“If we are successful, we may not only produce an objective test for fibromyalgia and chronic fatigue syndrome, but we may also be able to develop more effective treatments for those disorders.” – Dr. Jarred Younger
Jarred Younger dazzled attendees with his leptin and chronic fatigue syndrome presentation at the Stanford Symposium earlier this year. His pilot study that measured dozens of inflammatory markers every day in chronic fatigue syndrome patients produced one of the most visually startling graphics I’ve ever seen – an “all roads lead to Rome” type of plot that showed an array of immune factors converging on one… the putative trigger of them all: leptin. (See the video here.)
Younger has shown he’s willing to go “outside the box” of traditional treatments like pharmaceutical drugs to find relief for people with chronic pain and fatigue. His embrace of low dose naltrexone (LDN), for instance, has added a valuable treatment for many people with fibromyalgia and chronic fatigue syndrome.
Younger recently moved from Stanford University to the University of Alabama at Birmingham to open a Neuroinflammation, Pain and Fatigue Lab. Health Rising took the occasion of this move to review a recent video interview he did with Deborah Waroff of ME/CFS Alert, and then to ask him some questions.
When Deborah Waroff of the ME/CFS Alert asked Younger how he got started in ME/CFS research, Younger noted that while pain was the most “salient” part of fibromyalgia many patients told him that fatigue was the most debilitating part of their illness. [This fits with a recent ME/CFS and FM survey on Health Rising suggesting that post-exertional malaise was the biggest problem for ME/CFS and FM patients.] Even if the FM patients got rid of or reduced their pain, Younger said, it was the fatigue that was keeping them from going back to their jobs. That was what got him interested in the kind of pathological fatigue found in chronic fatigue syndrome.
Now, he’s traded the intellectual ferment (and pricey) environs of Silicon Valley to direct the new Neuroinflammation, Pain and Fatigue Lab at the University of Alabama at Birmingham. A step down, you might think? Maybe not. The University of Alabama at Birmingham contains a significant medical research center that enjoys robust NIH funding.
Deborah Waroff Talks to Jarred Younger
Younger said the decision to leave one of the top centers of medical research in the country – Stanford – was not an easy one, but he believes he’ll be able to move faster at UAB. Plus, it’s a return home in a way. Younger grew up in a small, small town (population 200) just a couple of hundred miles across the border in Tennessee.
Younger earned a Ph.D in Experimental Psychophysiology at the University of Tennessee, completed postdoctoral work at the University of Arizona in pain psychology, and then a post-doc in pain neuroscience at Stanford where he became an assistant professor. Now he’s back in the south.
“I now have more space, more people, and more resources – so now I can answer more questions.” – Younger
UAB made a good move. They snatched up a younger researcher focused on a medical topic that’s on the rise. They apparently lured Younger with the substantial commitment they’re making to this field. Younger brought two researchers, Joanne Lin, Ph.D., a pharmacist and neuroimaging specialist, and Luke Parkitny, Ph.D., a researcher in chronic pain immunology, as well as a lab manager from Stanford with him. Younger stated he will have access to the same leading-edge instruments he had as Director of the Adult and Pediatric Pain lab at Stanford.
“Prof. Younger’s goal is to end the chronic pain and fatigue that is caused by inflammation in the brain.” – Univ. of Alabama at Birmingham
Getting academic research centers dedicated to ME/CFS and FM at prominent universities is high on anyone’s list of “things needed to move these fields forward”, and now we have another one. Younger’s Neuroinflammation, Pain and Fatigue Lab is one of the few university labs dedicated to chronic fatigue syndrome and fibromyalgia research.
With Dr. Klimas’s and now Younger’s moves, we may be seeing an intriguing pattern emerging: ME/CFS and FM researchers being lured from higher ranked to lower ranked medical schools (#2 to #43 in Younger’s case). It suggests some Universities may be trying to get the early lead in what they envision to be a growth area in medicine. UAB’s creation of the Neuroinflammation, Pain and Fatigue lab may get other University directors thinking.
How the lab got created is unclear, but Younger and ME/CFS and fibromyalgia have some friends in the Alabama legislature. In 2013, an Alabama politician with Lyme disease, State Senator Slade Blackwell, helped pass a Senate Joint Resolution urging the state to establish a clinical care and research center for what Blackwell called “neuroinflammatory disorders”. Give some credit to Tina Tidmore and the folks at Pandora for preparing the ground in Alabama for this to happen.
