Advancing the Clinical Understanding of MS: Emerging Concepts Presented at ACTRIMS 2024

On day 1 of the Americas Committee for Treatment and Research in Multiple Sclerosis (ACTRIMS) Forum 2024, opening sessions detailed emerging concepts in multiple sclerosis (MS), including explorations into the impact of synaptic loss on disability in neurodegenerative disease and the relationship between inflammation and hypoxia in MS.

“I am tremendously excited today about telling you what we believe is an important story that can help solve the biggest mystery that we still have in MS,” Christian Cordano, of the University of California, San Francisco, began his presentation, “Synaptic Injury in the IPL of the Retina is a Predictor of Progression in Multiple Sclerosis.” His research has been focused on the worsening and accumulation of disability in MS and the lingering questions regarding the drivers of its progression.

Cordano and colleagues reflected on early evidence that began associating the loss of synapses and the worsening of disability neurodegenerative disease. He said that neurologists in MS neglect the role of synapses; however, focusing on the visual system and the inner plexiform layer (IPL) could provide unique insights into the pathophysiology of MS because not all the neurons are completely myelinated, and it has a fairly simple pathway.

Their study used experimental autoimmune encephalomyelitis (EAE) as an MS model. Beginning with a mouse model, they observed that there were fewer intact IPL synapses in the early development of EAE. From day 12-60 after immunization of the mice, the rate of synaptic loss grew drastically worse.¹

To investigate this phenomenon in human patients, they gathered a cohort of 19 patients from the University of California, San Francisco who exhibited a great longitudinal follow-up before their disease transitioned to the progressive stage. These 19 patients, classified as the secondary progressive (RR-SP) group, were matched with 38 patients with relapsing-remitting MS (RR-RR). Both groups were analyzed for over 3 years. Between the RR-RR and RR-SP groups, the only notable difference in characteristics was IPL thickness (37.00 µm vs 35.64 µm, respectively), with those in RR-SP exhibiting a loss of tissue. Thus, the researchers discerned that IPL thickness is a biomarker for an individual’s MS transitioning to a progressive stage.

After they identified the timing of synaptic loss, the research team became interested in the underlying mechanism driving this erosion. To explore this, they conducted an additional study referred to as the ReBUILD trial. This study consisted of an independent cohort that did not develop any radiological or clinical signs of relapse at follow-up. They followed SNAP-25 as a marker of synaptic loss alongside other proteins that were indicative of injuries and inflammation to the central nervous system (CNS). The strongest associations were found between SNAP-25 and MOG—indicating that demodulation was a driver of synaptic loss and that this effect was taking place independently from the damage that demyelination inflicts on axons.

Considering the results of their study, Cordano et al concluded that synaptic injury is related to the inflammatory demyelination impacting patients with EAE and the acceleration of this form of injury is linked to progressive disease in patients with MS.

Following Cordano's presentation, Ateyeh Soroush of the Univeristy of Calgary took the stage for her presentation titled “Hypoxia-Related Impairment of Brain Function in Multiple Sclerosis: Insights from Near-Infrared Spectroscopy.”

She began by citing a 2019 study that demonstrated an association between the inflammatory pathway and hypoxia (low oxygen saturation, defined as a rate below 55%). This relationship exists in a positive feedback loop where hypoxia induces more inflammation, lower vasoreactivity, and an influx of leukocytes. This process exacerbates more inflammation and mitochondrial damage, leading to more hypoxia and lower oxygen saturation.²

Additionally, a previous study gave a similar report on these effects through the use of a form of Frequency Domain Near Infra-Red Spectroscopy (fdNIRS) in which tissue oxygen saturation was quantified to compare healthy controls with hypoxic patients (those with oxygen saturation 2 standard deviations below the mean), Soroush explained. Among the identified hypoxic patients, the findings revealed that CO₂ significantly correlated with Expanded Disability Status Scale (EDSS) scores.³ These findings estimated that 43% of patients with MS experience hypoxia and expanded data in this area by indicating that lower oxygen saturation is contributes to disease progression and severity.

Furthermore, around the same time, a new form of NIRS called functional NIRS (fNIRS) was used to quantify the changes in oxy- and deoxyhemoglobin concentrations. These signals are utilized as a measure to determine brain functional activity between varying brain regions. Patients with MS demonstrated a significantly reduced coherence between the left and right motor cortexes during motor tasks compared with healthy patients in the cohort. These findings suggested patients with MS additionally experience lower degrees of functional connectivity.³

This prior research informed Soroush et al as they reflected on how NIRS and fNIRS can quantify hypoxia and functional brain connectivity. Therefore, they conducted a study to control for hypoxic patients with MS and investigate the prevalence of hypoxia and measure brain function. A total of 73 patients with MS were compared with 22 healthy controls who underwent a fdNIRS examination as well as various motor and neurocognitive tests measured with fNIRS.⁴

Their results revealed that 45% of patients with MS were hypoxic. The fdNIRS demonstrated that those with MS experienced a significantly lower rate of oxygen saturation compared with healthy controls (55.42 vs 63.73, P < .001). The fNIRS results showed that the values indicating brain connectivity were lower in non-hypoxic and hypoxic patients with MS compared with healthy controls. Comparing all of their groups, no significant differences were found between healthy controls and non-hypoxic patients with MS; however, significant correlations were observed regarding oxygen saturation, tissue oxygen saturation, and interhemispheric functional conductivity in the dorsal lateral prefrontal cortex.

As Soroush’s talk came to a close, she reflected on the lingering questions that stand in light of their research: How will these results impact disease management in hypoxic patients with MS? Should they be treated differently?

Cordano et al and Soroush et al’s research alike detailed the novel, exciting concepts that are emerging in the field of MS. These new approaches and explorations on the role of synaptic loss and hypoxia in MS demonstrate new avenues of thought that are expanding clinical understandings of MS pathophysiology. Both indicated that there is room to grow in these studies; however, the discoveries they made and the questions they opened up have furthered clinical understandings of MS and could potentially alter the future of patient care.

References

1. Cordano C, Ramos C, Arnow S, Cruz-Herranz A, Guglielmetti C, Iester M, Bandini F. Inflammation in the anterior visual pathway in multiple sclerosis: what do the animal models teach us?. Neurol Neuroimmunol Neuroinflamm. 2021;8(3):185-202. doi:10.20517/2347-8659.2020.54

2. Yang R, Dunn JF. Reduced cortical microvascular oxygenation in multiple sclerosis: a blinded, case-controlled study using a novel quantitative near-infrared spectroscopy method. Sci Rep. 2015;5:16477. doi:10.1038/srep16477

3. Jimenez JJ, Yang R, Nathoo N, et al. Detection of reduced interhemispheric cortical communication during task execution in multiple sclerosis patients using functional near-infrared spectroscopy. J Biomed Opt. 2014;19(7):076008. doi:10.1117/1.JBO.19.7.076008

4. Soroush A, Adingupu DD, Evans T, et al. NIRS studies show reduced interhemispheric functional connectivity in individuals with multiple sclerosis that exhibit cortical hypoxia. Adv Exp Med Biol. 2022;1395:145-149. doi:10.1007/978-3-031-14190-4_25