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Cited by 46Liver Disease Diagnosis and TreatmentLiver Disease and TransplantationDementia and Cognitive Impairment Research

Elevated C-reactive protein mediates the liver-brain axis: a preliminary study

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Jiang, Rongtao, Wu, Jing, Rosenblatt, Matthew, Dai, Wei, Rodriguez, Raimundo X., Sui, Jing, Qi, Shile, Liang, Qinghao +4 more·2023·eBioMedicine
DOI 10.1016/j.ebiom.2023.104679PMC PMC10320521
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Abstract

BACKGROUND: Chronic liver diseases of all etiologies exist along a spectrum with varying degrees of hepatic fibrosis. Despite accumulating evidence implying associations between liver fibrosis and cognitive functioning, there is limited research exploring the underlying neurobiological factors and the possible mediating role of inflammation on the liver-brain axis. METHODS: Using data from the UK Biobank, we examined the cross-sectional association of liver fibrosis (as measured by Fibrosis-4 score) with cognitive functioning and regional grey matter volumes (GMVs) while adjusting for numerous covariates and multiple comparisons. We further performed post-hoc preliminary analysis to investigate the mediating effect of C-reactive protein (CRP) on the association between liver fibrosis and both cognitive functioning and GMVs. FINDINGS: We analysed behaviour from up to 447,626 participants (N ranged from 45,055 to 447,533 per specific cognitive metric) 37 years and older. 38,244 participants (age range 44-82 years) had GMV data collected at a median 9-year follow-up. Liver fibrosis showed significant associations with cognitive performance in reasoning, working memory, visual memory, prospective memory, executive function, and processing speed. Subgroup analysis indicated larger effects sizes for symbol digital substitution but smaller effect sizes for trail making in middle-aged people than their old counterparts. Neuroimaging analyses revealed significant associations between liver fibrosis and reduced regional GMVs, primarily in the hippocampus, thalamus, ventral striatum, parahippocampal gyrus, brain stem, and cerebellum. CRP levels were significantly higher in adults with advanced liver fibrosis than those without, indicating an elevated systemic inflammation. Moreover, the serum CRP significantly mediated the effect of liver fibrosis on most cognitive measures and regional GMVs in the hippocampus and brain stem. INTERPRETATION: This study provides a well-powered characterization of associations between liver fibrosis, cognitive impairment, and grey matter atrophy. It also highlights the possibly mediating role of systemic inflammation on the liver-brain axis. Early surveillance and prevention of liver diseases may reduce cognitive decline and brain GMV loss. FUNDING: National Science Foundation, and National Institutes of Health.

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Cited by

Sorted by citations

Authors
Jiang, R., Wu, J., Rosenblatt, M., Dai, W., Rodriguez, R. X., Sui, J., Qi, S., Liang, Q., Xu, B., Meng, Q., Calhoun, V. D., & Scheinost, D.
Affiliations
  • Yale University (US)
  • Capital Medical University (CN)
  • Georgia Institute of Technology (US)
Corresponding author
  • Jiang, Rongtao
  • Xu, Bin
  • Scheinost, Dustin
ORCID
Venue
eBioMedicine
Publisher
Elsevier BV
Published
2023-07
Volume
93
Pages
104679
ISSN
2352-3964 (ISSN-L)
DOI
10.1016/j.ebiom.2023.104679
PMC
PMC10320521
OpenAlex
W4381847990
Cited by
46
References
10
Citations by year
2026: 14 · 2025: 18 · 2024: 11 · 2023: 3
FWCI
8.60
Type
journal article
Language
en
Open access
Licence
Locations
  • EBioMedicine (publishedVersion, cc-by-nc-nd)
  • PubMed Central (publishedVersion, cc-by-nc-nd)
  • PubMed (publishedVersion)
  • DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
Funders
  • National Institutes of Health
  • National Institute of Mental Health (R01MH117107, RF1AG063153)
  • Paul Mellon Centre for Studies in British Art, Yale University
  • Key Technologies Research and Development Program (2021YFE0202500)
  • National Key Research and Development Program of China
  • National Science Foundation (2112455)
Topics
  • Health Sciences › Medicine › Epidemiology › Liver Disease Diagnosis and Treatment
  • Health Sciences › Medicine › Hepatology › Liver Disease and Transplantation
  • Health Sciences › Medicine › Psychiatry and Mental health › Dementia and Cognitive Impairment Research
Keywords
liver fibrosis, C-reactive protein, liver-brain axis, systemic inflammation, cognitive impairment, gray matter volume, hippocampus, brain atrophy, Fibrosis-4 score, mediation analysis, chronic liver disease, UK Biobank
MeSH terms
Adult, Aged, Aged, 80 and over, Brain, C-Reactive Protein, Cross-Sectional Studies, Humans, Inflammation, Liver Cirrhosis, Magnetic Resonance Imaging, Middle Aged, United States

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