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.

阿尔茨海默氏病（AD）治疗的艾鉴定。我继续进行概念II阶段的证明，双盲，随机，安慰剂对照，临床试验，以评估MCI/早期AD参与者中艾塞那肽治疗的安全性和耐受性。到目前为止，已经招募了30名参与者，其中16个满足的纳入标准（MCI/早期AD的临床诊断，脑脊液AB（1-42）<192 pg/dl），并开始使用研究药物（AneNATIDE或安慰剂）进行治疗。八名参与者完成了这项研究，两名参与者被撤回研究，6名继续治疗。 AD的预测因素和生物标志物。与NIA生物统计学家拉里·布兰特（Larry Brant）合作，我研究了各种生理和实验室措施的表现，纵向遵循了AD的预测指标。我们发现，血压，脂质和抑郁症状的纵向变化是未来AD诊断时间长的较长交货时间的重要预测指标（该研究目前正在美国老年医学学会杂志上进行综述）。此外，我还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图像进行研究，并研究了结构协方差的模式如何预测临床诊断。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）；目前，该研究正在审查《衰老神经生物学》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，胰岛素抵抗与MCI阶段的海马新陈代谢不良有关，因此促进AD发病机理（目前正在制备中）。 我与David Reiter博士合作，在NIA 3T MRI设备上采用了一种新型的磁共振光谱（MRS）方法，这使我们能够在体内对脑代谢物（葡萄糖，乳酸）和神经递质（谷氨酸和GABA）（谷氨酸和GABA）的体内测量，与AD型相关。我对健康志愿者进行了一项研究，其中我将这些措施与静息fMRI相结合，该措施提供了大脑功能连通性的度量，该措施显示了这些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。此外，根据MRS措施，我研究了脑葡萄糖代谢与神经传递之间的关联。该研究目前正在《大脑研究》杂志上进行综述。我还研究了AD和CSF炎症标记中认知表现之间的关联，发现较高的CSF IL-12可以预测更好的认知。目前，这项研究正在审查《神经炎症杂志》中。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退行性的ABETA和TAU测量。这些联合横截面fMRI/MRS/CSF研究的初步（未发表）结果表明：葡萄糖，乳酸，谷氨酸和GABA之间存在关联。默认模式网络中的功能连接；和CSF生物标志物。 额颞叶变性的遗传和表型表征研究。我与国家神经疾病与中风研究所和德克萨斯理工大学的研究人员合作，在封闭的额颞痴呆群中进行遗传研究。去年，我们在衰老神经生物学中发表了C9orf72扩展的发现。此外，我为FTD中的GWAS研究做出了贡献，该研究目前正在自然遗传学中。