Proteomic profiling in cerebrospinal fluid reveal biomarkers for shunt outcome in idiopathic normal-pressure hydrocephalus

Yuqi Ying¹, Jingquan Lin², Wei Gao², Liang Yue³, Qingze Zeng⁴, Katrina Bartas⁵, Dayeon Cheong⁵, Hongjie Jiang², Zhe Zheng², Ligen Shi², An Ping², Yuanjian Fang², Feng Yan², Tiannan Guo³, Jianmin Zhang⁶, Hemmings Wu⁷, Kevin Beier⁸, Junming Zhu⁹, Zhoule Zhu¹⁰

Affiliations

¹ Department of Neurosurgery, Zhejiang University School of Medicine Second Affiliated Hospital, Hangzhou 310009, China; Clinical Research Center for Neurological Diseases of Zhejiang Province, Hangzhou 310009, China; Key Laboratory of Precise Treatment and Clinical Translational Research of Neurological Diseases of Zhejiang Province, Hangzhou 310009, China; Department of Neurosurgery, The Fourth Affiliated Hospital, International Institutes of Medicine, Zhejiang University School of Medicine, Yiwu 322000, China; State Key Laboratory of Transvascular Implantation Devices, Hangzhou 310009, China.
² Department of Neurosurgery, Zhejiang University School of Medicine Second Affiliated Hospital, Hangzhou 310009, China; Clinical Research Center for Neurological Diseases of Zhejiang Province, Hangzhou 310009, China; Key Laboratory of Precise Treatment and Clinical Translational Research of Neurological Diseases of Zhejiang Province, Hangzhou 310009, China; State Key Laboratory of Transvascular Implantation Devices, Hangzhou 310009, China.
³ Affiliated Hangzhou First People's Hospital, State Key Laboratory of Medical Proteomics, School of Medicine, Westlake University, Hangzhou, Zhejiang Province, China; Westlake Center for Intelligent Proteomics, Westlake Laboratory of Life Sciences and Biomedicine, Hangzhou, Zhejiang Province, China; Research Center for Industries of the Future, School of Life Sciences, Westlake University, Hangzhou, Zhejiang Province, China.
⁴ Department of Radiology, Zhejiang University School of Medicine Second Affiliated Hospital, Hangzhou 310009, China; State Key Laboratory of Transvascular Implantation Devices, Hangzhou 310009, China.
⁵ Department of Physiology and Biophysics, University of California, Irvine, CA 92697, USA.
⁶ Department of Neurosurgery, Zhejiang University School of Medicine Second Affiliated Hospital, Hangzhou 310009, China; Clinical Research Center for Neurological Diseases of Zhejiang Province, Hangzhou 310009, China; Key Laboratory of Precise Treatment and Clinical Translational Research of Neurological Diseases of Zhejiang Province, Hangzhou 310009, China; Department of Neurosurgery, The Fourth Affiliated Hospital, International Institutes of Medicine, Zhejiang University School of Medicine, Yiwu 322000, China; State Key Laboratory of Transvascular Implantation Devices, Hangzhou 310009, China. Electronic address: zjm135@zju.edu.cn.
⁷ Department of Neurosurgery, Zhejiang University School of Medicine Second Affiliated Hospital, Hangzhou 310009, China; Clinical Research Center for Neurological Diseases of Zhejiang Province, Hangzhou 310009, China; Key Laboratory of Precise Treatment and Clinical Translational Research of Neurological Diseases of Zhejiang Province, Hangzhou 310009, China; State Key Laboratory of Transvascular Implantation Devices, Hangzhou 310009, China. Electronic address: hemmings@zju.edu.cn.
⁸ Department of Physiology and Biophysics, University of California, Irvine, CA 92697, USA; Department of Pharmaceutical Sciences, University of California, Irvine, CA 92617, USA; Department of Biomedical Engineering, University of California, Irvine, CA 92617, USA; Department of Neurobiology and Behavior, University of California, Irvine, CA 92617, USA; Center for the Neurobiology of Learning and Memory, University of California, Irvine, CA 92617, USA; UCI Mind, University of California, Irvine, CA 92617, USA. Electronic address: kbeier@uci.edu.
⁹ Department of Neurosurgery, Zhejiang University School of Medicine Second Affiliated Hospital, Hangzhou 310009, China; Clinical Research Center for Neurological Diseases of Zhejiang Province, Hangzhou 310009, China; Key Laboratory of Precise Treatment and Clinical Translational Research of Neurological Diseases of Zhejiang Province, Hangzhou 310009, China; State Key Laboratory of Transvascular Implantation Devices, Hangzhou 310009, China. Electronic address: dr.zhujunming@zju.edu.cn.
¹⁰ Department of Neurosurgery, Zhejiang University School of Medicine Second Affiliated Hospital, Hangzhou 310009, China; Clinical Research Center for Neurological Diseases of Zhejiang Province, Hangzhou 310009, China; Key Laboratory of Precise Treatment and Clinical Translational Research of Neurological Diseases of Zhejiang Province, Hangzhou 310009, China; State Key Laboratory of Transvascular Implantation Devices, Hangzhou 310009, China. Electronic address: zhuqianle1231@zju.edu.cn.

