); baseline FW fraction and DTI-ALPS were associated with changes in cognitive index (FW fraction: β = −0.25, p-corrected < 0.001; DTI-ALPS: β = 0.20, p-corrected = 0.001) and processing speed over time (FW fraction: β = −0.29, p-corrected < 0.001; DTI-ALPS: β = 0.21, p-corrected < 0.001).

Discussion

Our results showed that increased BG-PVS volumes, increased FW fraction, and decreased DTI-ALPS are related to progression of MRI markers of SVD, along with SVD-related cognitive decline over time. These findings may suggest that the glymphatic dysfunction is related to SVD progression, but further studies are needed.

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Supplementary Material

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Information & Authors

Information

Published In

Neurology®
Volume 102Number 9May 14, 2024
PubMed: 38626373

Publication History

Received: October 20, 2023
Accepted: February 6, 2024
Published online: April 16, 2024
Published in print: May 14, 2024

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Disclosure

The authors report no relevant disclosures. Go to Neurology.org/N for full disclosures.

Study Funding

This work was supported by the funding of Stichting Alzheimer Nederland (WE.03-2023-21cb to A.M. Tuladhar), the China Scholarship Council (No 202106380078 to H. Li), a Dutch Brain Foundation personal fellowship (H04-12; F2009(1)-16 to F.-E. de Leeuw), and a VIDI innovational grant from the Netherlands Organization for Health Research and Development (ZonMw grant 016.126.351 to F.-E. de Leeuw); A.M. Tuladhar is a junior staff member of the Dutch Heart Foundation (grant number 2016T044).

