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: 8278568
• 负责人: HOWARD J. FEDEROFF
• 金额: $ 57.37万
• 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 2015-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8278568
• 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; Health; 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; 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）：阿尔茨海默氏病（AD）是一种慢性神经退行性疾病，通常在老年人中临床表现出来。有趣的是，各种死后证据表明，AD的病理标志，以及通过推断，疾病本身开始在个人的生活中开始发生。这导致了AD的新观点，从而在共同的生物化学途径上融合了一组不同的机械触发，以引起表型上相似的临床综合征和神经病理学状态。这种收敛的病理生理假设断言，特定的下游生化途径介导了AD中观察到的突触损失，细胞损伤和死亡。此外，这些病理生理的许多变化都将在外围系统中表现出来，它们共享这些信号通路。我们假设造血系统与神经系统共享许多细胞信号通路，并且受AD表征的许多相同的病理生理变化的影响。具体而言，我们建议外周白细胞受AD致病过程的影响，这将反映在蛋白质水平和功能的改变中。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疗法提供宝贵的见解。我们建议从三个队列中识别和收集串行临床测量和生物样本：患有高度认知障碍（MCI）/AD的受试者（> 75岁> 75岁，具有诊断为AD的第一级相对）；年龄和性别匹配的受试者的风险低；并新诊断为MCI/AD的药物受试者。在特定目标1中，我们将对所有高风险受试者进行广泛的临床和生物分子检查，与没有MCI/AD的低风险受试者的子集相比，这些受试者诊断为MCI/AD的诊断。在特定目标2中，我们将在没有MCI/AD的低风险队列和早期药物MCI/AD受试者的第二个子集中测试该轮廓的特异性和灵敏度。我们假设这些研究中鉴定出的临床生物分子特征对于我们对AD中疾病诊断，发病机理和治疗的理解至关重要。随着美国婴儿潮一代的衰老，需要充分了解这种疾病的发病机理，设计分子诊断和改进的药物治疗对我们的国家和我们的医疗保健系统至关重要。因此，有必要开发出早期AD的健壮，特异性和敏感的生物标志物，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鉴定出的临床生物分子特征对于我们对AD中疾病诊断，发病机理和治疗的理解至关重要。随着美国婴儿潮一代的衰老，需要充分了解这种疾病的发病机理，设计分子诊断和改进的药物治疗对我们的国家和我们的医疗保健系统至关重要。因此，有必要开发出早期AD的健壮，特异性和敏感的生物标志物，这将极大地促进该疾病的诊断和治疗。

项目成果

Apolipoprotein E genotype impact on memory and attention in older persons: the moderating role of personality phenotype.

载脂蛋白 E 基因型对老年人记忆和注意力的影响：人格表型的调节作用。

• DOI: 10.1002/gps.4748
• 发表时间: 2018
• 期刊: International journal of geriatric psychiatry
• 影响因子: 4
• 作者: Chapman,BenjaminP;Benedict,RalphHB;Lin,Feng;Roy,Shumita;Porteinsson,Antoine;Szigeti,Kinga;Federoff,Howard;Mapstone,Mark
• 通讯作者: Mapstone,Mark

Plasma phospholipids identify antecedent memory impairment in older adults.

• DOI: 10.1038/nm.3466
• 发表时间: 2014-04
• 期刊: Nature medicine
• 影响因子: 82.9
• 作者: Mapstone M;Cheema AK;Fiandaca MS;Zhong X;Mhyre TR;MacArthur LH;Hall WJ;Fisher SG;Peterson DR;Haley JM;Nazar MD;Rich SA;Berlau DJ;Peltz CB;Tan MT;Kawas CH;Federoff HJ
• 通讯作者: Federoff HJ

What success can teach us about failure: the plasma metabolome of older adults with superior memory and lessons for Alzheimer's disease.

• DOI: 10.1016/j.neurobiolaging.2016.11.007
• 发表时间: 2017-03
• 期刊: Neurobiology of aging
• 影响因子: 4.2
• 作者: Mapstone M;Lin F;Nalls MA;Cheema AK;Singleton AB;Fiandaca MS;Federoff HJ
• 通讯作者: Federoff HJ