Brain structure, chemistry and function investigations in aging and Alzheimer's disease using MRI/MRS

使用 MRI/MRS 对衰老和阿尔茨海默病的脑结构、化学和功能进行研究

基本信息

批准号：
10913182
负责人：
Dimitrios Kapogiannis
金额：
$ 31.29万
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/10913182
关键词：
Adopted Affective Age Aging Agonist Alzheimer&apos s Disease Alzheimer&apos s disease patient Amyloid beta-Protein Amyloid deposition Anterior Area Atrophic Biological Markers Brain CNR1 gene Caloric Restriction Cephalic Chemistry Clinical Research Clinical Trials Cognitive Collaborations Complex Data Data Analyses Deposition Desire for food Diet Disease Enrollment Esters Food Functional Magnetic Resonance Imaging Genes Glucose Glutamates Glutamine Glycine Goals Hypothalamic structure Image Insula of Reil Insulin Insulin Resistance Intervention Investigation Ketone Bodies Ketones Knowledge MRI Scans Machine Learning Magnetic Resonance Imaging Magnetic Resonance Spectroscopy Measurement Measures Metabolic Metabolic Control Metabolism Methodology Mitochondria Oral Outcome Participant Pathogenesis Pathogenicity Pattern Peripheral Placebo Control Play Positron-Emission Tomography Process Publishing Randomized Randomized Controlled Clinical Trials Reporting Research Research Personnel Rest Retina Role Structure Techniques Ventral Tegmental Area aging brain antagonist beta-Hydroxybutyrate brain metabolism cerebrovascular cognitive performance dietary control fluorodeoxyglucose positron emission tomography gamma-Aminobutyric Acid glucose metabolism improved insulin secretion ketogenesis memory encoding memory retrieval metabolic abnormality assessment multiple sclerosis patient neurochemistry neuroimaging neuroimaging marker neurotransmission novel novel marker response tau Proteins vascular abnormality visual stimulus white matter

项目摘要

We published a brain MRS study showing that patients with AD have higher glucose and lactate concentrations and lower glutamate and GABA concentrations in the precuneus, a critical area for Alzheimer's disease. MRS Glucose levels helped discriminate patients with Alzheimer's from controls and they may be a promising novel biomarker for the disease. We hypothesized that higher glucose concentration in Alzheimer's is the mirror image of decreased glucose utilization seen in FDG PET studies in the disease. Interestingly MRS glucose concentration increases monotonically with age. Recently, we modified MRS techniques to enable measurement of brain b-hydroxybutyrate and other ketone bodies. These MRS measures were used as outcomes in studies of metabolic interventions, such as 5-2 CR, empagliflozin and oral ketone ester. The randomized controlled clinical trial of 5-2 Calorie Restriction enrolled cognitively normal participants with insulin resistance and compared 5-2 CR and a continuous control diet. In collaboration with Prof. Frangou from Mt Sinai, structural MRI data were subjected to machine learning to calculate BrainAge, showing improvements with diets. In addition, fMRI data are being analyzed to determine functional connectivity during rest and correlate it with cognitive performance measures. In addition, MR spectroscopy data from the key default mode network node, the precuneus, were analyzed in a clinical study of empagliflozin in cognitively normal controls. We found that levels of glutamate and glutamine decreased with empagliflozin, perhaps reflecting decreased excitatory neurotransmission by empagliflozin inducing ketogenesis. In collaboration with Drs. Chia and Egan, we are in the process of analyzing MRI scans from the "RISE study", a multi-faceted randomized placebo-controlled cross-over clinical study on the effects of a CB1 receptor agonist and antagonist on peripheral metabolism, brain function and brain metabolic control. The study included a robust neuroimaging component including fMRI and MRS. We performed two activation-paradigm fMRI studies, one to discover brain correlates of cephalic insulin secretion and the effects of CB1 receptors, the second to assess the effects of CB1 receptors on food appetitiveness. The goal of the first study was to demonstrate a rise in insulin levels in response to food visual stimuli (cephalic insulin response) as a result of activation of certain brain areas (insula, anterior cingulate, hypothalamus, ventral tegmental area, etc). Moreover, given the presence of CB1 receptors in the candidate areas, we aimed to demonstrate a difference in their level of activation with CB1 agonists and antagonists. The goal of the second study was to demonstrate dissociable effects of CB1 receptor stimulation on food value (food choices) and salience (intensity of such choices). In addition, we performed a resting fMRI study to assess CB1 modulation of functional connectivity of the various brain networks. Finally, we performed MRS to assess CB1 modulation of brain metabolism (glucose, lactate) and neurotransmission (glutamate, GABA, glycine). We are currently in the process of analyzing and interpreting the data from these studies. In collaboration with Johns Hopkins investigators, we performed a study demonstrating relationships between the quantity and function of mitochondrial complexes in EVs and longitudinal brain and retinal atrophy in patients with Multiple Sclerosis. We performed a study demonstrating that the regional patterns of deposition of Tau and amyloid-beta, as well as glucose hypometabolism, are associated with regional expression of multiple genes. This study suggests that these genes may modulate regional vulnerability to AD pathogenic processes.

