Second study might confirm neuroinflammation in ME subcortical brain

[percyval577]

Note also that the Substantia Nigra is one of the most energy-intensive parts of the subcortical brain, probably because it must manufacture and transport the dopamine for other parts of the basal ganglia, or because the Substantia Nigra must continuously fire some of its neurons roughly 25 times per second.

I have no idea if 25 times is much or not, but I wouldn´t have been surprised about lots of other numbers.

However, with the dopamine system there might be some general vulnerability. Autooxidation of dopamine seems to be a possible problem, in general a vulnerability to oxidative stress. But then after induced oxidative stress in the striatum neurons in the Sn die without signs of oxidative stress, though maybe because of fast clearance of such markers, as Smith and Cass 2007 reason.

The dopamine system might be a good candidate for fatique, indeed, and I completely agree that the article @pattismith provided is very interesting, including that only a portion of PwMS get a MS-fatique, though quite a percentage.

I finally noticed, that in my CFSME selenium may turn out to be most important along with low manganese. This buffles me a bit. Mn is of course well known for its participation in the mitochondrial MnSOD, which convertes superoxide anions to hydrogen peroxide, which is then further processed (in a clearing manner) by gluatahione peroxidase which uses selenium. Could it really be that such an important way can be influenced simply by nutrition? Or is it any receptor side to hydrogen peroxide that would be hypersenstive?

Its complicate pathways anyway, which might be seen in Rodriguez-Rocha et al 2013 who conclude that energy failure and not oxidativee stress - which they investigated - might be the problem (in PD). I think the clue was that stressors in the mt matrix could not be countered by the (mostly in the matrix located) MnSOD, but MnSOD had an effect on a stressor which has additional, other actions.

I think that rather in such area the problem is located, not really in any infection. TSPO has many actions, and is not well understood. This molecule seems to have been investigated also in the MS finding, as the authors only in the disucussion one time mentioned, if I got it rightly. There should be a wide range of interpretation, with TSPO.

 

[pattismith]

Thanks, I hadn't heard about any studies with the Substantia Nigra and ME/CFS, but that study reporting neuroinflammation of the Substantia Nigra in Multiple Sclerosis is very interesting.

Yes, you are right, I checked for Substantia Nigra and ME/CFS and found no link, even though this part of the brain has already showed up in our discussions on PR...

I found another study (2017) about Hippocampus/NAD and Ketogenic diet, that may be of some interest:


"Consistent with our predictions we found clear evidence that metabolic therapy with a KD increases NAD+/NADH, a mechanism that could compensate for metabolic dysregulation and serve as a common start-point for the diverse beneficial metabolic and mitochondrial effects obtained with ketogenic treatments (Bough and Rho, 2007; Masino and Geiger, 2008).

As noted above, a comparison of the metabolic pathways of glucose and ketone bodies (Figure 1) suggests that the use of ketone bodies as main energy fuel requires fewer NAD+ molecules than glucose (by a factor of 4), which should lead to an increased cellular availability of this vital coenzyme.

Interestingly, β-OHB or a ketone ester precursor show protective effects by counterbalancing the decrease in NAD+/NADH ratio in cases of neurotoxicity (Maalouf et al., 2007; Zhang et al., 2013), confirming the ability of β-OHB to modulate NAD+/NADH levels.

Ketone ester treatment oxidizes the cytoplasmic NAD+/NADH couple in hippocampus and cortex in aged, affected Alzheimer’s disease model mice, and reverses an apparent overoxidation of the mitochondrial couple in the hippocampus (Pawlosky et al., 2017). Thus this study and our study of the whole-cell couple suggest clear positive metabolic effects of ketolytic metabolism.

In general, the hippocampus has been described as a seizure gate (Heinemann et al., 1992) and it is one of the first brain regions to be affected in Alzheimer’s type dementia; cortical changes appear later in the disease (Braak and Braak, 1998). Unexpectedly, our data show that a KD increased NAD+/NADH in the hippocampus but not in the cerebral cortex, indicating regional specificity at the time points sampled.

