News From Jarred Younger / Neuroinflammation, Pain, and Fatigue Laboratory at UAB, From Aug 2020

Jarred Younger: 077 - Seeing what I see: brain inflammation


ETA AI summary:
Summary: Brain Inflammation Patterns in ME/CFS Patients (Video Transcript)

0:00 — Introduction: Exploring Brain Inflammation Data​

The speaker begins by describing a Sunday research session in the laboratory. They have been analyzing MRI and PET scans from participants with ME/CFS (Myalgic Encephalomyelitis/Chronic Fatigue Syndrome). The images visualize neuroinflammation by using a tracer, 11FPA-714, which binds to activated microglia. Brighter red areas indicate higher inflammatory activity. By examining these scans, the researcher aims to understand where inflammation occurs in the brain and whether it follows specific patterns.

1:52 — Baseline: Healthy Control Example​

The first scan shown is from a healthy control subject. As expected, there is minimal neuroinflammatory activity, with only faint background signals caused by resting microglia. This example serves as a baseline for comparison with ME/CFS patients.

2:18 — Pattern 1: Localized Bilateral Inflammation​

In the first ME/CFS case, the inflammation appears as distinct, symmetrical hot spots in the amygdala and hippocampus—areas crucial for emotion and memory. Additional activity is seen in the periaqueductal gray (PAG), a region involved in pain modulation and anxiety responses. The researcher speculates that this pattern might be linked to symptoms such as anxiety and widespread musculoskeletal pain, similar to fibromyalgia.

3:35 — Pattern 2: Widespread Brain Inflammation​

The second group of ME/CFS scans shows diffuse inflammation throughout the gray matter, meaning nearly all neuron cell bodies exhibit inflammatory activity. Although this inflammation is less intense than in localized cases, its widespread presence might lead to many mild-to-moderate symptoms across cognitive, sensory, and emotional domains. The overall impact may still be significant due to the cumulative burden of numerous symptoms.

5:00 — Pattern 3: Brainstem and Thalamic Involvement​

The third group shows intense inflammation centered in the thalamus, midbrain, pons, and brainstem. This pattern closely resembles results from an earlier ME/CFS PET study by Dr. Nakatomi (over 10 years ago). Even though the inflammation is localized, the affected regions are essential for nearly all brain functions, potentially leading to widespread symptoms and post-exertional malaise (PEM).

6:06 — Reflections and Next Steps​

The researcher emphasizes that these are preliminary observations, not formal hypotheses. Further analysis—linking imaging data with symptom reports and performing statistical testing—may alter the current groupings before publication. The video aims to reveal the messy, iterative process of scientific discovery, rather than the polished final version found in papers.

7:00 — Conclusion: Evidence Supporting the Inflammation Hypothesis​

The preliminary findings support the hypothesis that ME/CFS involves brain inflammation. The researcher plans to continue analyzing data, finish a separate brain lactate paper, and provide future updates as more insights emerge from this ongoing investigation.

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He seemed to say "[11F]DPA-714" but based on my limited knowledge (Fluorine-18 and Carbon-11 are radio-isotopes, Fluorine-11 is not?) I'm guessing he meant [18F]DPA-714 or [11C]-PBR28? Or can you mix and match the radio-isotope and the TPSO connecting-part and get [11C]DPA-714?
 
Chandelier said:
Jarred Younger: 077 - Seeing what I see: brain inflammation


ETA AI summary:
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If what Younger presents in this video holds up then this is absolutely huge. But I guess we have to wait for the paper to make any real judgement. He says he's working on a brain lactate one first so might be a while.

I've been quite skeptical about some of his recent statements, but I'm interested to see how this plays out.
 
PolyBio cofounder Dr. Michael Van Elzakker described his lab’s research on neuroinflammation in Long Covid and pre-2018 ME/CFS. Via their PET scanning methodology, biological markers in patient samples (i.e. L-selectin, fibrinogen) are found to be correlated with neuroinflammation identified on imaging.
 
Jarred Younger: 078 - How I am going to fight brain inflammation


Dr. Younger, director of the Neuroinflammation, Pain and Fatigue Laboratory, outlines his plan to advance a treatment specifically targeting brain inflammation, which plays a key role in ME/CFS, fibromyalgia, and long COVID. He explains that no existing drug has been designed to directly modulate microglia, the immune cells responsible for neuroinflammation. Current treatments, such as low-dose naltrexone, only reduce inflammation as a secondary effect and come with limitations.

