Exploring Metabolic Links to Cognitive Impairment in MS

Potential predictors for cognitive impairment in patients with multiple sclerosis (MS)could include elevated fasting blood sugar (FBS), developed fasting insulin levels, and reduced insulin sensitivity, according to research published in Endocrinology, Diabetes & Metabolism.¹

Based on their research and on prior work, the authors believe notable connections likely exist among metabolic dysregulation, neurodegenerative pathways, and cognitive function in this population. Earlier studies on the correlation of blood sugar factors with cognitive impairment have primarily focused on insulin and insulin sensitivity,² whereas this research is the first to comprehensively examine the link between cognitive dysfunction and whole FBS, insulin sensitivity, and fasting insulin level, the authors explained.

The cross-sectional study included 85 patients with MS (mean age, 39.4 years; 72.9% female). Insulin sensitivity was determined using the Quantitative Insulin Sensitivity Check Index (Quicki) formula. The participants had a mean FBS of 87.05 mg/dL, mean insulin of 10.14 μU/mL, and a mean Quicki index of 0.36.

Cognitive function was evaluated using the subtests and delayed subtests of the Brief International Cognitive Assessment for MS: the California Verbal Learning Test second edition (CVLT-II), the Symbol Digit Modalities Test, and the Brief Visuospatial Memory Test-Revised (BVMT-R).

The inflammatory etiology of multiple sclerosis may precipitate hyperinsulinemia and elevate the risk of insulin resistance, further elevating blood glucose levels. | Image Credit: © arloo-stock.adobe.com

The investigators found that higher scores (ie, better performance) on the BVMT-R and the BVMT-R-Delayed recall subtests had a significant negative correlation with FBS (r, –0.32; P = .003; and r, –0.31; P = .004, respectively). Conversely, higher fasting insulin levels had a significant negative correlation with worse scores on the CVLT-II (r, –0.24; P = .031). Further, insulin sensitivity showed a positive correlation with better performance on the CVLT-II (r, 0.24; P = .027) and BVMT-R (r, 0.21; P = .054) subtests.

Prior investigations have shown that the particular types of cognitive dysfunction associated with MS seem to predominantly affect recent memory, information processing speed, sustained attention, and executive functioning.³

Enmeshed and Problematic Pathways

The intertwined nature of metabolic, inflammatory, and neurodegenerative processes in the context of MS can lead to cognitive deficits. Notably, it is a bidirectional relationship, the investigators emphasized: The inflammatory etiology of MS may precipitate hyperinsulinemia and elevate the risk of, or exacerbate, insulin resistance, further elevating blood glucose levels, for instance. Conversely, increased blood glucose can intensify inflammatory processes, thus raising the risk of cognitive impairment. Research indicates that the inflammatory sequelae of metabolic syndrome have links to the pathogenesis of neurodegenerative diseases.

The authors noted that both the pathology of MS and consequent related cognitive dysfunction are linked to various pathways: These include inflammation, demyelination and subsequent remyelination, oxidative stress, blood-brain barrier dysfunction, viral antigenic effects, and cellular metabolism disruptions. Further, a primary driver of MS pathology is the disruption of immune and inflammatory homeostasis. Contributing to the elevated incidence of insulin resistance in patients with MS may be an imbalance between activated inflammatory mediators and the quantity and functionality of Th17 cells and regulatory T cells. When T cells increase in patients with MS, the potential exists for an upsurge of inflammatory cytokines within central nervous system lesions. The back-and-forth continues.

“These inflammatory mediators, by interfering with metabolic processes, may dysregulate insulin signaling pathways, thereby promoting insulin resistance,” continued the researchers. Then, “insulin resistance can precipitate hyperglycemia, [known] for its proinflammatory characteristics.” It can stimulate an acute immune response involving inflammatory mediators, including leukocytes and cytokines, which are integral to glucose metabolism.

Internationally, investigators are delving into the reasons patients with MS may experience cognitive impairment, the authors concluded, adding that it is a question integral to patients’ broader quality of life. Once the underlying causes are well understood, lifestyle modifications or pharmacotherapy could potentially go a long way in managing the metabolic parameters involved.

References

1. Rezaeimanesh N, Kasbi NA, Saeedi R, Sahraian MA, Jahromi SR, Moghadasi AN. Investigating the correlation between cognitive function and fasting blood sugar, fasting insulin level and insulin sensitivity in patients with multiple sclerosis. Endocrinol Diabetes Metab. 2024;7(6):e70006. doi:10.1002/edm2.70006

2. Ayromlou H, Hosseini S, Khalili M, et al. Insulin resistance is associated with cognitive dysfunction in multiple sclerosis patients: a cross-sectional study. J Neuroendocrinol. 2023;35(6):e13288. doi:10.1111/jne.13288

3. Fischer M, Kunkel A, Bublak P, et al. How reliable is the classification of cognitive impairment across different criteria in early and late stages of multiple sclerosis? J Neurol Sci. 2014;343(1-2):91-99. doi:10.1016/j.jns.2014.05.042