It is possible that changes mobilized by a KD could be more rapid or pronounced in more metabolically active brain regions: the hippocampus displays a higher metabolic rate than the cerebral cortex (Feng et al., 1988). Related to this, an early decrease in metabolic rate of glucose in the hippocampus, but not in cerebral cortex, was detected in patients who received a postmortem diagnosis of Alzheimer’s disease (Mosconi et al., 2009). Because of its high metabolic rate and increased vulnerability to hypoxia, oxidative stress, and metabolic dysfunction, the hippocampus could benefit more—or more rapidly—than other regions from KD-induced metabolic changes, including increased NAD+ levels.

Rapid increases in NAD+/NADH ratio could partially explain the ability of a KD to stop seizures in many patients within a few days of KD treatment (Freeman and Vining, 1999). "

etc

 

[Pyrrhus]

However, with the dopamine system there might be some general vulnerability. Autooxidation of dopamine seems to be a possible problem, in general a vulnerability to oxidative stress. But then after induced oxidative stress in the striatum neurons in the Sn die without signs of oxidative stress, though maybe because of fast clearance of such markers, as Smith and Cass 2007 reason.

Its complicate pathways anyway, which might be seen in Rodriguez-Rocha et al 2013 who conclude that energy failure and not oxidativee stress - which they investigated - might be the problem (in PD).

Yes, I've heard before that the dopamine system is particularly vulnerable to oxidative stress, and that the targeted loss of neurons in the Substantia Nigra (in Parkinsons Disease) is correlated with oxidative stress. But the "energy failure" explanation would certainly explain it as well. Or both at the same or at different times...

It is possible that changes mobilized by a [ketogenic diet (KD)] could be more rapid or pronounced in more metabolically active brain regions: the hippocampus displays a higher metabolic rate than the cerebral cortex (Feng et al., 1988). Related to this, an early decrease in metabolic rate of glucose in the hippocampus, but not in cerebral cortex, was detected in patients who received a postmortem diagnosis of Alzheimer’s disease (Mosconi et al., 2009). Because of its high metabolic rate and increased vulnerability to hypoxia, oxidative stress, and metabolic dysfunction, the hippocampus could benefit more—or more rapidly—than other regions from KD-induced metabolic changes, including increased NAD+ levels.

That's a very interesting paper @pattismith . Thanks for sharing. Even though the hippocampus is more vulnerable to oxidative stress due to its higher metabolic rate, it's also a prominent site of neurogenesis, unlike in the cortical brain. So, to oversimplify it a little, the hippocampus may be easily damaged, but it is also easily repaired.

 

[MonkeyMan]

Hi @Pyrrhus - In your opinion, are we anywhere near an effective treatment for neuroinflammation?
Thanks in advance for any thoughts,

 

[Pyrrhus]

Hi @Pyrrhus - In your opinion, are we anywhere near an effective treatment for neuroinflammation?
Thanks in advance for any thoughts,

There may be some minor treatments that calm neuroinflammation a little, but the first step is to find out what's causing the neuroinflammation in the first place.

If we can identify the cause of a given patient's neuroinflammation, then treating that cause should resolve the neuroinflammation. Remember that neuroinflammation is a symptom of a disease, not the disease itself.

In the meantime, we can alleviate some of the downstream metabolic effects of neuroinflammation. For example, neuroinflammation tends to deplete glutathione in the affected areas of the brain, which can lead to new symptoms and may even worsen the neuroinflammation itself. So, by taking supplements to boost glutathione, we may resolve some symptoms and we may even alleviate some of the neuroinflammation itself. That's just one example, but an important one.

Hope this helps.

 

[MonkeyMan]

This is helpful, thank you Pyrrhus.

 

[Stretched]

Sure! If I use medical marijuana I become extraordinarily (100%) clear-headed for the whole day, and even extending into the next. But then after that, I pay the price: poor sleep, night after night, along with a heavy, swollen feeling in my head. And all the mental clarity I enjoyed is replaced with brain fog. It's terribly frustrating.

