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A neuroinflammatory reaction in Alzheimer disease (AD) brains involves reactive astrocytes that overexpress monoamine oxidase-B (MAO-B). 18 F-( S )-(2-methylpyrid-5-yl)-6-[(3-fluoro-2-hydroxy)propoxy]quinoline ( 18 F-SMBT-1) is a novel 18 F PET tracer highly selective for MAO-B. We characterized the clinical performance of 18 F-SMBT-1 PET across the AD continuum as a potential surrogate marker of reactive astrogliosis. Methods: We assessed 18 F-SMBT-1 PET regional binding in 77 volunteers (76 ± 5.5 y old; 41 women, 36 men) across the AD continuum: 57 who were cognitively normal (CN) (44 amyloid-β [Aβ]-negative [Aβ-] and 13 Aβ-positive [Aβ+]), 12 who had mild cognitive impairment (9 Aβ- and 3 Aβ+), and 8 who had AD dementia (6 Aβ+ and 2 Aβ-). All participants also underwent Aβ 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 Aβ burden was expressed in centiloids. 18 F-SMBT-1 outcomes were expressed as SUV ratio using the subcortical white matter as a reference region. Results: 18 F-SMBT-1 yielded high-contrast images at steady state (60-80 min after injection). When compared with the Aβ- CN group, there were no significant differences in 18 F-SMBT-1 binding in the group with Aβ- mild cognitive impairment. Conversely, 18 F-SMBT-1 binding was significantly higher in several cortical regions in the Aβ+ AD group but also was significantly lower in the mesial temporal lobe and basal ganglia. Most importantly, 18 F-SMBT-1 binding was significantly higher in the same regions in the Aβ+ CN group as in the Aβ- CN group. When all clinical groups were considered together, 18 F-SMBT-1 correlated strongly with Aβ burden and much less with tau burden. Although in most cortical regions 18 F-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. 18 F-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 18 F-SMBT-1 showed that Aβ+ AD patients, but most importantly, Aβ+ CN individuals, had significantly higher regional 18 F-SMBT-1 binding than Aβ- CN individuals. Moreover, in several regions in the brain, 18 F-SMBT-1 retention was highly associated with Aβ load. These findings suggest that increased 18 F-SMBT-1 binding is detectable at the preclinical stages of Aβ accumulation, providing strong support for its use as a surrogate marker of astrogliosis in the AD continuum., (© 2022 by the Society of Nuclear Medicine and Molecular Imaging.)

Tau PET tracers exhibit varying levels of specific signal and distinct off-target binding patterns that are more diverse than amyloid PET tracers. This study compared 2 frequently used tau PET tracers, 18 F-flortaucipir and 18 F-MK-6240, in the same subjects. Methods: 18 F-flortaucipir and 18 F-MK-6240 scans were collected within 2 mo in 15 elderly subjects varying in clinical diagnosis and cognition. FreeSurfer, version 5.3, was applied to 3-T MR images to segment Braak pathologic regions (I-VI) for PET analyses. Off-target binding was assessed in the choroid plexus, meninges, and striatum. SUV ratio (SUVR) outcomes were determined over 80-100 min ( 18 F-flortaucipir) or 70-90 min ( 18 F-MK-6240) normalized to cerebellar gray matter. Masked visual interpretation of images was performed by 5 raters for both the medial temporal lobe and the neocortex, and an overall (majority) rating was determined. Results: Overall visual ratings showed complete concordance between radiotracers for both the medial temporal lobe and the neocortex. SUVR outcomes were highly correlated ( r 2 > 0.92; P ≪ 0.001) for all Braak regions except Braak II. The dynamic range of SUVRs in target regions was approximately 2-fold higher for 18 F-MK-6240 than for 18 F-flortaucipir. Cerebellar SUVs were similar for 18 F-MK-6240 and 18 F-flortaucipir, suggesting that differences in SUVRs are driven by specific signals. Apparent off-target binding was observed often in the striatum and choroid plexus with 18 F-flortaucipir and most often in the meninges with 18 F-MK-6240. Conclusion: Both 18 F-MK-6240 and 18 F-flortaucipir are capable of quantifying signal in a common set of brain regions that develop tau pathology in Alzheimer disease; these tracers perform equally well in visual interpretations. Each also shows distinct patterns of apparent off-target binding. 18 F-MK-6240 showed a greater dynamic range in SUVR estimates, which may be an advantage in detecting early tau pathology or in performing longitudinal studies to detect small interval changes., (© 2022 by the Society of Nuclear Medicine and Molecular Imaging.)

In this review we examine, in the context of the amyloid, tau, and neurodegeneration framework, the available evidence and potential alternatives on how to establish tau positivity (T+) for multiple tau-imaging tracers in order to reach a consensus on normal and abnormal tau imaging values that can be universally implemented in clinical research and therapeutic trials., (© 2021 by the Society of Nuclear Medicine and Molecular Imaging.)