Peripheral Biomarkers for Early Diagnosis of Mixed Pathologies in AD/ADRD

我们所提出的研究的总体目标是开发可靠的死前生物标志物， 阿尔茨海默病（AD）、非AD tau蛋白病、路易体痴呆（LBD）及其 合并症。AD和其他tau蛋白病的病理学标志是tau蛋白聚集体的沉积 在脑中，而在LBD中，存在α-突触核蛋白（aSyn）聚集体的积累。引人注目的是，超过一半的 的临床诊断为AD或LBD的患者在尸检时具有伴随的tau和aSyn共病理。 此外，具有混合tau和aSyn病理的患者通常遭受更差的临床结果。目前它 由于症状重叠，在临床上区分AD、LBD和AD/LBD混合型具有高度挑战性。 此外，aSyn病理学的共存也经常发生在非AD tau蛋白病中。的最新进展 β淀粉样蛋白和磷酸化tau蛋白（p-tau）的脑成像和免疫测定极大地促进了诊断 典型的AD然而，这些测定不能鉴定非AD tau蛋白病和混合AD/LBD。因此，我们认为， 在容易获得的生物标本中，有必要采取替代措施，特别是如果它们能够同时 在患有混合性tau蛋白病和突触核蛋白病的患者中检测tau和aSyn聚集体。初步 研究中，我们利用了新出现的技术，称为实时地震感应转换 用于特异性检测AD和非AD患者皮肤中tau聚集体的测定（tau RT-QuIC） tau蛋白病结合最近成立的aSyn RT-QuIC，我们处于独特的位置，可以准确地 使用易于获取的皮肤标本诊断具有混合tau和aSyn病理的患者。我们假设 通过RT-QuIC检测的皮肤tau和aSyn是用于早期和鉴别诊断的新生物标志物， 在常规临床实践中，混合性tau蛋白病/共核蛋白病。我们建议通过以下方式来检验这一假设： 追求三个目标：1）建立用于混合性tau蛋白病/突触核蛋白病的双重皮肤RT-QuIC生物标志物测定 使用神经病理学证实的病例; 2）将通过RT-QuIC检测的皮肤tau和aSyn评估为可靠的 用于混合性tau蛋白病和突触核蛋白病的死前诊断的生物标志物;和3）评估皮肤tau/aSyn 用于通过以下方法改进混合性tau蛋白病/共核蛋白病的鉴别诊断的生物标志物测定 纵向跟踪。该转化项目拥有丰富的临床资源和强大的基础团队， 和临床神经科学家我们的建议的成功结果将建立一个强大的基于皮肤的诊断 检测AD和相关痴呆中常见的混合病理，从而促进更好的患者护理， 疾病修饰疗法的发展。

The overall goal of our proposed research is to develop robust premortem biomarkers for accurate and differential diagnosis of Alzheimer's disease (AD), non-AD tauopathies, Lewy body dementia (LBD), and their comorbidities. A pathological hallmark of AD and other tauopathies is the deposition of tau protein aggregates in the brain, whereas in LBD there is accumulation of α-synuclein (aSyn) aggregates. Strikingly, more than half of patients with clinically diagnosed AD or LBD have concomitant tau and aSyn co-pathologies at autopsy. Moreover, patients with mixed tau and aSyn pathologies often suffer from worse clinical outcomes. Currently, it is highly challenging to clinically differentiate AD, LBD, and mixed AD/LBD due to overlapping symptoms. Moreover, co-existence of aSyn pathology also occurs frequently in non-AD tauopathies. Recent advances in brain imaging and immunoassays of amyloid-β and phosphorylated tau (p-tau) have greatly facilitated diagnosis of typical AD. However, these assays fail to identify non-AD tauopathies and mixed AD/LBD. Therefore, alternative measures in easily accessible biospecimens are warranted, especially if they enable simultaneous detection of tau and aSyn aggregates in patients with mixed tauopathies and synucleinopathies. In preliminary studies, we have leveraged the newly emerged technology known as the real-time quaking-induced conversion assay (tau RT-QuIC) for specific detection of tau aggregates in the skin of patients with AD and non-AD tauopathies. In conjunction with recently established aSyn RT-QuIC, we are in a unique position to accurately diagnose patients with mixed tau and aSyn pathologies using easily accessible skin specimens. We hypothesize that skin tau and aSyn detected by RT-QuIC are novel biomarkers for early and differential diagnosis of mixed tauopathies/synucleinopathies in routine clinical practice. We propose to test this hypothesis by pursuing three Aims: 1) Establish dual skin RT-QuIC biomarker assays for mixed tauopathies/synucleinopathies using neuropathologically confirmed cases; 2) Assess skin tau and aSyn detected by RT-QuIC as reliable biomarkers for premortem diagnosis of mixed tauopathies and synucleinopathies; and 3) Evaluate skin tau/aSyn biomarker assays for improving the differential diagnosis of mixed tauopathies/synucleinopathies through longitudinal follow-up. This translational project is supported by rich clinical resources and a strong team of basic and clinical neuroscientists. The successful outcome of our proposal will establish a robust skin-based diagnostic test for mixed pathologies that is prevalent in AD and related dementias, thus facilitating better patient care and development of disease-modifying therapies.