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ResearchIn-Press PreviewNeuroscience Open Access | 10.1172/jci.insight.172286

Glymphatic influx and clearance are perturbed in Huntington’s disease

Hongshuai Liu,1 Lin Chen,2 Chuangchuang Zhang,1 Chang Liu,1 Yuguo Li,2 Liam Cheng,1 Yuxiao Ouyang,1 Catherine Rutledge,1 John Anderson,1 Zhiliang Wei,3 Ziqin Zhang,2 Hanzhang Lu,3 Peter C.M. Van Zijl,2 Jeffrey J. Iliff,4 Jiadi Xu,3 and Wenzhen Duan1

1Division of Neurobiology, Department of Psychiatry and Behavioral Sciences, Johns Hopkins University School of Medicine, Baltimore, United States of America

2F.M. Kirby Research Center, Kennedy Krieger Institute, Baltimore, United States of America

3The Russell H. Morgan Department of Radiology and Radiological Sciences, Johns Hopkins University School of Medicine, Baltimore, United States of America

4VISN 20 Mental Illness Research, Education and Clinical Center, VA Puget Sound Health Care System, Seattle, United States of America

Find articles by Liu, H. in: JCI | PubMed | Google Scholar

1Division of Neurobiology, Department of Psychiatry and Behavioral Sciences, Johns Hopkins University School of Medicine, Baltimore, United States of America

2F.M. Kirby Research Center, Kennedy Krieger Institute, Baltimore, United States of America

3The Russell H. Morgan Department of Radiology and Radiological Sciences, Johns Hopkins University School of Medicine, Baltimore, United States of America

4VISN 20 Mental Illness Research, Education and Clinical Center, VA Puget Sound Health Care System, Seattle, United States of America

Find articles by Chen, L. in: JCI | PubMed | Google Scholar

1Division of Neurobiology, Department of Psychiatry and Behavioral Sciences, Johns Hopkins University School of Medicine, Baltimore, United States of America

2F.M. Kirby Research Center, Kennedy Krieger Institute, Baltimore, United States of America

3The Russell H. Morgan Department of Radiology and Radiological Sciences, Johns Hopkins University School of Medicine, Baltimore, United States of America

4VISN 20 Mental Illness Research, Education and Clinical Center, VA Puget Sound Health Care System, Seattle, United States of America

Find articles by Zhang, C. in: JCI | PubMed | Google Scholar

1Division of Neurobiology, Department of Psychiatry and Behavioral Sciences, Johns Hopkins University School of Medicine, Baltimore, United States of America

2F.M. Kirby Research Center, Kennedy Krieger Institute, Baltimore, United States of America

3The Russell H. Morgan Department of Radiology and Radiological Sciences, Johns Hopkins University School of Medicine, Baltimore, United States of America

4VISN 20 Mental Illness Research, Education and Clinical Center, VA Puget Sound Health Care System, Seattle, United States of America

Find articles by Liu, C. in: JCI | PubMed | Google Scholar

1Division of Neurobiology, Department of Psychiatry and Behavioral Sciences, Johns Hopkins University School of Medicine, Baltimore, United States of America

2F.M. Kirby Research Center, Kennedy Krieger Institute, Baltimore, United States of America

3The Russell H. Morgan Department of Radiology and Radiological Sciences, Johns Hopkins University School of Medicine, Baltimore, United States of America

4VISN 20 Mental Illness Research, Education and Clinical Center, VA Puget Sound Health Care System, Seattle, United States of America

Find articles by Li, Y. in: JCI | PubMed | Google Scholar

1Division of Neurobiology, Department of Psychiatry and Behavioral Sciences, Johns Hopkins University School of Medicine, Baltimore, United States of America

2F.M. Kirby Research Center, Kennedy Krieger Institute, Baltimore, United States of America

3The Russell H. Morgan Department of Radiology and Radiological Sciences, Johns Hopkins University School of Medicine, Baltimore, United States of America

4VISN 20 Mental Illness Research, Education and Clinical Center, VA Puget Sound Health Care System, Seattle, United States of America

Find articles by Cheng, L. in: JCI | PubMed | Google Scholar

1Division of Neurobiology, Department of Psychiatry and Behavioral Sciences, Johns Hopkins University School of Medicine, Baltimore, United States of America

2F.M. Kirby Research Center, Kennedy Krieger Institute, Baltimore, United States of America

3The Russell H. Morgan Department of Radiology and Radiological Sciences, Johns Hopkins University School of Medicine, Baltimore, United States of America

4VISN 20 Mental Illness Research, Education and Clinical Center, VA Puget Sound Health Care System, Seattle, United States of America

Find articles by Ouyang, Y. in: JCI | PubMed | Google Scholar

1Division of Neurobiology, Department of Psychiatry and Behavioral Sciences, Johns Hopkins University School of Medicine, Baltimore, United States of America

2F.M. Kirby Research Center, Kennedy Krieger Institute, Baltimore, United States of America

3The Russell H. Morgan Department of Radiology and Radiological Sciences, Johns Hopkins University School of Medicine, Baltimore, United States of America

4VISN 20 Mental Illness Research, Education and Clinical Center, VA Puget Sound Health Care System, Seattle, United States of America

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1Division of Neurobiology, Department of Psychiatry and Behavioral Sciences, Johns Hopkins University School of Medicine, Baltimore, United States of America

2F.M. Kirby Research Center, Kennedy Krieger Institute, Baltimore, United States of America

3The Russell H. Morgan Department of Radiology and Radiological Sciences, Johns Hopkins University School of Medicine, Baltimore, United States of America

4VISN 20 Mental Illness Research, Education and Clinical Center, VA Puget Sound Health Care System, Seattle, United States of America

