New PET imaging approach captures inflammation before lesions evident

A new imaging technique was able to detect inflammation in a mouse model of multiple sclerosis (MS) before disease symptoms appeared, and to monitor the animals’ responses to treatment, a study reports.

“With this new non-invasive imaging approach, we can detect toxic inflammation that could help us better understand and treat diseases,” Michelle James, PhD, the study’s senior author and an assistant professor of radiology and neurology at Stanford University, said in a university news story.

The study, “PET imaging of TREM1 identifies CNS-infiltrating myeloid cells in a mouse model of multiple sclerosis,” was published in Science Translational Medicine.

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Multiple sclerosis is caused by inflammation in the brain and spinal cord, which damages nerve fibers. This damage can be visualized by MRI scans, where it appears in the form of lesions.

While an MRI assessment of lesions is a valuable tool for diagnosing MS and tracking the disease’s progression, this technology has a notable drawback: It can only identify areas where damage has already occurred.

In fact, it cannot identify the earliest signs of harmful inflammation, before damage is evident as abnormalities on MRI scans.

“Unfortunately MRI is not sensitive enough to image the earliest stages of disease. This is because it mainly detects structural or functional changes that occur later, as opposed to biochemical alterations that typically occur before significant damage to the brain,” James said.

Scientists at Stanford developed a novel method to image myeloid cells, a type of innate immune cell. These immune cells are the first line of defense against pathogens, and they are involved in the earliest steps of inflammation in MS.

While existing technologies can identify areas of inflammation generally, “the tools that have been around for the past couple of decades were not specific to just the innate immune cells,” James said.

Marker on a myeloid cell protein tracked inflammation in presymptomatic mice

A specialized marker was used to tag a protein called triggering receptor expressed on myeloid cells 1 (TREM1), which is found in innate myeloid cells. Then, the scientists used positron emission tomography (PET) imaging to track this marker’s movement in mice with experimental autoimmune encephalitis, or EAE, a common mouse model of MS.

TREM1 tracking was able to identify MS-driving inflammation with up to 17 times more sensitivity than other technologies used to image neuronal inflammation. Inflammation was clearly visible even before the mice showed obvious signs of disease.

“The mice looked completely normal, but we saw this blazing signal where cellular events were already occurring, creating damage,” James said.

Scientists further showed that treating mice with Mayzent (siponimod), an approved MS therapy, led to reductions in TREM1 signaling in the brain — which is consistent with this therapy’s known ability to lower disease-driving inflammation.

This suggests that TREM1-based imaging could help to monitor responses to treatment in people with MS. Theoretically, it may allow clinicians to tell whether a treatment is working without having to wait and see if the disease worsens.

“Experimenting with different drugs rather than targeting known molecular changes is currently a trial-and-error process, which is like playing dice with your brain,” James said.

Lowering levels of the TREM1 protein eased inflammation in the MS model

They also found that reducing TREM1, either through genetic manipulations or with a pharmacological treatment, inhibited MS-driving inflammation. This suggests that the TREM1 protein itself may be a viable therapeutic target, in addition to being useful as an imaging marker, the researchers said.

“Once you knock out that gene or reduce TREM1 signaling pharmacologically, you’re preventing the crazy wildfire that is inflammation,” James said. “And the good thing is you’re dampening down the maladaptive or toxic inflammation without affecting beneficial inflammation.”

Because these experiments were in mice, the researchers analyzed samples of human brain tissue to see whether the findings also might apply to people. Cells expressing TREM1 were detectable in brain samples from two MS patients, whereas these cells were not found in people without the disease.

Collectively, these data show that “TREM1-PET imaging has potential for aiding in the diagnosis of MS and monitoring of therapeutic responses to drug treatment,” the researchers concluded.

MRI scans are generally more easily accessible and cheaper than PET scans, so it’s unlikely that this new technology will fully replace MRI in clinical practice, James noted.

Nonetheless, the researchers proposed that, if this technology can be successfully translated for use in patients, it could help facilitate speedier diagnosis and better treatment monitoring of MS and other diseases characterized by brain inflammation.