White matter of the MS brain shows abnormalities even before inflammation

May 26, 2023
A new study finds that patients with multiple sclerosis show structural abnormalities in their white matter even before MS inflammation develops. The findings offer a target for a new treatment to prevent MS inflammation.

MS lesions are the inflammatory sites where the myelin is broken down and taken up by microglial cells (the brain’s immune cells). But do we see something in the tissue even before these inflammation spots appear? To answer this question, a team of researchers from the Netherlands Institute for Neuroscience, in Amsterdam, and the Max Planck Institute for Multidisciplinary Sciences, in Göttingen, looked into the human postmortem brains of MS patients and control patients that have been donated to the Dutch Brain Bank. Their focus was particularly on the so-called ‘normal-appearing white matter.’ These are areas where lesions have not formed yet, and so still appear normal.

The team took a detailed look at myelin to see if there are early changes in people with MS. At regular distances from each other there are interruptions of the myelin, these are the Nodes of Ranvier. During the transmission of electrical signals, the signal jumps from one Node of Ranvier to the next, allowing a myelin-containing fiber to transmit a signal 100 times faster than without myelin. In people with MS, myelin is damaged and signal transmission in the central nervous system is disrupted, which can impair functions such as walking and vision.

To be able to study myelin properly, the researchers looked at the optic nerve. In this area, all nerve fibers and their myelin follow the same direction, so the myelin can be well-visualized. In MS, myelin was found to be less tightly wrapped around the nerve-fiber. This means that the fiber is not properly insulated, which has major consequences – the signal can’t be transmitted as fast as it used to be. Researchers saw that where myelin was less attached to the fiber, there was a disruption of the Nodes of Ranvier combined with increased levels of T-cells and activated microglia. 

Furthermore, there were more mitochondria, the energy factories of the cell. This phenomenon may indicate that more energy is needed for signal movement and maintenance of the fibers. Although mitochondria are generally good for energy production, they also produce many byproducts, such as oxygen radicals. Researchers suspect this to be an amplifying factor for myelin breakdown. The myelin is already in a bad state, more mitochondria develop to provide more energy, which then makes conditions even worse. The theory is that a threshold value is needed to initiate the breakdown. It is also possible that the body recognizes the detached myelin as ‘abnormal,’ which could be the start of breakdown by immune cells.

For researchers, the next step is to see if myelin can be prevented from winding so loosely around nerve endings. They want to see if the wrapping of myelin can be made stronger. While the prevention of myelin detachment will not prevent the damage of the lesions that are already there, it might prevent the development of new lesions. The researchers suggest this would provide a whole new target for MS treatment.

The findings were published in the journal Annals of Neurology.

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