Studies in Dementia and Neurodegenerative Diseases

痴呆症和神经退行性疾病研究

• 批准号: 9147406
• 负责人: Dimitrios Kapogiannis
• 金额: $ 193.44万
• 依托单位: NATIONAL INSTITUTE ON AGING
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/9147406
• 关键词: Academy; Affect; Aging; Agonist; Alzheimer' s Disease; American; American Association for the Advancement of Science; Amyloid; Amyloid beta-Protein; Animals; Area; Baltimore; Biological Markers; Blood; Brain; Butyrylcholinesterase; Caloric Restriction; Case-Control Studies; Cathepsins; Cerebrospinal Fluid; Clinical; Clinical Research; Clinical Skills; Cognition; Collaborations; Controlled Clinical Trials; Data; Dementia; Deposition; Diabetes Mellitus; Diagnosis; Diagnostic; Disease; Disease Progression; Dose; Double-Blind Method; Drug Kinetics; Energy Metabolism; Enrollment; Episodic memory; Event; Fostering; France; Functional Magnetic Resonance Imaging; Future; Generations; Glucose; Glutamates; Glutamine; Glycolysis; Goals; HSF1; Health; Heat-Shock Proteins 70; Hippocampus (Brain); Human; Image; Immunoprecipitation; Inflammatory; Institutional Review Boards; Insulin Resistance; Intake; Interleukin-12; International; Intervention; Journals; Link; Longitudinal Studies; Magnetic Resonance Imaging; Magnetic Resonance Spectroscopy; Manuscripts; Measures; Memory; Metabolic; Metabolism; Methodology; NCAM1 gene; Nerve Degeneration; Neurodegenerative Disorders; Neurologic; Neurology; Neurons; Neuropsychology; Neurosciences; Neurotransmitters; Outcome Measure; Overweight; Participant; Pathogenesis; Patient Recruitments; Patients; Pattern; Peptides; Peripheral; Pharmaceutical Preparations; Phase; Placebo Control; Placebos; Plasma; Positron-Emission Tomography; Preparation; Primary Prevention; Process; Production; Prognostic Marker; Psychiatry; Publishing; Randomized; Research; Research Personnel; Rest; Safety; Sampling; Societies; Source; Specimen; Staging; Structure; Surface; Synapses; Techniques; Therapeutic; Universities; Vesicle; Wisconsin; aging brain; base; brain metabolism; cerebral atrophy; clinical Diagnosis; clinical care; cognitive performance; cohort; cytokine; data reduction; disease diagnosis; disorder control; exenatide; extracellular; frontal lobe function; gamma-Aminobutyric Acid; glucagon-like peptide; glucose metabolism; healthy volunteer; improved; in vivo; inclusion criteria; independent component analysis; inflammatory marker; inhibitor/antagonist; insulin sensitivity/resistance; interest; meetings; middle age; mild cognitive impairment; neuroimaging; neurotransmission; novel; novel therapeutic intervention; pre-clinical; receptor; symposium; systematic review; tau Proteins; treatment center

Predictors and biomarkers of Alzheimer's Disease (AD) In collaboration with Dr. Ed Goetzl from UCSF and other investigators, we developed a methodology for isolating blood exosomes and enriching them for neuronal origin by immunoprecipitation using neuronal surface markers NCAM and L1 CAM. To date, we have conducted four case control studies measuring exosomal Ab, tau, Ser and Tyr phosphorylated IRS-1 peptides, REST, LRP6, Cathepsin-D, LAMP1, Uniquitin, HSP70 and HSF1 in AD and control subjects. We found highly significant differences that, for some peptides, accurately discriminate between the two groups. In addition, exosomal differences may be present at the preclinical stage and may predict AD. I presented these findings at talks at several international meetings, including the annual meetings of the Alzheimer's Association International Conference (AAIC), the American Association for the Advancement of Science (AAAS), Neuroscience 2014 (SfN), American Academy of Neurology (AAN), American Neurological Association (ANA), International Society of Extracellular Vesicles (ISEV). In addition, I published four manuscript on the topic (in the journals Alzheimer's and Dementia, FASEB, Neurology, and Annals of Clinical and Translational Neurology). One major goal for the coming year is to validate exosomal markers as diagnostic and prognostic biomarkers of AD in large cohorts from the Baltimore Longitudinal Study of Aging (BLSA), the Alzheimer's Disease Neuroimaging Initiative (ADNI), The Harvard Aging Brain Study, and the WRAP (Wisconsin). The BLSA, Harvard Aging Brain Study, and WRAP are ideal to assess longitudinal changes in these markers and their potential to predict AD at the preclinical stage, whereas ADNI is ideal for assessing changes with disease progression and conversion from MCI to AD. I implemented a data reduction technique called Independent Component Analysis to structural MRI images of subjects with AD and MCI from ADNI