Journal Article

The combined effects of microglia activation and brain glucose hypometabolism in early-onset Alzheimer’s disease

Iannaccone, Sandro, Iaccarino, Leonardo, Tondo, Giacomo, Presotto, Luca, Santangelo, Roberto, Magnani, Giuseppe, Perani, Daniela, Caminiti, Silvia Paola

2020

Overview

Background Early-onset Alzheimer’s disease (EOAD) is characterized by young age of onset (< 65 years), severe neurodegeneration, and rapid disease progression, thus differing significantly from typical late-onset Alzheimer’s disease. Growing evidence suggests a primary role of neuroinflammation in AD pathogenesis. However, the role of microglia activation in EOAD remains a poorly explored field. Investigating microglial activation and its influence on the development of synaptic dysfunction and neuronal loss in EOAD may contribute to the understanding of its pathophysiology and to subject selection in clinical trials. In our study, we aimed to assess the amount of neuroinflammation and neurodegeneration and their relationship in EOAD patients, through positron emission tomography (PET) measures of microglia activation and brain metabolic changes. Methods We prospectively enrolled 12 EOAD patients, classified according to standard criteria, who underwent standard neurological and neuropsychological evaluation, CSF analysis, brain MRI, and both [ 18 F]-FDG PET and [ 11 C]-(R)-PK11195 PET. Healthy controls databases were used for statistical comparison. [ 18 F]-FDG PET brain metabolism in single subjects and as a group was assessed by an optimized SPM voxel-wise single-subject method. [ 11 C]-PK11195 PET binding potentials were obtained using reference regions selected with an optimized clustering procedure followed by a parametric analysis. We performed a topographic interaction analysis and correlation analysis in AD-signature metabolic dysfunctional regions and regions of microglia activation. A network connectivity analysis was performed using the interaction regions of hypometabolism and [ 11 C]-PK11195 PET BP increases. Results EOAD patients showed a significant and extended microglia activation, as [ 11 C]-PK11195 PET binding potential increases, and hypometabolism in typical AD-signature brain regions, i.e., temporo-parietal cortex, with additional variable frontal and occipital hypometabolism in the EOAD variants. There was a spatial concordance in the interaction areas and significant correlations between the two biological changes. The network analysis showed a disruption of frontal connectivity induced by the metabolic/microglia effects. Conclusion The severe microglia activation characterizing EOAD and contributing to neurodegeneration may be a marker of rapid disease progression. The coupling between brain glucose hypometabolism and local immune response in AD-signature regions supports their biological interaction.

• Publisher: BioMed Central,BioMed Central Ltd,Springer Nature B.V,BMC
• Subject: [11C]-(R)-PK11195 PET / [18F]-FDG PET / Advertising executives / Age groups / Algorithms / Alzheimer's disease / Analysis / Biomedical and Life Sciences / Biomedicine / Brain / Clustering / Data analysis / Data processing / Dementia / Development and progression / Drug dosages / Early-onset Alzheimer’s disease / Executive function / Geriatric Psychiatry / Geriatrics/Gerontology / Glucose / Medical research / Metabolism / Microglia activation / Neurodegeneration / Neurology / Neurons / Neurosciences / Positron emission tomography / Tomography