Great thread! FWIW, this is exactly how I (and others on this forum) feel while taking nitrous oxide, e.g. during dental work. There’s an earlier thread on the topic). Maybe one of the above posters could offer some insights why the two substances have nearly identical affects on some of us at least while each is active?

There’s some terrific insights above re @Pyrrhus et al. I’m crashed right now due to over stimulation earlier this week. I had to stop the heavy thinking after skimming these posts but I gleaned a lot of deducible logic available as to explaining what ‘is, is.’ I look forward to revisiting this enlightening thread when I get a clearer head. I do recall some of the referenced Japanese Study. I didn’t see them mentioned on first pass but some of discussion calls up the related topics in Jarred Younger’s work at UAB and the Dr L Bateman DB controlled studies re Protein T38?

 

[helen1]

@Stretched
Nitrous oxide is well known to cause B12 deficiency. There are many symptoms of this, including poor sleep (B12 is needed to synthesize melatonin) and poor cognition.

I’ve not heard that marijuana can decrease B12 though.

 

[leokitten]

Here's the abstract for the talk at ISMRM20 that @Pyrrhus mentioned in the OP

TSPO-PET/MRI Reveals Increased Neuroinflammation in Basal Ganglia of Chronic Fatigue Syndrome Patients

Mackenzie Leigh Carlson1, Jun-Hyung Park2, Tullia Lieb3, Bin Shen2, Marc Stevens2, Brian Mills2, Nicole Mouchawar2, Greg Zaharchuk2, Michael Zeineh2, and Michelle James2,4 1Bioengineering, Stanford University, Stanford, CA, United States, 2Radiology, Stanford University, Stanford, CA, United States, 3Medicine, Stanford University, Stanford, CA, United States, 4Neurology, Stanford University, Stanford, CA, United States

Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) is a debilitating disease affecting millions of people in the United States alone, but little is known about the underlying pathophysiology. We show that simultaneous TSPO-PET/MRI measurements using [11C]DPA-713, including SUV, SUVr, QSM, R2*, and volume can uncover new information about this disease. We find that the putamen has significantly higher TSPO-PET signal in ME/CFS subjects compared to healthy controls, indicating an elevated inflammatory response in this area. This finding corresponds to previous fMRI and diffusion imaging findings and may help with future diagnosis and tracking of this chronic, widespread disease.

 

[HABS93]

There may be some minor treatments that calm neuroinflammation a little, but the first step is to find out what's causing the neuroinflammation in the first place.

If we can identify the cause of a given patient's neuroinflammation, then treating that cause should resolve the neuroinflammation. Remember that neuroinflammation is a symptom of a disease, not the disease itself.

In the meantime, we can alleviate some of the downstream metabolic effects of neuroinflammation. For example, neuroinflammation tends to deplete glutathione in the affected areas of the brain, which can lead to new symptoms and may even worsen the neuroinflammation itself. So, by taking supplements to boost glutathione, we may resolve some symptoms and we may even alleviate some of the neuroinflammation itself. That's just one example, but an important one.

Hope this helps.

Would taking NAC (Glutithione pre cursor) be enough as well ? What's the difference between taken one opposed to the other?

 

[Pyrrhus]

Would taking NAC (Glutithione pre cursor) be enough as well ? What's the difference between taken one opposed to the other?

Yes, taking cysteine in the form of NAC is the most popular way to boost glutathione.

There are other ways, too, of course. Some people may find that they are more deficient in glycine than cysteine, so they take glycine, which is another precursor of glutathione. And some people try to directly take glutathione in different ways. But NAC happens to be the most popular way to boost glutathione.

 

[Hipsman]

Very interesting about NAC helping. Around 2 years ago when I started taking NAC it helped significantly with "wired-but-tired" symptom, but after some time the "wired" part of this symptom was reduced even when I stopped taking NAC (I stopped becouse taking it didn't give any effects at this point).

However, some months later I noticed "wired-but-tired" symptom creeping back in, so I continued taking NAC, witch reduced it (again) and just like the first time, the reduction effect remained for some time even after stopping...