PMID: 40311753
DOI: 10.1016/j.jare.2025.04.043

Free article

Proteomic profiling in cerebrospinal fluid reveal biomarkers for shunt outcome in idiopathic normal-pressure hydrocephalus

Yuqi Ying et al. J Adv Res. 2025.

Free article

. 2025 Apr 29:S2090-1232(25)00287-5.

doi: 10.1016/j.jare.2025.04.043. Online ahead of print.

Authors

Affiliations

¹ Department of Neurosurgery, Zhejiang University School of Medicine Second Affiliated Hospital, Hangzhou 310009, China; Clinical Research Center for Neurological Diseases of Zhejiang Province, Hangzhou 310009, China; Key Laboratory of Precise Treatment and Clinical Translational Research of Neurological Diseases of Zhejiang Province, Hangzhou 310009, China; Department of Neurosurgery, The Fourth Affiliated Hospital, International Institutes of Medicine, Zhejiang University School of Medicine, Yiwu 322000, China; State Key Laboratory of Transvascular Implantation Devices, Hangzhou 310009, China.
² Department of Neurosurgery, Zhejiang University School of Medicine Second Affiliated Hospital, Hangzhou 310009, China; Clinical Research Center for Neurological Diseases of Zhejiang Province, Hangzhou 310009, China; Key Laboratory of Precise Treatment and Clinical Translational Research of Neurological Diseases of Zhejiang Province, Hangzhou 310009, China; State Key Laboratory of Transvascular Implantation Devices, Hangzhou 310009, China.
³ Affiliated Hangzhou First People's Hospital, State Key Laboratory of Medical Proteomics, School of Medicine, Westlake University, Hangzhou, Zhejiang Province, China; Westlake Center for Intelligent Proteomics, Westlake Laboratory of Life Sciences and Biomedicine, Hangzhou, Zhejiang Province, China; Research Center for Industries of the Future, School of Life Sciences, Westlake University, Hangzhou, Zhejiang Province, China.
⁴ Department of Radiology, Zhejiang University School of Medicine Second Affiliated Hospital, Hangzhou 310009, China; State Key Laboratory of Transvascular Implantation Devices, Hangzhou 310009, China.
⁵ Department of Physiology and Biophysics, University of California, Irvine, CA 92697, USA.
⁶ Department of Neurosurgery, Zhejiang University School of Medicine Second Affiliated Hospital, Hangzhou 310009, China; Clinical Research Center for Neurological Diseases of Zhejiang Province, Hangzhou 310009, China; Key Laboratory of Precise Treatment and Clinical Translational Research of Neurological Diseases of Zhejiang Province, Hangzhou 310009, China; Department of Neurosurgery, The Fourth Affiliated Hospital, International Institutes of Medicine, Zhejiang University School of Medicine, Yiwu 322000, China; State Key Laboratory of Transvascular Implantation Devices, Hangzhou 310009, China. Electronic address: zjm135@zju.edu.cn.
⁷ Department of Neurosurgery, Zhejiang University School of Medicine Second Affiliated Hospital, Hangzhou 310009, China; Clinical Research Center for Neurological Diseases of Zhejiang Province, Hangzhou 310009, China; Key Laboratory of Precise Treatment and Clinical Translational Research of Neurological Diseases of Zhejiang Province, Hangzhou 310009, China; State Key Laboratory of Transvascular Implantation Devices, Hangzhou 310009, China. Electronic address: hemmings@zju.edu.cn.
⁸ Department of Physiology and Biophysics, University of California, Irvine, CA 92697, USA; Department of Pharmaceutical Sciences, University of California, Irvine, CA 92617, USA; Department of Biomedical Engineering, University of California, Irvine, CA 92617, USA; Department of Neurobiology and Behavior, University of California, Irvine, CA 92617, USA; Center for the Neurobiology of Learning and Memory, University of California, Irvine, CA 92617, USA; UCI Mind, University of California, Irvine, CA 92617, USA. Electronic address: kbeier@uci.edu.
⁹ Department of Neurosurgery, Zhejiang University School of Medicine Second Affiliated Hospital, Hangzhou 310009, China; Clinical Research Center for Neurological Diseases of Zhejiang Province, Hangzhou 310009, China; Key Laboratory of Precise Treatment and Clinical Translational Research of Neurological Diseases of Zhejiang Province, Hangzhou 310009, China; State Key Laboratory of Transvascular Implantation Devices, Hangzhou 310009, China. Electronic address: dr.zhujunming@zju.edu.cn.
¹⁰ Department of Neurosurgery, Zhejiang University School of Medicine Second Affiliated Hospital, Hangzhou 310009, China; Clinical Research Center for Neurological Diseases of Zhejiang Province, Hangzhou 310009, China; Key Laboratory of Precise Treatment and Clinical Translational Research of Neurological Diseases of Zhejiang Province, Hangzhou 310009, China; State Key Laboratory of Transvascular Implantation Devices, Hangzhou 310009, China. Electronic address: zhuqianle1231@zju.edu.cn.