and studied how patterns of structural covariance predict clinical diagnosis and MCI conversion. This approach allowed us to classify subjects according to their future diagnosis with a high degree of accuracy (arguably, the highest ever achieved); the study was published in the journal Psychiatry Research Neuroimaging. In addition, I studied how peripheral insulin resistance is associated with regional brain glucose metabolism on FDG-PET in ADNI participants. We found that insulin resistance is associated with decreased glucose metabolism in patients with AD in a number of brain areas affected by AD. In addition, insulin resistance is associated with a maladaptive increase in metabolism at the hippocampus during the MCI stage, therefore, promoting AD pathogenesis; the study was published in the journal Diabetes. In collaboration with the NIA 3T MRI Facility manager, Dr. David Reiter, I have employed a novel Magnetic Resonance Spectroscopy (MRS) methodology at the NIA 3T MRI facility, which allows us to obtain in vivo measures on brain metabolites (glucose, lactate) and neurotransmitters (glutamate and GABA), which are relevant to AD pathogenesis. First, I conducted a study of healthy volunteers combining MRS with resting fMRI, which provides measures of brain functional connectivity, and showed a link between neurotransmitter levels and brain connectivity. The study was pubmished in Neuroimage. In a case-control study of patients with MCI/AD and healthy volunteers, we showed higher glucose and lactate, and lower glutamate and GABA in patients compared to controls, suggesting that these MRS markers may be used as diagnostic biomarkers for AD. The manuscript is currently under preparation. In addition, we are exploring associations of MRS measures with cognitive performance, functional connectivity within the default mode network; and CSF biomarkers. I also studied the association between cognitive performance and clinical status in AD and CSF inflammatory markers and found that higher levels of one particular pro-inflammatory cytokine, IL-12, predicts better cognition and less brain atrophy; this manuscript is currently under review. In collaboration with Dr. Mohamad El Haj from University of Lille, France, we conducted two studies on autobiographical generation of past and future events in a cohort of AD patients compared to controls. We found that future and past events are more similar in patients compared to controls and that the ability to generate future events is closely related with the patient's episodic memory. In addition, the ability to generate future events was associated with Frontal Lobe functions. These findings suggest that remembering the past and imagining the future rely on common brain structures, which are both impaired in AD. We published two studies describing these finings in the journals Neuropsychology, and Hippocampus. In addition, we published a systematic review on Episodic Memory in aging and AD, in the journal Aging Research Reviews. Treatment studies in AD I conduct a proof of concept Phase II, double blind, randomized, placebo-controlled, clinical trial to assess the safety and tolerability of exendin-4 (exenatide) treatment in participants with Mild Cognitive Impairment (MCI)/early AD. Inclusion criteria include clinical diagnosis of MCI/early AD, and cerebrospinal fluid Ab(1-42) < 192 pg/dl. To this date, 47 participants have been enrolled and started on treatment with study drug (exenatide or placebo). Participants receive study drug for 18 months and outcome measures are being collected every six months. Fourteen participants completed the study, six participants withdrew from the study, and five continue participation. My goal for the new year is to reach the enrollment target of forty participants. I also continue to conduct a Phase I, double-blind, placebo-controlled, ascending, single-dose, safety, tolerability and pharmacokinetic study of Bisnorcymserine, a selective butyrylcholinesterase inhibitor, in healthy volunteers. Inhibition of butyrylcholinesterase is a novel therapeutic approach for symptomatic treatment in moderate/advanced AD. Finally, this year we acquired final IRB approval for a study of Intermittent caloric restriction (ICR)implementing 5-2 CR (alternating 5 days of regular calorie intake and 2 days of CR). This is a 8-week study of 5-2 CR in overweight middle aged subjects to assess potential beneficial effects on insulin resistance, metabolism, cognitive performance, fMRI activity and biomarkers. If this study is positive, ICR may be a candidate intervention for primary prevention of AD at midlife.