After that there was a few more episodes like this, but it became more "blurry" and only required me to take NAC in the evening/before sleep for a week or two, instead of taking it 3 times daily for few months.

Also, it's interesting that in the later episodes I experienced increase in "wired-but-tired" symptom only in the evening/before sleep (hence I took NAC only 1 time daily), as in general, inflammation increases in the evening.
Thou, in my case, I have sublingual temperature witch remains around 37.0-37.4 °C throughout the day (I've been tracking it for more that a year and it didn't really change).

All this just gives more reasons to believe that neuroinflammation is definitely there...

 

[Pyrrhus]

There are two interesting discussions about reviews of neuroimaging in ME and the relation to neuroinflammation:


Neuroinflammation and Cytokines in Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS): A Critical Review of Research Methods
https://forums.phoenixrising.me/thr...-a-critical-review-of-research-methods.76890/


A systematic review of neurological impairments in myalgic encephalomyelitis/chronic fatigue syndrome using neuroimaging techniques
https://forums.phoenixrising.me/thr...syndrome-using-neuroimaging-techniques.81884/

 

[Pyrrhus]

To detect an immune-activated tissue-resident macrophage in a living brain, you have to find a biomarker that is expressed by an immune-activated tissue-resident macrophage but that is NOT expressed by an inactive tissue-resident macrophage. This is where the translocator (TSPO) protein comes into play. (This protein used to be called the peripheral benzodiazepine receptor, or just PBR).

TSPO is expressed by a tissue-resident macrophage when it becomes immune-activated. Therefore, if we can image the regions where TSPO is expressed, we can get a good idea of where the neuroinflammation is. In general, this approach has proved itself quite useful over the last decade or so.

The japanese PET study, here now replicated for the basal ganglia, found TSPO elevated, if I remember rightly, a molecule which is known to be elevated in inflammation. But there might be other tasks for it, not only in typical inflammation or so.

Perspective: Evolving understanding of translocator protein 18 kD (TSPO)

The review paper by Michael Van Elzakker also describes some issues with the use of TSPO for detecting neuroinflammation:
https://forums.phoenixrising.me/thr...-a-critical-review-of-research-methods.76890/

Excerpt:

There are several potential ways to interpret differences in TSPO-binding radioligand signal in patients vs. controls. Isolating and addressing potential confounding variables will make interpretation easier but also adds difficulty and considerable cost to a study. Type 1 or type 2 errors in studies of TSPO-binding PET radioligand uptake in brain could potentially be explained by the following methodological confounds:

• Standard neuroimaging techniques were not designed for brainstem study
• The first-generation radioligand PK11195 has high non-specific binding and low signal-to-background ratio
• PET signal calculated with an anatomical reference brain region relies on equal radioligand uptake in that region across cases and controls
• Radioligand access to brain is modified by general metabolism, which can differ across cases and controls
• Activated peripheral immune cells bind radioligand and can differ in quantity across cases and controls
• A single nucleotide polymorphism (SNP) in the TSPO gene causes differential radioligand binding
• Use of healthy controls harms discriminant validity

 

[leokitten]

This is a long paper but important as it discusses the advantages and limitations of various radiotracers and targets in quantifying neuroinflammation.

Emerging PET Radiotracers and Targets for Imaging of Neuroinflammation in Neurodegenerative Diseases: Outlook Beyond TSPO. Narayanaswami et al. Mol Imaging (2018)

