ELEVATED CSF STREM2 IN AUTOSOMAL DOMINANTLY INHERITED ALZHEIMER’S DISEASE ASSOCIATED WITH REGIONAL FIBER TRACT INJURY: RESULTS FROM THE DIAN STUDY

Abstract

The soluble fraction of the protein “triggering receptor expressed on myeloid cell 2” (sTREM2) is detectable in cerebrospinal fluid (CSF) and is a biomarker of microglial activation. In autosomal dominantly inherited Alzheimer's disease (ADAD), we recently showed that CSF-TREM2 levels are elevated up to seven years before the onset of dementia symptoms (Suárez-Calvet et al., Science Transl. Med. 2016). However, it is unclear whether higher microglia activation is associated with increased neurodegeneration. Here we assessed the association between CSF-sTREM2 levels and fiber-tract changes in ADAD, as measured by diffusion-tensor imaging (DTI). We included 59 mutation carriers (MC) and 44 non-carriers (NC) from the Dominantly Inherited Alzheimer Network (DIAN). Concentration of sTREM2 in CSF was determined with ELISA. Based on DTI, we used tract-based spatial statistics (TBSS) to produce skeletonized maps of mean diffusivity (MD). As a global measure of white matter damage, histogram peak-width of skeletonized-MD (PSMD) was applied. Estimated years from symptom onset (EYO), based on parental age-of-onset, were used as a measure of disease progression. First, we tested in regression analyses whether regional increases in MD (TBSS) and global PSMD were stronger in MC than NC (interaction EYOxMutation group), controlled for gender and education. Next, using similar regression models, we tested CSF-sTREM2 levels as a predictor of regional MD and global PSMD. For TBSS, the voxel-wise significance threshold was p<0.01 (uncorrected) and the cluster-extent threshold p<0.05 (FWE-corrected). The interaction EYOxMutation (t(73.6)=4.14, p<0.001) on PSMD indicated faster global fiber-tract alterations in MC compared to NC (Fig. 1A). TBSS analysis showed the increase in MD to be predominantly present within posterior fiber-tracts (inferior fronto-occipital fasciculus and forceps major) in MC (Fig. 1B, red colored). For CSF-sTREM2, higher levels were associated with increased global PSMD in MC but not NC (interaction: t(63.8)=2.34, p=0.021; Fig. 1C), where the regional effects clustered in the vulnerable posterior regions of the fiber-tracts (Fig. 1D, red colored).