AbstractBackgroundActivated microglia is present in both Alzheimer’s subjects (AD) and mild cognitive impairment (MCI) subjects and can be visualised by both pathological evaluation and in‐vivo imaging studies. It has been established that neuroinflammation plays a vital role in Alzheimer’s trajectory and disruption in structural and functional connectivity is also a key event in Alzheimer’s disease. However, the mechanism by which microglial activation influence brain structural and functional connectivity remains to be elucidated. 11C‐PBR28 PET is a marker of translocator protein (TSPO) reflecting microglial activation and 18F‐Flutematemol PET is a marker of amyloid deposition.Method25 amnestic MCI and 17 healthy controls (HC) were recruited and underwent T1‐weighted, diffusion tensor and resting‐state functional MRI, 11C‐PBR28 and 18F‐Flutemetamol PET scans. 11C‐PBR28 and 18F‐Flutemetamol scans were analysed using target‐to‐cerebellar ratio. Tract‐Based Spatial Statistics was performed on DTI scans. RS‐fMRI scans were analysed using medial prefrontal cortex (MPFC) as a seed. The relationship between tracer uptake and structural integrity of white matter tracts or brain functional connectivity with MPFC was analysed using linear regression corrected for age and gender.ResultMCI cohort showed significantly decreased functional connectivity between MPFC and posterior cingulate and precuneous regions. Cortical 11C‐PBR28 uptake but not 18F‐Flutemetamol was negatively correlated with FA in the corpus callosum, bilateral inferior frontal‐occipital fasciculi and inferior longitudinal fasciculi. MPFC 11C‐PBR28 uptake was correlated with increased MPFC functional connectivity to anterior frontal regions and reduced connectivity to posterior frontal, temporal, parietal and cingulate regions; while frontal amyloid load was correlated with reduced MPFC connectivity with frontal and temporal cortices. Regression analysis with both 18F‐Flutemetamol and 11C‐PBR28 demonstrated that MPFC 11C‐PBR28 was significantly associated MPFC connectivity with posterior frontal, parietal and cingulate regions.ConclusionThe findings suggest that MPFC microglial activation is associated with increased functional connectivity with the nearby regions and decreased connectivity with the distal regions to MPFC in MCI subjects. Findings from DTI analysis showed negative correlation with structural integrity of the long fibre tracts which are connecting distal regions. These findings suggest that neuroinflammation is involved in the structural and functional connectivity disruption and probably remodelling in AD trajectory.