Head-to-Head Comparison of 18 F-SynVest-1 PET and 18 F-FDG PET in the Differentiation of Patients with Cognitive Decline

Although 18F-FDG PET is commonly used in the differential diagnosis of cognitive decline, synaptic vesicle glycoprotein 2A PET may offer a more direct assessment of synaptic integrity and address limitations associated with 18F-FDG, such as sensitivity to sensory stimuli and glycemic variations. In this study, a head-to-head comparison of 18F-SynVesT-1 and 18F-FDG was performed for differentiating causes of cognitive decline in a tertiary clinical setting. Methods: Patients with cognitive decline referred for 18F-FDG PET were recruited to undergo 18F-SynVesT-1 PET/MRI (49 ± 26 d after 18F-FDG PET). Diagnosis was determined by routine clinical follow-up (median, 11 mo) and classified as Alzheimer disease (AD), frontotemporal degeneration (FTD), dementia with Lewy bodies (DLB), other neurodegenerative disorders (ONDs), or nonneurodegenerative disorders (NoNDs). Volume-wise and voxelwise semiquantitative analyses were performed using tracer-specific healthy volunteers. Diagnostic accuracy for both tracers was evaluated through logistic regression and by consensus from 3 readers. Noninferiority was defined by an area-under-the-curve margin (ΔAUC) of −0.10 within a 95% CI, using the clinical follow-up diagnosis as the gold standard. Results: Ninety-four patients were included: 44 with AD, 12 with FTD, 4 with DLB, 5 with ONDs, and 29 with NoNDs. Volume-wise and voxelwise analyses showed that, in patients with AD and DLB, reductions in the temporoparietal and precuneus/posterior cingulate were less pronounced with 18F-SynVesT-1 PET than with 18F-FDG PET (e.g., posterior cingulate in AD, −10% vs. −20%). In FTD, the most impacted areas showed greater variability, typically affecting the anterior temporal and frontal cortices, depending on the FTD subtype. Visual assessment showed lower sensitivity for AD with 18F-SynVesT-1 PET than with 18F-FDG PET (0.57 vs. 0.73) with equal specificity (0.76), whereas quantitative analysis yielded a lower area under the curve (0.71 vs. 0.81; ΔAUC, −0.10; 95% CI, −0.21 to 0.01). For FTD, 18F-SynVesT-1 visual classification yielded similar sensitivity and specificity (0.58 and 0.90) compared with 18F-FDG (0.50 and 0.93) but a lower quantitative area under the curve (0.64 vs. 0.76; ΔAUC, −0.12; 95% CI, −0.27 to 0.04). Conclusion:18F-SynVesT-1 PET enabled accurate classification of disease-specific patterns of cognitive decline. Although classification performance for FTD was similar to that of 18F-FDG PET, the lower effect size in neocortical binding resulted in lower sensitivity for AD. Larger study samples are needed to formally evaluate tracer noninferiority in this clinical context for all subgroups.