Advancements in clinical therapies have identified the need for biomarkers of early Alzheimer’s disease (AD) that distinguish the earliest stages of pathology and target those patients that are likely to gain the most benefit. The aim of this study was to characterize the longitudinal metabolic changes measured by 1H magnetic resonance spectroscopy (MRS) in correlation to neuropsychological indices of episodic memory, attention and mental processing speed, language facility, and executive function in subjects with mild cognitive impairment (MCI). Quantitative 1HMRS of the posterior cingulate gyrus was performed and repeated at 11.56 ± 4.3 months. N-acetyl aspartate (NAA), total choline (Cho), total creatine (Cr), myo-inositol (mI) and glutamate/glutamine (Glx) metabolite levels were measured, corrected for CSF dilution, and ratios calculated in MCI and cognitively normal subjects. In the first study MCI subjects showed lower NAA levels, NAA/Cho and NAA/mI ratios and increased Cho/Cr and mI/Cr compared to controls. In the follow-up study, 36% of the MCI subjects (atypical MCI, atMCI) showed interval increases in NAA, Cr and Glx levels compared to 64% of MCI subjects (typical MCI, tMCI) that showed an interval decrease in NAA, Cr, and Glx. Both MCI subgroups had higher Clinical Dementia rating (CDR) scores and lower scores on episodic memory, phonemic and semantic word fluency tasks, compared to controls. The annualized rate of change in metabolic and cognitive status did not differ between normal aging and MCI subjects. atMCI subjects showed significant negative correlations between metabolite levels and executive function task scores, with NAA/mI showing a significant positive correlation with phonemic and semantic word fluency. There were no significant correlations between metabolite levels and cognitive performance in atMCI subjects however; NAA/mI and mI/Cr were negatively correlated with executive function tasks. These results indicate two distinct evolving metabolite profiles that correlate with changes in executive function and can be used to differentiate MCI from normal aging. 

The metabolism of [1, 2 13C2] glucose via the tricarboxylic acid (TCA) cycle yields a number of key glutamate mass isotopomers whose formation is a function of pyruvate carboxylase (PC) and pyruvate dehydrogenase (PDH). Analysis of the isotopomer distribution patterns was used to determine the relative flux of glucose entry into the TCA cycle through anaplerotic and oxidative pathways in the cerebral cortex of both uninjured and traumatically injured adult male rats. In the cerebral cortex of uninjured animals the PC/PDH ratio showed greater metabolism of glucose via pyruvate carboxylase, which is consistent with the notion that the majority of glucose taken up at rest is used as a substrate for anaplerotic processes and not as an energy source. While traumatic brain injury did not change the overall 13C enrichment of glutamate indicating a continued oxidation of glucose, the PC/PDH ratio was reduced in the injured cortex at 3.5 h after injury. This suggests that glucose metabolism is primarily directed through pathways associated with energy production in the early post-injury period. By 24 h, the anaplerotic flux decreased and the PC/PDH ratio increased in both the injured and non-injured cortex indicating a switch away from energy production to pathways associated with anabolic and/or regenerative processes.

The present study determined the metabolic fate of [1, 2 13C2] glucose in male control rats and in rats with moderate lateral fluid percussion injured (FPI) at 3.5 h and 24 h post-surgery. After a 3 h infusion, the amount of 13C-labeled glucose increased bilaterally (26% in left/injured cerebral cortex and 45% in right cerebral cortex) at 3.5 h after FPI and in injured cortex (45%) at 24 h after injury, indicating an accumulation of unmetabolised glucose not seen in controls. No evidence of an increase in anaerobic glycolysis above control levels was found after FPI, as 13C-labeled lactate tended to decrease at both time points and was significantly reduced (33%) in the injured cortex at 24 h post-FPI. A bilateral decrease in the 13C-labeling of both glutamate and glutamine was observed in the FPI rats at 3.5 h and the glutamine pool remained significantly decreased in the injured cortex at 24 h, suggesting reduced oxidative metabolism in both neuronal and astrocyte compartments after injury. The percentage of glucose metabolism through the pentose phosphate pathway (PPP) increased in the injured (13%) and contralateral (11%) cortex at 3.5 h post-FPI and in the injured cortex (9%) at 24 h post-injury. Based upon the changes in metabolite pools, our results show an injury-induced decrease in glucose utilization and oxidation within the first 24 h after FPI. Increased metabolism through the PPP would result in increased NADPH synthesis, suggesting a need for reducing equivalents after FPI to help restore the intracellular redox state and/or in response to free radical stress.