• High blood oxygen levels entering the brain and low blood oxygen levels leaving the brain suggest the brains of ME/CFS patients are sucking up all the energy (oxygen) they can to keep going.
  • Why this is happening isn’t clear. It could be due to low blood flows to the brain, but since the patients were tested while lying down, that seems less likely, at least in the prone position. More likely causes are problems with energy production and/or widespread inflammation.
  • As researchers dig up more and more evidence that neuroinflammation is taking place, much of this blog will focus on inflammation, and who better to find out about that than Jarred Younger (“the neuroinflammation man” :)) who runs the Neuroinflammation, Pain, and Fatigue lab at the University of Alabama at Birmingham.
  • Younger believes that immune cells in the brain called microglial cells are primed to spew out inflammatory factors at the slightest stress in ME/CFS: a bit of exercise, a psychological stressor, an infection. He found, for instance, that it took just a small dose of a bacterial toxin to inflame the brains of fibromyalgia patients (but not healthy controls).
  • Younger is ready to close the door on the neuroinflammation or brain inflammation question in ME/CFS. He believes that the evidence is incontrovertible and that over the next year, there will be consensus on that question.
  • In a nice fit with the first presentation, Younger found increased lactate – the substance the brain turns to when it can’t produce enough energy using the oxygen it’s getting – in ME/CFS patients’ brains.
  • Younger is doing an “arterial spin labeling” study to assess, in more detail than has been done before, whether reduced blood flows to the brain are contributing to the neuroinflammation he’s finding.
  • Younger has spent about 10 years trying to figure out how to determine whether immune cells from the body are getting into the brain. Because these powerful immune cells can cause all sorts of damage, only in the most dire circumstances will the brain call them in.
  • With Younger’s new approach (created with two collaborators at UAB) ready to go, he expects to start testing ME/CFS patients over the next month or so. Finding that immune cells are getting into the brains of people ME/CFS could explain a lot and open the door to new treatments.
  • In a recent YouTube video, Younger noted that the extensive testing he does uncovers, in about 35% of the cases, problems like diabetes, thyroid issues, and anemia that have been undetected. Since he believes that inflammation is a huge driver of illness in ME/CFS/FM, he does lots of inflammatory tests and came up with 8 tests that people with these diseases can pretty readily get done to assess their inflammation levels. See the blog for more.
  • Michelle James Neuroimaging Research and Discovery lab at Stanford is on the cutting edge of imaging technique technology. Besides studying Alzheimer’s disease, multiple sclerosis and stroke, she’s also studying ME/CFS.
  • Like Younger she believes that chronic inflammation is driving the fatigue, pain, PEM, etc. in ME/CFS.
  • Recently, she’s been doing the first whole-body PET imaging ever done in ME/CFS (and perhaps in other diseases). Besides indications of inflammation in the brain, she’s also found it in the salivary glands (site of intense mast cell activity), the muscles, and, interestingly, the bone marrow (where many immune cells are produced).  (Check out the images in the blog).
  • The brain session, then, pointed to more evidence of neuroinflammation – and inflammation elsewhere (the muscles!) – as well of energy systems gone awry.
  • We should learn a lot more over the next year as a host of Younger’s studies get published about the immune-brain interface.

The second post on the NIH’s ME/CFS and long COVID Conference focuses on a timely issue – the brain. The Nath study proposed that ME/CFS was an immune-driven brain disorder. This part of the conference made it clearer than ever that the immune system and the brain are indeed involved.

Brain Metabolites

Xiang Xu

Xiang Xu is working with Benjamin Natelson at Mt. Sinai.

Xiang Xu of Mt. Sinai gave one of the young investigator talks. She’s working with Dr. Benjamin Natelson – a longtime ME/CFS/FM investigator –  on a long-COVID ME/CFS subset study.

Her structural MRI didn’t find any alterations and that’s not a surprise. While we’ve seen evidence of spinal problems we’ve seen little evidence of overt structural changes inside the brains of ME/CFS/FM patients. That’s a good thing given how difficult it is to turn that kind of damage around.

