Analysis of [18F]SMBT-1 binding to reactive astrogliosis in postmortem brain tissues from patients with Alzheimer’s disease and frontotemporal lobar degeneration

Introduction: Reactive astrogliosis is morphological and functional changes of astrocytes. Loss of homeostatic functions and gain of detrimental functions of astrocytes may drive disease progression in neurodegenerative diseases. PET tracer targeting monoamine oxidase-B (MAO-B) enables in vivo imaging of reactive astrogliosis. A newly developed PET tracer [¹⁸F]SMBT-1 possess high affinity and high selectivity for MAO-B in a reversible binding fashion. In this study, we investigated the binding properties of [¹⁸F]SMBT-1 to postmortem brains from Alzheimer's disease (AD) and frontotemporal lobar degeneration (FTLD).

Methods: In vitro autoradiography of [¹⁸F]SMBT-1 (MAO-B), [¹⁸F]Florbetaben (amyloid-ß (Aß)) and [³H]MK-6240 (tau) was performed using postmortem brain sections from Aß-positive/Tau-negative cognitively normal elderly and Aß-positive/Tau-positive AD patient. The specific binding of [¹⁸F]SMBT-1 was measured in postmortem brain homogenates of cognitively normal elderly and FTLD patients. We also investigated the correlation of [¹⁸F]SMBT-1 binding with MAO-B, glial fibrillary acidic protein (GFAP), and insoluble TAR DNA-binding protein 43 (TDP-43) levels.

Results: In Aß-positive/Tau-positive AD brain sections, specific binding of [¹⁸F]SMBT-1 was observed in regions close to Aß and tau deposits where [¹⁸F]florbetaben and [³H]MK-6240 binding was observed. Furthermore, significant [¹⁸F]SMBT-1 binding was also observed in Aß-positive/Tau-negative cognitively normal elderly brains. In FTLD-TDP brain tissues, specific [¹⁸F]SMBT-1 binding was significantly elevated compared to healthy control brains. The amount of [¹⁸F]SMBT-1 binding was significantly correlated with MAO-B, GFAP, and insoluble TDP-43 levels.

Conclusions: Significant [¹⁸F]SMBT-1 binding was observed in the brains of patients with AD dementia as well as amyloid-positive cognitively normal elderly, reflecting reactive astrogliosis induced by Aß accumulation. [¹⁸F]SMBT-1 can also detect reactive astrogliosis in FTLD-TDP, suggesting that SMBT-1 PET is potentially useful for early diagnosis of FTLD.