The associations between synaptic density and "A/T/N" biomarkers in Alzheimer's disease: An 18F-SynVesT-1 PET/MR study

Abstract

A newly developed SV2A radiotracer, ¹⁸F-SynVesT-1, was used in this study to investigate synaptic density and its association with Alzheimer's disease (AD) "A/T/N" biomarkers. The study included a cohort of 97 subjects, consisting of 64 patients with cognitive impairment (CI) and 33 individuals with normal cognition (CU). All subjects underwent ¹⁸F-SynVesT-1 PET/MR and ¹⁸F-florbetapir PET/CT scans. Additionally, a subgroup of individuals also underwent ¹⁸F-MK-6240, ¹⁸F-FDG PET/CT, plasma Aβ42/Aβ40 and p-tau181 tests. The differences in synaptic density between the groups and the correlations between synaptic density and AD "A/T/N" biomarkers were analyzed. The results showed that compared to the CU group, the CI with Aβ+ (CI+) group exhibited the most pronounced synapse loss in the hippocampus, with some loss also observed in the neocortex. Furthermore, synaptic density in the hippocampus and parahippocampal gyrus showed associations with AD biomarkers detected by both imaging and plasma tests in the CI group. The associations between synaptic density and FDG uptake and hippocampal volume were also observed in the CI+ group. In conclusion, the study demonstrated significant synaptic density loss, as measured by the promising tracer ¹⁸F-SynVesT-1, and its close correlation with "A/T/N" biomarkers in patients with both Alzheimer's clinical syndrome and pathological changes.

Keywords: Synaptic vesicle glycoprotein 2A; amyloid-β deposition; cognitive performance; glucose metabolism; plasma biomarkers.

Figure 1.

Group differences between (a) overall CI and CU, (b) CI+ and CU, (c) CI+ and CI− and (d) CI− and CU by voxelwise analysis. The color bar represents the t value with a statistical threshold of p < 0.05, cluster-level FWE correction.

Figure 2.

Association of “A/T/N” biomarkers with synaptic density in all the subjects by voxelwise analysis. (a) Negative correlation of global ¹⁸F-Flobetapir SUVRs with synaptic density; (b) Negative correlation of ¹⁸F-MK-6240 SUVRs in the MTL with synaptic density; (c) Positive correlation of glucose metabolism in the MTL with synaptic density and (d) Positive correlation of hippocampal volume with synaptic density. The color bar represents the t value with a statistical threshold of p < 0.05, cluster-level FWE correction.

Figure 3.

Correlations of “A/T/N” biomarkers with synaptic density by ROI-based analysis in the CI+, CI− and CU groups. (a–d) Correlations of hippocampal ¹⁸F-SynVesT-1 SUVRs with global ¹⁸F-Flobetapir SUVRs, ¹⁸F-MK-6240 SUVRs in the MTL, ¹⁸F-FDG SUVRs in the MTL and hippocampal volume and (e–h) Correlations of ¹⁸F-SynVesT-1 SUVRs in the PHG with global ¹⁸F-Flobetapir SUVRs, ¹⁸F-MK-6240 SUVRs in the MTLs, ¹⁸F-FDG SUVRs in the MTL and hippocampal volume.

Figure 4.

Correlations between synaptic density and plasma biomarkers. The correlations of (a) plasma Aβ42/40 and (b) plasma p-tau181 levels with synaptic density in the overall cohort. The correlations of hippocampal synaptic density with (c) plasma Aβ42/40 and (d) plasma p-tau181 levels in the CI+ and CU groups. The correlations of synaptic density in the PHG with (e) plasma Aβ42/40 and (f) plasma p-tau181 levels in the CI+ and CU groups. The color bar in the voxelwise results represents the T value with a statistical threshold of p < 0.05, cluster-level FWE correction.