Studies in Dementia and Neurodegenerative Diseases

痴呆症和神经退行性疾病研究

• 批准号: 8736682
• 负责人: Dimitrios Kapogiannis
• 金额: $ 59.51万
• 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/8736682
• 关键词: Acetylcholine; Aging; Agonist; Alzheimer' s Disease; American; Amyloid; Amyloid beta-Protein; Amyloidosis; Animals; Appointment; Biological Markers; Blood Pressure; Brain; Butyrylcholinesterase; C9ORF72; Caloric Restriction; Cerebrospinal Fluid; Clinical; Clinical Research; Cognition; Cognitive; Collaborations; Complement; Controlled Clinical Trials; Data; Dementia; Deposition; Diagnosis; Disease; Dose; Double-Blind Method; Drug Kinetics; Energy Metabolism; Enrollment; Frontotemporal Dementia; Frontotemporal Lobar Degenerations; Functional Magnetic Resonance Imaging; Future; Genetic; Geriatrics; Glucose; Glutamates; Glutamine; Goals; Health; Hippocampus (Brain); Human; Image; Inflammatory; Insulin Resistance; Intake; Interleukin-12; Journals; Laboratories; Lead; Link; Lipids; Magnetic Resonance Imaging; Magnetic Resonance Spectroscopy; Manuscripts; Measures; Memory; Metabolism; Methodology; National Institute of Neurological Disorders and Stroke; Nature; Nerve Degeneration; Neurobiology; Neurodegenerative Disorders; Neurotransmitters; Participant; Pathogenesis; Patient Recruitments; Patients; Pattern; Performance; Peripheral; Pharmaceutical Preparations; Phase; Physiological; Placebo Control; Placebos; Plasma; Positron-Emission Tomography; Preparation; Process; Production; Publishing; Randomized; Research Personnel; Rest; Safety; Sampling; Societies; Specimen; Staging; Synapses; Techniques; Texas; Therapeutic; Time Study; Universities; Visit; Work; base; brain metabolism; brain research; clinical Diagnosis; clinical care; cohort; data reduction; depressive symptoms; disease diagnosis; exenatide; follow-up; gamma-Aminobutyric Acid; genome wide association study; glucagon-like peptide; glucose metabolism; healthy volunteer; improved; in vivo; inclusion criteria; independent component analysis; indexing; inflammatory marker; inhibitor/antagonist; mild cognitive impairment; neuroimaging; neuroinflammation; neurotransmission; novel; novel therapeutic intervention; receptor; safety study; tau Proteins

Exenatide for the treatment of Alzheimer's Disease (AD). I continued to conduct a proof of concept Phase II, double blind, randomized, placebo-controlled, clinical trial to assess the safety and tolerability of exenatide treatment in participants with MCI/early AD. To this date, 30 participants have been enrolled, out of which 16 fulfilled inclusion criteria (clinical diagnosis of MCI/early AD, cerebrospinal fluid Ab(1-42) < 192 pg/dl) and were started on treatment with the study drug (exenatide or placebo). Eight participants completed the study, two participants were withdrawn from the study, and 6 continue treatment. Predictors and biomarkers of AD. In collaboration with NIA biostatistician, Larry Brant, I examined the performance of various physiological and laboratory measures followed longitudinally as predictors for AD. We found that longitudinal changes in blood pressure, lipids and depressive symptoms are significant predictors of future AD diagnosis with long lead times (the study is currently under review in the Journal of the American Geriatrics Society). In addition, 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. 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 is currently under review in the journal Neurobiology of Aging. 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 a maladaptive increase in metabolism at the hippocampus during the MCI stage, therefore, promoting AD pathogenesis (manuscript is currently under preparation). In collaboration with 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. I conducted a study in healthy volunteers, in which I combined these measures with resting fMRI, which provides measures of brain functional connectivity, which showed a link between these neurotransmitter levels and brain connectivity. The study was pubmished in Neuroimage. In addition, based on MRS measures, I examined the association between brain glucose metabolism and neurotransmission; the study is currently under review in the journal Brain Research. I also examined the association between cognitive performance in AD and CSF inflammatory markers and found that higher CSF IL-12 predicts better cognition; this study is currently under review in the Journal of Neuroinflammation. Finally, I combined MRS and fMRI with CSF sampling to obtain Abeta and tau measures of brain amyloidosis and neurodegeneration. Preliminary (unpublished) results from these combined cross-sectional fMRI/MRS/CSF studies suggest the presence of associations between: glucose, lactate, glutamate and GABA in the precuneus; functional connectivity within the default mode network; and CSF biomarkers. Genetic and phenotypic characterization studies in Frontotemporal Lobar Degeneration. I collaborated with researchers from the National Institute of Neurological Disorders and Stroke and Texas Tech University to perform genetic studies in a closed Frontotemporal Dementia cohort. This last year, we published our findings of C9ORF72 expansions in our Frontotemporal Dementia cohort in Neurobiology of Aging. In addition, I contributed to a GWAS study in FTD, which is currently under review in Nature Genetics.

