Synaptic Loss in Primary Tauopathies Revealed by [¹¹C]UCB‐J Positron Emission Tomography

Abstract

A BS TRACT: 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 PET with the radioligand [ 11 C]UCB-J, which binds to synaptic vesicle glycoprotein 2A, a marker of synaptic density; participants also had 3 Tesla MRI 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 amyloidnegative 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 postmortem data. Reductions of 20% to 30% were widespread even in 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 Addenbrooke's 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.

In vivo coupling of dendritic complexity with presynaptic density in primary tauopathies

“…Post-hoc paired T-Tests of the regional Fisher's transformed Cohen's D indicated that the regional effect sizes were significantly larger for ODI compared to grey matter atrophy ( Figure 3C). As expected, the PSP-RS group showed extensive and severe reductions of [ 11 C]UCB-J BP ND across the cortex and subcortical regions compared to controls, replicating our previous findings in a smaller sample (Holland et al, 2020). Across the whole brain, reductions in [ 11 C]UCB-J BP ND yielded the largest effect size relative to both ODI and grey matter atrophy.…”

“…Both conditions are associated with cortical and subcortical atrophy (Jabbari et al, 2019) but we have previously shown significant widespread presynaptic loss extending beyond atrophic areas (Holland et al, 2020) concordant with findings from studies utilising electromagnetoencephalography where impairment in cortical physiology is seen in both atrophic and minimally atrophic regions (Cope et al, 2018;Hughes et al, 2014;Sami et al, 2018). Having illustrated presynaptic loss as a potential explanation for impairment in cortical physiology, we aimed to investigate the synaptic bouton at large by also focusing on .…”

“…In contrast, the recently, developed radioligand [ 11 C]UCB-J ((R)-1-((3-(methyl-11C)pyridin-4-yl)methyl)-4-(3,4,5trifluorophenyl)pyr-rolidin-2-one), allows direct quantification of synaptic density based on its affinity for the ubiquitously expressed presynaptic vesicle glycoprotein SV2A (Finnema et al, 2017(Finnema et al, , 2016. This ligand shows up-to 40% loss of hippocampal synapses in patients with Alzheimer's disease (Chen et al, 2018), and a 20-50% global reduction in PSP-RS/CBD (Holland et al, 2020) correlating with cognitive dysfunction. However, PET has limited scalability in diagnostics and trials, because of cost, specialist facilities required, and radiation limitations on repeated assessment.…”

A synergistic core for human brain evolution and cognition

“…In-vivo estimates of regional synaptic density in the human brain were obtained from positron emission tomography (PET) with the radioligand [ 11 C]UCB-J ((R)-1-((3-(methyl-11 C)pyridin-4-yl)methyl)-4-(3,4,5-trifluorophenyl)pyr-rolidin-2-one) 49 . This ligand quantifies synaptic density 23 based on its affinity for the presynaptic vesicle glycoprotein 2A (SV2A) which is ubiquitously expressed in all brain synapses 25 .…”

“…The research protocol was approved by an NHS Research Ethics Committee (REC:18/EE/0059) and the Administration of Radioactive Substances Advisory Committee (ARSAC), and all participants provided written informed consent in accordance with the Declaration of Helsinki. Participant recruitment and exclusion criteria are described in detail in the original publication49 . Here, we included data from the healthy volunteers (N=15, 8 females; age: 68 ± 7 years).The radioligand [ 11 C]UCB-J was synthesised at the Radiopharmacy Unit, Wolfson BrainImaging Centre, Cambridge University, using the methodology previously described24 .…”