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

National Institute On Aging

Investigators

Linked publications, trials & patents

Abstract

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.