Development of blood lipid biomarkers for Alzheimer's disease progression

开发阿尔茨海默病进展的血脂生物标志物

• 批准号: 7491658
• 负责人: Michelle M Mielke
• 金额: $ 20.49万
• 依托单位: JOHNS HOPKINS UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-09-01 至 2010-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7491658
• 关键词: 27-hydroxycholesterol; Affect; Age; Alzheimer' s Disease; Apolipoprotein E; Area; Biological Assay; Biological Markers; Blood; Blood specimen; Brain; Brain imaging; Ceramides; Cholesterol; Clinical; Clinical Trials; Cognition; Cognitive; Condition; Data; Data Reporting; Dementia; Demographic Factors; Development; Disease; Disease Progression; Fasting; Genotype; Hydroxycholesterols; Impaired cognition; Individual; Invasive; Isoprostanes; Light; Lipid Peroxidation; Lipids; Literature; Longitudinal Studies; Measures; Medical; Membrane Lipids; Memory; NIH Program Announcements; Nerve Degeneration; Neurodegenerative Disorders; Neurons; Outcome Measure; Participant; Pathology; Patients; Performance; Phase; Plasma; Population; Process; Range; Rate; Recruitment Activity; Research; Research Design; Research Project Grants; Running; Sampling; Schedule; Smoking Status; Sphingomyelins; Sum; Surrogate Markers; Testing; Time; Variant; Visit; base; blood lipid; cognitive change; cognitive function; concept; cost; executive function; follow-up; interest; mild neurocognitive impairment; outcome forecast; pre-clinical; prognostic

DESCRIPTION (provided by applicant): Alzheimer's disease (AD) is a progressive neurodegenerative disorder. Findings from the literature, and preliminary data reported in this application, suggest lipid measures, including brain-derived cholesterol species and lipid peroxidation products, may produce unique, readily detectable signatures in the blood of AD patients. These signatures may be indicators of AD-associated neurodegeneration, producing candidate biomarkers of disease progression. Thus far no longitudinal studies have been conducted in this area. This is important because the rate of change or accumulation of a biomarker may be a better indicator of disease progression than a single value or range at one time point. Such a biomarker could be used as a surrogate or secondary outcome measure in clinical trials of emerging therapies for AD, or may be a prognostic indicator of disease progression. A blood-based biomarker would be superior to CSF-based or brain imaging biomarkers with regard to cost, invasiveness and feasibility. We propose a proof-of-concept study to explore the clinical utility of 24S-hydroxycholesterol (24S-OHC), 24S-OHC/27- hydroxycholesterol ratio, 24S-OHC/cholesterol ratio and F2a-isoprostanes as blood-based biomarkers of AD-associated neurodegeneration using a longitudinal study design. We will recruit well-characterized patients with mild probable AD (pAD), amnestic mild cognitive impairment (MCI), and age-matched cognitively normal controls, 30 per group, from the Johns Hopkins Alzheimer Disease Research Center (JHADRC). These individuals are already followed annually as part of the Center's Clinical Core. For the proposed study, individuals will be asked to provide fasting blood samples at three time points, during two regularly scheduled annual visits, and during a six month visit in between, at which point they will undergo additional cognitive testing. Additional years of follow-up beyond the duration of this study will be available through the JHADRC. Analyses will (1) Estimate the variability of plasma levels of each biomarker both within and between individuals at baseline, 6 months and 1 year and determine factors that effect this variability; (2) Compare the cross-sectional and longitudinal variations and trajectories in biomarkers for the three groups of individuals with varying AD pathology; (3) Determine whether baseline biomarker levels predict one-year cognitive decline; (4) Assess change in biomarker levels as subsequent predictors of cognition decline; and (5) Determine whether the sum of the biomarker levels over one year are related to intra-individual cognitive change. This R21 application proposes a proof-of-concept study to explore the clinical utility of blood- based lipid biomarkers, including 24S-hydroxycholesterol and F2a-isoprostanes, as indicators of Alzheimer's disease (AD)-associated neurodegeneration. Such a biomarker of neurodegeneration would have several applications, including prognosis after the onset of dementia, prognosis of conversion from mild cognitive impairment to dementia, or prognosis in the preclinical phases of the disease. A major application would be as a surrogate or secondary outcome measure in clinical trials of emerging therapies for AD.

