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

我们发表了一项大脑MRS研究，显示AD患者楔前叶的葡萄糖和乳酸浓度较高，谷氨酸和GABA浓度较低，楔前核是阿尔茨海默病的关键区域。MRS的血糖水平有助于区分阿尔茨海默氏症患者和对照组，它们可能是一种有前途的新的疾病生物标记物。我们假设阿尔茨海默病患者较高的葡萄糖浓度是该疾病FDG PET研究中所见的葡萄糖利用降低的镜像。有趣的是，MRS的葡萄糖浓度随着年龄的增长而单调增加。最近，我们对磁共振波谱技术进行了改进，使其能够测量大脑中的b-羟基丁酸和其他酮体。这些MRS测量被用作代谢干预研究的结果，例如5-2CR、依帕格列酮和口服酮酯。 5-2卡路里限制的随机对照临床试验纳入了认知正常的胰岛素抵抗参与者，并比较了5-2卡路里限制和持续控制饮食。在与来自西奈山的Frangou教授的合作下，对结构性MRI数据进行了机器学习，以计算大脑年龄，显示出饮食的改善。此外，正在分析fMRI数据，以确定休息时的功能连接性，并将其与认知表现测量相关联。 此外，在一项认知正常对照组的临床研究中，分析了来自关键默认模式网络节点--楔前叶的磁共振波谱数据。我们发现，谷氨酸和谷氨酰胺水平随着依帕格列酮的降低而降低，这可能反映了依帕格列酮诱导酮的生成导致兴奋性神经传递的减少。 与Chia博士和Egan博士合作，我们正在分析“RISE研究”的MRI扫描结果，这是一项多方面、随机、安慰剂对照的交叉临床研究，研究CB1受体激动剂和拮抗剂对外周代谢、大脑功能和大脑代谢控制的影响。这项研究包括一个强大的神经成像部分，包括fMRI和MRS。我们进行了两项激活范式fMRI研究，一项是发现头部胰岛素分泌与CB1受体的作用之间的大脑相关性，另一项是评估CB1受体对食物食欲的影响。第一项研究的目的是证明，由于某些大脑区域(脑岛、前扣带回、下丘脑、腹侧被盖区等)的激活，食物视觉刺激(头部胰岛素反应)导致胰岛素水平上升。此外，考虑到候选区域存在CB1受体，我们的目的是证明它们与CB1激动剂和拮抗剂的激活水平不同。第二项研究的目标是证明CB1受体刺激对食物价值(食物选择)和显着性(此类选择的强度)的分离影响。此外，我们进行了一项静息fMRI研究，以评估CB1对各种大脑网络功能连接的调节。最后，我们进行了MRS来评估CB1对大脑代谢(葡萄糖、乳酸)和神经传递(谷氨酸、GABA、甘氨酸)的调节。我们目前正在分析和解释这些研究的数据。 与约翰霍普金斯大学的研究人员合作，我们进行了一项研究，展示了EVS中线粒体复合体的数量和功能与多发性硬化症患者的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β蛋白沉积的区域模式，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，这些基因可能调节对AD致病过程的区域性易感性。

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.