Assessing Reactive Astrogliosis with ¹⁸F-SMBT-1 Across the Alzheimer Disease Spectrum

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- & 13 Aβ+), 12 mild cognitively impaired (MCI, 9 Aβ- & 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.