Abstract
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 11C-UCB-J and 18F-AV-1451, respectively. Patients with corticobasal syndrome also underwent amyloid PET imaging with 11C-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 11C-UCB-J and 18F-AV-1451 were estimated in regions of interest from the Hammersmith Atlas, excluding those with known off-target binding for 18F-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 11C-UCB-J and 18F-AV-1451 non-displaceable binding potentials (β = 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 (β = −0.02, t = −2.9, P = 0.007, R = −0.41). Between regions, cortical 18F-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 18F-AV-1451 binding in progressive supranuclear palsy/corticobasal degeneration, but this association diminishes with disease severity. Moreover, higher cortical 18F-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.
Highlights
Synaptic loss is a feature of many neurodegenerative disorders [1,2,3]
Eligible participants underwent clinical and cognitive assessments (Table 1) including the revised Addenbrooke’s Cognitive Examination (ACE-R), the mini-mental state examination (MMSE), and the Institute of Cognitive Neurology (INECO) frontal screening; disease severity was measured with the Progressive Supranuclear Palsy (PSP) rating scale, and the Cortical Basal ganglia Functional Scale (CBFS) 40
The patients (PSP and Corticobasal Degeneration (CBD)) and control groups were similar in age, sex, education and injected activity of [11C]UCB-J and [18F]AV-1451 (Table 1)
Summary
Synaptic loss is a feature of many neurodegenerative disorders [1,2,3]. It is closely related to cognitive decline in symptomatic stages of disease [4, 5], but can begin long before symptom onset and neuronal loss 6. The mechanisms of synapse loss following tau pathology include both direct and indirect pathways (reviewed in Spires-Jones and Hyman 18), the severity of synaptic toxicity in the related tauopathy of Alzheimer’s disease appears to be dependent on the stage of disease in preclinical models, and in patients post-mortem and in vivo. In animal models of Alzheimer’s disease, and at human post-mortem, there is differential expression of synaptic proteins in the early stages with increases in some proteins and reductions in others [19, 20]. This may be an attempt to maintain cellular physiology in early disease, which fails as the disease progresses, leading to loss of synaptic function and synapse numbers in moderate and advanced disease. The pathology of Alzheimer’s disease is multifaceted with amyloid and tau aggregation, vascular changes and neuroinflammation 23
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