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

我们发表了一项脑MRS研究，显示AD患者在楔前叶（阿尔茨海默病的关键区域）具有较高的葡萄糖和乳酸浓度以及较低的谷氨酸和GABA浓度。MRS葡萄糖水平有助于区分阿尔茨海默病患者和对照组，它们可能是这种疾病的一种有前途的新生物标志物。我们假设阿尔茨海默氏症中较高的葡萄糖浓度是FDG PET研究中葡萄糖利用率降低的镜像。有趣的是，MRS葡萄糖浓度随年龄单调增加。最近，我们修改了MRS技术，使脑b-羟基丁酸和其他酮体的测量。这些MRS指标用作代谢干预研究的结局，如5-2 CR、恩格列净和口服酮酯。 5-2卡路里限制的随机对照临床试验招募了认知正常的胰岛素抵抗参与者，并比较了5-2 CR和连续控制饮食。与来自西奈山的Frangou教授合作，结构MRI数据经过机器学习来计算BrainAge，显示饮食的改善。此外，功能磁共振成像数据正在分析，以确定在休息时的功能连接，并将其与认知性能指标相关联。 此外，在认知正常对照的恩格列净临床研究中，分析了关键默认模式网络节点楔前叶的MR波谱数据。我们发现恩格列净组的谷氨酸和谷氨酰胺水平降低，这可能反映了恩格列净诱导生酮引起的兴奋性神经传递降低。 我们与Chia和埃根博士合作，正在分析“RISE研究”的MRI扫描，这是一项多方面的随机安慰剂对照交叉临床研究，旨在研究CB 1受体激动剂和拮抗剂对外周代谢、脑功能和脑代谢控制的影响。这项研究包括一个强大的神经影像学组件，包括功能磁共振成像和磁共振成像。我们进行了两个激活范式功能磁共振成像研究，一个是发现大脑相关的头部胰岛素分泌和CB 1受体的影响，第二个是评估CB 1受体对食物食欲的影响。第一项研究的目的是证明胰岛素水平响应食物视觉刺激（头部胰岛素反应）的升高，这是由于某些脑区（小脑、前扣带回、下丘脑、腹侧被盖区等）的激活。此外，鉴于候选区域中存在CB 1受体，我们旨在证明CB 1激动剂和拮抗剂的激活水平存在差异。第二项研究的目的是证明CB 1受体刺激对食物价值（食物选择）和显着性（这种选择的强度）的可分离影响。此外，我们进行了静息功能磁共振成像研究，以评估CB 1调制的各种大脑网络的功能连接。最后，我们进行了MRS评估CB 1的脑代谢（葡萄糖，乳酸）和神经传递（谷氨酸，GABA，甘氨酸）的调制。我们目前正在分析和解释这些研究的数据。 我们与约翰霍普金斯研究人员合作，进行了一项研究，证明了多发性硬化患者EV中线粒体复合物的数量和功能与纵向脑和视网膜萎缩之间的关系。 我们进行了一项研究，证明Tau和淀粉样蛋白β沉积的区域模式以及葡萄糖代谢低下与多个基因的区域表达相关。这项研究表明，这些基因可能调节区域的脆弱性，AD的致病过程。

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.