描述（由申请人提供）：阿尔茨海默病（AD）是一种进行性神经退行性疾病。来自文献的结果和本申请中报告的初步数据表明，脂质测量（包括脑源性胆固醇物质和脂质过氧化产物）可能在AD患者的血液中产生独特的、易于检测的特征。这些特征可能是AD相关神经变性的指标，产生疾病进展的候选生物标志物。迄今为止，尚未在这一领域进行纵向研究。这一点很重要，因为生物标志物的变化率或累积率可能是比一个时间点的单个值或范围更好的疾病进展指标。这样的生物标志物可用作AD新兴疗法的临床试验中的替代或次要结果测量，或者可以是疾病进展的预后指标。基于血液的生物标志物在成本、侵入性和可行性方面上级基于CSF或脑成像的生物标志物。我们提出了一项概念验证研究，采用纵向研究设计，探讨24 S-羟基胆固醇（24 S-OHC）、24 S-OHC/27-羟基胆固醇比值、24 S-OHC/胆固醇比值和F2 a-异前列腺素作为AD相关神经退行性变的血液生物标志物的临床效用。我们将从约翰霍普金斯阿尔茨海默病研究中心（JHADRC）招募特征明确的轻度可能AD（pAD）、遗忘型轻度认知障碍（MCI）患者和年龄匹配的认知正常对照组，每组30例。这些人已经作为中心临床核心的一部分每年进行随访。对于拟议的研究，将要求个人在三个时间点提供空腹血液样本，在两次定期安排的年度访视期间，以及在其间的六个月访视期间，他们将接受额外的认知测试。将通过JHADRC获得本研究持续时间以外的额外随访年数。分析将（1）估计在基线、6个月和1年时个体内和个体之间的每种生物标志物的血浆水平的变异性，并确定影响这种变异性的因素;（2）比较具有不同AD病理学的三组个体的生物标志物的横截面和纵向变异和轨迹;（3）确定基线生物标志物水平是否预测一年的认知衰退;（4）评估生物标志物水平的变化作为认知下降的后续预测因子;和（5）确定一年内生物标志物水平的总和是否与个体内认知变化相关。该R21申请提出了一项概念验证研究，以探索基于血液的脂质生物标志物（包括24 S-羟基胆固醇和F2 a-异前列烷）作为阿尔茨海默病（AD）相关神经变性的指标的临床效用。这种神经变性的生物标志物将具有几种应用，包括痴呆发作后的预后、从轻度认知障碍向痴呆转化的预后或疾病临床前阶段的预后。一个主要的应用将是作为替代或次要结果的措施，在临床试验的新兴疗法的AD。

项目成果

Blood-based biomarkers of microvascular pathology in Alzheimer's disease.

• DOI: 10.1016/j.exger.2009.09.005
• 发表时间: 2010-01
• 期刊: EXPERIMENTAL GERONTOLOGY
• 影响因子: 3.9
• 作者: Ewers, Michael;Mielke, Michelle M.;Hampel, Harald
• 通讯作者: Hampel, Harald

Alterations of the sphingolipid pathway in Alzheimer's disease: new biomarkers and treatment targets?

• DOI: 10.1007/s12017-010-8121-y
• 发表时间: 2010-12
• 期刊: NEUROMOLECULAR MEDICINE
• 影响因子: 3.5
• 作者: Mielke, Michelle M.;Lyketsos, Constantine G.
• 通讯作者: Lyketsos, Constantine G.

Comparison of conventional ELISA with electrochemiluminescence technology for detection of amyloid-β in plasma.

• DOI: 10.3233/jad-2010-100456
• 发表时间: 2010
• 期刊: Journal of Alzheimer's disease : JAD
• 作者: Oh ES;Mielke MM;Rosenberg PB;Jain A;Fedarko NS;Lyketsos CG;Mehta PD
• 通讯作者: Mehta PD

Plasma ceramides are altered in mild cognitive impairment and predict cognitive decline and hippocampal volume loss.

• DOI: 10.1016/j.jalz.2010.03.014
• 发表时间: 2010-09
• 期刊: Alzheimer's & dementia : the journal of the Alzheimer's Association
• 作者: Mielke MM;Haughey NJ;Bandaru VV;Schech S;Carrick R;Carlson MC;Mori S;Miller MI;Ceritoglu C;Brown T;Albert M;Lyketsos CG
• 通讯作者: Lyketsos CG

Elevated plasma ceramides in depression.

抑郁症时血浆神经酰胺升高。

• DOI: 10.1176/jnp.23.2.jnp215
• 发表时间: 2011
• 期刊: The Journal of neuropsychiatry and clinical neurosciences
• 作者: Gracia-Garcia,Patricia;Rao,Vani;Haughey,NormanJ;Bandaru,VeeraVenkataRatnam;Banduru,VeeraVenkataRatnam;Smith,Gwenn;Rosenberg,PaulB;Lobo,Antonio;Lyketsos,ConstantineG;Mielke,MichelleM
• 通讯作者: Mielke,MichelleM