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

Abstract

Background: Neuroinflammatory reaction in Alzheimer's disease (AD) brains involves reactive astrocytes which overexpress monoamine oxidase-B (MAO-B). 18 F-SMBT-1 is a novel F-18 PET tracer highly selective for MAO-B. We characterized the clinical performance of 18 F-SMBT-1 PET across the Alzheimer's disease (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.o.; 41F/36M) across the AD continuum: 57 cognitively unimpaired controls (CN, 44 A-& 13 A+), 12 mild cognitively impaired (MCI, 9 A-& 3 A+), and 8 AD dementia patients (6 A+ and 2 A-). All participants also underwent A 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 A burden was expressed in Centiloids. 18 F-SMBT-1 outcomes were expressed as SUVR using the subcortical white matter as reference region.Results: 18 F-SMBT-1 yielded high contrast images at steady state (60-80 min after injection). When compared to A-CN, there were no significant differences in 18 F-SMBT-1 binding in the A-MCI group.Conversely, 18 F-SMBT-1 binding was significantly higher in several cortical regions in the A+AD group, but also was significantly lower in mesial temporal and basal ganglia. Most importantly, 18 F-SMBT-1 binding was significantly higher in the same regions in A+CN when compared to A-CN. When all clinical groups were considered together, 18 F-SMBT-1 was highly correlated with A burden, and much less with tau burden. While in most cortical regions 18 F-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. 18 F-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.Conclusions: Cross-sectional human PET studies with 18 F-SMBT-1, showed that A+AD, but most importantly, A+CN have significantly higher regional 18 F-SMBT-1 binding than A-CN. Moreover, in several regions in the brain, 18 F-SMBT-1 retention was highly associated with A load. These findings suggest that increased 18 F-SMBT-1 binding is detectable at the preclinical stages of A accumulation, providing strong support for its use as surrogate marker of astrogliosis in the AD continuum.

Astrocytes in Neurodegeneration: Inspiration From Genetics

“…Astrocyte transcriptome analysis of AD brain tissue revealed gene changes associated with Aβ and pTau pathology in inflammation, protein regulation, oxidative stress, antioxidant function, lipid metabolism, and ion homeostasis (Viejo et al, 2022). Positron emission tomography (PET) and magnetic resonance imaging (MRI) (Choo et al, 2014;Vilemagne et al, 2022a) revealed dynamic changes in reactive astrocytes and Aβ due to mild cognition impairment. At preclinical stages, astrogliosis was induced by early Aβ deposition and loss of gray matter cells (Choo et al, 2014;Vilemagne et al, 2022a), whereas astrocyte atrophy appeared subsequently with greater Aβ deposition (Hsu et al, 2018).…”

“…Positron emission tomography (PET) and magnetic resonance imaging (MRI) (Choo et al, 2014;Vilemagne et al, 2022a) revealed dynamic changes in reactive astrocytes and Aβ due to mild cognition impairment. At preclinical stages, astrogliosis was induced by early Aβ deposition and loss of gray matter cells (Choo et al, 2014;Vilemagne et al, 2022a), whereas astrocyte atrophy appeared subsequently with greater Aβ deposition (Hsu et al, 2018). Astroglia tracer also revealed that reactive astrogliosis increased and reached a peak in preclinical stages of AD, followed by a decrease of astrogliosis and then rise again in dementia stages, exerting neurotoxic functions (Kumar et al, 2021).…”

“…A selective monoamine oxidase-B (MAO-B) tracer is also used to detect reactive astrogliosis since MAO-B is overexpressed in reactive astrocytes. The tracer identified the reactive astrogliosis in mild cognitive impairment (MCI) and AD (Vilemagne et al, 2022b) when compared to controls, and it was detectable at the preclinical stages of Aβ accumulation (Vilemagne et al, 2022a). Markers secreted by reactive astrocytes could also be implemented as a diagnostic tool in patients.…”

Aquaporin 4 is differentially increased and depolarized in association with tau and amyloid-beta

“…Removing senescent glial cells prevented tau-dependent pathology and cognitive decline in PS19 mice [111]. Early astrocytosis has been demonstrated by positron emission tomography tracers in both patients with AD and amyloidosis animal models [112][113][114][115][116][117][118]. Tau accumulates in hilar astrocytes of the dentate gyrus in postmortem brains from patients with AD [119][120][121] and induces neuronal dysfunction and memory deficits in a mouse model [122].…”

Imaging of Reactive Astrogliosis by Positron Emission Tomography

“…Preclinical studies of [ 18 F]SMBT-1 demonstrated that high binding affinity and high binding selectivity to MAO-B with low non-specific binding as well as good PK and metabolic profiles (Harada et al, 2021). Preliminary cross-sectional human PET studies in a wide range of ages are indicating that [ 18 F]SMBT-1 is a selective MAO-B tracer with low non-specific binding, high entry into the brain while displaying favorable reversible kinetics, and have significantly higher binding in Aβ + AD (Figure 4) and Aβ + cognitively unimpaired controls (Villemagne et al, 2022), similarly to what has been reported with plasma GFAP (Verberk et al, 2020;Chatterjee et al, 2021). These findings suggest that reactive astrogliosis as measured by MAO-B through [ 18 F]SMBT-1 is associated with early Aβ accumulation, providing strong support for its use as surrogate marker of astrogliosis.…”