Peripheral Tissue Biomarker for Premortem Diagnosis of Lewy Body Dementia

摘要 我们项目的总体目标是验证路易体痴呆(DLB)的诊断工具，以及 帕金森病痴呆(PDD)是两种常见的神经退行性疾病，影响着全球140万人 目前，在美国，确诊的DLB和PDD通常需要死后检测疾病- 相关的α-突触核蛋白(α-Synd)聚集在大脑中。临床上，DLB和PDD可以很容易地 被误诊为其他痴呆症和帕金森症，如阿尔茨海默病(AD)和神经官能症。一个 尚未满足的医学需求是识别生物标志物，以便更容易地对DLB和PDD进行早期诊断和鉴别诊断 无障碍纸巾。我们已经利用了被称为实时震动的新兴技术 诱导转化(RT-QIC)法建立α综合征超灵敏检测平台 周围组织。在初步研究中，我们能够在小鼠皮肤中检测到αSynd的普恩样种子活性。 DLB和PD患者的特异性和敏感性均为100%。此外，我们在以下方面取得了显著成功 检测皮肤、乙状结肠和颌下腺等多个外周组织中αSynd种子的活性 身体解剖标本中的腺体。我们推测外周α综合征的RT-QuIC是一种高度敏感和 用于DLB和PDD生前诊断的可靠诊断生物标记物。为了检验这一假设，我们建议 目的：(1)建立外周α综合征作为尸检诊断的生物标志物 (2)评价皮肤α综合征作为生前诊断DLB和PDD的生物标志物。 (3)确定外周αSynd和tau作为区分DLB和Pd的生物标志物。 痴呆症和帕金森症，如阿尔茨海默病和变态反应症；(4)探索肠道α综合征作为死亡前的生物标志物 结肠活检诊断DLB和PDD。这项建议的成功实施将建立RT- 使用现成的外周血标本，应用定量分析方法早期诊断DLB和PDD。

Abstract The overall goal of our project is to validate a diagnostic tool for dementia with Lewy bodies (DLB), and Parkinson’s disease dementia (PDD), two common neurodegenerative diseases affecting 1.4 million people in the U.S. Currently, definitive diagnosis of DLB and PDD often requires the postmortem detection of disease- associated alpha-synuclein (αSynD) aggregates in the brain. Clinically, DLB and PDD can be easily misdiagnosed with other dementias and parkinsonisms such as Alzheimer’s disease (AD) and tauopathies. An unmet medical need is to identify biomarkers for early and differential diagnosis of DLB and PDD in more easily accessible tissues. We have taken advantage of the emerging technology known as the real-time quaking induced conversion (RT-QuIC) assay to develop a robust platform for ultrasensitive detection of αSynD in peripheral tissues. In preliminary studies, we are able to detect prion-like seeding activity of αSynD in the skin of DLB and PD patients with 100% specificity and sensitivity. In addition, we were remarkably successful in detecting αSynD seeding activity in multiple peripheral tissues including skin, sigmoid colon, and submandibular glands in autopsied specimens. We hypothesize that RT-QuIC of peripheral αSynD is a highly sensitive and robust diagnostic biomarker for premortem diagnoses of DLB and PDD. To test this hypothesis, we propose to pursue the following four Aims: (1) Establish peripheral αSynD as a biomarker for postmortem diagnosis of DLB and PDD using RT-QuIC assay; (2) Assess skin αSynD as a biomarker for premortem diagnosis of DLB and PDD; (3) Determine peripheral αSynD and tau as a biomarker for differentiating DLB and PDD from other dementias and parkinsonisms such as AD and tauopathies; (4) Explore gut αSynD as a biomarker for premortem diagnosis of DLB and PDD using colon biopsy. Successful implementation of this proposal will establish RT- QuIC assay utilization for early diagnosis of DLB and PDD using readily available peripheral specimens.