The association between c-reactive protein and human brain microstructure: A systematic review of diffusion imaging studies

Abstract

Background

This study systematically reviews the relationship between C-reactive protein (CRP) levels, CRP-related DNA methylation, and diffusion MRI metrics (DTI and NODDI) in a variety of populations.

Methods

The review was conducted according to PRISMA guidelines, using databases such as Scopus and PubMed. Selected studies were analyzed for methodologies including TBSS, ROI-based, volume-based DTI analysis, NODDI-based analysis, structural connectometry, and graph theory approaches.

Results

29 studies from a broad spectrum of populations (healthy individuals, aging populations, patients with major depressive disorder, bipolar disorder, schizophrenia spectrum disorders, HIV, obesity, COPD, COVID-19, preterm birth, and asymptomatic carriers of the Apo-E4 gene) were included, highlighting relationship between CRP levels/DNAm signatures and white matter integrity, with notable correlations in specific brain regions. Specific results showed that higher CRP levels were generally associated with lower fractional anisotropy values in critical brain regions such as the Corpus Callosum, cingulum, and anterior thalamic radiation. Moreover, DTI metrics of other neural pathways including superior longitudinal fasciculus, arcuate fasciculus, uncinate fasciculus, inferior fronto-occipital fasciculus, inferior longitudinal fasciculus, external capsule, fornix and corticospinal tract were consistently correlated with CRP levels. Epigenetic studies revealed that DNA methylation might offer a more stable indicator of chronic inflammation's impact on the brain compared to serum CRP levels. While some studies identified significant correlations between CRP levels (or DNAm) and DTI metrics, others reported no significant correlations after false discovery rate correction suggesting potential moderating factors such as age, disease severity, or treatment status.

Conclusion

This comprehensive review emphasizes the complex and varied relationship between systemic inflammation, as indicated by CRP levels and brain microstructural integrity. These insights are crucial for understanding the role of inflammation in neuropsychiatric disorders and the potential impact on cognitive functions and neural connectivity.