HAI Book 2025 - Flipbook - Page 385
Kulagowska, Laura
91
Evaluation of [³H]SynVesT - 1 binding in post-mortem brain tissue
from control and Alzheimer9s Disease as a biomarker of synaptic loss
Laura Kulagowska1, Laetitia Lemoine1, Declan King2, Scott Gladstein3, Amanda Bevis4, David
Bonsall1, Sjoerd Finnema3, Tara Spires-Jones2, Lisa Wells1, FNIH SV2A project team4
1
Perceptive, London, GB
University of Edinburgh, Edinburgh, GB
3
AbbVie, Chicago, IL, US
4
Foundation for the National Institutes of Health, Rockville, MD, US
2
Backgrounds and Methods: This study aims to use homogenate binding techniques to evaluate [³H]SynVesT-1
binding to synaptic vesicle glycoprotein 2A (SV2A), found in the pre-synaptic terminals, to understand its potential
as a synaptic density biomarker. Binding parameters (binding affinity (KD), and maximal binding sites (BMAX)) from
412 postmortem samples (70 subjects, 3 regions) were analysed. Subjects were divided into 3 groups: control (BS
0-II), early Alzheimer9s Disease (E-AD) (BS III-IV) and Alzheimer's Disease (AD) (BS V-VI). Three regions were
analysed: entorhinal cortex (EC), cerebellum and centrum semiovale; for each total homogenate (TH) and
synaptoneurosome.
Results: Initial results show a saturable specific binding signal of [³H]SynVesT-1 in EC and cerebellum
homogenates from all three subject groups. The centrum semiovale does not fit a suitable binding curve, with less
specific binding observed, and greater variability across cases. The binding affinity of [³H]SynVesT-1 was
comparable across groups and homogenate preparations (TH and synaptoneurosome).
The KD ranged from 3-7 nM. In EC TH, BMAX ranged from 2320 ± 104 fmol/mg protein in AD, to 2788 ± 109 fmol/mg
protein in control. In EC synaptoneurosome homogenates, BMAX ranged from 3969 ± 200 fmol/mg protein in AD, to
5380 ± 319 fmol/mg protein in E-AD. In cerebellum TH, BMAX ranged from 2274 ± 91 fmol/mg protein in control, to
2997 ± 224 fmol/mg protein in E-AD. In cerebellum synaptoneurosome homogenates, BMAX ranged from 2725 ± 148
fmol/mg protein in AD, to 4469 ± 284 fmol/mg protein in E-AD.
Conclusions: Initial results show group-wise differences in the BMAX of [³H]SynVesT-1 in EC, with E-AD subjects
showing a greater binding signal. This trend could suggest a compensatory mechanism early in the progression of
the disease. This is part of the SV2A PET Project, a program of the FNIH Biomarker Consortium.
Keywords: Biomarker, Synaptic loss, Neurodegeneration, radioligand binding
HAI2025 - 385
