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

Rongtao Jiang; Jing Wu; Matthew Rosenblatt; Wei Dai; Raimundo X Rodriguez; Jing Sui; Shile Qi; Qinghao Liang; Bin Xu; Qinghua Meng; Vince D Calhoun; Dustin Scheinost

doi:10.1016/j.ebiom.2023.104679

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

EBioMedicine. 2023 Jul:93:104679. doi: 10.1016/j.ebiom.2023.104679. Epub 2023 Jun 23.

Authors

Rongtao Jiang¹, Jing Wu², Matthew Rosenblatt³, Wei Dai⁴, Raimundo X Rodriguez⁵, Jing Sui⁶, Shile Qi⁷, Qinghao Liang³, Bin Xu⁸, Qinghua Meng⁹, Vince D Calhoun⁷, Dustin Scheinost¹⁰

Affiliations

¹ Department of Radiology and Biomedical Imaging, Yale School of Medicine, New Haven, CT 06510, USA. Electronic address: rongtao.jiang@yale.edu.
² Second Department of Liver Disease Center, Youan Hospital, Capital Medical University, Beijing, 100069, China.
³ Department of Biomedical Engineering, Yale University, New Haven, CT 06520, USA.
⁴ Department of Biostatistics, Yale University, New Haven, CT 06520, USA.
⁵ Interdepartmental Neuroscience Program, Yale University, New Haven, CT 06520, USA.
⁶ State Key Laboratory of Cognitive Neuroscience and Learning, Beijing Normal University, Beijing, 100088, China.
⁷ Tri-institutional Center for Translational Research in Neuroimaging and Data Science (TReNDS), Georgia State University, Georgia Institute of Technology, and Emory University, Atlanta, GA 30303, USA.
⁸ Second Department of Liver Disease Center, Youan Hospital, Capital Medical University, Beijing, 100069, China. Electronic address: xubin1016@ccmu.edu.cn.
⁹ Department of Medical Oncology, Beijing You-An Hospital, Capital Medical University, Beijing, 100069, China.
¹⁰ Department of Radiology and Biomedical Imaging, Yale School of Medicine, New Haven, CT 06510, USA; Department of Biomedical Engineering, Yale University, New Haven, CT 06520, USA; Interdepartmental Neuroscience Program, Yale University, New Haven, CT 06520, USA; Department of Statistics & Data Science, Yale University, New Haven, CT 06520, USA; Child Study Center, Yale School of Medicine, New Haven, CT 06510, USA; Wu Tsai Institute, Yale University, 100 College Street, New Haven, CT 06510, USA. Electronic address: dustin.scheinost@yale.edu.

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.

Keywords: Cognitive functioning; Fibrosis-4 score; Grey matter atrophy; Hepatic fibrosis; Systemic inflammation.

MeSH terms

Adult
Aged
Aged, 80 and over
Brain / pathology
C-Reactive Protein* / metabolism
Cross-Sectional Studies
Humans
Inflammation / pathology
Liver Cirrhosis / metabolism
Magnetic Resonance Imaging* / methods
Middle Aged
United States

Substances

C-Reactive Protein

Grants and funding

UL1 TR001863/TR/NCATS NIH HHS/United States