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

TL;DR

This study shows that increased MAO-B tracer binding in reactive astrocytes can predict amyloid accumulation in Alzheimer's disease before symptoms appear.

Contribution

The study introduces 18F-SMBT-1 as a potential early prognostic marker for Alzheimer's by linking reactive astrogliosis to amyloid accumulation.

Findings

18F-SMBT-1 binding is higher in cognitively unimpaired individuals with preclinical Alzheimer's.

High 18F-SMBT-1 retention predicts faster amyloid accumulation in cognitively unimpaired individuals.

18F-SMBT-1 provides regional insights into reactive astrogliosis across Alzheimer's disease stages.

Abstract

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.

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‐.

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).

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.

Figures