Synapse loss in Progressive Supranuclear Palsy post-mortem reflects clinical and pathological disease severity and 11 C-UCB-J PET in vivo
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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.
