Synapse loss in Progressive Supranuclear Palsy post-mortem reflects clinical and pathological disease severity and 11C-UCB-J PET in vivo
Nolan, G.; Holland, N.; Yang, S. W.; Dall'O, G. M.; Chen, Q.; Allinson, K.; Savulich, G.; Halliday, K.; Naessens, M.; Hong, Y. T.; Fryer, T. D.; Aigbirhio, F. I.; Malpetti, M.; Kaalund, S. S.; O'Brien, J. T.; Lakatos, A.; Rowe, J. B.; Quaegebeur, A.
Show abstract
Synapse loss is an early feature of neurodegeneration and may provide sensitive biomarkers for experimental medicine. Positron emission tomography (PET) with the synaptic vesicle glycoprotein 2A radioligand [11C]UCB-J shows widespread signal reduction across dementias. However, it remains unclear which aspects of synaptic integrity [11C]UCB-J PET measures. We developed a histological-imaging pipeline to quantify structurally intact synapses in post-mortem brain tissue. We applied it to six donors with the tauopathy progressive supranuclear palsy (PSP) who had ante-mortem [11C]UCB-J-PET, alongside six controls across 11 brain regions. Synapse loss in PSP was widespread but region-specific across cortical, subcortical, and brainstem regions. Greater synapse loss was associated with higher tau burden and pathology, and cortical synaptic density correlated with ante-mortem cognition. Post-mortem synaptic density correlated with in vivo [11C]UCB-J-PET signal. This study provides validation of SV2A PET as a biomarker of synaptic density and supports integration of imaging with histopathology in neurodegenerative disease research.
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