ALZHEIMERS RESEARCH PROJECT / CLINICAL PROJECT: Brain structure, chemistry and function investigations in aging and Alzheimer's disease using MRI/MRS

National Institute On Aging

Investigators

Linked publications & trials

Abstract

We published a brain MRS study showing that patients with AD have higher glucose, ascorbate and lactate concentrations and lower glutamate and GABA concentrations in the precuneus, a critical area for Alzheimer's disease (AD). MRS Glucose levels helped discriminate patients with AD from controls and they may be a promising novel biomarker for the disease. We hypothesized that higher glucose concentration in AD is the mirror image of decreased glucose utilization seen with FDG PET. Interestingly, we found that 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 Intermittent Fasting (IF), empagliflozin and oral ketone ester. The randomized controlled clinical trial of 5-2 Intermittent Fasting enrolled cognitively normal participants with insulin resistance and compared 5-2 Intermittent Fasting and a continuous control diet (Healthy Living 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, MR spectroscopy data from the key default mode network node, the precuneus, revealed decreased glucose concentration (indicating optimized glucose metabolism) with both 5-2 Intermittent Fasting and the Healthy Living diet. MRS was implemented 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. We are in the process of analyzing BrainAge and MRS in the clinical trial of the oral ketone ester. Moreover, in collaboration with Dr. Bouhrara, we will implement novel measures of neuritic and myelin density, as well as BrainAge and MRS in the upcoming clinical trial of psilocybin and cognitive training in AD. Finally, in collaboration with Johns Hopkins investigators, we performed a study demonstrating relationships between the quantity and function of mitochondrial complexes and synaptic proteins in EVs and longitudinal brain (and retinal) atrophy in patients with Multiple Sclerosis.