Plasma Proteomics and Sensitive Imaging Biomarkers of Vascular Brain Injury

Identifying proteomic biomarkers associated with neuroimaging endophenotypes of cerebrovascular dysfunction and generalized neurodegeneration may provide insights into pre-Alzheimer disease pathological processes. This study aims to examine a broad panel of circulating proteins in relation to two diffusion tensor imaging (DTI) measures:free water (FW) and peak width of skeletonized mean diffusivity (PSMD), which are sensitive indicators of early white matter injury.

Using data from the Framingham Heart Study (FHS) Offspring and Third Generation cohorts, who underwent proteomic profiling with SomaScan version 1.3K, we evaluated the associations between individual proteins and DTI measures. Proteins with p-values < 0.01 for associations with either FW or PSMD in the FHS cohort (exploratory phase) were selected for replication in the Age, Gene/Environment Susceptibility (AGES) - Reykjavik Study. AGES participants were profiled using a custom 5K SomaScan platform. For proteins that replicated, two-sample Mendelian randomization was conducted to explore potential causal relationships with neuroimaging traits, global cognitive function, stroke, and AD.

A total of 48 proteins were associated with either FW or PSMD in FHS (N=1,106, 56% female, mean age=48 at protein profiling) at an uncorrected p-value < 0.01. Of these, six proteins were validated in AGES (N=2,586, 58% female, mean age=76) at p-value < 0.05/48: TFF3 (beta=0.015), LG3BP (beta=0.0089), and heparin cofactor II (HCII, beta=0.0097) showed positive associations with FW, while CCL28 was positively associated with PSMD (beta=0.01). Conversely, BMPR1A (beta=-0.016) and gelsolin (beta=-0.011) were negatively associated with PSMD, all with SE=0.002. Mendelian randomization analyses further suggested potential causal effects (p-value<0.05), including positive effects of HCII, LG3BP, and TFF3 on WMH; HCII on small vessel stroke; LG3BP on any stroke and ischemic stroke; and a negative effect of gelsolin on large artery stroke.

This cohort and Mendelian randomization study identified several proteins significantly associated with FW and PSMD, which are potential imaging biomarkers of ischemia, neuroinflammation, and axonal degeneration. Mendelian randomization analyses suggested potential causal effects of certain proteins on white matter hyperintensities and stroke, highlighting the need for functional studies to explore whether elevated protein levels represent protective mechanisms or contribute to brain injury.