Genetic Associations Among Inflammation, White Matter Architecture, and Extracellular Free Water

Area of Science:

• Neuroimaging
• Inflammation Biology
• Quantitative Genetics

Background:

• Peripheral inflammation and white matter microstructure show genetic links, crucial for understanding health and disease.
• Previous studies using standard diffusion tensor imaging (DTI) models are limited in distinguishing tissue-specific architecture from free water effects.

Purpose of the Study:

• To investigate whether genetic correlations between white matter microstructure and peripheral inflammation are attributable to tissue-specific architecture or extracellular free water.
• To compare findings from a two-compartment DTI model with traditional one-compartment FA measures.

Main Methods:

• Applied a two-compartment model to DTI data to estimate tissue-specific white matter microstructure (FA_T) and free water volume (FW).
• Quantified heritability and genetic correlations of FA_T, FW, and circulating cytokines (IL-8, TNFα).
• Compared genetic correlations derived from the two-compartment model with those from standard one-compartment FA measures.

Main Results:

• Standard FA measures showed significant genetic correlations with IL-8 and TNFα.
• These correlations became non-significant when using FA_T from the two-compartment model, suggesting free water confounds.
• Significant genetic correlations were found between free water volume (FW) and both IL-8 and TNFα.

Conclusions:

• The association between white matter integrity and peripheral inflammation is significantly influenced by free water content.
• Using a two-compartment DTI model is crucial for accurately assessing white matter microstructure and its relationship with inflammatory processes.
• Findings caution against relying solely on single-compartment models when investigating the interplay between brain structure and inflammation.