Imaging Neuroinflammation: Quantification of Astrocytosis in a Multitracer PET Approach.

The recent progress in the development of in vivo biomarkers is rapidly changing how neurodegenerative diseases are conceptualized and diagnosed and how clinical trials are designed today. Alzheimer's disease (AD) - the most common neurodegenerative disorder - is characterized by a complex neuropathology involving the deposition of extracellular amyloid-ß (Aß) plaques and intracellular neurofibrillary tangles (NFTs) of hyperphosphorylated tau proteins, accompanied by the activation of glial cells, i.e., astrocytes and microglia, and neuroinflammatory response, leading to neurodegeneration and cognitive dysfunction. An increasing diversity of positron emission tomography (PET) imaging radiotracers is available to selectively target the different pathophysiological processes of AD. Along with the success of Aß PET and the more recent tau PET imaging, there is a great interest to develop PET tracers to image glial reactivity and neuroinflammation. While most research to date has focused on imaging microgliosis, there is an upsurge of interest in imaging reactive astrocytes in the AD continuum. There is increasing evidence that reactive astrocytes are morphologically and functionally heterogeneous, with different subtypes that express different markers and display various homeostatic or detrimental roles across disease stages. Therefore, multiple biomarkers are desirable to unravel the complex phenomenon of reactive astrocytosis. In the field of in vivo PET imaging in AD, the research concerning reactive astrocytes has predominantly focused on targeting monoamine oxidase B (MAO-B), most often using either 11C-deuterium-L-deprenyl (11C-DED) or 18F-SMBT-1 PET tracers. Additionally, imidazoline2 binding (I2BS) sites have been imaged using 11C-BU99008 PET. Recent studies in our group using 11C-DED PET imaging suggest that astrocytosis may be present from the early stages of disease development in AD. This chapter provides a detailed description of the practical approach used for the analysis of 11C-DED PET imaging data in a multitracer PET paradigm including 11C-Pittsburgh compound B (11C-PiB) and 18F-fluorodeoxyglucose (18F-FDG). The multitracer PET approach allows investigating the comparative regional and temporal patterns of in vivo brain astrocytosis, fibrillar Aß deposition, glucose metabolism, and brain structural changes. It may also contribute to understanding the potential role of novel plasma biomarkers of reactive astrocytes, in particular the glial fibrillary acidic protein (GFAP), at different stages of disease progression. This chapter attempts to stimulate further research in the field, including the development of novel PET tracers that may allow visualizing different aspects of the complex astrocytic and microglial response in neurodegenerative diseases. Progress in the field will contribute to the incorporation of PET imaging of glial reactivity and neuroinflammation as biomarkers with clinical application and motivate further investigation on glial cells as therapeutic targets in AD and other neurodegenerative diseases.

Astrocyte Signature in Alzheimer's Disease Continuum through a Multi-PET Tracer Imaging Perspective.

Reactive astrogliosis is an early event in the continuum of Alzheimer's disease (AD). Current advances in positron emission tomography (PET) imaging provide ways of assessing reactive astrogliosis in the living brain. In this review, we revisit clinical PET imaging and in vitro findings using the multi-tracer approach, and point out that reactive astrogliosis precedes the deposition of Aß plaques, tau pathology, and neurodegeneration in AD. Furthermore, considering the current view of reactive astrogliosis heterogeneity-more than one subtype of astrocyte involved-in AD, we discuss how astrocytic body fluid biomarkers might fit into trajectories different from that of astrocytic PET imaging. Future research focusing on the development of innovative astrocytic PET radiotracers and fluid biomarkers may provide further insights into the heterogeneity of reactive astrogliosis and improve the detection of AD in its early stages.