Find articles by Anderson, J. in: JCI | PubMed | Google Scholar

1Division of Neurobiology, Department of Psychiatry and Behavioral Sciences, Johns Hopkins University School of Medicine, Baltimore, United States of America

2F.M. Kirby Research Center, Kennedy Krieger Institute, Baltimore, United States of America

3The Russell H. Morgan Department of Radiology and Radiological Sciences, Johns Hopkins University School of Medicine, Baltimore, United States of America

4VISN 20 Mental Illness Research, Education and Clinical Center, VA Puget Sound Health Care System, Seattle, United States of America

Find articles by Wei, Z. in: JCI | PubMed | Google Scholar

1Division of Neurobiology, Department of Psychiatry and Behavioral Sciences, Johns Hopkins University School of Medicine, Baltimore, United States of America

2F.M. Kirby Research Center, Kennedy Krieger Institute, Baltimore, United States of America

3The Russell H. Morgan Department of Radiology and Radiological Sciences, Johns Hopkins University School of Medicine, Baltimore, United States of America

4VISN 20 Mental Illness Research, Education and Clinical Center, VA Puget Sound Health Care System, Seattle, United States of America

Find articles by Zhang, Z. in: JCI | PubMed | Google Scholar

1Division of Neurobiology, Department of Psychiatry and Behavioral Sciences, Johns Hopkins University School of Medicine, Baltimore, United States of America

2F.M. Kirby Research Center, Kennedy Krieger Institute, Baltimore, United States of America

3The Russell H. Morgan Department of Radiology and Radiological Sciences, Johns Hopkins University School of Medicine, Baltimore, United States of America

4VISN 20 Mental Illness Research, Education and Clinical Center, VA Puget Sound Health Care System, Seattle, United States of America

Find articles by Lu, H. in: JCI | PubMed | Google Scholar

1Division of Neurobiology, Department of Psychiatry and Behavioral Sciences, Johns Hopkins University School of Medicine, Baltimore, United States of America

2F.M. Kirby Research Center, Kennedy Krieger Institute, Baltimore, United States of America

3The Russell H. Morgan Department of Radiology and Radiological Sciences, Johns Hopkins University School of Medicine, Baltimore, United States of America

4VISN 20 Mental Illness Research, Education and Clinical Center, VA Puget Sound Health Care System, Seattle, United States of America

Find articles by Van Zijl, P. in: JCI | PubMed | Google Scholar

1Division of Neurobiology, Department of Psychiatry and Behavioral Sciences, Johns Hopkins University School of Medicine, Baltimore, United States of America

2F.M. Kirby Research Center, Kennedy Krieger Institute, Baltimore, United States of America

3The Russell H. Morgan Department of Radiology and Radiological Sciences, Johns Hopkins University School of Medicine, Baltimore, United States of America

4VISN 20 Mental Illness Research, Education and Clinical Center, VA Puget Sound Health Care System, Seattle, United States of America

Find articles by Iliff, J. in: JCI | PubMed | Google Scholar

1Division of Neurobiology, Department of Psychiatry and Behavioral Sciences, Johns Hopkins University School of Medicine, Baltimore, United States of America

2F.M. Kirby Research Center, Kennedy Krieger Institute, Baltimore, United States of America

3The Russell H. Morgan Department of Radiology and Radiological Sciences, Johns Hopkins University School of Medicine, Baltimore, United States of America

4VISN 20 Mental Illness Research, Education and Clinical Center, VA Puget Sound Health Care System, Seattle, United States of America

Find articles by Xu, J. in: JCI | PubMed | Google Scholar

1Division of Neurobiology, Department of Psychiatry and Behavioral Sciences, Johns Hopkins University School of Medicine, Baltimore, United States of America

2F.M. Kirby Research Center, Kennedy Krieger Institute, Baltimore, United States of America

3The Russell H. Morgan Department of Radiology and Radiological Sciences, Johns Hopkins University School of Medicine, Baltimore, United States of America

4VISN 20 Mental Illness Research, Education and Clinical Center, VA Puget Sound Health Care System, Seattle, United States of America

Find articles by Duan, W. in: JCI | PubMed | Google Scholar

Published September 3, 2024 - More info

JCI Insight. https://doi.org/10.1172/jci.insight.172286.
Copyright © 2024, Liu et al. This work is licensed under the Creative Commons Attribution 4.0 International License. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.
Published September 3, 2024 - Version history
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Abstract

The accumulation of mutant huntingtin protein aggregates in neurons is a pathological hallmark of Huntington’s disease (HD). The glymphatic system, a brain-wide perivascular network, facilitates the exchange of interstitial fluid (ISF) and cerebrospinal fluid (CSF), supporting interstitial solute clearance of brain wastes. In this study, we employed dynamic glucose-enhanced (DGE) MRI to measure D-glucose clearance from CSF as a tool to predict glymphatic function in a mouse model of HD. We found significantly diminished CSF clearance efficiency in HD mice prior to phenotypic onset. The impairment of CSF clearance efficiency worsened with disease progression. These DGE MRI findings in compromised glymphatic function were further confirmed with fluorescence-based imaging of CSF tracer influx, suggesting an impaired glymphatic function in premanifest HD. Moreover, expression of the astroglial water channel aquaporin-4 (AQP4) in the perivascular compartment, a key mediator of glymphatic function, was significantly diminished in both HD mouse brain and human HD brain. Our data, acquired using a clinically translatable MRI, indicate a perturbed glymphatic network in the HD brain. Further validation of these findings in clinical studies will provide insights into the potential of glymphatic clearance as a therapeutic target as well as an early biomarker in HD.

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