用于治疗阿尔茨海默病（AD）的艾塞那肽。我继续进行了一项II期、双盲、随机、安慰剂对照的概念验证临床试验，以评估艾塞那肽治疗MCI/早期AD受试者的安全性和耐受性。到目前为止，已经招募了30名参与者，其中16名符合入选标准（MCI/早期AD的临床诊断，脑脊液Ab（1-42）< 192 pg/dl），并开始用研究药物（艾塞那肽或安慰剂）治疗。8名参与者完成了研究，2名参与者退出研究，6名继续治疗。 AD的预测因子和生物标志物。与NIA生物统计学家Larry Brant合作，我检查了各种生理和实验室指标的表现，这些指标作为AD的预测因子。我们发现，血压、血脂和抑郁症状的纵向变化是未来AD诊断的重要预测因素，且提前时间较长（该研究目前正在美国老年病学会杂志上进行审查）。此外，我实施了一种称为独立成分分析的数据简化技术，对来自ADNI的AD和MCI受试者的结构MRI图像进行分析，并研究了结构协方差模式如何预测临床诊断。这种方法使我们能够根据他们未来的诊断对受试者进行分类，准确度很高（可以说是有史以来最高的）;这项研究目前正在《衰老神经生物学》杂志上进行审查。此外，我研究了ADNI参与者的外周胰岛素抵抗如何与FDG-PET上的局部脑葡萄糖代谢相关。我们发现，胰岛素抵抗与MCI阶段海马代谢的不适应性增加有关，因此，促进了AD的发病机制（手稿目前正在编写中）。 与大卫赖特博士合作，我在NIA 3 T MRI设备上采用了一种新的磁共振波谱（MRS）方法，该方法使我们能够获得与AD发病机制相关的脑代谢物（葡萄糖，乳酸）和神经递质（谷氨酸和GABA）的体内测量结果。我在健康志愿者中进行了一项研究，将这些测量与静息功能磁共振成像结合起来，它提供了大脑功能连接的测量结果，显示了这些神经递质水平和大脑连接之间的联系。这项研究发表在Neuroimage上。此外，基于MRS测量，我检查了大脑葡萄糖代谢和神经传递之间的关联;该研究目前正在《大脑研究》杂志上进行审查。我还检查了AD的认知表现与CSF炎症标志物之间的关系，发现CSF IL-12水平越高，认知能力越好;这项研究目前正在《神经炎症杂志》上进行综述。最后，我将MRS和fMRI与CSF采样相结合，以获得脑淀粉样变性和神经变性的Abeta和tau测量值。这些联合横断面fMRI/MRS/CSF研究的初步（未发表）结果表明：楔前叶中的葡萄糖、乳酸盐、谷氨酸盐和GABA;默认模式网络内的功能连接;和CSF生物标志物之间存在相关性。 额颞叶变性的遗传和表型特征研究。我与美国国家神经疾病和中风研究所以及德克萨斯理工大学的研究人员合作，在一个封闭的额颞叶痴呆症队列中进行遗传研究。去年，我们在《衰老神经生物学》上发表了我们在额颞叶痴呆队列中C9 ORF 72扩增的发现。此外，我还参与了FTD的GWAS研究，该研究目前正在Nature Genetics上进行审查。