226 Reduced synaptic density in progressive supranuclear palsy and corticobasal syndrome, revealed by [11C]UCB-J PET

Abstract

Synaptic loss is prominent in several human neurodegenerative diseases. We tested the hypothesis that synaptic density is reduced by the primary tauopathies of progressive supranuclear palsy (PSP) and cor- ticobasal syndrome (CBS). Thirty-three participants (10 CBS, 10 PSP, and thirteen age-/sex-/education- matched controls) underwent clinical and neuropsychological assessment, 3T-magnetic resonance imaging, and positron emission tomography with the radioligand [11C]UCB-J which targets the Synaptic Vesicle Glycoprotein 2A (SV2A). Eight CBS patients had negative β-amyloid biomarker. As expected, PSP and CBS groups were impaired in executive, memory and visuospatial tasks. [11C]UCB-J binding was reduced across frontal, temporal, parietal, and occipital lobes, cingulate, hippocampus, insula, amygdala and subcortical structures in both PSP and CBS patients compared to controls (p<0.001), with reductions up to 50%, consistent with post mortem data. The revised Addenbrooke’s Cognitive Examination score correlated positively with cortical [11C]UCB-J binding (frontal, temporal, parietal, and occipital lobes, hippocampus, insula and amygdala, all p<0.05); putamen and precentral [11C]UCB-J binding correlated inversely with the PSP rating scale (both p<0.05). In conclusion, we confirm severe synaptic loss in PSP and CBS, which correlates with disease severity, providing critical insights into the underlying pathophysiology of primary degenerative tauopathies and supporting potential treatment strategies based on synaptic maintenance or restoration.nda26@cam.ac.uk