我们发表了一项大脑MRS研究，表明AD患者的葡萄糖和乳酸浓度较高，较低的谷氨酸和GABA浓度是阿尔茨海默氏病的关键领域。葡萄糖夫人水平有助于将阿尔茨海默氏症患者与对照区分开，这可能是该疾病的新型生物标志物。我们假设阿尔茨海默氏症中较高的葡萄糖浓度是在该疾病的FDG PET研究中看到的葡萄糖利用率降低的镜像。有趣的是，葡萄糖浓度随着年龄的增长而单调增加。最近，我们修改了MRS技术，以实现脑B-羟基丁酸和其他酮体的测量。这些MRS测量被用作代谢干预措施的研究，例如5-2 CR，empagliflozin和口服酮酯。 5-2卡路里限制的随机对照临床试验使认知正常参与者具有胰岛素抵抗，并比较了5-2 CR和连续控制饮食。与西奈山的Frangou教授合作，对结构性MRI数据进行了机器学习，以计算脑部，并显示出饮食的改善。此外，正在分析fMRI数据，以确定休息期间的功能连接性，并将其与认知绩效指标相关联。此外，在认知正常对照中对empagliflozin的临床研究中分析了来自关键默认模式网络节点的MR光谱数据。我们发现，谷氨酸和谷氨酰胺的水平随雌糖苷的降低，也许反映出伴有雌激素诱导生酮发生的兴奋性神经传递降低。与Drs合作。 Chia和Egan，我们正在分析“ RISE研究”中的MRI扫描，这是一项多面的随机安慰剂对照的跨界临床研究，该研究对CB1受体激动剂和拮抗剂对外周代谢，脑功能和脑功能和脑机构代谢控制的影响。该研究包括包括fMRI和MRS在内的强大神经影像成分。我们进行了两项激活 - 范式pRADIGM FMRI研究，其中一项发现头孢氨胰岛素分泌的脑相关性和CB1受体的作用，第二种是评估CB1受体对食物食欲的影响的第二种。第一项研究的目的是证明胰岛素水平响应于食物视觉刺激（头孢酸胰岛素反应），这是由于某些大脑区域的激活（岛状，前扣带回，下丘脑，腹侧段盖面积等）的结果。此外，鉴于候选区域中CB1受体的存在，我们旨在证明它们与CB1激动剂和拮抗剂的激活水平有所不同。第二项研究的目的是证明CB1受体刺激对食物价值（食物选择）和显着性（这种选择的强度）的可分离作用。此外，我们进行了静止的功能磁共振成像研究，以评估各种大脑网络功能连通性的CB1调制。最后，我们进行了MRS评估脑代谢（葡萄糖，乳酸）和神经传递（谷氨酸，GABA，甘氨酸）的CB1调节。目前，我们正在分析和解释这些研究的数据。我们与约翰·霍普金斯（Johns Hopkins）的调查员合作，进行了一项研究，证明了多发性硬化症患者的电动汽车和纵向大脑和视网膜萎缩的线粒体复合物的数量和功能之间的关系。我们进行了一项研究，表明TAU和淀粉样蛋白β的沉积区域模式以及葡萄糖低代谢与多个基因的区域表达有关。这项研究表明，这些基因可能调节区域脆弱性对AD致病过程。