Alzheimer's Imaging Consortium

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.