Development of cell free messenger RNA-based non-invasive diagnostic biomarker for Alzheimer's Disease

开发基于无细胞信使 RNA 的阿尔茨海默病非侵入性诊断生物标志物

• 批准号: 10761661
• 负责人: John Sninsky
• 金额: $ 108.61万
• 依托单位: MOLECULAR STETHOSCOPE, INC.
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-09-01 至 2025-06-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10761661
• 关键词: Affect; Age; Alzheimer' s Disease; Alzheimer' s disease diagnosis; Alzheimer' s disease diagnostic; Alzheimer' s disease pathology; Alzheimer' s disease patient; Alzheimer' s disease test; Alzheimer’s disease biomarker; Amyloid beta-Protein; Autopsy; Bioinformatics; Biological Assay; Biological Markers; Blood; Blood specimen; Brain; Cells; Cerebrospinal Fluid; Cerebrospinal Fluid Proteins; Characteristics; Circulation; Clinical; Dementia; Development; Diagnosis; Diagnostic; Diagnostic tests; Disease; Evaluation; Gene Expression Profile; Genes; Human; Image; Impaired cognition; Individual; Inflammation; Lead; Liver diseases; Machine Learning; Malignant Neoplasms; Malignant neoplasm of liver; Measures; Messenger RNA; Molecular; Monitor; Neurodegenerative Disorders; Neurofibrillary Tangles; Nucleic Acids; Outcome; Pathologic; Performance; Persons; Plasma; Plasma Cells; Positron-Emission Tomography; Procedures; Prognosis; Protocols documentation; Research Personnel; Resources; Sampling; Severities; Signal Transduction; Solid; Source; Specimen; Symptoms; Synapses; Talents; Testing; Thinness; Tissue Sample; Transcript; Validation; abeta deposition; biomarker development; brain dysfunction; brain tissue; cohort; comparative efficacy; cost; cost effective; diagnostic biomarker; disease prognosis; imaging modality; liquid biopsy; mild cognitive impairment; misfolded protein; mitochondrial dysfunction; nervous system disorder; neuron loss; next generation sequencing; noninvasive diagnosis; oxidation; patient stratification; predictive marker; profiles in patients; prognostic; protein biomarkers; tau Proteins; transcriptome; transcriptome sequencing

Alzheimer’s disease (AD) is the most common cause of dementia, affecting over 40 million people and is projected to triple by 2050. Although post-mortem examination is the gold standard for establishing AD pathology, assessment of amyloid β (Aβ) and tau levels in cerebrospinal fluid (CSF) and/or positron-emission tomography (PET) are currently used widely as surrogates. However, imaging modalities are costly and CSF procedure is invasive. Therefore, there is a need for highly accessible and cost-effective non-invasive diagnostic tests for AD and patients with mild cognitive impairment (MCI) who will eventually develop AD. Over the last two decades, circulating nucleic acids have emerged as a viable source of liquid biopsy in multiple diseases. Recent whole-transcriptome characterization studies using post-mortem human brain tissue samples have demonstrated that the transcriptional profile of AD patients differ significantly from healthy individuals. Therefore, circulating messenger RNA (mRNA) appear to be a promising non-invasive diagnostic biomarker source for AD. Although quantification of cell-free mRNAs (cf-mRNAs) was once considered challenging due to their low abundance in the circulation, we and others have developed a robust next generation sequencing (NGS) based platform for accurate quantification of cf-mRNA. Subsequently, we have conducted preliminary cf-mRNA profiling studies in multiple diseases including neurodegenerative diseases, liver diseases and cancers and demonstrated its utility as a platform to develop non-invasive biomarkers for diagnosis and monitoring of diseases. In particular, we have recently profiled plasma cf-mRNA transcriptomes of 126 AD subjects and compared to those of 115 age matched controls. We discovered that a substantial number of genes were dysregulated in plasma of AD subjects and some of these genes correlated with severity of cognitive impairment in AD subjects. These AD associated dysregulated cf-mRNA transcripts were able to robustly identify AD subjects and demonstrated the potential of cf-mRNA as a source for non-invasive biomarker development. In this proposal, we will first optimize and establish clinical-grade protocols to minimize potential variabilities for the downstream cf-mRNA Seq profiling. We will then profile the cf-mRNA transcriptome of well-characterized AD and MCI subject samples as well as other neurological diseases and build diagnostic and prognostic classifiers for AD and MCI using comprehensive bioinformatic approaches. We will subsequently validate the performance of these classifiers in intended-use clinical validation cohorts.

阿尔茨海默病 (AD) 是导致痴呆症的最常见原因，影响超过 4000 万人，并且 预计到 2050 年将增加两倍。尽管尸检是建立 AD 的黄金标准 病理学、脑脊液 (CSF) 中淀粉样蛋白 (Aβ) 和 tau 蛋白水平的评估和/或正电子发射 断层扫描（PET）目前被广泛用作替代方法，但是成像方式昂贵且脑脊液检查。 因此，需要一种易于使用且具有成本效益的非侵入性诊断。 对 AD 和最终将在过去两年发展为 AD 的轻度认知障碍 (MCI) 患者进行测试。 几十年来，循环核酸已成为多种疾病液体活检的可行来源。 使用死后人脑组织样本进行全转录组表征研究 因此，AD 患者的转录谱与健康个体存在显着差异。 循环信使 RNA (mRNA) 似乎是 AD 的一种有前景的非侵入性诊断生物标志物来源。 尽管无细胞 mRNA (cf-mRNA) 的定量一度被认为具有挑战性，因为它们的低 循环中的丰富性，我们和其他人开发了基于下一代测序（NGS）的强大的 随后，我们对cf-mRNA进行了初步定量。 包括神经退行性疾病、肝脏疾病和癌症在内的多种疾病的分析研究 它作为一个平台来开发用于诊断和监测的非侵入性生物标志物 特别是，我们最近对 126 名 AD 受试者的血浆 cf-mRNA 转录组进行了分析。 与 115 名年龄匹配的对照相比，我们发现大量基因发生了变化。 AD 受试者血浆中的失调，其中一些基因与认知障碍的严重程度相关 这些与 AD 相关的失调 cf-mRNA 转录本能够可靠地识别 AD 患者。 并证明了 cf-mRNA 作为非侵入性生物标志物开发来源的潜力。 在此提案中，我们将首先优化并建立临床级方案，以最大程度地减少潜在的变异性 然后我们将分析已充分表征的 AD 的下游 cf-mRNA 转录组。 和 MCI 受试者样本以及其他神经系统疾病，并建立诊断和预后分类器 我们随后将使用综合生物信息学方法验证 AD 和 MCI 的性能。 这些分类器在预期用途的临床验证队列中的应用。