In its later phases, multiple sclerosis, or MS, shifts to a steady decline, with no relief of worsening symptoms. In this second, progressive phase, the outer shell of the brain — the cortex — actually shrinks away from the skull. Researchers still don’t understand why that shrinkage happens, nor which of the disease’s symptoms are caused by the atrophy.

Now, a team of scientists led by researchers at the University of California, San Francisco, and the University of Cambridge has discovered that one particular type of neuron receives the brunt of the damage in this phase of the neurological disease.

That finding not only provides an explanation for why brains shrink in MS patients in late stages of the disease — the brains seem to be losing this type of neuron in particular — but also points to therapeutic avenues to halt the atrophy, said David Rowitch, M.D., Ph.D., a neuroscientist at UCSF and the University of Cambridge who led the study, which was published today in the journal Nature, along with UCSF’s Arnold Kriegstein, M.D., Ph.D. Their findings indicate that the newest types of treatment for early-stage MS, known as biologics, might also halt this late-stage brain shrinkage.

“Lots of arrows were pointing to this particular cell,” which is a type of human neuron known as a projection neuron, said Rowitch, who is also an Allen Distinguished Investigator. “That hadn’t been understood before for MS, that there was a particular cell type that was vulnerable. But the data just really screamed out: This neuron is in trouble.”

Looking for the missing neurons

To get a better grasp on what causes the dramatic brain shrinkage, Rowitch, Kriegstein and their colleagues used post-mortem brains from people with and without MS who had died and donated their bodies to science. They looked at the genes these brain cells switch on, cell by cell, to capture differences between people with MS and those with healthy brains.

They weren’t actually expecting to find large differences in neurons, Rowitch said. The early stages of MS are caused by autoimmune-triggered damages to a type of brain “support cell” that forms an insulating layer around nerve fibers. When that protective layer is lost, the underlying nerves sustain damage. The team thought they might find differences in support cells in late-stage disease as well.

The researchers also used a technique that shows changes in gene expression, or the genes that are switched on, in cells in their natural environment in the brain. That technique, which Rowitch and his colleagues developed through support directed from The Paul G. Allen Frontiers Group via his Allen Distinguished Investigator award, allowed the researchers to verify that the projection neurons were missing in large quantities from the brains of patients with MS.

“If you look for these neurons in the layer of the cortex where they’re supposed to live, we can show that they’re missing,” Rowitch said. “Seeing it in the tissue makes it much more convincing.”

Implications for treatment

The researchers also found that a type of immune cell known as B cells seemed to be invading the brains of late-stage MS patients, remaining behind where projection neurons were lost. Newly developed biological therapies for early-stage MS target these immune cells, so their findings suggest that these new therapies could also protect against brain shrinkage, Rowitch said. The patients in their study had all received other, older therapies.

Their study uncovered differences in one gene, ATF4, in the damaged neurons in MS patients which could point to a new avenue for a different type of MS treatment. In an earlier study of brain cells from people with autism spectrum disorder, the researchers also found changes in the same projection neurons, even though MS and autism affect the brain very differently.

“We think that this is a very interesting and perhaps understudied type of neuron that could be susceptible in a number of brain conditions,” Rowitch said. “Why would the same neuron be popping up in these two very different situations? We’re really interested in exploring that further.”