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.

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.

The Julia–Kocienski olefination is a direct connective synthesis of alkenes via the addition of metalated aryl alkyl sulfones to carbonyl compounds. The activating aromatic group associated with the sulfone must possess electrophilic character, and alkene formation occurs via β‐alkoxy sulfone formation, transfer of the aryl group from sulfur to oxygen via a Smiles rearrangement, and then elimination of sulfur dioxide and an aryloxide anion from the resulting β‐aryloxy sulfinate anion. The olefination process itself and the methods used to prepare the requisite sulfone substrates are tolerant of a wide variety of functional groups, and a variety of alkene targets can be prepared. Stereoselectivity is dependent on the nature of the sulfone, the carbonyl compound, the activating aryl moiety, and the reaction conditions. This chapter describes theoretical and operational aspects of the Julia–Kocienski olefination such that the reader will be able to obtain optimal results in his/her own research. A detailed mechanistic overview is included to account for the factors that influence stereoselectivity and yield. Methods for introducing sulfone activators into fragments of interest, best practices for generating sulfone anions, and optimal strategies for targeting different classes of alkene targets are discussed. Functional group compatibilities, reaction variants, and a comparison to other methods of alkene synthesis are also presented. Tabular surveys are organized according to type of alkene synthesized, with an emphasis on the degree of substitution and the level of conjugation about the newly formed double bond. The literature is covered from the initial disclosure of the Julia–Kocienski olefination in 1991 to the first quarter of 2016.

Objective Dementia with Lewy bodies (DLB) is a common cause of dementia, but atrophy is mild compared to Alzheimer’s disease. We propose that DLB is associated instead with severe synaptic loss, and we test this hypothesis in vivo using positron emission tomography (PET) imaging of 11C-UCB-J, a ligand for presynaptic vesicle protein 2A (SV2A), a vesicle membrane protein ubiquitously expressed in synapses. Methods We performed 11C-UCB-J PET in two DLB patients (an amyloid-negative male and an amyloid-positive female in their 70s) and 10 similarly aged healthy controls. The DLB subjects also underwent PET imaging of amyloid (11C-PiB) and tau (18F-AV-1451). 11C-UCB-J binding was quantified using non-displaceable binding potential (BPND) determined from dynamic imaging. Changes in 11C-UCB-J binding were correlated with MRI regional brain volume, 11C-PiB uptake and 18F-AV-1451 binding. Results Compared to controls, both patients had decreased 11C-UCB-J binding, especially in parietal and occipital regions (FDR-corrected p < 0.05). There were no significant correlations across regions between 11C-UCB-J binding and grey matter, tau (18F-AV1451) or amyloid (11C-PiB) in either patient. Conclusions Quantitative imaging of in vivo synaptic density in DLB is a promising approach to understanding the mechanisms of DLB, over and above changes in grey matter volume and concurrent amyloid/tau deposition.