PT - JOURNAL ARTICLE AU - Victor L Villemagne AU - Ryuichi Harada AU - Vincent Dore AU - Shozo Furumoto AU - Rachel Mulligan AU - Yukitsuka Kudo AU - Samantha Burnham AU - Natasha Krishnadas AU - Pierrick Bourgeat AU - Ying Xia AU - Simon Laws AU - Svetlana Bozinovski AU - Kun Huang AU - Milos D Ikonomovic AU - Jurgen Fripp AU - Kazuhiko Yanai AU - Nobuyuki Okamura AU - Christopher C Rowe TI - Assessing reactive astrogliosis with <sup>18</sup>F-SMBT-1 across the Alzheimer’s disease spectrum AID - 10.2967/jnumed.121.263255 DP - 2022 Feb 01 TA - Journal of Nuclear Medicine PG - jnumed.121.263255 4099 - http://jnm.snmjournals.org/content/early/2022/02/03/jnumed.121.263255.short 4100 - http://jnm.snmjournals.org/content/early/2022/02/03/jnumed.121.263255.full AB - Background: Neuroinflammatory reaction in Alzheimer’s disease (AD) brains involves reactive astrocytes which overexpress monoamine oxidase-B (MAO-B). 18F-SMBT-1 is a novel F-18 PET tracer highly selective for MAO-B. We characterized the clinical performance of 18F-SMBT-1 PET across the Alzheimer’s disease (AD) continuum as a potential surrogate marker of reactive astrogliosis Methods: We assessed 18F-SMBT-1 PET regional binding in 77 volunteers (76±5.5 y.o.; 41F/36M) across the AD continuum: 57 cognitively unimpaired controls (CN, 44 Aβ- &amp; 13 Aβ+), 12 mild cognitively impaired (MCI, 9 Aβ- &amp; 3 Aβ+), and 8 AD dementia patients (6 Aβ+ and 2 Aβ-). All participants also underwent Aβ and tau PET imaging, 3T MRI and neuropsychological evaluation. Tau imaging results were expressed in standard uptake value ratios (SUVR) using the cerebellar cortex as reference region, while Aβ burden was expressed in Centiloids. 18F-SMBT-1 outcomes were expressed as SUVR using the subcortical white matter as reference region. Results: 18F-SMBT-1 yielded high contrast images at steady state (60-80 min after injection). When compared to Aβ-CN, there were no significant differences in 18F-SMBT-1 binding in the Aβ-MCI group. Conversely, 18F-SMBT-1 binding was significantly higher in several cortical regions in the Aβ+AD group, but also was significantly lower in mesial temporal and basal ganglia. Most importantly, 18F-SMBT-1 binding was significantly higher in the same regions in Aβ+CN when compared to Aβ-CN. When all clinical groups were considered together, 18F-SMBT-1 was highly correlated with Aβ burden, and much less with tau burden. While in most cortical regions 18F-SMBT-1 was not correlated with brain volumetrics, regions known for high MAO-B concentrations presented a direct association with hippocampal and grey matter volumes, while the occipital lobe was directly associated with white matter hyperintensities. 18F-SMBT-1 binding was inversely correlated with MMSE and AIBL PACC in some neocortical regions such as the frontal cortex, lateral temporal and supramarginal gyrus. Conclusion: Cross-sectional human PET studies with 18F-SMBT-1, showed that Aβ+AD, but most importantly, Aβ+CN have significantly higher regional 18F-SMBT-1 binding than Aβ- CN. Moreover, in several regions in the brain, 18F-SMBT-1 retention was highly associated with Aβ load. These findings suggest that increased 18F-SMBT-1 binding is detectable at the preclinical stages of Aβ accumulation, providing strong support for its use as surrogate marker of astrogliosis in the AD continuum.