The physiological MRI was another deal. While it found abnormalities in the thymus and other areas, the big finding from her study involved one of our favorite subject – oxygen and energy production. First, she found reduced oxygen levels in the venous circulation in ME/CFS-like long-COVID patients. (The venous circulation involves the blood that’s leaving the brain after the brain has sucked up all the nutrients and oxygen it can from it.)

Interestingly, arterial oxygenation taken at the finger was significantly higher in the long-COVID group. That brought up an interesting question – if higher oxygen levels are present in the blood feeding the brain – why would lower oxygen levels be found in the blood leaving the brain? In other words, why were the brain cells of the ME/CFS-like long-COVID patients eating up so much oxygen? (Oxygen is the substance that generates ATP (energy) for the brain.)

venous oxygen

Dramatically reduced high arterial oxygen, reduced venous oxygen, and increased brain oxygen consumption suggested the brains of the long-COVID patients were snatching up all the oxygen they could find.

A reduction in blood flows to the brain could do it. If not enough blood is getting to the brain, then what blood made it to it would surely get stripped of all the oxygen possible.

To determine whether that was happening, she took MRIs of the blood vessels leading to the brain and calculated the “metabolic rate of oxygen”. That refers to the amount of oxygen being used by the brain. It’s considered “a direct index of energy homeostasis and brain health” and is usually maintained at a constant rate in healthy people.

While lying down, the ME/CFS patients exhibited normal blood flows to the brain but higher rates of oxygen consumption in the brain. ((Note that reduced blood flows to the brains of people with ME/CFS have been found when they’re upright (sitting, standing) and this study was done while they were lying down.) With that finding, what was happening became clear. The reduced venous oxygen levels found in the ME/CFS patients resulted from abnormally active brains that were stripping out just as much energy (oxygen) as they could from the blood.

That’s potentially a big deal. When we’re at rest, the brain consumes over 20% of the body’s total energy. Because the brain doesn’t have a lot of “storage capacity”, it needs to get constantly fed properly to function normally. Because increased oxygen consumption has also been found in various nasty neurological diseases, this finding again suggests that ME/CFS, at least in part, is a neurological disease.

Because the low venous oxygen levels were positively correlated with the physical fatigue scores; i.e. the lower the venous oxygen levels, the higher the physical fatigue, it’s possible the physical fatigue could result from the long-COVID patients’ brains’ voracious appetite for energy (oxygen).

Or is an overactive immune system sucking the energy from the rest of the body, as Mark Davis suggested. Again, we see a similar theme emerging – overactive systems in the brain, the immune system, and the autonomic nervous system that could be putting a big hurt on energy production.

That set the stage nicely for Jarred Younger’s talk.

Jarred Younger: “Brain inflammation in ME/CFS – how we measure it and how we treat it.”

Younger noted that he does “high-risk” experimental studies (high risk / high reward, that is) and boy, is he right about that. He’s been right out there on the skinny branches developing new techniques to study brain inflammation and immune infiltration in the brain. Plus, unlike most other research scientists, Younger has had a strong interest in assessing treatments. It was Younger’s small studies that birthed the interest in low-dose naltrexone in fibromyalgia and ME/CFS.

Younger noted that in their primed state, microglia can look relatively normal but explode into action at the slightest trigger. Many possible microglial triggers exist: lots of fat cells, any peripheral inflammatory state, an altered gut microbiome, normal aging, reduced oxygen in the brain, chronic stress, and viral/bacterial infections – particularly when a series of them occurs together.

lactate brain

The high lactate levels (red – ME/CFS patients at bottom) suggested their brain cells had switched to an alternative energy source.

Once those microglial cells are activated in ME/CFS, Younger believes that even something as small as a bit of exercise can activate them. The goal is to get the microglia back into their resting state.