阿尔茨海默氏病的预测因素和生物标志物（AD） 与UCSF和其他研究人员的Ed Goetzl博士合作，我们开发了一种方法，用于通过使用神经元表面标记NCAM和L1 CAM和L1 CAM通过免疫沉淀来隔离血液外泌体并富含神经元来源。迄今为止，我们已经进行了四项案例对照研究，测量了外泌体AB，Tau，Ser和Tyr磷酸化的IRS-1肽，REST，LRP6，Catherpsin-D，Lamp1，lamp1，Uniquitin，Hsp70，Hsp70和HSF1在AD和控制受试者中。我们发现，对于某些肽，可以准确区分两组的差异高度显着。此外，外骨骼差异可能在临床前阶段存在，并且可以预测AD。我在几次国际会议上的会谈中介绍了这些发现，包括阿尔茨海默氏症协会国际会议（AAIC）的年度会议，美国科学进步协会（AAAS），Neuroscience 2014（SFN），美国神经学会（AAN），美国神经学协会（ANA），国际神经学会（ANA），国际外脑外静脉外伏氏牛sicles（ISEV）。此外，我发表了有关该主题的四个手稿（在《阿尔茨海默氏症和痴呆症》，《临床和翻译神经病学》中的痴呆症，faseb，神经病学和年鉴）中。来年的主要目标是验证外泌体标志物作为Baltimore衰老纵向研究（BLSA），阿尔茨海默氏病神经影像学计划（ADNI）的大型诊断和预后生物标志物（ADNI），哈佛大学的衰老大脑研究，以及WISCONSIN（WISCSONSIN）。 BLSA，哈佛大学衰老的大脑研究和包裹是评估这些标记中纵向变化及其在临床前阶段预测AD的潜力的理想选择，而ADNI是评估疾病进展和从MCI转化为AD的变化的理想选择。 我实施了一种称为独立组件分析的数据还原技术，以对ADNI的AD和MCI的受试者的结构MRI图像进行了研究，并研究了结构协方差的模式如何预测临床诊断和MCI转换。这种方法使我们可以根据受试者的未来诊断对受试者进行高度准确的诊断（可以说是有史以来最高的）；该研究发表在《精神病学研究》杂志上。 此外，我研究了周围胰岛素抵抗如何与ADNI参与者中FDG-PET的区域脑葡萄糖代谢有关。我们发现，在受AD影响的许多大脑区域的AD患者中，胰岛素抵抗与葡萄糖代谢降低有关。此外，胰岛素抵抗与MCI阶段期间海马的代谢不良有关，因此促进了AD发病机理。该研究发表在《糖尿病》杂志上。 在与NIA 3T MRI设施经理David Reiter博士合作的情况下，我在NIA 3T MRI设施上使用了一种新颖的磁共振光谱（MRS）方法，这使我们能够在体内对脑代谢物（葡萄糖，乳酸）和神经脱位（Glutamatate和Glutamatate和Glutamatate and Gaba和Gaba）的体内措施，该方法相关。首先，我对将MRS与静止fMRI结合的健康志愿者进行了研究，该志愿者提供了脑功能连通性的度量，并显示了神经递质水平与大脑连通性之间的联系。这项研究在神经图像中进行了公开。与对照组相比，在对MCI/AD和健康志愿者的患者和健康志愿者患者的病例对照研究中，我们显示出更高的葡萄糖和乳酸，以及患者的较低谷氨酸和GABA，这表明这些MRS标记物可以用作AD的诊断生物标志物。手稿目前正在准备。此外，我们正在探索MRS度量与认知性能，默认模式网络中功能连接性的关联；和CSF生物标志物。 我还研究了AD和CSF炎症标志物中认知性能与临床状况之间的关联，发现一种特定的促炎细胞因子IL-12的较高水平可以预测更好的认知和更少的脑萎缩。此手稿目前正在审查中。 与法国里尔大学的Mohamad El Haj博士合作，与对照组相比，我们在一系列AD患者中进行了两项关于过去和未来事件的自传生成的研究。我们发现，与对照组相比，患者的未来和过去事件更相似，并且产生未来事件的能力与患者的情节记忆密切相关。此外，生成未来事件的能力与额叶功能有关。这些发现表明，记住过去并想象未来依赖于广泛的大脑结构，这两者在AD中都受到损害。我们发表了两项研究，这些研究描述了日记神经心理学和海马。此外，我们在《衰老研究评论》杂志上发表了有关衰老和AD中情节记忆的系统评价。 AD的治疗研究 我进行了概念第二阶段的证明，双盲，随机，安慰剂对照，临床试验，以评估轻度认知障碍（MCI）/早期AD的参与者中Exendin-4（Exenatide）治疗的安全性和耐受性。纳入标准包括MCI/早期AD的临床诊断，脑脊液AB（1-42）<192 pg/dl。到目前为止，已有47名参与者被招募并开始接受研究药物（艾替尼或安慰剂）的治疗。参与者接受研究药物18个月，并且每六个月收集每六个月的结果指标。 14名参与者完成了这项研究，六名参与者退出了研究，有5名参与者继续参与。我的新年目标是达到40名参与者的入学目标。 我还继续进行I期，双盲，安慰剂对照，上升，单剂量，安全性，耐受性和药代动力学研究，对健康的志愿者的选择性丁酰胆碱酯酶抑制剂是一种选择性的丁香糖酶抑制剂。抑制丁乙酸酯酶是一种新型的治疗方法，用于中等/晚期AD的症状治疗。 最后，今年，我们获得了最终IRB批准，以研究实施5-2 CR的间歇性热量限制（ICR）（交替使用常规卡路里摄入和2天的CR）。这是对超重中年受试者的5-2 CR的一项为期8周的研究，以评估对胰岛素抵抗，代谢，认知性能，fMRI活性和生物标志物的潜在有益影响。如果这项研究是积极的，那么ICR可能是中期主要预防AD的候选干预措施。