Authors

Affiliations & Disclosures

From the Department of Neurology (H.L., M.A.J., M.C., F.-E.D.L., A.M.T.), Radboud University Medical Center, Donders Center for Medical Neurosciences, Nijmegen, the Netherlands; Department of Neurology (M.C.), Guangdong Neuroscience Institute, Guangdong Provincial People's Hospital, Guangdong Academy of Medical Sciences, Southern Medical University, Guangzhou, China; Donders Institute for Brain (R.P.C.K.), Cognition and Behaviour, Radboud University, Nijmegen; Vincent van Gogh Institute for Psychiatry (R.P.C.K.), Venray; Department of Medical Psychology and Radboudumc Alzheimer Center (R.P.C.K.), Radboud University Medical Center; Donders Institute for Brain (D.G.N.), Cognition and Behaviour, Center for Cognitive Neuroimaging, Radboud University, Nijmegen, the Netherlands; Medical Image Analysis Center (MIAC AG) and Department of Biomedical Engineering (M.D.), University of Basel, Switzerland; and Institute for Stroke and Dementia Research (ISD) (M.D.), University Hospital, LMU Munich, Germany.
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From the Department of Neurology (H.L., M.A.J., M.C., F.-E.D.L., A.M.T.), Radboud University Medical Center, Donders Center for Medical Neurosciences, Nijmegen, the Netherlands; Department of Neurology (M.C.), Guangdong Neuroscience Institute, Guangdong Provincial People's Hospital, Guangdong Academy of Medical Sciences, Southern Medical University, Guangzhou, China; Donders Institute for Brain (R.P.C.K.), Cognition and Behaviour, Radboud University, Nijmegen; Vincent van Gogh Institute for Psychiatry (R.P.C.K.), Venray; Department of Medical Psychology and Radboudumc Alzheimer Center (R.P.C.K.), Radboud University Medical Center; Donders Institute for Brain (D.G.N.), Cognition and Behaviour, Center for Cognitive Neuroimaging, Radboud University, Nijmegen, the Netherlands; Medical Image Analysis Center (MIAC AG) and Department of Biomedical Engineering (M.D.), University of Basel, Switzerland; and Institute for Stroke and Dementia Research (ISD) (M.D.), University Hospital, LMU Munich, Germany.
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From the Department of Neurology (H.L., M.A.J., M.C., F.-E.D.L., A.M.T.), Radboud University Medical Center, Donders Center for Medical Neurosciences, Nijmegen, the Netherlands; Department of Neurology (M.C.), Guangdong Neuroscience Institute, Guangdong Provincial People's Hospital, Guangdong Academy of Medical Sciences, Southern Medical University, Guangzhou, China; Donders Institute for Brain (R.P.C.K.), Cognition and Behaviour, Radboud University, Nijmegen; Vincent van Gogh Institute for Psychiatry (R.P.C.K.), Venray; Department of Medical Psychology and Radboudumc Alzheimer Center (R.P.C.K.), Radboud University Medical Center; Donders Institute for Brain (D.G.N.), Cognition and Behaviour, Center for Cognitive Neuroimaging, Radboud University, Nijmegen, the Netherlands; Medical Image Analysis Center (MIAC AG) and Department of Biomedical Engineering (M.D.), University of Basel, Switzerland; and Institute for Stroke and Dementia Research (ISD) (M.D.), University Hospital, LMU Munich, Germany.
Disclosure
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NONE
Research Support:
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NONE
Stock, Stock Options & Royalties:
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NONE
Legal Proceedings:
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From the Department of Neurology (H.L., M.A.J., M.C., F.-E.D.L., A.M.T.), Radboud University Medical Center, Donders Center for Medical Neurosciences, Nijmegen, the Netherlands; Department of Neurology (M.C.), Guangdong Neuroscience Institute, Guangdong Provincial People's Hospital, Guangdong Academy of Medical Sciences, Southern Medical University, Guangzhou, China; Donders Institute for Brain (R.P.C.K.), Cognition and Behaviour, Radboud University, Nijmegen; Vincent van Gogh Institute for Psychiatry (R.P.C.K.), Venray; Department of Medical Psychology and Radboudumc Alzheimer Center (R.P.C.K.), Radboud University Medical Center; Donders Institute for Brain (D.G.N.), Cognition and Behaviour, Center for Cognitive Neuroimaging, Radboud University, Nijmegen, the Netherlands; Medical Image Analysis Center (MIAC AG) and Department of Biomedical Engineering (M.D.), University of Basel, Switzerland; and Institute for Stroke and Dementia Research (ISD) (M.D.), University Hospital, LMU Munich, Germany.
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Research Support:
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NONE
Stock, Stock Options & Royalties:
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NONE
Legal Proceedings:
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From the Department of Neurology (H.L., M.A.J., M.C., F.-E.D.L., A.M.T.), Radboud University Medical Center, Donders Center for Medical Neurosciences, Nijmegen, the Netherlands; Department of Neurology (M.C.), Guangdong Neuroscience Institute, Guangdong Provincial People's Hospital, Guangdong Academy of Medical Sciences, Southern Medical University, Guangzhou, China; Donders Institute for Brain (R.P.C.K.), Cognition and Behaviour, Radboud University, Nijmegen; Vincent van Gogh Institute for Psychiatry (R.P.C.K.), Venray; Department of Medical Psychology and Radboudumc Alzheimer Center (R.P.C.K.), Radboud University Medical Center; Donders Institute for Brain (D.G.N.), Cognition and Behaviour, Center for Cognitive Neuroimaging, Radboud University, Nijmegen, the Netherlands; Medical Image Analysis Center (MIAC AG) and Department of Biomedical Engineering (M.D.), University of Basel, Switzerland; and Institute for Stroke and Dementia Research (ISD) (M.D.), University Hospital, LMU Munich, Germany.
