Biomarkers for Alzheimer’s Disease Drug Development

Elena Rodriguez-Vieitez, Agneta Nordberg

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-β (Aβ) plaques and intracellular neurofibrillary tangles (NFT) of hyperphosphorylated tau proteins, accompanied by the activation of glial cells-astrocytes and microglia-and neuroinflammatory responses, leading to neurodegeneration and cognitive dysfunction. An increasing diversity of positron emission tomography (PET) imaging radiotracers are available to selectively target the different pathophysiological processes of AD. Along with the success of Aβ PET and the more recent tau PET imaging, there is also a great interest to develop PET tracers to image glial activation and neuroinflammation. While most research to date has focused on imaging microgliosis, recent studies using 11C-deuterium-L-deprenyl (11C-DED) PET imaging suggest that astrocytosis may be present from very 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 Aβ deposition, and glucose metabolism in patients 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 responses in neurodegenerative diseases. Progress in the field will contribute to the incorporation of PET imaging of glial activation and neuroinflammation as biomarkers with clinical application, and motivate further investigation on glial cells as therapeutic targets in AD and other neurodegenerative diseases.