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

Abstract

A neuroinflammatory reaction in Alzheimer disease (AD) brains involves reactive astrocytes that overexpress monoamine oxidase-B (MAO-B). 18F-(S)-(2-methylpyrid-5-yl)-6-[(3-fluoro-2-hydroxy)propoxy]quinoline (18F-SMBT-1) is a novel 18F PET tracer highly selective for MAO-B. We characterized the clinical performance of 18F-SMBT-1 PET across the AD continuum as a potential surrogate marker of reactive astrogliosis. Methods: We assessed 18F-SMBT-1 PET regional binding in 77 volunteers (76 6 5.5 y old; 41 women, 36 men) across the AD continuum: 57 who were cognitively normal (CN) (44 amyloid-b [Ab]–negative [Ab2] and 13 Ab-positive [Ab1]), 12 who had mild cognitive impairment (9 Ab2 and 3 Ab1), and 8 who had AD dementia (6 Ab1 and 2 Ab2). All participants also underwent Ab and tau PET imaging, 3-T MRI, and neuropsychologic evaluation. Tau imaging results were expressed in SUV ratios using the cerebellar cortex as a reference region, whereas Ab burden was expressed in centiloids. 18F-SMBT-1 outcomes were expressed as SUV ratio using the subcortical white matter as a reference region. Results: 18F-SMBT-1 yielded high-contrast images at steady state (60–80 min after injection). When compared with the Ab2 CN group, there were no significant differences in 18F-SMBT-1 binding in the group with Ab2 mild cognitive impairment. Conversely, 18F-SMBT-1 binding was significantly higher in several cortical regions in the Ab1 AD group but also was significantly lower in the mesial temporal lobe and basal ganglia. Most importantly, 18F-SMBT-1 binding was significantly higher in the same regions in the Ab1 CN group as in the Ab2 CN group. When all clinical groups were considered together, 18F-SMBT-1 correlated strongly with Ab burden and much less with tau burden. Although in most cortical regions 18F-SMBT-1 did not correlate with brain volumetrics, regions known for high MAO-B concentrations presented a direct association with hippocampal and gray matter volumes, whereas the occipital lobe was directly associated with white matter hyperintensity. 18F-SMBT-1 binding was inversely correlated with Mini Mental State Examination and the Australian Imaging Biomarkers and Lifestyle’s Preclinical Alzheimer Cognitive Composite in some neocortical regions such as the frontal cortex, lateral temporal lobe, and supramarginal gyrus. Conclusion: Cross-sectional human PET studies with 18F-SMBT-1 showed that Ab1 AD patients, but most importantly, Ab1 CN individuals, had significantly higher regional 18F-SMBT-1 binding than Ab2 CN individuals. Moreover, in several regions in the brain, 18F-SMBT-1 retention was highly associated with Ab load. These findings suggest that increased 18F-SMBT-1 binding is detectable at the preclinical stages of Ab accumulation, providing strong support for its use as a surrogate marker of astrogliosis in the AD continuum.