Younger showed how on edge the microglia are in fibromyalgia. Injecting fibromyalgia patients with a vanishingly small amount of bacterial toxins caused the microglial cells to act up across much of their brain. They also showed a huge increase in a microglia activator called leptin, and a reduction in a microglial inhibitor called fractalkine. Since about half of the FM patients met the Fukuda criteria for ME/CFS, Younger felt there was a good chance the same is occurring in ME/CFS.

He’s about half done with a NINDS-funded study in ME/CFS that will, if positive, he said, constitute “very powerful evidence” that the microglia are in an inflamed and agitated state in ME/CFS patients’ brains; i.e. that neuroinflammation is present.

Younger noted that many studies, including his, have found elevated lactate throughout the brain in a subset of ME/CFS patients and he has found very high elevations in lactate in a subgroup of patients. Lactate is what the brain turns to to produce energy when it runs out of oxygen; i.e. it’s what we would expect the brain to do given the results of first study cited above.

Combining the PET and MRS studies done so far gives Younger great confidence that neuroinflammation in present in ME/CFS. A few more data points – which he expects to come this year – and that finding will be incontrovertible.

Instead of a brain-centered problem, the inflammation could also, as noted above, be due to problems with orthostatic intolerance and/or blood vessel issues that prevent enough oxygen from getting to the brain. Younger is testing for that with his arterial spin labeling study. Because his study is being done with the participants lying down, if it does not show hypoperfusion, he’ll test the participants while lying supine, then get them upright, and put them back into the scanner.

(Who’s to say it’s not both, though? Brains that are battling for all the energy they can get while also getting whipsawed by a further reduction in oxygen levels while upright?)

A Huge Step for ME/CFS? The Immune Cell Invasion Study 

Younger has proposed that immune cells from the body (leukocytes) may be making their way into the brain, causing inflammation, brain fog, profound fatigue, anxiety/depression, etc. Only in extraordinary situations (raging infection) would the brain ever call immune cells from the body into it. Whether or not the infection is resolved, damage is going to ensue. It’s like calling missiles in on your own position as it’s about to become overrun.

In multiple sclerosis (MS), T-cells make their way into the brain and, mistaking the myelin sheaths of the neurons for foreign entities, attack them. Nothing in ME/CFS suggests that this kind of damage is present. Instead, ME/CFS, fibromyalgia, and Gulf War Syndrome appear to be diseases of general inflammation. Younger does not lump ME/CFS into the neurodegenerative disease basket (MS, Parkinson’s, etc.) where you find damaged neurons and structurally altered brains. He believes they are a different class of disorders.

first Leukocyte tracing image - from Jarred Younger

The first human leukocyte tracing image done. Note how the white blood cells (red) are concentrated in the middle of the body around the lungs and the heart, where most of the blood is. Younger will soon start assessing people with ME/CFS.

Younger has spent about ten years trying to figure out how to image white blood cells entering the brain. After digging a lot of dry holes during that time, two of his colleagues at the University of Alabama came up with a new technique: leukocyte tracking using PET scans examining radio-labeled leukocytes.

The leukocytes are taken out of the patient – get labeled with a radiotracer – and then are reinserted back into the patient. A PET scan then determines where the leukocytes went. If immune cells from the body show up in the brain – you’ve got problems. Four healthy controls demonstrated that the technique was safe and effective; i.e. it found that none of immune cells entered the brain.

Younger predicted finding leukocytes in the brains of ME/CFS – if it happens – would be a huge step forward for this disease and point very strongly to new treatments. He has submitted safety data from the healthy controls to the FDA. In February when this video was made, he hoped to get the first patient – an ME/CFS patient – into the study in 2 months – so we should know more in about a month from now. Once Younger had a few patients done, he promised to start spilling the results on his lab’s YouTube channel.

Big props to ME Research UK for stepping in and funding what can only be termed as a high-risk/high-reward study. Their funding allowed Younger and colleagues to develop a technique that could help not just with ME/CFS but with many other diseases as well.

