Preliminary results investigating synaptic density across the Alzheimer’s Disease continuum

Abstract

AbstractBackgroundProgressive loss of synapses occurs throughout the Alzheimer’s Disease (AD) continuum and is closely associated with cognitive impairment. Here, we present pilot data investigating variation in synaptic density across aging and AD using 18F‐SynVesT‐1 molecular imaging, a ligand for the SV2A site.Method26 participants underwent 18F‐SynVesT‐1 imaging to estimate synaptic density in‐vivo. Participants were young adults (Y) (n = 7; Age = 26.1+‐3.8; Sex(F) = 4), cognitively unimpaired older adults (O) (n = 13; Age = 79.7+‐4.27; Sex(F) = 7) or patients (P) (n = 6; Age = 66.3 +‐8.2; Sex (F) = 1; Diagnoses EOAD = 3, MCI = 1, PCA(AD) = 1; lvPPA(AD)). We collected a 90 min dynamic sequence after injection of 5 mCi of tracer. Participant whole brain Distribution Volume Ratio (DVR) images were generated using a cerebellar grey matter reference region. O and P groups also underwent tau and β‐amyloid (Aβ) PET imaging (O: 18F‐flortaucipir,11C‐PiB; P: 18F‐PI‐2620, 18F‐Florbetaben) and a visual assessment of tau and Aβ positivity for AD was determined by an expert reviewer (DSM).ResultWe contrasted 18F‐SynVesT‐1 uptake in four cortical regions for Y, O and P. In each region, we observed a significant effect of group (Hippocampus F(1,23) = 4.35, p = 0.025 (uncorrected); Meta‐Temporal ROI F(1,23) = 4.36, p = 0.025 (uncorrected); Temporal F(1,23) = 9, p<0.01(FWE corrected); F(1,23) = 14.4, p<0.001 (FWE corrected)) Figure 1. Further, we observe non‐significant numerical differences suggesting lower synaptic density in participants with biomarker evidence of Aβ and tau Figure 1. Finally, we observe a positive partial correlation between temporal cortical thickness and temporal 18F‐SynVesT‐1 uptake controlling for age (r(23) = 0.54,p = 0.006) Figure 2. We observe no relationship between age and tracer uptake in the cerebral white matter (r(24) = ‐0.01,p = 0.95), suggesting the reference region selected does not introduce systematic biases in the DVR image.ConclusionThis demonstrates 18F‐SynVesT‐1 PET can capture age and AD related decreases in synaptic density across the cortex. Further, we show an association between cortical thickness and synaptic density in the temporal cortex controlling for biases due to age. Future work will incorporate additional participants and investigate participant level associations between regional 18F‐SynVesT‐1 uptake, cognition, and in‐vivo AD pathologies.