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Chemotherapy can make patients much more forgetful than normal, but pinning down the cause of and solution to this phenomenon is an ongoing process.

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[INTRO ♪].

You know that feeling of walking into a room and, like, instantly forgetting why you're there? That's normal every now and again, but for people who go through chemotherapy, that kind of thing can happen all the time—and it's more than just forgetfulness, too.

Undergoing chemo is also associated with trouble with working memory, the ability to learn new things, and motor functioning. As if going through cancer treatments wasn't hard enough by itself. Many people call this experience “chemo brain”, but scientists generally call it chemotherapy-induced cognitive impairment, or some variation on that.

Researchers really started to acknowledge CICI back in the 1990s, but they still can't figure out exactly why it happens or how to treat it—even though it seems like it should be a simple “cause and effect”-type thing. But just because something is hard to understand, doesn't mean it's impossible. And by taking the problem one step at a time, they're making progress.

Thankfully, CICI isn't anything lethal, but it does have an impact on everyday life—especially because the symptoms can last more than a decade after treatment. Unfortunately, there are so many factors behind our current understanding of this condition that it can be hard to figure out what's causing it. Some of these problems are research-related.

For instance, most studies in this area are performed on breast cancer survivors, but the condition affects patients with all cancer types and we can't just assume that the results will transfer smoothly. Since cancer involves mutating cells, it's as personal as someone's genetics. Also, researchers have inconsistent methods to study this phenomenon, which makes finding patterns difficult.

For example, a handful of studies might all use fMRIs to visualize brain activity and blood flow during a test. But one study might involve tests of working memory, while another tests verbal memory. Or one might follow up with patients a week after chemo while another waits ten years.

Point is, there's a lot of variation. And even once you get past the research problems—as much as you can do that—CICI still doesn't seem to have a clear explanation. That's partly because chemotherapy itself isn't just one or two drugs—it's not like you only have a couple of variables to look at.

Since cancer is so personal, prescriptions can vary a lot, too. Also—and this is a big one—researchers aren't even sure the cognitive impairments are entirely due to chemotherapy. A lengthy 2013 review noticed structural differences in the brains of people with cancer and those without, even before the cancer patients underwent chemo.

For example, cancer patients tended to have widespread decreases in the volume of certain brain tissues, which suggested that other factors played a role in their cognitive symptoms. So maybe something like stress was involved. Regardless, between the different types of cancer, methodologies, and treatments, it's really hard to find a general explanation for CICI.

So scientists have had to figure out a more complex way to approach this problem. Instead of just looking at one cause or solution, they've had to tackle this like this do with a lot of other brain-related questions: one piece at a time. And that's allowed them to make some progress.

For the most part, research into CICI has focused on chemotherapy drugs, because even though there might be other mechanisms, this one is relatively easy to study. After all, it's a lot easier to measure the amounts and types of medication someone got than to measure how stressed out they feel. One popular hypothesis is that the cognitive impairment is due to oxidative stress: a process caused by some chemo drugs that creates byproducts called free radicals.

When it comes to cancer, these radicals are actually important, because they can keep cancer cells from spreading, so we might not want to get rid of them entirely. The problem is, they can also kick off a chain of events that leads to dangerous proteins entering the brain and killing neurons. So researchers have been looking for a way to fight this—a way to keep the helpful effects of free radicals without allowing them to cause brain damage.

Basically, they've been trying to find a drug to protect people from their drugs. And while it might sound a little silly, this research does seem to be going well. Take a 2018 study published in PLOS One.

In it, researchers wanted to see whether a compound called PAN-811 might protect against free radicals. The compound is called a ribonucleotide reductase inhibitor, or RNRI, and in things like Petri dishes, it has previously been shown to help protect against free radicals. In the 2018 experiment, researchers injected one group of rats with chemotherapy drugs and the other with harmless saline.

Then, they injected some of the rats with PAN-811 and left the others untreated. A month later, they gave the rats memory and learning tests to gauge their cognitive abilities. And they found that PAN-811 seemed to reduce the cognitive impairment caused by the chemo drugs.

The team suggested that this might have happened because PAN-811 interrupts the pathway that allows the free radicals to kill neurons. And although that has potential to be awesome news, we will need to keep studying it to be sure it is effective and safe. But someday, it could be a way to prevent or reduce CICI.

At the end of the day, CICI is a simple sounding problem with a really complicated answer that we're still unraveling. But as it becomes an issue for more and more people, it's something researchers will need to keep focusing on. We will keep breaking it down into smaller and smaller pieces, and we will keep getting our answers.

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