Big Year Coming Up For Younger and Possibly ME/CFS

Younger has gotten some big ME/CFS grants (good day / bad day; neuroinflammation; leukocyte infiltration) funded but has lacked the post-docs needed to complete them. That issue has apparently been solved, as Younger reported this year will be a year of data analysis and writing up papers.

Clinical Trials

Putting on his clinical trials hat, Younger reported that he has a long and growing list of potential treatments – probably around 100 – he would love to get tested in ME/CFS. If one of his studies finds immune cell infiltration into the brain, drugs that knock out those immune cells or that repair the blood-brain barrier could be used. If he finds problems with cerebral perfusion, he mentioned methylene blue – an over-the-counter supplement that calms microglia and helps with cerebral blood flow.

A Methylene Blue Boost? Could a Blue Dye Help with ME/CFS, Long COVID and Fibromyalgia?

Citing the fact that many of the FM patients in his LDN trial met the criteria for ME/CFS, he called for large low-dose naltrexone (LDN) trials in ME/CFS. He noted, though, that a recent fibromyalgia study of 99 people using 6 mg/day for 12 weeks did not find LDN helped more than placebo. It looked like the study was well done, but a companion commentary asserting that physicians should not give LDN to any new patients went too far given the many ME/CFS/FM patients who have benefited from it.

Plus, 48% of FM patients in the study had a “clinically significant reduction in their symptoms”. Younger proposed that the study may have been too small for its type (parallel study) and asserted that a properly powered trial of LDN is needed. Then he recommended testing a different form of LDN called dextro-naltrexone that could be used in much higher amounts.

Easy Tests For Inflammation

Speaking of his lab’s YouTube channel, Younger has been back releasing videos of late. Two weeks ago, his “Simple blood tests to detect inflammation” YouTube presentation provided tests that will “generally” tell you if your pain/fatigue/symptoms might be caused by inflammation.

He noted that this is not medical advice, and that researchers are often ahead of doctors in this realm and may not conform to what the doctors know of as “best practices”. Younger runs lots of blood tests and about 35% of them detect a problem that the patients didn’t know they had. They find diabetes, thyroid disorders, autoimmune disorders, anemia and others.

Because Younger suspects ME/CFS/FM, Gulf War Syndrome, and long COVID are chronic inflammatory conditions, he does lots of tests of inflammation, many of which are not available at medical labs. Noting that sustained inflammation tends to beget more inflammation, it’s clear that Younger believes tests of inflammation should be part of a yearly package of standardized blood tests and that doctors should be more concerned when they see more moderate levels of inflammation than they are now.

Direct-to-Consumer Medical Testing Labs

I was astonished several years ago to find that some medical labs don’t need a doctor’s order to get tests run. Dr. Younger said he has used these direct-to-consumer labs to good effect. They include Request a Test (directs you to labs), Direct LabsLabCorp on DemandWalk-In Labs, Wellness Mama, Everlywell, and others. Some of these send test kits to your home.

Inflammation Tests

The BIG Two – These are readily available.

High sensitivity C-reactive protein – tracks well with inflammatory activity. Want values below 1. If the number reaches as high as 4, you have a “greatly increased risk of having something serious happen”. If it gets above 10, you have something that needs to be figured out.

After the lab opened during the pandemic, he saw lots of healthy controls with 10 values which was a lingering effect of COVID-19 and/or vaccines. They have dropped since then.

Erythrocyte sedimentation rate (ESR) – you want something below 20; 60 = moderately high; above 100 – high inflammation. A bit more consistent than hi-sensitivity C-reactive protein. ESR levels have been a good predictor of who will respond to low dose naltrexone. Fibromyalgia patients with higher ESR levels tend to respond better to LDN. (ESR- 60 mm/hr – 50% reduction in pain; 30 mm/hr – 30% reduction; 15 mm/hr – 20% reduction)

The Next Six

If you have good insurance, can afford them and your doctor will run them, Younger suggests these as well. Most are inexpensive. Some can be ordered labs on your own:

If all of these tests are low, Younger believes you probably do not have a problem with inflammation.