Younger’s bringing a considerable portfolio of research projects with him. Here are some examples:
- He’s examining the effectiveness of low dose naltrexone (LDN) in FM.
- He’s doing daily immune monitoring and assessing the efficacy of anti-inflammatories in Gulf War syndrome.
- He’s doing neuroimaging to understand the effects opioid use has on the brain.
- He’s finding new and more accurate ways to test for low levels of neuroinflammation in the brain.
To top it off, he just got a nice, big NIH grant to study chronic fatigue syndrome.
Big Chronic Fatigue Syndrome Study
In his last ten-person study, Younger was able to accurately predict whether an ME/CFS patient was having a low or high fatigue day about 80% of the time simply by looking at their inflammatory markers. This new ME/CFS study, which will go much further, is a whopper.
The projected five-year study will test no less than fifty-one inflammatory immune markers every day for 25 days in 70 ME/CFS patients, 20 healthy controls and, significantly, 20 fatigue controls (people with hypothyroidism). The AHRQ report took the research community to task for not including fatigued patients without ME/CFS in their diagnostic biomarker studies. This study includes those patients. Everyone will assess their levels of fatigue regularly on handheld computers.
Younger appears to be measuring just about every inflammatory marker he can find — this is exactly the kind of exhaustive study ME/CFS needs and so rarely gets. It should reveal much about the inflammatory component of ME/CFS and is big enough that Younger expects to be able to identify subsets. Younger will also attempt to “develop a temporal pathway between immune factors and fatigue that identifies early drivers of fatigue.” I asked him what he meant by a “temporal pathway”:
“The temporal pathway is really about determining what comes first. We may identify 20 or so inflammatory agents that are associated with fatigue. But we really want to know where we can intervene in order to stop the process. So, we need to know what leads to what. We want to get as early in the causal chain as possible so we can stop the problem at the source. So, determining the temporal pathway is really about figuring out where the problem begins.” – Younger
It could start with leptin. They say all roads lead to Rome, and Younger’s last ME/CFS study suggested that all roads did in fact lead to leptin. Leptin appeared to be the ball that got the immune cascade rolling in ME/CFS.
In the video interview with Deborah Waroff, Younger said that leptin, which is produced by the fat tissues in the body, is able to cross over and sensitize the microglia in the brain. Activating the microglia is one thing, but sensitization is a more serious issue since it could cause the microglia to respond to factors they shouldn’t be responding to. That would set the stage for the kind of low-level neuroinflammation Younger believes is present in FM and ME/CFS and which Japanese researchers produced evidence of last year in chronic fatigue syndrome. Leptin was correlated with fatigue levels in people with chronic hepatitis C infections.
Ironically, the home-based things one can do to reduce leptin levels are particularly difficult for people with ME/CFS and FM. The enforced sedentariness of the disorders makes it easier to gain weight – which increases leptin. Exercise can help reduce leptin levels, but significant exercise is, of course, pretty much out of the picture. Stress eating – which has got to be more common in any chronic illness – increases leptin levels.
Banking for the Future
Younger will also bank his samples and make them available to other researchers. Several biobanks have emerged recently, but it’s not clear that any of them, except Klimas’s at Nova Southeastern University, will have what Younger will have – thousands of samples categorized by the degree of fatigue present when the samples were taken. That’s an enormously useful data point to have.
The big ME/CFS study started in March of 2014 and it’s slated to end in February of 2019. I asked him – is it really going to take five long years?
“I hope the project does not take 5 years. We will push to get it done as fast as possible. And once we have enough people (maybe around 30), we will run preliminary analyses and publish them. We don’t have to wait for the entire project to finish.” – Younger
Temperature Rising – Neuroinflammation, ME/CFS, and Fibromyalgia
Neuroinflammation is a hot topic in both ME/CFS and fibromyalgia. You can easily spot the inflammation in disorders like multiple sclerosis where the nerves are literally being destroyed, but finding the low levels of inflammation Younger believes are present in the brains of ME/CFS and FM patients has been difficult.
I asked him if any methods accurately assess microglial activation/neuroinflammation in the brain at this point.
“Regarding directly assessing microglia activation or neuroinflammation – no, there is nothing currently available that provides a direct measure. What we have now are proxy measurements, and the question is how closely they reflect true changes in microglia activation. The closest seems to be positron emission tomography (PET) assessment of the translocator protein (TSPO). It is a receptor that seems to be expressed more in activated microglia. So, if we inject someone with a ligand for that receptor that has a radio tag, we can measure the uptake of that chemical and get a rough idea of microglia activation. Unfortunately, the receptor is expressed on other cells, and there are individual differences in uptake. So, even the PET method is not perfect. Many people are working on this problem.” – Younger
Younger is trying to assess the amount of neuroinflammation present by taking the temperature of the brain. Just as when you’re sick the temperature of your body often goes up, Younger thinks low-level inflammation in the brain may be causing the temperature of ME/CFS and FM patients’ brains to increase slightly.
