Diagnostic reactive astrogliosis biomarkers in Alzheimer´s disease continuum

Abstract

AbstractBackgroundThe Alzheimer’s disease (AD) biomarker field is moving rapidly. Creating a platform where multi‐PET tracer approaches and various fluid biomarkers with discriminative power in the early pathological stages could provide deeper insight into the role of reactive astrogliosis in the AD continuum. Accumulating data indicates that reactive astrogliosis may play a critical role in the early stages and, perhaps, precedes other pathological hallmarks of AD. Different PET tracers for imaging reactive astrogliosis are now available along with plasma GFAP showing a direct correlation with increased brain amyloid‐PET. We also propose that alpha‐7‐nicotinic acetylcholine receptors (α7nAChRs) might be early modulators of reactive astrogliosis and Aβ‐pathology in AD. New α7nAChRs‐PET‐tracers might be promising future new biomarkers of reactive astrogliosis with potential early diagnostic properties.MethodTranslational molecular imaging studies including in vivo multimodal PET investigations ([11C]‐deprenyl, [11C]‐PIB, [18F]‐Flutemematol, [18F]‐FDG, [18F]‐RO‐948), MRI, plasma GFAP analyses in control, presymptomatic ADAD, MCI to AD dementia and in vitro PET tracer binding studies (deprenyl, SMBT‐1, and BU99008) in postmortem brains using small/large section‐autoradiography and tissue‐homogenates.ResultWe hypothesize from our in vivo PET/in vitro brain imaging translational/clinical studies a ‘first and second wave of reactive astrogliosis’ with distinct close‐loop relationships with other pathological biomarkers across AD continuum. Validation of newly developed PET‐tracers BU99008 and SMBT‐1 for mapping and visualizing reactive astrogliosis in the brain demonstrated multiple binding properties in AD brain and highlighted the crucial need of multi‐PET tracer approach for understanding the complexity of reactive astrogliosis in AD. We have observed a significant positive correlation between plasma GFAP levels and [18F]‐flutemetamol binding in patients undergoing memory assessment. In presymtomatic ADAD patients, high [11C] deprenyl binding is observed earlier in the disease evolution than increase in plasma GFAP levels following a divergent direction. This clearly suggests plasma GFAP as a later biomarker than [11C]‐deprenyl in AD trajectory, possibly reflecting different types of reactive astrocytes at different stages of AD.ConclusionIt’s an exciting time for the AD field with several new biomarkers/PET‐tracers for reactive astrogliosis, which will improve our understanding of underlying astrocytic complexity and add power to the existing diagnostic criteria in AD.