These are general indicators of inflammation and if they are high, the next step is to talk with your physician and hopefully get more tests run to try to figure out where it is coming from.

The complete blood test (CBC) that is often run can also give some indications if inflammation is present.

A big thanks to Jarred Younger for taking on this field when so few would, and showing that it’s possible to be successful in it.

Michelle James Ph.D – Illuminating Whole Body Immune Responses Using PET

Michelle James

Michelle James Ph.D received an NIH grant to study ME/CFS

Michelle James Ph.D is originally from Sydney, Australia (and sounds like it 🙂 but is now an Assistant Professor at Stanford. The winner of a long list of awards, James now runs the James Neuroimaging Research and Discovery lab which is researching Alzheimer’s disease, multiple sclerosis, myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS), and stroke.

The lab’s goal is to develop novel, state-of-the-art medical imaging methods to enable highly accurate and ultra-sensitive detection of these diseases – particularly in their earlier stages. How sensitive is sensitive? PET scans can detect molecular changes at the nanomolar level. James showed a slide of raging inflammation found in mice given a bacterial toxin before they showed any symptoms.

In the last half of her talk, James relayed the wide variety of specialized tracers the lab is developing to allow researchers to see, through their imaging studies, exactly what is going on in these diseases; i.e. what parts of the body, what cells, what immune factors are involved in them. She asked for ME/CFS researchers to send her their tissue samples so she could test them.

The NIH Grant

It was great to see such a high-level approach being used in ME/CFS. In December 2021, James received an R21 (exploratory) grant, “Imaging inflammation in the whole body and brain of ME/CFS patients“, to do the first whole-body PET imaging of ME/CFS from the National Institutes of Neurology and Stroke (NINDS) at the NIH. She noted that “encouraging preliminary data” found evidence of increased neuroinflammation in the brains of people with ME/CFS.

Pet Scan

The first PET scans found more signs of activation; i.e. inflammation in the brains of ME/CFS patients.

In the grant, she hypothesized, “chronic, unresolved inflammation driven by innate immune cells underlies the central clinical problems of fatigue, pain, and cognitive dysfunction observed in ME/CFS”.

Because they’ll be assessing markers of inflammation and pathogen activity, the oxidative stress study should illuminate many factors in ME/CFS including immune activity (cytokine signatures), herpesvirus activity, the blood-brain barrier disruption, white matter changes in the brain, and disease severity. (That’s a lot – think what she could do with a full R01 grant from the NIH. )

So far they’ve gotten through 4 pairs of ME/CFS patients and healthy controls. They found evidence of increased activity in the thalamus, pons, and other parts of the brain. As other studies have found, the inflammation was more pronounced in the women than the men.

Full body PET scans

Early full-body PET scans found more activation in the muscles and bone marrow of ME/CFS patients.

One finding, though, intrigued her. After finding increased inflammation in the salivary gland – a site of high mast cell activity – she was eager to do whole-body PET scans. Her colleagues were skeptical they could be done, but she found a way to make it work in ME/CFS and received NINDS funding to do the entire body.

The scan found increased activity in the muscles and bone marrow (in the females). (The bone marrow produces red blood cells, immune cells (white blood cells) and platelets). With a new, more sensitive scanner coming, and with better tracers for the microglia and macrophages on the way, she should be able to dig deeper into ME/CFS physiology.

Besides the whole body approach, she’ll also do in-depth scans of the spleen (immune cell producer, blood filterer), lungs, and gut. Collaborators will use machine learning to assess the results. (Jarred Younger was a named collaborator in her NINDS grant).

Check out the 1st NIH ME/CFS Conference Blog

The Vampire: Is the Immune System Sucking the Energy Out of People with ME/CFS? – the NIH ME/CFS Conference Pt. I


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