The relationship between in vivo synaptic density and tau burden 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 (PSP) and Corticobasal Degeneration (CBD), as a function of disease severity. Twenty three patients with PSP, and twelve patients with Corticobasal Syndrome (CBS) 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 CBS 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 CBD although acknowledge other pathologies exist. Disease severity was assessed with the PSP rating scale; regional non-displaceable binding potentials (BP_ND) 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 connected subcortical areas. Across brain regions, there was a positive correlation between [¹¹C]UCB–J and [¹⁸F]AV–1451 BP_ND (β=0.4, t=4.7, p<0.0001). However, the direction of this correlation became less positive as a function of disease severity in patients (β = -0.03, T = -4.0, p = 0.002). Between brain regions, cortical [¹⁸F]AV-1451 binding was negatively correlated with synaptic density in subcortical areas (caudate nucleus, putamen, and substantia nigra). Brain regions with higher synaptic density are associated with a higher [¹⁸F]AV–1451 binding in PSP/CBD, 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 tauopathy, with synapse rich regions vulnerable to accrual of pathology, followed by a loss of synapses in response to pathology. Given the importance of synaptic function for cognition, our study elucidates the pathophysiology of primary tauopathies and may inform the design of future clinical trials.

中文翻译：

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原发性颅骨病变的分子病理学和突触丧失：[18F] AV-1451和[11C] UCB-J PET研究

体内突触密度与原发性颅脑疾病中的tau负担之间的关系是了解tauopathy对功能衰退的影响以及提供新的早期治疗策略的关键。在这项横断面观察研究中，我们确定了进行性核上性麻痹（PSP）和皮质基底变性（CBD）的原发性病变中突触密度与分子病理学之间的体内关系，取决于疾病严重程度。从三级转诊中心招募了23例PSP患者和12例糖皮质激素综合症（CBS）患者。从美国国立卫生研究院加入痴呆症研究平台招募了19名受过教育，性别和性别匹配的对照者。所有参与者的脑突触密度和分子病理学，¹¹ C] UCB–J和[ ¹⁸ F] AV–1451。患有CBS的患者还接受了[11C] PiB进行淀粉样蛋白PET成像，以排除那些可能患有阿尔茨海默氏病的患者-我们将淀粉样蛋白阴性人群称为CBD，尽管也承认存在其他病理。疾病严重程度以PSP评分量表评估；区域非替位的结合的电位（BP _ND）的¹¹ C] UCB-J和[ ¹⁸在Hammersmith Atlas感兴趣的区域中估计了F] AV-1451，但不包括与[18F] AV-1451脱靶结合的区域。作为探索性分析，我们还研究了皮质大脑区域的分子病理学与相连的皮质下区域的突触密度之间的关系。在整个大脑区域，[ ¹¹ C] UCB–J和[ ¹⁸ F] AV–1451 BP _ND之间呈正相关（β= 0.4，t = 4.7，p <0.0001）。然而，随着患者疾病严重程度的增加，这种相关性的方向变得越来越不积极（β= -0.03，T = -4.0，p = 0.002）。在大脑区域之间，皮层[ ¹⁸F] AV-1451结合与皮层下区域（尾状核，壳状核和黑质）的突触密度负相关。具有较高突触密度的大脑区域与PSP / CBD中较高的[ ¹⁸ F] AV–1451结合相关，但这种关联随着疾病的严重程度而减弱。此外，高级皮质[ ¹⁸F] AV-1451结合与较低的皮层突触密度相关。纵向成像是必需的，以通过分子病理学确认突触损失的介导。但是，疾病严重程度的影响表明突触密度与tauopathy之间存在两相关系，富含突触的区域容易发生病理，继而对病理作出反应而失去突触。鉴于突触功能对认知的重要性，我们的研究阐明了原发性tauopathies的病理生理学，并可能为将来的临床试验设计提供依据。