Peripheral Tissue Biomarker for Premortem Diagnosis of Lewy Body Dementia

用于路易体痴呆死前诊断的外周组织生物标志物

• 批准号: 10705299
• 负责人: SHU G. CHEN
• 金额: $ 109.02万
• 依托单位: UNIVERSITY OF ALABAMA AT BIRMINGHAM
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-12-15 至 2025-06-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10705299
• 关键词: Affect; Age; Alzheimer' s Disease; Autopsy; Biological Assay; Biological Markers; Biopsy; Biopsy Specimen; Brain; Cadaver; Caring; Central Nervous System; Cerebrospinal Fluid; Clinical; Clinical Trials; Colon; Colonoscopy; Dementia; Dementia with Lewy Bodies; Deposition; Detection; Diagnosis; Diagnostic tests; Differential Diagnosis; Disease; Early Diagnosis; Emerging Technologies; Enteric Nervous System; Functional disorder; Goals; Hypersensitivity skin testing; Immunologics; Lewy Body Dementia; Measures; Medical; Methods; Neurodegenerative Disorders; Nose; Parkinson' s Dementia; Parkinsonian Disorders; Patient Care; Patient Recruitments; Patients; Peripheral; Persons; Progressive Supranuclear Palsy; Reporting; Salivary Glands; Sampling; Sensitivity and Specificity; Severity of illness; Sigmoid colon; Sigmoidoscopy; Skin; Specimen; Spinal Puncture; Submandibular gland; Symptoms; Tauopathies; Testing; Time; Tissues; alpha synuclein; atypical parkinsonism; biomarker identification; cohort; comorbidity; comparison group; corticobasal degeneration; diagnostic biomarker; diagnostic strategy; diagnostic tool; follow-up; improved; nervous system disorder; neuropathology; participant enrollment; patient stratification; prion-like; protein aggregation; synucleinopathy; tau Proteins; tau aggregation; therapeutic development; tissue biomarkers

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.

抽象的 我们项目的总体目标是验证路易体 (DLB) 痴呆症的诊断工具，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 140 万人 美国目前，DLB 和 PDD 的明确诊断通常需要死后疾病检测 - 相关的α-突触核蛋白（αSynD）在大脑中聚集，DLB 和 PDD 很容易发生。 被误诊为其他痴呆症和帕金森病，例如阿尔茨海默病 (AD) 和 tau蛋白病。 未满足的医疗需求是更轻松地识别用于 DLB 和 PDD 早期和鉴别诊断的生物标志物 我们利用了称为实时震动的新兴技术。 诱导转化 (RT-QuIC) 检测，开发一个强大的平台，用于超灵敏检测 αSynD 在初步研究中，我们能够检测到 αSynD 在皮肤中的类似朊病毒的播种活性。 DLB 和 PD 患者具有 100% 的特异性和敏感性 此外，我们在治疗中取得了异常成功。 检测多个外周组织（包括皮肤、乙状结肠和下颌下组织）中的 αSynD 播种活性 我们勇敢地说，外周 αSynD 的 RT-QuIC 是一种高度敏感且可靠的方法。 用于 DLB 和 PDD 死前诊断的强大诊断生物标志物 为了检验这一假设，我们提出。 追求以下四个目标：（1）建立外周αSynD作为死后诊断的生物标志物 使用 RT-QuIC 检测进行 DLB 和 PDD；（2）评估皮肤 αSynD 作为 DLB 死前诊断的生物标志物 PDD；（3）确定外周αSynD和tau作为区分DLB和PDD与其他疾病的生物标志物 痴呆症和帕金森病，例如 AD 和 tau蛋白病 (4) 探索肠道 αSynD 作为死前生物标志物； 使用结肠活检诊断 DLB 和 PDD 的成功实施将建立 RT-。 QuIC 检测利用现成的外周样本进行 DLB 和 PDD 的早期诊断。

项目成果

Tau seeds occur before earliest Alzheimer's changes and are prevalent across neurodegenerative diseases.

Tau 种子出现在最早的阿尔茨海默病变化之前，并且在神经退行性疾病中普遍存在。

• 发表时间: 2023-07
• 影响因子: 12.7
• 作者: Manca, Matteo;Standke, Heidi G;Browne, Danielle F;Huntley, Mikayla L;Thomas, Olivia R;Orrú, Christina D;Hughson, Andrew G;Kim, Yongya;Zhang, Jing;Tatsuoka, Curtis;Zhu, Xiongwei;Hiniker, Annie;Coughlin, David G;Galasko, Douglas;Kraus, Allison
• 通讯作者: Kraus, Allison

Discrimination of MSA-P and MSA-C by RT-QuIC analysis of olfactory mucosa: the first assessment of assay reproducibility between two specialized laboratories.

通过嗅粘膜 RT-QuIC 分析区分 MSA-P 和 MSA-C：首次评估两个专业实验室之间的测定重现性。

• 发表时间: 2021-12-11
• 影响因子: 15.1
• 作者: Bargar, Connor;De Luca, Chiara Maria Giulia;Devigili, Grazia;Elia, Antonio Emanuele;Cilia, Roberto;Portaleone, Sara Maria;Wang, Wen;Tramacere, Irene;Bistaffa, Edoardo;Cazzaniga, Federico Angelo;Felisati, Giovanni;Legname, Giuseppe;Di Fonzo, Al
• 通讯作者: Di Fonzo, Al

Selective tau seeding assays and isoform-specific antibodies define neuroanatomic distribution of progressive supranuclear palsy pathology arising in Alzheimer's disease.

选择性 tau 接种测定和同工型特异性抗体定义了阿尔茨海默病中出现的进行性核上性麻痹病理学的神经解剖学分布。

• 发表时间: 2022-10
• 影响因子: 12.7
• 作者: Coughlin, David G;Goodwill, Vanessa S;Standke, Heidi G;Kim, Yongya;Coley, Nicolas;Pizzo, Donald P;Galasko, Douglas;Kraus, Allison;Hiniker, Annie
• 通讯作者: Hiniker, Annie