Molecular pathology and synaptic loss in primary tauopathies: an F-18-AV-1451 and C-11-UCB-J PET study

The relationship between in vivo synaptic density and molecular pathology in primary tauopathies is key to understanding the impact of tauopathy on functional decline and in informing new early therapeutic strategies. In this cross-sectional observational study, we determine the in vivo relationship between synaptic density and molecular pathology in the primary tauopathies of progressive supranuclear palsy and corticobasal degeneration as a function of disease severity. Twenty-three patients with progressive supranuclear palsy and 12 patients with corticobasal syndrome were recruited from a tertiary referral centre. Nineteen education-, sex- and gender-matched control participants were recruited from the National Institute for Health Research 'Join Dementia Research' platform. Cerebral synaptic density and molecular pathology, in all participants, were estimated using PET imaging with the radioligands C-11-UCB-J and F-18-AV-1451, respectively. Patients with corticobasal syndrome also underwent amyloid PET imaging with C-11-PiB to exclude those with likely Alzheimer's pathology-we refer to the amyloid-negative cohort as having corticobasal degeneration, although we acknowledge other underlying pathologies exist. Disease severity was assessed with the progressive supranuclear palsy rating scale; regional non-displaceable binding potentials of C-11-UCB-J and F-18-AV-1451 were estimated in regions of interest from the Hammersmith Atlas, excluding those with known off-target binding for F-18-AV-1451. As an exploratory analysis, we also investigated the relationship between molecular pathology in cortical brain regions and synaptic density in subcortical areas. Across brain regions, there was a positive correlation between C-11-UCB-J and F-18-AV-1451 non-displaceable binding potentials (beta = 0.4, t = 3.6, P = 0.001), independent of age or time between PET scans. However, this correlation became less positive as a function of disease severity in patients (beta = -0.02, t = -2.9, P = 0.007, R = -0.41). Between regions, cortical F-18-AV-1451 binding was negatively correlated with synaptic density in subcortical areas (caudate nucleus, putamen). Brain regions with higher synaptic density are associated with a higher F-18-AV-1451 binding in progressive supranuclear palsy/corticobasal degeneration, but this association diminishes with disease severity. Moreover, higher cortical F-18-AV-1451 binding correlates with lower subcortical synaptic density. Longitudinal imaging is required to confirm the mediation of synaptic loss by molecular pathology. However, the effect of disease severity suggests a biphasic relationship between synaptic density and molecular pathology with synapse-rich regions vulnerable to accrual of pathological aggregates, followed by a loss of synapses in response to the molecular pathology. Given the importance of synaptic function for cognition and action, our study elucidates the pathophysiology of primary tauopathies and may inform the design of future clinical trials.

Automated summary

The relationship between in vivo synaptic density and molecular pathology in primary tauopathies, especially in progressive supranuclear palsy and corticobasal degeneration, is investigated in this study. It is found that there is a biphasic correlation between synaptic density and molecular pathology, with regions rich in synapses more vulnerable to pathological aggregates accumulation, followed by synaptic loss as a response to the molecular pathology. These findings contribute to a better understanding of the pathophysiology of primary tauopathies and may inform the design of future clinical trials.