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

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-Richardson's syndrome) and corticobasal syndrome (CBS). Thirtyseven participants (12 CBS, 10 PSP, and 15 age-/sex-/education-matched controls) underwent clinical and neuropsychological assessment, 3T magnetic resonance imaging, and positron emission tomography with the radioligand [ 11 C]UCB-J which targets the Synaptic Vesicle Glycoprotein 2A (SV2A). 10 CBS patients had negative β -amyloid biomarkers (Pittsburgh Compound B PET). As expected, 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 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 [ 11 C]UCB-J binding in frontal, temporal, parietal, occipital, and cingulate cortices, as well as in the hippocampus, insula and amygdala, p<0.05); putamen and frontal lobe [ 11 C]UCB-J binding correlated inversely with the PSP rating scale ( 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. Keywords: Synaptic Vesicle Protein 2A, UCB-J, PET, tauopathy, PSP. Abbreviations: [ 11 C]UCBJ = (R)-1-((3-(methyl-11C)pyridin-4-yl)methyl)-4-(3,4,5trifluorophenyl)pyr-rolidin-2-one); BP ND = non-displaceable binding potential; PSP = Progressive Supranuclear Palsy, CBS = corticobasal syndrome, CBD = Corticobasal Degeneration; [ 11 C]PiB = (methyl-11C) Pittsburgh compound B; UPDRS = Unified Parkinson's Disease Rating Scale; PSPRS = Progressive Supranuclear Gaze Palsy Rating Scale; ACE-R = Addenbrooke's Cognitive Examination -Revised; MMSE = Mini-mental State Examination; CDR = Clinical Dementia Rating Scale; CBI = Cambridge Behavioural Inventory -Revised; SEADL = Schwab and England Activities of Daily Living Scale. ns = non-significant at p<0.05.

Fluid Biomarkers for Synaptic Dysfunction and Loss

“…The reduction in hippocampal binding is in line with the early loss of entorhinal cortical cell projections to the hippocampus, and reductions of hippocampal SV2A seen in postmortem studies in AD brain tissue. 255,256 More recently, changes in [ 11 C]UCB-J PET have been observed in PD, 257 PSP, 258 cortical basal syndrome, and epilepsy 247 suggesting that SV2A could be a global marker for synaptic density, unlike CSF synaptotagmin-1, SNAP-25, GAP-43, and neurogranin, which are rather specific to AD or amyloidopathies. Recently, SV2A has been detected in CSF and shown to be reduced in AD 259 ; however it is yet to be determined whether CSF SV2A can be used as a marker for synaptic density in other dementias and whether it has a meaningful correlation with [ 11 C]UCB-J ( Figure 1).…”

Synaptic density in carriers of C9orf72 mutations: a [11C]UCB‐J PET study

“…This ligand offers a direct measure of synaptic density, 5 reflects disease-specific regional synaptic loss, and is related to other biomarkers and clinical severity. [12][13][14][15][16]…”

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

“…Twenty three people with probable PSP-Richardson Syndrome 19 , and twelve people with probable CBS in whom Alzheimer's disease was excluded with [ 11 C]PiB PET 7 , were recruited from a regional specialist National Health Service clinic at the Cambridge University Centre for Parkinson-plus. We refer to our amyloid-negative CBS cohort as having CBD but acknowledge other pathologies are possible 20…”

“…Here, we use the term CBD to refer to patients with CBS in whom Alzheimer's disease is excluded by [ 11 C]PiB PET, whereby in the absence of amyloid pathology there is a high clinicopathological correlation with 4R-tauopathy at post mortem. Both PSP and CBD demonstrate synaptic loss in vivo 7,8 and at post-mortem 1,2 . The distribution of tau pathology in both diseases is well characterised with cortical and subcortical involvement 21,22 .…”

“…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 . Synaptic loss and dysfunction may be an important mediator of decline even where atrophy is minimal or absent 7,8 . Conversely, synaptic connectivity may facilitate the spread of oligomeric mis-folded proteins such as tau 9,10 .…”