#ECTRIMS2021 – Problems in Thalamus Linked to Severe Progressive MS
Editor’s note: The Multiple Sclerosis News Today team is providing in-depth coverage of the virtual 37th Congress of the European Committee for Treatment and Research in Multiple Sclerosis (ECTRIMS), Oct. 13–15. Go here to see the latest stories from the conference.
In people with progressive multiple sclerosis (MS), neuron loss is highly pronounced in the thalamus — a brain area involved in motor function, memory, learning, language, and sensation — with more active inflammatory lesions and higher complement system activation, a study shows.
These features correlated with disease severity and duration, further supporting their contribution to primary MS severity and likely helping to identify potential targets for the disease.
The findings were shared by Owain Howell, PhD, of Swansea University, U.K., at the 37th Congress of the European Committee for Treatment and Research in Multiple Sclerosis (ECTRIMS), held virtually Oct. 13–15.
MS is characterized by brain inflammation and demyelination, or the loss of myelin — a fatty protective sheath around nerve cell fibers that is key for proper neuronal communication.
Previous studies in MS patients have highlighted “how extensive the atrophy [shrinkage] of the thalamus can be and how it predicts later disability and cognitive decline,” Howell said in his oral presentation, “The contribution of active inflammatory pathology and local complement activation in the thalamus to progressive multiple sclerosis outcome.”
The thalamus is a brain structure mainly involved in relaying motor signals and sensory information, that also participates in cognitive functions. It is mostly constituted by grey matter, made of nerve cells’ central bodies, as opposed to white matter, which mainly consists of nerve cell fibers.
In MS, thalamus integrity is thought to be affected both directly by neuronal death, and indirectly by lesions in other brain areas that connect with the thalamus.
Increasing evidence suggests that the complement system, a group of blood proteins that form part of the immune system, is activated early in MS development and associated with disease severity. Also, this system is known to activate microglia, the brain’s own immune cells that are chronically activated in progressive MS.
While the complement system and microglia are known to be involved in tissue atrophy, “their relative contribution to the overall [disease-associated] burden of the thalamus is unclear,” the researchers wrote.
To address this, Howell and his team analyzed forebrain tissue from 21 deceased progressive MS patients (17 with secondary-progressive MS and three with primary progressive disease), 10 matched healthy people (used as controls), and four people with neuroinflammatory conditions.
The forebrain is the front part of the brain that is important for processing cognitive, sensory, and motor information, and where the thalamus is located.
The researchers found that most patients (76.2%) had active inflammatory lesions in the thalamus and that this region was characterized by a “far greater number and proportion of active and chronic active demyelinating lesions” relative to other forebrain regions, Howell said.
Also, neuron loss in the thalamus was significantly greater among progressive MS patients than in controls, and the extent of thalamic neuron loss in non-lesion areas was significantly associated with greater white matter lesion load in other forebrain areas, shorter disease duration, and younger age at the time of death.
This meant that “the cases with greatest cellular losses experienced the shorter and more aggressive multiple sclerosis,” Howell said.
Similar associations were not found for lesion areas in the thalamus.
This was further confirmed in a separate group of 27 deceased patients, in which there were significant associations “between neuron loss in normal [appearing] thalamus and age at wheelchair [requirement], age died, and disease duration,” Howell said.
In addition, activation of the complement system and levels of microglia in the thalamus was significantly increased in progressive MS patients relative to controls.
Microglia activation was associated with local demyelination in the thalamus, but not with the extent of white matter atrophy or with clinical outcomes.
Complement system was mostly active within the edges of chronic, active demyelinated thalamic lesions, and the levels of C1-inhibitor, a complement molecule that suppresses the system’s activity, were significantly reduced in these areas.
This suggested some abnormal regulation of the complement pathway in these thalamic tissues, Howell noted.
These findings highlight that the thalamus is characterized by significant active inflammatory lesions and widespread neuronal loss “that associates with a more severe disease,” the researchers wrote.
Further studies are needed to clarify whether thalamic neurodegeneration is a primary or secondary event in MS, Howell noted.
Moreover, the data support thalamic complement activation as an important contributor to the severity and clinical outcome of progressive forms of MS.
Assessing complement activation in the thalamus may help to “monitor and modify the disease course and to identify [patients] who may benefit from active immunosuppression,” Howell concluded.