He’s using magnetic resonance spectroscopy (MRS) to determine the concentrations of certain chemicals in the brain and then creating temperature maps by running calculations on some of those chemicals. He’s working with several Institutes to produce point by point temperature maps of temperature in the brain. Ultimately these maps could produce a diagnostic biomarker for ME/CFS.
Low Dose Naltrexone… Plus
“All the research is about finding new treatments.” – Jarred Younger
A leader, make that the leader in the charge to validate the use of low dose naltrexone – a basically unmarketable substance (thus far) for drug companies – in fibromyalgia, Younger has shown that he’s willing to open up new ground in the treatment of the disease. LDN, when it works, appears to work on a variety of levels, reducing pain, improving energy, and reducing feelings of stress and negative moods.
One LDN study underway to determine if LDN reduces inflammatory markers in the blood may be able also to isolate which types of FM patients benefit from the drug. Younger also has several grant applications in the pipeline to run LDN studies in larger groups.
Younger is not stopping at LDN, though. In the Waroff interview, Younger stated, with some surprise in his voice, that his lab is finding that some Chinese botanicals, such as stinging nettle and curcumin, are very effective at suppressing the microglia as well. His lab is currently testing about 30 different substances. In the drug realm very low dose dextromethorphan (30 mg) and 3-hydroxymorphinan (not used in humans yet) are promising candidates.
Blogs on microglial inhibitors
- Microglial Inhibiting Drugs – Providing Hope for Fibromyalgia and Chronic Fatigue Syndrome (ME/CFS)?
- Marijuana, the Microglia and Reducing Nerve Pain
- Drug Repurposing I: Antibiotics to Reduce Microglial Activation in ME/CFS and Fibromyalgia?
- Palmitoylethanolamide (PEA) – A Medical Food for Fibromyalgia and (ME/CFS)?
A recent fibromyalgia study found reductions in anti-inflammatory cytokines during and directly after exercise, but not in the days following the exercise – when the patients were still symptomatic. I asked him if a transient immune disruption like that might set the stage for microglial activation and post-exertional malaise in FM and ME/CFS. He thought yes.
“There are proteins designed to put the brakes on microglia activity. One that is mentioned frequently is fractalkine. Fractalkine allows neurons to exert control over microglia function, generally by maintaining microglia in their “resting” state. Anti-inflammatory cytokines such as IL-10 can control the expression of fractalkine from neurons.
“A hypothesized scenario would go like this: During exercise, there is a decrease of anti-inflammatory cytokines in patients, which in turn lowers fractalkine activity in the CNS, which results in microglia becoming sensitized and moving to an activated state. The microglia then remain in the activated state for a few days until fractalkine activity normalizes and the brakes are restored. There is no analysis examining that entire sequence of events, but the pieces are all established.”
A small study just recently found reduced fractalkine levels in people with fibromyalgia. A review of that study will be coming up in our next blog.
Younger’s and Dr. Klimas’s moves from higher to lower ranked academic centers willing to provide them with more resources may suggests some academic centers may be trying to get a head start in what they believe will be a growth field.
Younger’s commitment to leave no stone unturned in his search for effective treatments and his embrace of new technologies that merge sophisticated data mining techniques with personalized data gathering tools is probably emblematic of a younger generation of researchers. His ability to turn a small pilot study into a $2 million dollar or so NIH grant is very gratifying as well. It’s going to be interesting.
The most difficult task Younger may have going forward is finding ME/CFS or FM patients in a state with few (if any) ME/CFS or FM experts. If you have ME/CFS or fibromyalgia and live in or near Alabama and might be interested in participating in one of Younger’s studies, email the lab at firstname.lastname@example.org or call them at 205-975-5907. You can sign up for the lab’s newsletter here.
Jarred Younger will be featured in Pandora’s first webinar on January 23rd
- Research Report: Leptin in the Role of Neuroinflammation, Pain and Fatigue
- Jan 23, 2015 at 1:30 PM EST.
- Register at https://attendee.gotowebinar.
After registering, you will receive a confirmation email containing information about joining the webinar.
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