The white matter of the brain with MS shows abnormalities even before inflammation

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Multiple sclerosis (MS) is a chronic inflammatory disease of the central nervous system. In early MS, as well as in advanced progressive MS, lesions arise along with substantial inflammatory activity. Lesions are the inflammatory sites where myelin breaks down and is taken up by microglial cells (our brain’s immune cells). But do we see anything in the tissue even before these flash points appear?

To answer this question, Aletta van den Bosch, from the research team of Inge Huitinga (NIN) and Wiebke Moebius (MPI), investigated post-mortem human brains of MS patients and controls that had been donated to the Dutch Brain Bank. Her attention was particularly focused on the so-called “normal-appearing white matter.” As the name suggests, these are areas where the lesions have not yet formed, so they still appear normal. How is it possible that people with MS develop lesions here later and people without MS don’t?

The team took a detailed look at myelin to see if there are any early changes in people with MS. Myelin is an insulating white fatty substance that wraps up to 150 times around nerve fibers. At regular distances from each other there are interruptions in myelin, these are the Nodes of Ranvier. During the transmission of electrical signals, the signal jumps from one Node or 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 affect functions such as walking and vision. What kind of changes in brain tissue can we see in the early stages of MS?

ultra strong microscope

Aletta van den Bosch: ‘To be able to study the myelin correctly, we analyzed the optic nerve. In this area, all the nerve fibers and their myelin follow very well the same direction, so we can visualize the myelin well. We did this using electron microscopy. With this technique we magnify a cross section of a nerve fiber from 5,000 to 30,000 times.’

‘In MS, the myelin was found to be less tight around the nerve fiber. This means that the fiber is not properly isolated, which has major consequences: the signal cannot be transmitted as fast as before. We saw that where the myelin was less attached to the fiber, there was a disruption of Ranvier’s nodules combined with higher levels of T cells and activated microglia. Also, there were more mitochondria. Mitochondria are the energy factories of the cell, so this phenomenon may indicate that more energy is needed for signal movement and fiber maintenance.’

harmful byproducts

‘Although mitochondria are generally good for energy production, they also produce many byproducts, such as oxygen radicals. We suspect this is a factor amplifying the breakdown of myelin: the myelin is already in bad shape, more mitochondria develop to provide more energy, making conditions even worse. The theory is that a threshold value is needed to initiate the fault. Shedding myelin may also be recognized by the body as “abnormal,” which could be the start of breakdown by immune cells.

“Never before have we been able to look at human tissue in such detail, which means that almost all of the research to date has been done on laboratory animals. Although this is very valuable research, it could sometimes be more difficult to translate the results directly to humans. This is the first look at what happens at an ultrastructural level in people with MS and what exactly leads to the lesions. You need very good tissue to do this, which is why the brain bank is so crucial to our research.”

future perspective

“The next step is to see if we can prevent the myelin from wrapping so loosely around the nerve endings. First, we want to experiment in culture dishes to see if we can make the myelin sheath stronger. Subsequently, we will have to carry out tests on laboratory animals and, finally, we will be able to make the move to humans. It would be great if we could find something to prevent the shedding of myelin. While this will not prevent damage to existing lesions, it may prevent new lesions from developing. This would provide a completely new target for the treatment of MS.”