Cognitive problems are a common side effect after chemotherapy. A new study suggests how one type of chemo may contribute.

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For the millions of people treated for cancer, “chemo brain” can be an unnerving and disabling side effect. It causes memory lapses, trouble concentrating, and an all-around mental fog, which appear linked to the treatment and not the disease. Although the cognitive effects often fade after chemotherapy ends, for some people the fog persists for years, even decades. And doctors and researchers have long wondered why. Now, a new study suggests an answer in the case of one chemotherapy drug: Brain cells called microglia may orchestrate chemo brain by disrupting other cells that help maintain the brain’s communication system.

“I can’t tell you how many patients I see who look at me when I explain [chemo brain] and say, ‘I’ve been living with this for 10 years and thought I was crazy,’” says Michelle Monje, a pediatric neuro-oncologist and neuroscientist at Stanford University in Palo Alto, California. It’s still mostly a mystery how common long-term cognitive impairment is after chemo. In one recent study by clinical neuropsychologist Sanne Schagen at the Netherlands Cancer Institute in Amsterdam, it affected 16% of breast cancer survivors 6 months after treatment.

Monje began to probe the cognitive effects of cancer treatment in the early 2000s, starting with radiation, a therapy that can be far more debilitating than chemotherapy. A Science paper she and her colleagues published in 2003 suggested radiation affected a type of brain cell called microglia, which protect the brain against inflammation. Just like immune cells in the blood, microglia—which make up at least 10% of all brain cells—become activated during injury or infection.

The symptoms of chemotherapy-related cognitive dysfunction pointed to abnormalities in myelin, the fatty sheath around nerve fibers that helps them transmit brain signals. More than 10 years ago, stem cell biologist Mark Noble at the University of Rochester in New York and his colleagues reported that brain cells called oligodendrocyte precursor cells (OPCs), which ultimately help form myelin, were exquisitely sensitive to chemotherapy. But later work suggested OPCs could rapidly repopulate in a healthy brain, and the long-term effects of chemotherapy on OPC cells remained mysterious.

Monje began the new study almost 7 years ago. First, she and her colleagues examined stored brain tissue samples from children and young adults who had died from various cancers, and control patients who’d died of something else. Some had received a host of chemotherapy drugs, and some had never gotten chemotherapy. In those who’d had chemo, OPCs were markedly depleted, but only in the white matter of the brain, which is a heavily myelinated brain region. The researchers focused on a particular chemotherapy drug, methotrexate, which is especially associated with long-term cognitive problems.

Monje’s team wanted to confirm the findings in just-donated tissue, which was offered to them by the families of two children: a 3-year-old whose brain cancer was treated with high doses of methotrexate, and a 10-year-old whose brain cancer progressed so rapidly that there was no time to administer much therapy. Again, the child who’d received methotrexate—with the last dose well over a month before he died—had a near-wipeout of OPCs in white matter. The other child did not.

Next up for the scientists was designing a mouse model of chemo brain caused by methotrexate. The mice got the same chemotherapy treatment as the 3-year-old, adjusted for their tiny body size. The animals “have a very clear impairment in attention and short-term memory,” Monje says. The animals also had the same decrease in white matter OPCs. Studying the organ 6 months after chemotherapy ended—a long time in the life of a mouse—the researchers saw that “the myelin sheaths were thinner,” Monje says, which would disrupt brain signaling.

The big question for Monje was whether chemotherapy was directly killing OPCs or creating an environment that was hostile to them. To answer this, her team transplanted healthy OPCs into the brains of mice previously administered methotrexate. Those healthy cells showed the same disregulation, Monje says. Typically, the brain replenishes OPCs as needed, but in the mice, it didn’t. Something in the brain’s environment was causing the cells’ decay and disappearance.

Ultimately, the story came full circle back to the microglia that Monje had first eyed more than 15 years ago. Additional experiments on brain cells revealed methotrexate activates microglia in the brain’s white matter, causing a cascade of effects and ultimately depleting OPCs. Because several compounds that deplete microglia are in clinical trials for cancer and other indications, the scientists were able to test one of them on their chemo brain–affected animals. They found that depleting microglia was effective: It restored OPCs, normalized myelin, and rescued short-term memory, the research team reports today in Cell. That means, they write, that the microglia are likely behind chemo brain for this particular drug.

“The authors did a great job at trying to look at this phenomenon from very different angles,” says Schagen, making sure, for example, that findings in brain tissue also held true in mice. The activation of microglia, Schagen says, looks like an “important” direct mechanism. But Schagen, who has studied the effects of several chemotherapy drugs on mouse brains, also stresses that these findings are limited to methotrexate; other chemotherapy drugs may cause cognitive problems in different ways. The dose and its timing may also affect a drug’s brain effects, Schagen says.

Monje says there’s a lot left to do before launching a clinical trial of any potential chemo brain fighter. One question is how long any such drug must be used. Another is what molecular mechanisms are driving the brain cells to behave as they do. But she’s hopeful that, after many years of trying, she and others are moving in the right direction.

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