The dynamic and multicellular processes of neuroinflammation are mediated by the nonneuronal cells of the central nervous system, which include astrocytes and the brain’s resident macrophages, microglia. Although initiation of an inflammatory response may be beneficial in response to injury of the nervous system, chronic or maladaptive neuroinflammation can have harmful outcomes in many neurological diseases. An acute neuroinflammatory response is protective when activated neuroglia facilitate tissue repair by releasing anti-inflammatory cytokines and neurotrophic factors. On the other hand, chronic neuroglial activation is a major pathological mechanism in neurodegenerative diseases, likely contributing to neuronal dysfunction, injury, and disease progression. Therefore, the development of specific and sensitive probes for positron emission tomography (PET) studies of neuroinflammation is attracting immense scientific and clinical interest. An early phase of this research emphasized PET studies of the prototypical imaging biomarker of glial activation, translocator protein-18 kDa (TSPO), which presents difficulties for quantitation and lacks absolute cellular specificity. Many alternate molecular targets present themselves for PET imaging of neuroinflammation in vivo, including enzymes, intracellular signaling molecules as well as ionotropic, G-protein coupled, and immunoglobulin receptors. We now review the lead structures in radiotracer development for PET studies of neuroinflammation targets for neurodegenerative diseases extending beyond TSPO, including glycogen synthase kinase 3, monoamine oxidase-B, reactive oxygen species, imidazoline-2 binding sites, cyclooxygenase, the phospholipase A2/arachidonic acid pathway, sphingosine-1-phosphate receptor-1, cannabinoid-2 receptor, the chemokine receptor CX3CR1, purinergic receptors: P2X7 and P2Y12, the receptor for advanced glycation end products, Mer tyrosine kinase, and triggering receptor expressed on myeloid cells-1. We provide a brief overview of the cellular expression and function of these targets, noting their selectivity for astrocytes and/or microglia, and highlight the classes of PET radiotracers that have been investigated in early-stage preclinical or clinical research studies of neuroinflammation.

 

[Pyrrhus]

This is a long paper but important as it discusses the advantages and limitations of various radiotracers and targets in quantifying neuroinflammation.

Emerging PET Radiotracers and Targets for Imaging of Neuroinflammation in Neurodegenerative Diseases: Outlook Beyond TSPO. Narayanaswami et al. Mol Imaging (2018)

Great find!

 

[Pyrrhus]

The James Lab at Stanford has received funding to study imaging inflammation in the whole body and brain of ME patients:

https://twitter.com/i/web/status/1346567779743375362

 

[Pyrrhus]

Related discussion:

No signs of neuroinflammation in women with chronic fatigue syndrome or Q fever fatigue syndrome using the TSPO ligand [11C]-PK11195, 2021
https://forums.phoenixrising.me/thr...using-the-tspo-ligand-11c-pk11195-2021.83547/

 

[Pyrrhus]

But the thalamus is more than just a relay station that provides all the body's sensory information to the cortical brain. As you mention, the cortical brain provides "feedback" nerves to the thalamus, allowing the thalamus to suppress certain sensory information. It is thought that this cortical "feedback" is how the conscious brain decides which sensory information to pay attention to, and which sensory information to ignore. If there is a problem with this "feedback", then the conscious brain may be inundated with too much sensory information. (photophobia, hyperacusis?)

The Wikipedia page on Sensory Gating is surprisingly good:

Information from sensory receptors make their way to the brain through neurons and synapse at the thalamus. The pulvinar nuclei of the thalamus plays a major role in attention, and has a major role in filtering out unnecessary information in regards to sensory gating.
[...]
The pulvinar nuclei in the thalamus function as the gatekeeper, deciding which information should be inhibited, and which should be sent to further cortical areas.[3] The CNS (Central Nervous System), after the pulvinar nuclei deems the information to be irrelevant, acts as an essential inhibitory mechanism that prevents the information from flowing into higher cortical centers.
[...]
Other areas of the brain associated with sensory gating include the amygdala, striatum, medial prefrontal cortex, and mid-brain dopamine cell region (GABAergic neurons only).
[...]
Studies on rats also show the brainstem, thalamus, and primary auditory cortex play a role in sensory gating for auditory stimuli.[4]

Source: https://en.wikipedia.org/wiki/Sensory_gating

 

[Inara]

Ok, I confess I don't have much knowledge in this area... Are PET-TSPO and PET-FDG somehow linked with each other, i.e. if I have knowledge from PET-TSPO, can I deduce knowledge from PET-FDG and vice versa? E.g. would glucose hypermetabolism in PET-FDG mean neuroinflammation in PET-TSPO? What would be the PET-TSPO analogon of glucose hypometabolism, if there exists any? Could I use knowledge from both to get a better idea of what is going on? Or are they completely different?