Association of Glutamate and N-Acetylaspartate Levels with Abnormal Protein Deposition in Alzheimer's Disease: Insights from Magnetic Resonance Spectroscopic Imaging

Background Accumulating evidence indicated decreased levels of glutamate (Glu) and N-acetylaspartate (NAA) in the posterior cingulate cortex (PCC) in Alzheimer's disease (AD) brains. However, the levels of these metabolites in the other brain regions and the associations with abnormal protein of AD remain to be elucidated. Methods We enrolled 19 patients with AD and 26 healthy controls (HC). We performed magnetic resonance spectroscopic imaging (MRSI) to evaluate Glu/creatine (Cr) and NAA/Cr ratios and measure plasma neurofilament light chain (NfL) levels. We examined tau and amyloid-β depositions with standardized uptake value ratios (SUVRs) of florzolotau (18F) and 11C-PiB positron emission tomography, respectively. Heatmaps were created to visualize Z scores of Glu/Cr and NAA/Cr ratios using HC data. Results In the AD brains, Z-score maps demonstrated reduced Glu/Cr and NAA/Cr ratios in the gray matter, including the right dorsolateral prefrontal cortex (DLPFC) and PCC; Glu/Cr ratios negatively correlated with florzolotau (18F) SUVRs in the PCC; mini-mental state examination total scores correlated with Glu/Cr (P < 0.001, r = 0.72) and NAA/Cr ratios (P < 0.001, r = 0.75) in the right DLPFC; and blood NfL levels were increased and negatively correlated with the Glu/Cr (P = 0.040, r = −0.50) and NAA/Cr ratios (P = 0.003, r = −0.68) in the right DLPFC. Conclusions Our findings indicated that decreased Glu/Cr levels correlated with tau pathologies of AD in the PCC. MRSI is capable of providing spatial information on neural function, enabling the identification of vulnerabilities in the right DLPFC in AD pathology. ### Competing Interest Statement H.S. (Hitoshi Shimada), M.-R.Z., T.S., and M.H. hold patents on compounds related to the present report (JP 5422782/EP 12 884 742.3/CA2894994/HK1208672). All other authors report no biomedical financial interests or potential conflicts of interest. ### Funding Statement This study was also supported in part by AMED under grant numbers JP18dm0207018, JP19dm0207072, JP18dk0207026, JP19dk0207049, and 22dk0207063, and JSPS KAKENHI grant numbers JP19H01041, JP16H05324, JP18K07543, and JP20K16681. ### Author Declarations I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained. Yes The details of the IRB/oversight body that provided approval or exemption for the research described are given below: This study was approved by the Institutional Review Board of the NIRS. I confirm that all necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived, and that any patient/participant/sample identifiers included were not known to anyone (e.g., hospital staff, patients or participants themselves) outside the research group so cannot be used to identify individuals. Yes I understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance). Yes I have followed all appropriate research reporting guidelines, such as any relevant EQUATOR Network research reporting checklist(s) and other pertinent material, if applicable. Yes Data are available upon reasonable request. Anonymized raw data supporting the findings of the present study may be shared upon request with the corresponding author.