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

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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 will be used as outcomes in studies of metabolic interventions, such as 5-2 CR, empagliflozin and oral ketone ester. In collaboration with Drs. Chia and Egan, we are 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.