An imaging biomarker to detect non-glucogenic shift in brain energy metabolism in Alzheimer's disease.

BACKGROUND

Cerebral glucose hypometabolism in Alzheimer's disease (AD) leads to enhanced metabolism of fatty acids (FAs) and branched-chain amino acids (BCAAs) as a compensatory mechanism. While there have been some 13C labeled studies investigating the metabolism of FAs and BCCAs, their clinical translation is challenging. In this study, we investigated the potential of measuring neurometabolic perturbations through macromolecular signal at 0.9 ppm (MM09) in proton magnetic resonance (1H MR) spectrum. This signal represents a composite macromolecular signal with contributions from lipids and BCAA associated methyl resonances and may be sensitive to metabolic alterations occurring during glucose hypometabolism in AD.

METHODS

MM09 levels were measured from localized 1H MR spectra in the hippocampus and thalamus/hypothalamus of male and female APPNL-F/NL-F (AD) mice. In addition, the levels of glutamate in these regions were also recorded as it is known to be reduced under glucose hypometabolism in AD. We further studied the metabolic association of MM09 with glutamate in Pearson correlation plots. To find the statistical significance of difference two-way ANOVA analysis with post-hoc Tukey HSD tests were used.

RESULTS

Male AD mice exhibited significantly reduced MM09 (15.42 ± 1.32 vs. 16.93 ± 1.15 mM; p = 0.008) and glutamate levels (15.27 ± 1.65 vs. 17.24 ± 1.21 mM; p = 0.004) in the hippocampus. Female AD mice did not show any changes in glutamate or MM09 levels. MM09 also showed a strong positive correlation with glutamate (R = 0.74; p < 0.0001).

CONCLUSION

The observed reductions in MM09 and glutamate in male AD mice are consistent with neurometabolic alterations associated with impaired glucose metabolism, whereas the absence of such changes in female AD mice may reflect sex-specific metabolic resilience. The strong association between MM09 and glutamate suggests that MM09 may capture neurochemical changes linked to metabolic adaptations in AD. Because the MM09 resonance occurs in a relatively uncrowded region of the 1H MR spectrum, it may represent a promising spectroscopic marker for investigating metabolic shifts in AD and warrants further evaluation in clinical studies.