Imaging of Reactive Astrogliosis by Positron Emission Tomography

Many neurodegenerative diseases are neuropathologically characterized by neuronal loss, gliosis, and the deposition of misfolded proteins such as beta-amyloid (A beta) plaques and tau tangles in Alzheimer's disease (AD). In postmortem AD brains, reactive astrocytes and activated microglia are observed surrounding A beta plaques and tau tangles. These activated glial cells secrete pro-inflammatory cytokines and reactive oxygen species, which may contribute to neurodegeneration. Therefore, in vivo imaging of glial response by positron emission tomography (PET) combined with A beta and tau PET would provide new insights to better understand the disease process, as well as aid in the differential diagnosis, and monitoring glial response disease-specific therapeutics. There are two promising targets proposed for imaging reactive astrogliosis: monoamine oxidase-B (MAO-B) and imidazoline(2) binding site (I2BS), which are predominantly expressed in the mitochondrial membranes of astrocytes and are upregulated in various neurodegenerative conditions. PET tracers targeting these two MAO-B and I2BS have been evaluated in humans. [F-18]THK-5351, which was originally designed to target tau aggregates in AD, showed high affinity for MAO-B and clearly visualized reactive astrocytes in progressive supranuclear palsy (PSP). However, the lack of selectivity of [F-18]THK-5351 binding to both MAO-B and tau, severely limits its clinical utility as a biomarker. Recently, [F-18]SMBT-1 was developed as a selective and reversible MAO-B PET tracer via compound optimization of [F-18]THK-5351. In this review, we summarize the strategy underlying molecular imaging of reactive astrogliosis and clinical studies using MAO-B and I2BS PET tracers.

Automated summary

Neurodegenerative diseases are characterized by neuronal loss, gliosis, and the deposition of misfolded proteins. Imaging the glial response in vivo using PET combined with A beta and tau PET can provide insights into the disease process and aid in diagnosis and monitoring of therapeutic response.