Studies in Dementia and Neurodegenerative Diseases

痴呆症和神经退行性疾病研究

基本信息

批准号：
9549402
负责人：
Dimitrios Kapogiannis
金额：
$ 529.61万
依托单位：
NATIONAL INSTITUTE ON AGING
依托单位国家：
美国
项目类别：
财政年份：
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/9549402
关键词：
Aging Agonist Alzheimer&apos s Disease Amyloid Animals Baltimore Biological Markers Blood Brain Butyrylcholinesterase Caloric Restriction Calories Case-Control Studies Cerebrospinal Fluid Clinical Clinical Research Clinical Trials Collaborations Controlled Clinical Trials Data Data Analyses Dementia Deposition Diagnosis Disease Disease Progression Dose Double-Blind Method Drug Kinetics Energy Metabolism Episodic memory Event Fostering France Functional Magnetic Resonance Imaging Future GLP-I receptor Generations Glucose Goals Hallucinations Human Immunoprecipitation Impairment Inflammatory Informed Consent Insulin Resistance Intake Intervention Journals Link Longitudinal Studies Magnetic Resonance Imaging Magnetic Resonance Spectroscopy Manuscripts Measures Metabolism Methodology Multiple Sclerosis Multiple System Atrophy NCAM1 gene Nerve Degeneration Neurodegenerative Disorders Neurology Neurons Neurosciences Neurotransmitters Outcome Measure Overweight Parkinson Disease Participant Pathogenesis Patients Pharmaceutical Preparations Phase Placebo Control Placebos Plasma Primary Prevention Process Production Prognostic Marker Proteins Publishing RNA Randomized Research Personnel Rest Safety Sampling Source Specimen Structure Surface Synapses Therapeutic Time Universities aging brain brain health brain metabolism case finding cognitive performance cohort diagnostic biomarker disease diagnosis disorder control disorder prevention exenatide exosome frontal lobe function frontier healthy volunteer improved in vivo inhibitor/antagonist insulin sensitivity/resistance interest middle age mild cognitive impairment neuroimaging neurotransmission novel novel marker novel therapeutic intervention pre-clinical predictive marker symptom treatment systematic review tau Proteins

项目摘要

Predictors and biomarkers of Alzheimer's Disease (AD) and other neurodegenerative diseases 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 several case control studies measuring exosomal Ab, tau, Ser and Tyr phosphorylated IRS-1, synaptic markers, and other proteins, in AD and control subjects. We found highly significant differences that, for some proteins, accurately discriminate between the two groups. In addition, exosomal differences may be present at the preclinical stage and may predict AD. I published several manuscript on the topic (in the journals Alzheimer's and Dementia, FASEB J (four times), Neurology, Annals of Clinical and Translational Neurology, Frontiers in Neuroscience, and WIRES RNA. 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 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, disease progression and conversion from MCI to AD. In addition to a main focus on AD, I am conducting exosome biomarker studies in Parkinson's disease, Multiple Systems Atrophy, and Multiple Sclerosis. 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 show 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 review. In collaboration with Dr. Mohamad El Haj from University of Lille, France, we conducted three 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. In addition, we published a systematic review of hallucinations in AD and a review on time distortions in AD. Treatment studies in AD I completed a pilot 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. A total of 57 participants were accrued in this study (i.e. signed informed consent), twenty-seven (27) participants received the experimental drug (exenatide or placebo), and 18 completed the study. Participants received study drug for 18 months and outcome measures were collected every six months. My goal for the new year is to complete data analysis and publish the results. I 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, I am conducting 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（AD）和其他神经退行性疾病的预测因素和生物标志物与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，我们已经在AD和控制受试者中进行了几项测量外泌体AB，Tau，Ser和Tyr磷酸化IRS-1，突触标记和其他蛋白质的病例对照研究。我们发现，对于某些蛋白质而言，非常重要的差异可以准确区分两组。此外，外骨骼差异可能在临床前阶段存在，并且可以预测AD。我发表了几本有关该主题的手稿（在《阿尔茨海默氏症和痴呆症》中，Faseb J（四次），神经病学，临床和翻译神经病学，神经科学的前沿以及RNA。（BLSA），哈佛大学的大脑研究和包裹（威斯康星州），哈佛大学衰老的大脑研究和包裹是评估这些标记的纵向变化，以及它们在临床前阶段的潜力，在疾病阶段，疾病的进展和从MCI转化为AD的AD和AD的焦点。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和健康志愿者患者和健康志愿者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，以及患者的谷氨酸和GABA较低的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患者中进行了三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。此外，我们发表了对AD中幻觉的系统评价，并对AD中的时间扭曲进行了综述。 AD的治疗研究我完成了一次试点II期，双盲，随机，安慰剂对照的临床试验，以评估在轻度认知障碍（MCI）/早期AD的参与者中Exendin-4（Exenatide）治疗的安全性和耐受性。在这项研究中，共有57名参与者（即签署的知情同意），27（27）参与者接受了实验药物（Etenatide或安慰剂），并完成了研究。参与者接受了18个月的学习药物，每六个月收集一次结果指标。我的新年目标是完成数据分析并发布结果。我继续进行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，对健康志愿者的选择性丁酰胆碱酯酶抑制剂是一种选择性的丁酰胆碱酯酶抑制剂。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，我正在研究实施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。