Funding for 2019

Detecting Neuroinflammation in Fibromyalgia with the Positron Emission Tomography (PET) Radioligand [18F]DPA-714

Principal Investigator: Jarred Younger, Ph.D.
University of Alabama at Birmingham
(February 2019)

Any threat to the brain can change your microglia from a resting (M0) state to an activated (M1) state that produces pro-inflammatory agents. These inflammatory substances can include cytokines and even neurotoxic factors, all of which can change or interfere with the way your neurons function. When a significant number of microglia are in the M1 state, it produces a sickness response that includes symptoms of pain, fatigue, cognitive dysfunction, sleep disturbance, and depressed mood. Sound like fibro? Maybe it is.

Younger hypothesizes that the M1 state will be shown to be dominant in the brains of people with fibro, causing the symptoms and a state of inflammation (e.g., neuroinflammation). In healthy people, this pro-inflammatory role is just temporary. The microglia eventually transition into an anti-inflammatory (M2) state to resolve the symptoms and then go back to their resting (M0) state. See diagram below.

“An excessive number of microglia in the pro-inflammatory (M1) state is a known indicator of abnormal neuroinflammation,” says Younger. When microglia are in the M1 state, they express a receptor called the translocator protein (TSPO) receptor. Younger plans to measure the amount of TSPO with a brain imaging technique called positron emission tomography (PET) using a newly developed tracer that binds to the TSPO to illuminate them on the scans. The tracer is called radioligand [18F]DPA-714. Simultaneous MRI scans will be done to identify the structures within the brain with the greatest amount of neuroinflammation.

To use a tracer that tags the TSPO receptor, one has to first inject it intravenously into the study participants before imaging their brains. This technology has been around for a few years to show brain inflammation in conditions such as multiple sclerosis and Alzheimer’s disease. However, the older tracers had two drawbacks. First, they quickly passed through the body (half was gone in 20 minutes) and the imaging procedure proposed by Younger takes 30 minutes to complete. Second, the tracers were not specific enough to just latch onto microglia in the M1 state. They also bond to other cells, casting doubt over data interpretation.

Younger’s university has developed a longer-acting tracer that sticks around for 110 minutes, providing ample time to accurately obtain imaging results. It’s also more selective at tagging microglia in the M1 state so that the fibro skeptics will have one less issue with the study findings. “We are now in an excellent position to use this process in fibromyalgia,” says Younger about the tracer developed by his radiology colleagues. “Doing so may provide the clearest, most robust, and replicable view of fibro pathophysiology to date.”

This two-year study, which was extended to three because of COVID, includes three study groups. There will be 15 fibro patients who have been thoroughly assessed for pain thresholds and degree of severity of all major symptoms for this condition. There will be 10 healthy, symptom-free controls to show what a normal brain is supposed to look like. Finally, a group of 10 patients with multiple sclerosis will also be included.

Why assess people with multiple sclerosis (MS) for a study designed to look for neuroinflammation in fibromyalgia? MS patients have been shown to have microglia activation throughout their brain, but the studies used a less accurate tracer. The blood brain barrier, which usually stops “most” threats from reaching the level of the brain, is broken down in MS. Their microglia are expected to be in the M1 state. The MS patients represent a positive control group for illustrating neuroinflammation using Younger’s PET/tracer technique.

Younger’s study should form the foundation for future research studies in fibro by highlighting the microglia’s role. This is the upside of a technology that can illuminate what is going on inside your brain. The downside is expense, and that’s why Younger’s study includes a list of blood tests that may correlate with his findings in the brain.

Younger has evaluated hundreds of fibro patients and found some blood tests tend to correspond to symptom severity. These tests may not be abnormal or out of the standard range, but slight increases or decreases might correlate with key symptoms. “The goal is to determine if a simple blood test (or group of them) could serve as a proxy for the more expensive PET imaging,” says Younger.

