Featured ArticleCerebrospinal fluid sTREM2 levels are associated with gray matter volume increases and reduced diffusivity in early Alzheimer's disease

- We identify for the first time the cerebral structural alterations associated to increased levels of CSF sTREM2, a marker of microglial activation, in the Alzheimer's disease (AD) spectrum. Our results show a positive correlation between gray matter volume and CSF sTREM2 levels in MCI subjects after adjusting for p-tau related atrophy.
- To confirm the inflammatory nature of this relative volume increase, we analyzed cerebral water diffusion by MRI. In the same patients, we observed restricted mean diffusivity, a marker of cytotoxic edema, in association with increased CSF sTREM2 in a spatially overlapping pattern. To our knowledge, this is also the first report of an association between CSF markers of neuroinflammation and restricted water diffusivity in the brain.
- Our findings suggest that CSF sTREM2 increments in early AD are associated to MRI features typical of neuroinflammation, namely increased gray matter volume and restricted water diffusivity. These results support the involvement of microglial activation in early AD which is mediated by TREM2 expression.
- These findings may open new therapeutical pathways for intervention in early AD.

IntroductionTREM2 is involved in the regulation of inflammatory response and phagocytosis. A soluble fragment (sTREM2) is often found abnormally increased in cerebrospinal fluid (CSF) in Alzheimer's disease (AD).MethodsOne hundred fourteen participants (45 control, 19 preclinical, 27 mild cognitive impairment [MCI], and 23 AD) underwent CSF sTREM2 determination and magnetic resonance imaging (MRI). We studied the association between CSF sTREM2, gray matter volume, and water motion diffusivity and anisotropy across groups.ResultsIn MCI patients, a positive correlation between CSF sTREM2 and gray matter volume was found in the bilateral inferior and middle temporal cortices, precuneus, the supramarginal, and angular gyri, after controlling by age, sex, and p-tau. A negative correlation with mean diffusivity was detected in overlapping regions, among others.DiscussionIn early AD, augmented CSF sTREM2 levels correspond with cerebral MRI features typical of brain swelling, supporting a role for TREM2 in the regulation of the neuroinflammatory response to early neurodegeneration.