Increased regional brain inflammation predicts longitudinal brain atrophy in individuals in the Alzheimer’s disease continuum

Abstract

AbstractBackgroundNeuroinflammation typically involves the activation of microglial cells in the brain and has been linked to Alzheimer’s disease (AD) pathology. However, how microglial activation influences brain neurodegeneration in individuals across the AD continuum is still poorly understood. Here, we aimed to investigate the influence of microglial activation in longitudinal brain atrophy in individuals across the AD continuum. We hypothesize that high levels of regional brain inflammation predict widespread brain atrophy.MethodWe assessed 95 individuals from the TRIAD cohort (60 cognitively unimpaired and 35 cognitively impaired) with available [11C]PBR28‐PET, a measure of microglial activation, and a 2‐year longitudinal MRI (mean = 2.07 years). We generated grey matter voxel‐based morphometry (VBM) images using SPM12 and DARTEL, smoothed with a Gaussian kernel of full‐width half maximum of 8mm. We built the uncorrected (p < 0.05) association matrix between the [11C]PBR28‐PET SUVR and longitudinal VBM ROIs (z‐score) with the ß‐estimates from linear regressions accounting for age, sex, and diagnosis. We divided the [11C]PBR28‐PET levels into terciles (low, intermediate, and high) to generate the averages of longitudinal VBM changes.ResultBaseline ROI‐based [11C]PBR28‐PET levels associate with longitudinal brain atrophy not only locally but also in distinct brain regions (Fig 1a). After FDR‐correction, the inferior temporal cortex was the region where [11C]PBR28‐PET levels were better associated with widespread longitudinal brain atrophy (Fig. 1b). Brain atrophy was observed in AD‐related regions, including the amygdala, insula, and the superior temporal cortex, independently of global amyloid load and tau (Fig. 1b). Accordingly, individuals with higher [11C]PBR28‐PET levels in the inferior temporal cortex presented increased longitudinal brain atrophy compared to individuals with lower [11C]PBR28‐PET (Fig. 1c).ConclusionWe identified increased baseline [11C]PBR28‐PET levels in the inferior temporal cortex that were highly associated with longitudinal brain atrophy in individuals across the AD continuum. Our results demonstrated that higher levels of inflammation in key brain regions could predict widespread longitudinal brain atrophy, suggesting that microglial activation has a detrimental impact on AD‐related neurodegeneration progression.