PMC

Brain atrophy associated with elevated plasma LBP in GRN carriers. Abbreviations: FWE, familywise error; LBP, lipopolysaccharide; unc, uncorrected. Note: The depicted clusters were obtained via voxel-based morphometry (VBM) analysis modeling an interaction between GRN mutation carriers status and plasma LBP in determining atrophy in our study cohort (including controls and mutation carriers).

Plasma markers of innate immunity by clinical group. Circles represent individual people in the study. Whiskers represent the highest and lowest adjacent values (±1.5 × interquartile range) with a median line in between. The p-values associated with brackets for the sCD163 and CCL18 plots are post-hoc pairwise Tukey tests (after ANOVA p < 0.05) between controls and symptomatic carriers.

Abbreviated summary of monocyte activation pathways. Proteins depicted as red ovals were selected as candidate markers of monocyte activation. Bacterial lipopolysaccharide (LPS) requires the presence of LBP (lipopolysaccharide binding protein) and sCD14 (soluble cluster of differentiation 14), to TLR4 (toll-like receptor 4) and the NF-κB (nuclear factor kappa-light-chain-enhancer of activated B cells) (). Activating monocytes cleave surface CD163 (Cluster of Differentiation 163) in to a soluble form (sCD163) (). Monocytes may also be activated by pathogen-associated molecular patterns (PAMPS) which lead to release IL-18 via the inflammasome pathway (). Classical monocytes (CD14⁺, CD16⁻) eventually transition to intermediate (CD14⁺CD16⁺) and eventually non-classical monocytes (CD14^low, CD16⁺) (), the latter of which are a source of CCL18 (chemokine C-C motif ligand 18) ().

Plasma LBP correlates with white matter integrity and clinical severity. Circles represent uncorrected plotted values for individual GRN mutation carriers within our study, with yellow circles representing asymptomatic individuals and red circles representing symptomatic individuals. The left frontal (A) and right frontal (B) regions of interest (ROIs) depicted were defined by the left frontal pole white matter and right inferior frontal operculum white mater clusters described in . A linear regression line [controlling for age and sex, as well as total intracranial volume (TIV) for models with volumetric measures] with a gray 95% confidence interval has been superimposed on each plot [(A) R² = 0.85, p = 0.024 uncorrected; (B) R² = 0.86, p < 0.0005 uncorrected; (C) R² = 0.59, p = 0.009; (D) R² = 0.75, p = 0.003 uncorrected].