Synaptic loss in primary tauopathies revealed by [11C]UCB-J positron emission tomography

Abstract:

Background

Synaptic loss is a prominent and early feature of many neurodegenerative diseases.

Objectives

We tested the hypothesis that synaptic density is reduced in the primary tauopathies of progressive supranuclear palsy (PSP-Richardson’s syndrome) and amyloid-negative corticobasal syndrome (CBS).

Methods

Forty four participants (15 CBS, 14 PSP, and 15 age-/sex-/education-matched controls) underwent positron emission tomography (PET) with the radioligand [ 11 C]UCB-J, which binds to synaptic vesicle glycoprotein 2A (SV2A), a marker of synaptic density; participants also had 3T magnetic resonance imaging and clinical and neuropsychological assessment.

Results

Nine CBS patients had negative amyloid biomarkers determined by [ 11 C]PiB PET and hence were deemed likely to have corticobasal degeneration (CBD). Patients with PSP-Richardson’s syndrome and amyloid-negative CBS were impaired in executive, memory and visuospatial tasks. [ 11 C]UCB-J binding was reduced across frontal, temporal, parietal, and occipital lobes, cingulate, hippocampus, insula, amygdala and subcortical structures in both PSP and CBD patients compared to controls (p<0.01), with median reductions up to 50%, consistent with post mortem data. Reductions of 20-30% were widespread even in the areas of the brain with minimal atrophy. There was a negative correlation between global [ 11 C]UCB-J binding and the PSP and CBD rating scales (R= −0.61 p<0.002, R= −0.72 p<0.001, respectively) and a positive correlation with the revised Addenbrookes Cognitive Examination (R=0.52, p=0.01).

Conclusions

We confirm severe synaptic loss in PSP and CBD in proportion to disease severity, providing critical insight into the pathophysiology of primary degenerative tauopathies. [ 11 C]UCB-J may facilitate treatment strategies for disease-modification, synaptic maintenance or restoration.