Unravelling neuroinflammation-mediated mitochondrial dysfunction in mild cognitive impairment: Insights from targeted metabolomics

Background: The prevalence of Type-2 Diabetes Mellitus (T2DM) is rising rapidly among the elderly due to age-related metabolic changes. Older adults with T2DM have a 50–65 % increased risk of developing cognitive impairment, particularly mild cognitive impairment (MCI), which may progress to neurodegenerative conditions like Alzheimer's disease (AD). Recent studies underscore the significant roles of mitochondrial dysfunction, disrupted glutamate-glutamine cycling, hyperglycemia, and hyperprolinemia in cognitive decline. These interconnected metabolites—glucose, glutamine, glutamate, and proline—are potential targets for understanding the relationship between T2DM and cognitive impairment. Material and method: The present targeted NMR based metabolomics study aims to compare the blood plasma/serum metabolic profiles of these four metabolites in age and sex matched MCI (N = 27) and T2DM patients (N = 38) with respect to normal control (NC, N = 23) subjects. The metabolic profiling was performed using 1 H NMR spectroscopy. Results: Compared to NC group, both T2DM and MCI groups exhibited elevated glucose levels. Circulatory glucose and glutamine levels were significantly higher in T2DM subjects than in MCI and NC subjects, while glutamate levels followed a similar trend in both T2DM and MCI groups. However, in MCI patients, circulatory levels of proline, proline-to-glutamine (PQR) and glutamate-to-glutamine ratio (EQR) were significantly elevated compared to T2DM, while circulatory glutamine was significantly reduced. Conclusion: The decreased circulatory levels of glutamine and PQR demonstrated statistically significant correlation with the severity of the cognitive impairment as assessed based on Mini Mental State Examination (MMSE) score suggested augmented utilization of glutamine in MCI patients and accumulation of proline due to active neuro-inflammatory processes and impaired mitochondrial functioning in MCI brain.