[${}^{18}$F]-D3FSP β-amyloid PET imaging in older adults and alzheimer's disease

[${}^{18}$F]-D3FSP is a new β-amyloid (Aβ) PET imaging tracer designed to decrease nonspecific signals in the brain by reducing the formation of the N-demethylated product. However, its optimal reference region for calculating the standardized uptake value ratio (SUVR) and its relation to the well-established biomarkers of Alzheimer's disease (AD) are still unclear. We recruited 203 participants from the Greater Bay Area Healthy Aging Brain Study (GHABS) to undergo [${}^{18}$F]-D3FSP Aβ PET imaging. We analyzed plasma Aβ${}_{42}$/Aβ${}_{40}$, p-Tau${}_{181}$, glial fibrillary acidic protein (GFAP), and neurofilament light (NfL) using the Simoa platform. We compared the standardized uptake value (SUV) of five reference regions (cerebellum, cerebellum cortex, brainstem/PONs, white matter, composite of the four regions above) and AD typical cortical region (COMPOSITE) SUVR among different clinical groups. The association of D3FSP SUVR with plasma biomarkers, imaging biomarkers, and cognition was also investigated. Brainstem/PONs SUV showed the lowest fluctuation across diagnostic groups, and COMPOSITE D3FSP SUVR had an enormous effect distinguishing cognitively impaired (CI) individuals from cognitively unimpaired (CU) individuals. COMPOSITE SUVR (Referred to brainstem/PONs) was positively correlated with p-Tau${}_{181}$ (p < 0.001), GFAP (p < 0.001), NfL (p = 0.014) in plasma and temporal-metaROI tau deposition (p < 0.001), and negatively related to plasma Aβ${}_{42}$/Aβ${}_{40}$ (p < 0.001), temporal-metaROI cortical thickness (p < 0.01), residual hippocampal volume (p < 0.001) and cognition (p < 0.001). The voxel-wise analysis replicated these findings. This study suggests brainstem/PONs as an optimal reference region for calculating D3FSP SUVR to quantify cortical Aβ plaques in the brain. [${}^{18}$F]-D3FSP could distinguish CI from CU and strongly correlates with well-established plasma biomarkers, tau PET, neurodegeneration, and cognitive decline. However, future head-to-head comparisons of [${}^{18}$F]-D3FSP PET images with other validated Aβ PET tracers or postmortem results are crucial.