Young Investigators Explore Aerobic Glycolysis, Paramagnetic Rim Lesions in MS

On day 2 of the Americas Committee for Treatment and Research in Multiple Sclerosis (ACTRIMS) Forum 2024, a session on cutting edge developments in multiple sclerosis (MS) was conducted by multiple young investigators. These talks included research on aerobic glycolysis (AG) in MS by Bradley Judge, Washington University in St. Louis, and a presentation by Hannah Schwartz, Cornell University, on paramagnetic rim lesions (PRLs) and cognitive performance.

Breaking Barriers in MS ACTRIMS Forum 2024 | image credit: forum.actrims.org

Aerobic Glycolysis in MS

Judge and his colleagues' research began with 3 questions: Why are cerebral metabolism and AG important in MS? Is AG abnormal in early MS? Is AG affected by MS treatment? These questions are significant because dysregulation in cerebral metabolism has been connected to tissue injury and neurodegeneration; however, at present, the origins of metabolic variation and the means through which oxygen and glucose metabolism change in MS remain uncertain. Judge et al investigated alterations in oxygen and glucose metabolism in MS brain tissues to discern whether these alterations were an early or late feature of MS. Additionally, they assessed the effect MS treatments have on cerebral metabolism.

The study cohort consisted of 21 treatment-naïve patients with relapsing MS (RMS) with new diagnoses, 9 patients with non-relapsing MS (NRMS) with 10 years of disease duration, and 12 healthy control individuals (HC). All participants underwent fluorodeoxyglucose (FDG)-positron emission tomography (PET)/MRI. FDG PET was used to quantify participants’ cerebral metabolic rate of glucose (CMRglc) while MRI was used to quantify cerebral metabolic rate of oxygen (CMRO₂). AG is calculated from these measures by subtracting CMRO₂ from CMRglc. The patients with RMS underwent 3 to 6 months of treatment with either anti-CD20 or sphingosine 1-phosphate (S1P) therapy before returning for analysis. As they assessed their results, they were primarily interested in regions of normal appearing white matter (NAWM) and lesions.

Patients with RMS and NRMS exhibited increased CMRglc (P = .0031 and P = .0012) compared with HC. No significant differences were seen in CMRO2 between groups; however, AG was significantly higher in both RMS and NRMS (P = .015 and P = .0093) compared with HC.

“We could maybe expect that this development of abnormal metabolism is not in a stepwise manner. And so you could see that there's metabolic abnormalities that start to form even before you get diagnosed with MS in the clinic,” Judge added.

A significantly reduced hypermetabolism of glucose was seen in the NAWM of those who received S1P therapy (P =.0012), but this significance was not seen in those who underwent anti-CD20 therapy.

There was a great amount of variability in white matter lesions (WMLs). WMLs that were hypometabolic for both oxygen and glucose; however, many were also observed that were hypermetabolic for both. “And there could be many reasons for this variability in here. One of which that we have access to investigate immediately was lesion damage.” Subsequently, T1 hypointensity (a sign of tissue damage) was utilized as a proxy for tissue damage and it was seen that T1 hypointense WMLs had increased levels of AG.

In this study, metabolic alterations were not a consequence of tissue damage but an earlier feature of MS. Considering this finding, Judge et al were still left with a few lingering questions about the driver of these changes as they appear to be impacted by MS treatment type. As lesions or inflammation could drive the increases of AG in NAWM, the reverse was also considered possible, as was the potential of a positive feedback look between these factors or the possibility of a third, unknown actor.

Paramagnetic Rim Lesions and Cognitive Performance in MS

Schwartz contextualizes the importance of her study by emphasizing the high prevalence of cognitive impairment in patients with MS and the impact of PRLs in this population. PRLs are known as a type of chronic active lesion (CAL) that contain denser rims riddled with iron-laden, pro-inflammatory immune cells that are indicative of progressing demyelination and loss of axons. As PRLs contribute to a worsened disease state, cognitive impairment in patients with MS is also known to get worse with MS progression.

Although prior studies have found connections between worse cognitive function and the presence of PRLs, there is not sufficient data on the influence of PRLs on long-term cognitive function (CF). To address this gap, Schwartz and her colleagues conducted a study to explore any associations between the baseline presence of PRLs in patients with MS and their CF 4 years afterwards.

Their cohort consisted of 106 patients from an ongoing longitudinal study, 98 of which had relapsing remitting MS (RRMS). All participants had complete records of CF and MRI that included quantitative susceptibility mapping (QSM, which identifies PRLs). CF was taken at baseline with the Symbol Digit Modality Test (SDMT) Brief Visuospatial Memory Test-Revised (BVMT-R), and the California Verbal Learning Test-II (CVLT-II).

Patients had an average disease duration of nearly 11 years and 38.7% (n = 41) had at least 1 PRL. Compared to those without PRLs (n = 65), patients with PRLs scored worse on each cognitive test but these scores were not significantly different. This gap grew at the 4-year mark across the board and at this point was statistically significant in SDMT scores (60.54 vs 54.27, P = .013). While patients with PRLs consistently scored worse than those without, Schwartz noted that degrees of CF improvement were seen for all patients after 4 years.

A linear analysis revealed that, after 4 years, SDMT was significantly linked with the interaction between PRL presence and SDMT at baseline (β = –0.3368, P = .0434). Another linear model showed that BVMT was significantly worse for patients who had at least 1 baseline PRL (β = –2.5390, P = .0292).

“So what we concluded is that while we did see overall improvement or stabilization in the cohort as a whole, which we think we can attribute to that 70% of patients being on these highly effective disease modifying therapies, patients with PRLs still consistently demonstrated a poor performance, and that became even more apparent after the 4 years,” Schwartz commented.

Due to the impact on SDMT scores, Schwartz et al discerned that PRLs impacted processing speeds the most. Considering this, future studies in this area should explore whether QSM is a reliable method for identifying PRLs. Being able to personalize treatment approaches to address CF and processing speeds could provide great benefits for patients if PRLs can be identified as a marker for patients with MS who are vulnerable to cognitive decline.