Increased Aerobic Glycolysis in Normal Appearing White Matter Revealed as Metabolic Abnormality in Multiple Sclerosis

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A recent study presented at the 2024 ACTRIMS Forum suggests that increased aerobic glycolysis in normal appearing white matter may be an early feature of multiple sclerosis.

Matthew R. Brier, MD, PhD, neurology chief resident at Washington University in St. Louis

Matthew R. Brier, MD, PhD

Credit: Washington University in St. Louis

New findings from a study presented at the 2024 Americas Committee for Treatment and Research in Multiple Sclerosis (ACTRIMS) Forum, February 29 to March 2, revealed increased aerobic glycolysis (AG) in normal appearing white matter (NAWM), demonstrated by increases in cerebral metabolic rate of glucose (CMRglc) relative to cerebral metabolic rate of oxygen (CMRO2), which characterized disrupted cerebral metabolism in multiple sclerosis (MS). These findings suggest that metabolic abnormalities may be an early feature of MS and not a late consequence of acquired tissue injury.1

In the study, investigators observed an increase in CMRglc in NAWM among patients with relapsing MS (P = 0.0031) and in those with nonrelapsing MS (P = .0012) in comparison with healthy controls (HCs). Between the groups, there was no differences in CMRO2 and NAWM AG increased in relapsing MS (P = .015) and nonrelapsing MS (P = .0093). Treatment with sphingosine 1-phosphate (S1P) modulating therapy and not an anti-CD20 therapy, reduced hypermetabolism of glucose in NAWM (P = .0012). In addition, researchers observed that normal metabolic gradients, such as acceleration of CMRglc with distance from the ventricular surface, were more distinguished in MS.

Top Clinical Takeaways

  • Increased aerobic glycolysis in normal appearing white matter (NAWM) suggests early metabolic abnormalities in multiple sclerosis (MS).
  • Sphingosine 1-phosphate (S1P) modulating therapy, not anti-CD20 therapy, demonstrated a reduction in hypermetabolism of glucose in NAWM.
  • White matter lesions (WMLs) in MS patients exhibited variable metabolic abnormalities, potentially reflecting diverse underlying tissue damage or repair potential.

Conducted by senior author Matthew R. Brier, MD, PhD, neurology chief resident at Washington University in St. Louis, and colleagues, 21 treatment naïve patients with relapsing MS, 9 patients with non-relapsing MS (who had 10 years disability duration with no relapses in over 2 years), and 12 HCs underwent simultaneous FDG PET/MR imaging. Patients with relapsing MS returned approximately between 3 and 6 months after starting S1P modulating (n = 8) or anti-CD20 therapy (n = 12). Authors calculated CMRglc through Patlak analysis of FDG PET utilizing blood-calibrated image-derived input functions. Researchers then computed CMRO2 from cerebral blood flow and oxygen extraction fraction images derived from MRI. AG, otherwise the over-utilization of glucose relative to oxygen, was also calculated stoichiometrically from both CMRglc and CMRO2. Using linear models, authors compared the CMRglc, CMRO2, and AG in NAWM and white matter lesions (WML).

READ MORE: Study Reveals Expanded CD8+ T Cell Clonotypes in Cerebrospinal Fluid in Patients With Multiple Sclerosis

Despite the fact that many WMLs displayed as hypometabolic for both glucose and oxygen, authors observed a significant fraction of WMLs revealed hypermetabolism of both. After modeling WML metabolism as a function of lesion features including size, location, and MRI characteristics, investigators reported that T1 hypointense WMLs as an indicator of tissue damage had higher levels of AG without evidence of ischemia, or decreased CMRO2. Overall, authors noted that individual WMLs demonstrated variable metabolic abnormalities, which may relate to underlying tissue damage or repair potential. Furthermore, investigators noted that disease modifying therapies could impact the observed abnormal metabolic profile from the study differentially.

Findings in a prior study published in Journal of Cerebral Blood Flow & Metabolismsuggested that changes in brain physiology may precede MRI-detectable grey-matter (GM) loss and may contribute to disease progression and neurodegeneration in MS.2 Investigators used novel dual-calibrated functional MRI to map GM deoxy-hemoglobin sensitive cerebral blood volume (CBVdHb), cerebral blood flow (CBF), oxygen extraction fraction (OEF), and CMRO2 in patients with MS and age/sex matched controls.

By integrating a flow-diffusion model of oxygen transport, researchers assessed the effective oxygen diffusivity of the capillary network (DC) and the partial pressure of oxygen at the mitochondria (PmO2). Authors observed significant between-group differences as decreased CBF (P = 0.010), CMRO2 (P <.001) and DC (P = .002), and increased PmO2 (P = .043) in patients compared to controls. Researchers also observed no significant differences for CBVdHb (P = .389), OEF (P = .358), or GM volume (P = .302). In the regional analysis, results demonstrated widespread reductions in CMRO2 and DC for patients with MS.

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REFERENCES
1. Judge BA, Chunwei Y, Hongyu A, et al. Increased Aerobic Glycolysis is Present in Early Multiple Sclerosis and Varies by Treatment. Presented at ACTRIMS Forum 2024; February 29 to March 2; West Palm Beach, Florida. CE2.2.
2. Chandler HL, Stickland RC, Patitucci E, et al. Reduced brain oxygen metabolism in patients with multiple sclerosis: Evidence from dual-calibrated functional MRI. J Cereb Blood Flow Metab. 2023;43(1):115-128. doi:10.1177/0271678X221121849
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