Evaluation of glial activation in alzheimer’s trajectory using novel tspo pet marker, [18f]-ge180, and novel astrocyte marker [11c]-bu99008; evaluating its influence on microstructural alterations

Abstract

Background. The neuropathology of Alzheimer’s disease (AD) is still not fully understood. The activation of microglia and astrocytes plays a significant role in neurodegeneration, with debated relationship with amyloid, tau deposition, atrophy and glucose metabolism. This project evaluated two different PET tracers targeting microglia and astrocytes in volunteers with AD or MCI, and the relationship between microstructural alteration (fractional anisotropy and mean diffusivity) and microglial activation. Methods. The TSPO [18F]-GE180 and the Imidazolin-2 binding-site [11C]-BU99008 tracers were examined in volunteers with cognitive impairment (AD/MCI) and healthy controls (HC). The subjects underwent neuropsychological testing, MRI, amyloid-β PET scans, [18F]-GE180 or [11C]-BU99008 PET scan, [18F]-FDG PET scan (for the astrocyte study). For [18F]-GE180 and [11C]-BU99008, spectral analysis was used; SUVR analysis was conducted for [18F]- flutemetamol, [18F]-florbetaben and [18F]-FDG. DTI analysis (fractional anisotropy, FA, and mean diffusivity, MD) was performed for the GE180 study. Group comparisons and correlations analysis were done at regional and voxel-level. Results: [18F]-GE180 and [11C]-BU99008 uptake were higher in AD and MCI compared to HC, particularly in the amyloid-positive patients. Positive correlation was found between hippocampal volumes and [18F]-GE180 in AD and MCI. Reduced FA and increased MD were found in AD and MCI subjects compared to HC. No correlation was found between DTI measures and [18F]-GE180 uptake. Positive correlation was found between [11C]-BU99008 IRF120 and [18F]-FDG in the disease group; negative correlation was found between [11C]-BU99008 IRF120 and [18F]- florbetaben in occipital lobe and amygdala and between [11C]-BU99008 IRF120 in medial temporal lobes and [18F]-florbetaben in amygdala. 13 Conclusions. Microglial and astrocytes activation represent a common feature in the neurodegenerative trajectory of AD, with complex interplay between the hallmark of AD. The low penetration of the [18F]-GE180 tracer in the brain represents a limitation for its use. In vivo quantification of neuroinflammation remains crucial, considering its important role in neurodegeneration.