“Cognitive impairment in patients with multiple sclerosis (MS) is related to functional network changes, based on previous cross-sectional research,” explains Marijn Huiskamp, MSc. “My colleagues previously found dysfunction of the default-mode network (DMN) in patients with cognitive deficits. However, we do not know how these network changes develop over time. Is the DMN the first network to become dysfunctional? Can we determine when exactly during the course of the disease these changes arise?”

For a paper published in Neurology, Huiskamp and colleagues sought to determine how cognitive conversion (ie, progressing from cognitive preserved [CP] or mild cognitive impairment [MCI] to cognitive impairment [CI]) was related to changes in network function. They examined a large sample of patients and healthy controls twice during a 5-year period, with extensive neuropsychological testing and an MRI scan that measured brain function at rest.

19% of Patients Experienced Cognitive Decline in 5 Years

“The scan allowed us to determine how much the brain networks communicate with each other and thereby, how central they are,” Huiskamp says. “We classified participants as CP, MCI, or CI and tracked them to see if they remained stable or converted to one of the other groups during the study period. We also measured the major resting state networks since we know that these are aberrant in cognitive impairment. Our aim was to track how patients progress cognitively, but also how they progress in their network centrality.”

The researchers found that 19% of participants worsened in their cognitive status during the 5-year period. The findings also show that the DMN deviates in patients with MS with overt cognitive problems, but that another network, the ventral attention network (VAN) starts to deviate in patients who remain cognitively intact. “The increase in VAN centrality was related to a decrease in visuospatial memory performance, so our findings likely mean that the VAN increase is not beneficial to cognition,” Huiskamp notes. “However, it could still be that this is compensatory and the VAN is attempting to regulate other networks, such as DMN.”

Of major importance, according to the study team, is that they can now begin to formulate a timeframe that indicates which networks start to deviate during the MS disease course. “It could be that the VAN, which has an important regulatory function, starts to become dysfunctional and show stronger deviations in CP patients,” Huiskamp says. “If this becomes worse over time, the VAN may start to lose its central position and DMN dysfunction may become more apparent, and the whole brain network may start to ‘collapse,’ leading to more severe cognitive impairment. This timeframe could offer insight into which network starts to fail first and where we could intervene by trying to limit the dysfunction of the DMN in patients with a more severe disease course or try to prevent this by restoring the VAN function.”

Creating a More Complete Timeline of Cognitive Changes

The study team also discovered that patients who had a better cognition at baseline had a larger increase in VAN communication over time. “This relationship is most likely driven by the CP patients, who remained cognitively stable, as this group increased in VAN communication,” says Huiskamp. “It suggests that it is beneficial to have stronger VAN communication, because it relates to higher cognition at baseline. However, when we looked at baseline VAN communication, this was higher in the CI patients, possibly indicating that CP patients have lower VAN communication at first that increases over time (Figure).”

Although he believes that it is too early to translate these findings into clinical practice, Huiskamp stresses the importance of monitoring cognition routinely in patients with MS. “Since approximately one in five patients with MS deteriorates cognitively over 5 years, creating a more complete timeline of when cognitive and network changes arise will help neurologists know when to consider intervention,” he adds.

As for future research, Huiskamp and colleagues expressed interest in measuring network function in early MS stages. “This would allow us to see how the VAN changes arise and to what clinical and MRI measures they relate,” she says. “For example, could the VAN changes be related to damage to specific white matter tracts or atrophy patterns? When we understand better which network changes are related to cognitive changes, we will want to see if that also works at the individual versus group level.”