Reactive Astrogliosis predicts Amyloid Accumulation before the Preclinical Stage of Alzheimer's Disease

Abstract

Background

Monoamine Oxidase‐B (MAO‐B) is overexpressed in reactive astrocytes, playing a crucial role in neurodegeneration. Recently, increased binding of the PET MAO‐B tracer ¹⁸F‐SMBT‐1 has been shown in preclinical Alzheimer's disease (AD) stages. However, the regional distribution and effect on Ab of abnormal ¹⁸F‐SMBT‐1 binding along the AD continuum remains unclear.

Method

144 Cognitively Unimpaired (CU), 24 A+ Mild Cognitive Impairment (MCI), and 20 A+ AD subjects underwent PET imaging with ¹⁸F‐NAV4694, ¹⁸F‐MK6240, and ¹⁸F‐SMBT‐1.

Aβ and tau PET SUVR were transformed into Centiloid (CL) and CenTauR (CTR) using CapAIBL. A+ was defined as >15CL and T+ >14 CTR in the Meta‐Temporal. SMBT‐1 scans were spatially normalised using MR‐based CapAIBL, scaled to the cerebellar cortex and several cortical regions sampled. The relationship between SMBT‐1 binding and Aβ accumulation was assessed in a subset of 81 CU A‐.

Result

Distinct regional ¹⁸F‐SMBT‐1 binding was observed across brain regions (Figure 1). ¹⁸F‐SMBT‐1 binding was higher in CU A+ compared to the CU A‐ in most regions, while binding in A+ MCI/AD either remained higher (in parietal/cingulate/occipital) or decreased (in frontal/caudate/putamen). Higher ¹⁸F‐SMBT‐1 binding was also significant in CU A+ T‐ (n = 43) (Figure 2). In CU A‐ participants with high ¹⁸F‐SMBT‐1 retention, significantly higher Ab accumulation rates were observed compared to low ¹⁸F‐SMBT1 (1.20CL/yr vs 0.01CL/yr, respectively, p = 0.001) (Figure 3). Furthermore, 92% of CU A‐ individuals with high ¹⁸F‐SMBT‐1 were classified as Ab accumulators (58% in CU A‐/low ¹⁸F‐SMBT‐1).

Conclusion

Unlike fluid neuroinflammation markers, ¹⁸F‐SMBT‐1 facilitates quantitative assessment of regional differences in reactive astrogliosis across the AD continuum, as well as longitudinal change. Elevated ¹⁸F‐SMBT‐1 in CU A‐ predicted Ab accumulation, highlighting the potential of ¹⁸F‐SMBT‐1 as a prognostic marker in early‐stage AD while suggesting modulation of astrocytic function may be a target for AD prevention and treatment.