Disclosure
Financial Disclosure:
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Research Support:
1.
(1) Foundation - Mercur Foundation: Laminar fMRI hippocampus (2) Foundation - NWO: Laminar fMRI in cognitive control (3) Foundation - NWO: Dutch 14T initiative (4) Governmental - EU: CITRUS. Development focussed untrasound (5) Foundation - NWO: Diffusion-weighted HASTE imaging
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From the Department of Neurology (H.L., M.A.J., M.C., F.-E.D.L., A.M.T.), Radboud University Medical Center, Donders Center for Medical Neurosciences, Nijmegen, the Netherlands; Department of Neurology (M.C.), Guangdong Neuroscience Institute, Guangdong Provincial People's Hospital, Guangdong Academy of Medical Sciences, Southern Medical University, Guangzhou, China; Donders Institute for Brain (R.P.C.K.), Cognition and Behaviour, Radboud University, Nijmegen; Vincent van Gogh Institute for Psychiatry (R.P.C.K.), Venray; Department of Medical Psychology and Radboudumc Alzheimer Center (R.P.C.K.), Radboud University Medical Center; Donders Institute for Brain (D.G.N.), Cognition and Behaviour, Center for Cognitive Neuroimaging, Radboud University, Nijmegen, the Netherlands; Medical Image Analysis Center (MIAC AG) and Department of Biomedical Engineering (M.D.), University of Basel, Switzerland; and Institute for Stroke and Dementia Research (ISD) (M.D.), University Hospital, LMU Munich, Germany.
Disclosure
Financial Disclosure:
1.
Personal Compensation: (1) Served on a scientific advisory board - Biogen (2) Served on a adjudication board - Hovid Berhad (3) Served as a consultant - Roche (4) Received speaker honoraria - Sanofi Genzyme
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Frank-Erik De Leeuw, MD, PhD https://orcid.org/0000-0003-2221-3026
From the Department of Neurology (H.L., M.A.J., M.C., F.-E.D.L., A.M.T.), Radboud University Medical Center, Donders Center for Medical Neurosciences, Nijmegen, the Netherlands; Department of Neurology (M.C.), Guangdong Neuroscience Institute, Guangdong Provincial People's Hospital, Guangdong Academy of Medical Sciences, Southern Medical University, Guangzhou, China; Donders Institute for Brain (R.P.C.K.), Cognition and Behaviour, Radboud University, Nijmegen; Vincent van Gogh Institute for Psychiatry (R.P.C.K.), Venray; Department of Medical Psychology and Radboudumc Alzheimer Center (R.P.C.K.), Radboud University Medical Center; Donders Institute for Brain (D.G.N.), Cognition and Behaviour, Center for Cognitive Neuroimaging, Radboud University, Nijmegen, the Netherlands; Medical Image Analysis Center (MIAC AG) and Department of Biomedical Engineering (M.D.), University of Basel, Switzerland; and Institute for Stroke and Dementia Research (ISD) (M.D.), University Hospital, LMU Munich, Germany.
Disclosure
Financial Disclosure:
1.
Personal Compensation: (1) none - Ass Editor Int J of Stroke
Research Support:
1.
(1) Governmental - Dutch Organization Scientific Research (016.126.351): VIDI grant on causes and consequences of small vessell disease (2) Foundation - Dutch Heart Foundation (2014T060): Clinical Established Investigator grant
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Anil Man Tuladhar, MD, PhD https://orcid.org/0000-0002-4815-2834
From the Department of Neurology (H.L., M.A.J., M.C., F.-E.D.L., A.M.T.), Radboud University Medical Center, Donders Center for Medical Neurosciences, Nijmegen, the Netherlands; Department of Neurology (M.C.), Guangdong Neuroscience Institute, Guangdong Provincial People's Hospital, Guangdong Academy of Medical Sciences, Southern Medical University, Guangzhou, China; Donders Institute for Brain (R.P.C.K.), Cognition and Behaviour, Radboud University, Nijmegen; Vincent van Gogh Institute for Psychiatry (R.P.C.K.), Venray; Department of Medical Psychology and Radboudumc Alzheimer Center (R.P.C.K.), Radboud University Medical Center; Donders Institute for Brain (D.G.N.), Cognition and Behaviour, Center for Cognitive Neuroimaging, Radboud University, Nijmegen, the Netherlands; Medical Image Analysis Center (MIAC AG) and Department of Biomedical Engineering (M.D.), University of Basel, Switzerland; and Institute for Stroke and Dementia Research (ISD) (M.D.), University Hospital, LMU Munich, Germany.
Disclosure
Financial Disclosure:
1.
NONE
Research Support:
1.
(1) Dutch Heart Foundation - Junior Staff Member (2016T044): Junior Staff Member
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1.
NONE
Legal Proceedings:
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Notes

Correspondence Dr. Tuladhar [email protected]
Go to Neurology.org/N for full disclosures. Funding information and disclosures deemed relevant by the authors, if any, are provided at the end of the article.
Submitted and externally peer reviewed. The handling editor was Editor-in-Chief José Merino, MD, MPhil, FAAN.

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  1. Bridging the Gap in Small Vessel Disease Research, Neurology, 102, 9, (2024)./doi/10.1212/WNL.0000000000209379
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