One final point: Fibro doesn’t go away, so can threats to the brain really lead to sustained neuroinflammation that lasts for decades? The answer is YES. Younger points to a recent study in mostly retired National Football League players that used PET with a tracer similar to the one he will use. The athletes tested were young (averaging 31 years old), but their last brain trauma event was roughly seven years ago. “After having their head hit for years, there is increased uptake of the tracer,” says Younger. “It suggests that the brain damage gave them persistent neuroinflammation that can last for years, and perhaps for their entire lives.”

Study Update

Evidence of Brain Inflammation Found

“This study shows that fibromyalgia (FM) involves a low level of neuroinflammation that is spread across multiple regions of the brain,” says Jarred Younger, Ph.D., the principal investigator for the project.* More specifically, a larger portion of the immune cells in the brain, called microglia, are activated in FM patients compared to healthy controls. Once activated, these cells release pain-enhancing chemicals and produce the symptoms seen in FM.

But how did Younger determine that the microglia were the cells responsible for driving neuroinflammation? “When the microglia are in an inflammatory state,” says Younger, “they absorb more of the chemical tracer we injected into the study participants, called DPA-714. By using a positron emission tomography (PET) scanner, we can measure how much of the brain’s microglia are absorbing DPA-714 and therefore the relative quantity that are in an activated or inflamed state.”

Thirty-four brain regions were assessed for microglia activation. Most areas showed a mild to moderate level of increased activity, with a few regions displaying a stronger degree of inflammation. Of particular interest were areas in the parietal lobe.

Why is the parietal lobe important? “This is where the sensations of the body are integrated and interpreted,” says Younger, adding that this includes the experience of both pain and fatigue. “Within the parietal lobe is a region called the somatosensory cortex, and it processes pain signals coming from everywhere in the body. Neuroinflammation in the parietal lobe would very likely cause enhanced pain processing.”

Perhaps it is no surprise that Younger was able to show significant correlations between the level of inflammation in the parietal lobe and the following symptoms:

• decreased quality of life
• reduced energy
• greater pain
• more severe cognitive problems

Until a few years ago, the pain and other symptoms of FM were explained as being a problem with the way neurons function in the central nervous system. The microglia were viewed as playing a supportive role in nourishing the neurons and removing toxic chemicals from the synapse (the transmitting space between neurons). However, activated microglia can be like a thorn in the side of neurons. Whether these immune cells are solely responsible for the symptoms of FM, or just making matters worse, is still unclear.

How does Younger’s finding of neuroinflammation in FM impact treatment strategies? Younger says “treatments that can cross the blood brain barrier and push the microglia out of their activated/inflamed state” are needed. One possible medication is low-dose naltrexone or LDN. An AFSA-funded trial of LDN at 4.5 mg/day significantly reduced the pain and related FM symptoms in one-third of patients.** For more details on the LDN trial and how to use this drug, click here.

Factors that can contribute to microglia activation are stress and sleep disruption, so therapies that relieve these symptoms may be beneficial. In fact, mild movement therapies that incorporate relaxation breathing, such as yoga and tai chi, have been found to ease the impact of FM. Ironically, the most potent class of medications to relieve pain are opioids, yet they are strong microglia activators. So chronic use of this class of medications may make pain worse in the long run. It is possible that some medical and botanical anti-inflammatories can reach the brain and calm microglia, though clinical trials are needed to test that idea.

* Mueller C, Younger JW, et al. Evidence of neuroinflammation in fibromyalgia syndrome: a [18F]DPA-714 positron emission tomography study. PAIN. 2023 Oct; 164(10)2285-2295. Click here for the full report.
** Younger J, Noor N, McCue R, Mackey S. Low-dose naltrexone for the treatment of fibromyalgia: findings of a small, randomized, double-blind, placebo-controlled, counterbalanced, crossover trial assessing daily pain levels. Arthritis Rheum. 2013 Feb;65(2):529-38.