He highlights a promising candidate—dextrorphan (referred to as dextrone/dextronome)—which has shown strong scientific support for microglial modulation for more than a decade, backed by researchers like Linda Watkins and Mark Hutchinson. Although he has long wanted to test this compound in human clinical trials, progress stalled because the idea is already publicly documented, preventing patent protection. Without a patent, companies cannot secure profits, making investment unlikely despite encouraging animal studies.

Because no one has moved it forward, Dr. Younger has decided to take the lead himself. He acknowledges the process will be long, expensive, and high-risk, estimating around 5 million USD to reach early clinical trials. He is seeking donors rather than investors and provides a university-managed donation page where supporters can contribute. He plans to give occasional updates and encourages viewers to watch his earlier video explaining how the compound works.
 
The other reason it’s probably not getting interest is because, as far as I know, the only positive support for this medication on microglia modulation comes from animal studies. It was trialed for mitigating negative outcomes after stroke (strong support that microglia play a big role) in the 90s, with a completely null result and high rate of negative events.

pubmed.ncbi.nlm.nih.gov

Safety, tolerability, and pharmacokinetics of the N-methyl-D-aspartate antagonist dextrorphan in patients with acute stroke. Dextrorphan Study Group - PubMed

The highest doses of dextrorphan administered were associated with serious adverse experiences in some patients. Lower doses (loading doses of 145 to 180 mg, maintenance infusions of 50 to 70 mg/h) were better tolerated and rapidly produced potentially neuroprotective plasma concentrations of...
pubmed.ncbi.nlm.nih.gov pubmed.ncbi.nlm.nih.gov
 
Google AI says:

"Dextrorphan (DXO), also known as 3-hydroxy-N-methylmorphinan, is the primary active metabolite of dextromethorphan (DXM), a common over-the-counter cough suppressant. Dextrorphan itself is a psychoactive drug that acts as a cough suppressant and, at high doses, a dissociative hallucinogen."

PwME already use DXM. What's the difference?
 
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jnmaciuch said:
The other reason it’s probably not getting interest is because, as far as I know, the only positive support for this medication on microglia modulation comes from animal studies. It was trialed for mitigating negative outcomes after stroke (strong support that microglia play a big role) in the 90s, with a completely null result and high rate of negative events.

pubmed.ncbi.nlm.nih.gov

Safety, tolerability, and pharmacokinetics of the N-methyl-D-aspartate antagonist dextrorphan in patients with acute stroke. Dextrorphan Study Group - PubMed

The highest doses of dextrorphan administered were associated with serious adverse experiences in some patients. Lower doses (loading doses of 145 to 180 mg, maintenance infusions of 50 to 70 mg/h) were better tolerated and rapidly produced potentially neuroprotective plasma concentrations of...
pubmed.ncbi.nlm.nih.gov pubmed.ncbi.nlm.nih.gov
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Are Dextrorphan and Dextro-naloxone the same drug?
 
Sounds like he's pretty convinced neuroinflammation is the cause of ME/CFS and others. $5m may be a pittance in this age of billions and unicorns, but you have to have some conviction to move forward with the project that requires committing years of effort and fund raising to develop the compound.
 
poetinsf said:
Sounds like he's pretty convinced neuroinflammation is the cause of ME/CFS and others. $5m may be a pittance in this age of billions and unicorns, but you have to have some conviction to move forward with the project that requires committing years of effort and fund raising to develop the compound.
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He does seem pretty convinced. But I’ve seen plenty of researchers spend years on something that was very clearly a dead end in hindsight, but they had just enough noisy data to see what they wanted to see. More than I can count, really. Publishing the data proving chronic microglial activation would be a necessary step before asking for public funding for a trial.
 
jnmaciuch said:
Publishing the data proving chronic microglial activation would be a necessary step before asking for public funding for a trial.
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That's my thought. And my guess is that he feels pretty confident about the paper he is about to publish. I'd contribute myself if the paper pans out -- a chance at being able to jog 4x150m without crashing the next day will be worth substantial sum to me. He's asking donation to fabricate the compound, and get it approved, btw. He'll have to have the compound before he can trial.
 
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