PMID: 40311753
DOI: 10.1016/j.jare.2025.04.043

Abstract

Background: The pathophysiology of idiopathic normal pressure hydrocephalus (iNPH) remains unclear, and the treatment strategy remains suboptimal. This study aims to identify biomarkers for shunt prognosis by cerebrospinal fluid (CSF) proteomic profiling.

Methods: CSF samples collected from 37 iNPH patients from the discovery cohort and 12 iNPH patients from an independent validation cohort (71.9 ± 6.1 years (mean ± SD)), and 16 age-balanced controls (69.9 ± 7.6 years (mean ± SD)) were collected from September 2020 to December 2023. 53 CSF samples were analyzed using a mass spectrometry-based proteomic workflow. Clinical evaluations were performed on all iNPH patients, and 44 patients underwent ventriculoperitoneal shunting. Postoperative CSF were also collected from 10 iNPH patients who underwent shunting surgery. Bioinformatics, machine learning, and enzyme-linked immunosorbent assay (ELISA) were performed to identify CSF proteome changes related to pathophysiology in iNPH, and screen for biomarkers associated with shunt response.

Results: 39 and 285 proteins significantly increased and decreased in iNPH CSF compared to the control group. Gene ontology analysis revealed that the noticeably increased proteins were mainly associated with myeloid leukocyte migration and extracellular matrix organization, and significantly decreased proteins were primarily associated with axon development and synapse organization. Machine learning identified 6 candidate biomarkers that potentially predicted the response to shunt surgery. Among these, QPCT levels were found to be elevated in non-responders, while RBP4 levels were decreased, and both of these changes were validated through ELISA.

Conclusions: Our findings provide support for the hypothesis that the pathophysiology of iNPH is characterized by a state of neuroinflammation, extracellular matrix remodeling, and neurodegeneration, and CSF shunting can reverse such pathological state. Machine learning using preoperative proteomic profiles satisfactorily predicted the clinical outcome of the shunt procedure in iNPH. Future research targeting specific proteins in iNPH may be warranted to better comprehend the disease mechanism and design patient-tailored treatments.

Keywords: Cerebrospinal fluid; Idiopathic normal pressure hydrocephalus; Machine learning; Proteomics; Shunt surgery response.

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Conflict of interest statement

Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.

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Proteomic profiling in cerebrospinal fluid reveal biomarkers for shunt outcome in idiopathic normal-pressure hydrocephalus

Affiliations

Proteomic profiling in cerebrospinal fluid reveal biomarkers for shunt outcome in idiopathic normal-pressure hydrocephalus

Authors

Affiliations

Abstract

Conflict of interest statement

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