The search for biomarkers that can detect and track the disease progression in individuals with Alzheimer’s disease (AD) has been a major pursuit. Regional hypo-metabolism measured by fluorodeoxyglucose positron emission tomography (FDG PET) has been found to scale with AD severity¹. Several studies reported areas of hypo-perfusion measured by arterial spin labeling (ASL) MRI overlap considerably with hypo-metabolism. However, some studies have also noted increased regional cerebral blood flow (CBF) of individuals with early stage clinical AD, which may indicate an initial compensatory response to neurodegeneration². Brain metabolites obtained through MRS are related to post-mortem neuropathological changes in individuals with Alzheimer’s disease; in particular decreases in N-Acetylaspartate/creatine (NAA/Cr), a marker of neuronal integrity and myo-inositol/Cr an index of gliosis/inflammation were found to be associated with higher Braak stage, and greater likelihood of AD³. A recent review of 705 distinct metabolite reports concluded that alterations in glutamate clearance from the synaptic cleft may contribute an excitotoxic component to AD pathology⁴. The purpose of this study was to find associations between metabolites measures by MRS and glucose metabolism using FDG PET and CBF measured by ASL MRI.15 participants (8 men, 7 women, mean 79 age ± 9y/o) were consented and enrolled in this study. Of the 15 participants 6 had been diagnosed with AD, 5 with mild cognitive impairment (MCI) and 4 participants served as matched cognitively healthy older adults (CHOA). Imaging consisted of a 18F-FDG PET scan using a 3 Tesla mMR PET-MRI (Siemens, Erlangen), ASL MRI, and MR spectroscopy using a Trio (Siemens, Erlangen). Cerebral blood flow (CBF) was calculated from the ASL data. Single voxel 1H MR spectra were acquired from the posterior cingulate gyrus (VOI=2x2x2cm³) using a point resolved spectroscopy sequence with water suppression enhanced through T1 effects, and the following parameters: TE=30 ms, TR=1700 ms, and 128 acquisitions. In addition, water unsuppressed spectra were acquired from the same region to estimate ‘absolute’ concentrations. All spectra were processed offline using LCModel software to determine the quantities of the brain metabolites NAA, Cr, choline (Cho), mI, and glutamine+glutamate (Glx). Cortical reconstructions were performed on each individual from T1 data using Freesurfer (surfer.nmr.mgh.harvard.edu) and FDG and CBF measures were mapped to the cortical surface. General linear models tested for the association between metabolites and surface based CBF and FDG measures using the mri_glmfit tool provided in Freesurfer. ANOVA and Student t tests were used to compare metabolite concentrations between groups. Discriminant analysis was used to determine which variables discriminate between AD and MCI or CHOA. All analyses were conducted using JMP 11.0.ANOVA showed a trend toward significant differences in mI between the 3 groups (ANOVA p=0.08) with higher mI levels found in individuals with AD compared to CHOA (p=0.05) and MCI (p=0.05). None of the other MRS metabolic markers showed significant differences between groups which can be attributed to a limited sample size. There was an association between increased mI and regional hypo-metabolism in the brain measured by FDG (Figure 1) as well hypo-perfusion measured by ASL (Figure 2). Discriminant analysis showed a good separation between individuals with AD and MCI or CHOA when combining mI and FDG or CBF as variables. In contrast, other MRS metabolites such as Cr and Glx showed a non-group dependent association with cerebral FDG-uptake or CBF. Liner regression analysis across all participants revealed that Cr, a marker of altered energy metabolism positively correlated with increased glucose uptake by FDG PET (Figure 3). Increased Glx was related to decreased metabolic activity by PET (Figure 4) and decreased CBF (Figure 5). Of note, levels of NAA had the least associations with FDG PET or CBF in our population. A few studies have investigated multimodal approaches to establish biomarkers for AD⁵. Our study compared MRS markers of inflammation, (mI), altered energy metabolism (Cr) and excitotoxicity (Glx) to glucose metabolism (FDG PET) and perfusion. Both markers of energy metabolism, Cr measured by MRS and FDG uptake measured by PET showed associations across all groups. Combining markers of inflammation and hypo-metabolism or hypo-perfusion provided a good classification between individuals with AD and MCI or CHOA. Lastly, these data may support the idea that excitotoxic pathology may be a feature of AD which results in or is the result of hypometabolism and hypo-perfusion. However, these conclusions are highly speculative given the small sample size examined here and future work will be necessary to clarify these results.Multi-parametric imaging may be used to detect multipathologic conditions in AD and MCI individuals varying in their combined pathology.