Leukocyte-derived Biomarkers as Predictors of Risk and Progression in AD

白细胞衍生的生物标志物作为 AD 风险和进展的预测因子

• 批准号: 7619445
• 负责人: HOWARD J. FEDEROFF
• 金额: $ 61.94万
• 依托单位: GEORGETOWN UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-05-15 至 2013-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7619445
• 关键词: Activities of Daily Living; Affect; Age; Aging; Alzheimer disease detection; Alzheimer' s Disease; Alzheimer' s disease risk; Americas; Autopsy; Biochemical Pathway; Biological; Biological Markers; Blood; Cessation of life; Chronic; Clinical; Clinical Data; Cognitive deficits; Dementia; Detection; Development; Diagnosis; Diagnostic; Disease; Disease Progression; Elderly; Family history of; First Degree Relative; Functional disorder; Future; Gender; Genes; Healthcare Systems; Hematopoietic System; Individual; Late Onset Alzheimer Disease; Leukocytes; Life; Measurement; Mediating; Molecular; Molecular Profiling; Nervous system structure; Neurodegenerative Disorders; Newly Diagnosed; Pathogenesis; Pathology; Patients; Peripheral; Pharmaceutical Preparations; Pharmacotherapy; Process; Proteins; Recording of previous events; Recruitment Activity; Research; Risk; Risk Factors; Sampling; Sensitivity and Specificity; Signal Pathway; Symptoms; Synapses; Syndrome; System; Testing; Therapeutic; Time; Transcript; Treatment Efficacy; Validation; cell injury; clinical Diagnosis; cohort; cost; design; disease diagnosis; high risk; improved; insight; mild neurocognitive impairment; normal aging; prospective; public health relevance; research clinical testing

DESCRIPTION (provided by applicant): Alzheimer's disease (AD) is a chronic neurodegenerative disorder that typically manifests clinically in the elderly. Interestingly, a variety of postmortem evidence suggests that the pathological hallmarks of AD, and by inference the disease itself, begin to occur early in an individual's life. This has led to an emerging view of AD whereby a set of disparate mechanistic triggers over a life-time converge upon shared biochemical pathways to elicit a phenotypically similar clinical syndrome and neuropathological state. This convergent pathophysiological hypothesis asserts that specific downstream biochemical pathways mediate the synaptic loss, cellular injury, and death observed in AD. Furthermore, many of these pathophysiological changes will be manifest in peripheral systems, which share these signaling pathways. We hypothesize that the hematopoietic system shares many cellular signaling pathways with the nervous system and is affected by many of the same pathophysiological changes that characterize AD. Specifically, we propose that peripheral leukocytes are affected by AD pathogenic processes, which will be reflected in alterations in protein levels and functions. As such, these changes will serve as important biomarkers for AD diagnosis and progression and will provide valuable insights into its pathophysiology and potential therapeutics. We propose to identify and collect serial clinical measurements and biological samples from three cohorts: subjects at high risk for developing mild-cognitive impairment (MCI)/AD (>75 years old with a first degree relative diagnosed with AD); age-and gender-matched subjects at low risk; and newly diagnosed, drug-naive subjects with MCI/AD. In Specific Aim 1 we will undertake an extensive clinical and biomolecular examination of all high risk subjects that progress to a diagnosis of MCI/AD compared to an appropriately matched subset of low risk subjects without MCI/AD to discover and validate a potential biomarker profile of disease. In Specific Aim 2 we will test the specificity and sensitivity of this profile in a second subset of the low risk cohort without MCI/AD and early, drug-naive MCI/AD subjects. We hypothesize that the clinical-biomolecular profile identified in these studies will be important to our understanding of disease diagnosis, pathogenesis, and therapy in AD. With the aging of America's baby boomers the need to fully understand the pathogenesis of this disease and to design molecular diagnostics and improved pharmacotherapies is vitally important to our nation and our health care systems. As such, it is necessary to develop robust, specific, and sensitive biomarkers of early AD, which would greatly facilitate the diagnosis and treatment of this disease. PUBLIC HEALTH RELEVANCE: We hypothesize that the clinical-biomolecular profile identified in these studies will be important to our understanding of disease diagnosis, pathogenesis, and therapy in AD. With the aging of America's baby boomers the need to fully understand the pathogenesis of this disease and to design molecular diagnostics and improved pharmacotherapies is vitally important to our nation and our health care systems. As such, it is necessary to develop robust, specific, and sensitive biomarkers of early AD, which would greatly facilitate the diagnosis and treatment of this disease.

描述（由申请人提供）：阿尔茨海默病（AD）是一种慢性神经退行性疾病，临床上通常表现为老年人。有趣的是，各种尸检证据表明，AD 的病理特征以及疾病本身在个体生命的早期就开始出现。这导致了一种新的 AD 观点，即一生中一系列不同的机械触发因素汇聚到共享的生化途径上，从而引发表型相似的临床综合征和神经病理状态。这种趋同的病理生理学假说断言，特定的下游生化途径介导了 AD 中观察到的突触丢失、细胞损伤和死亡。此外，许多病理生理变化将在共享这些信号传导途径的外周系统中表现出来。我们假设造血系统与神经系统共享许多细胞信号传导途径，并受到许多与 AD 特征相同的病理生理变化的影响。具体来说，我们提出外周白细胞受到AD致病过程的影响，这将反映在蛋白质水平和功能的改变上。因此，这些变化将作为 AD 诊断和进展的重要生物标志物，并将为其病理生理学和潜在治疗提供有价值的见解。我们建议从三个队列中识别和收集连续的临床测量和生物样本：患有轻度认知障碍（MCI）/ AD 的高风险受试者（> 75 岁，一级亲属诊断患有 AD）；年龄和性别匹配的低风险受试者；以及新诊断、未接受药物治疗的 MCI/AD 受试者。在具体目标 1 中，我们将对所有进展为 MCI/AD 诊断的高风险受试者与适当匹配的无 MCI/AD 的低风险受试者子集进行广泛的临床和生物分子检查，以发现和验证潜在的生物标志物谱疾病。在具体目标 2 中，我们将在没有 MCI/AD 的低风险队列的第二个子集和早期未接受药物的 MCI/AD 受试者中测试该特征的特异性和敏感性。我们假设这些研究中确定的临床生物分子特征对于我们理解 AD 疾病诊断、发病机制和治疗非常重要。随着美国婴儿潮一代的老龄化，充分了解这种疾病的发病机制并设计分子诊断和改进药物疗法对于我们的国家和我们的医疗保健系统至关重要。因此，有必要开发稳健、特异且敏感的早期AD生物标志物，这将极大地促进该疾病的诊断和治疗。公共卫生相关性：我们假设这些研究中确定的临床生物分子特征对于我们理解 AD 疾病诊断、发病机制和治疗非常重要。随着美国婴儿潮一代的老龄化，充分了解这种疾病的发病机制并设计分子诊断和改进药物疗法对于我们的国家和我们的医疗保健系统至关重要。因此，有必要开发稳健、特异且敏感的早期AD生物标志物，这将极大地促进该疾病的诊断和治疗。