Imbalanced Brain Neurochemicals in long COVID and ME/CFS: A Preliminary Study using MRI

[SWAlexander]

Abstract​

Purpose​

Long COVID and Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) patients experience multiple complex symptoms, potentially linked to imbalances in brain neurochemicals. This study aims to measure brain neurochemical levels in long COVID and ME/CFS patients as well as healthy controls to investigate associations with severity measures.

Methods​

Magnetic resonance spectroscopy (MRS) data was acquired with a 3T Prisma MRI scanner. We measured absolute levels of brain neurochemicals in the posterior cingulate cortex in long COVID (n=17), ME/CFS (n=17), and healthy controls (n=10) using Osprey software. The statistical analyses were performed using SPSS version 29. Age and sex were included as nuisance covariates.

Results​

Glutamate levels were significantly higher in long COVID (p=0.02) and ME/CFS (p=0.017) than in healthy controls. No significant difference was found between the two patient cohorts. Additionally, N-acetyl-aspartate levels were significantly higher in long COVID patients (p=0.012). Importantly, brain neurochemical levels were associated with self-reported severity measures in long COVID and ME/CFS.

Conclusion​

Our study identified significantly elevated Glutamate and N-acetyl-aspartate levels in long COVID and ME/CFS patients compared with healthy controls. No significant differences in brain neurochemicals were observed between the two patient cohorts, suggesting a potential overlap in their underlying pathology. These findings suggest that imbalanced neurochemicals contribute to the complex symptoms experienced by long COVID and ME/CFS patients.
https://www.sciencedirect.com/science/article/pii/S000293432400216X

 

[linusbert]

another marker found for diagnostics,
but whats the reason for the chemical imbalance?

 

[SlamDancin]

Could this be a clue as to why benzodiazepines seem to increase capacity/functionality acutely?

This is anecdotal of course but it seems to at least be true for other patients as well.

“Thus, in vivo low concentrations of benzodiazepines may reduce synaptic glutamate concentrations by increased uptake, providing an additional mechanism to modulate neuronal excitability.”

https://pubmed.ncbi.nlm.nih.gov/10582598/

 

[SWAlexander]

whats the reason for the chemical imbalance

Good question.

 

[SWAlexander]

benzodiazepines

I would look toward sodium cotransporters such as the sodium/D-glucose cotransporter SGLT1, stably transfected in CHO cells.

Sodium cotransporters, including the sodium/D-glucose cotransporter SGLT1, play vital roles in cellular functions by using the sodium gradient across the cell membrane to drive the transport of other substances into the cell. While SGLT1 is primarily recognized for its role in glucose absorption in the intestines and kidneys, understanding its involvement in the context of extracellular glutamate in glial cells requires a bit of indirect connection through cellular energy metabolism and the support of neuronal and glial functions.

 

[SlamDancin]

@SWAlexander I’m not so sure about that. A quick read into currently available SGLT inhibitors seems to show an increase in glutamate through, in part, inhibiting Glutamate dehydrogenase.

The anticonvulsant Lamotrigine on the other hand can block Glutamate release in certain contexts.

 

[SWAlexander]

Just in. Mitochondria again.

Powering Brain Repair: Mitochondria Key to Neurogenesis​

Summary: Researchers made a groundbreaking discovery about the maturation process of adult-born neurons in the brain, highlighting the critical role of mitochondrial fusion in these cells. Their study shows that as neurons develop, their mitochondria undergo dynamic changes that are crucial for the neurons’ ability to form and refine connections, supporting synaptic plasticity in the adult hippocampus.

This insight, which correlates altered neurogenesis with neurological disorders, opens new avenues for understanding and potentially treating conditions like Alzheimer’s and Parkinson’s by targeting mitochondrial dynamics to enhance brain repair and cognitive functions.
https://neurosciencenews.com/mitochondira-neurogenesis-neuropplasticity-25869/

and this:
Enhanced mitochondrial fusion during a critical period of synaptic plasticity in adult-born neurons
https://www.cell.com/neuron/fulltext/S0896-6273(24)00167-3

 

[SlamDancin]

“In total, 75 healthy participants were investigated in a double blind, placebo-controlled, randomized, parallel-group study and underwent two scanning sessions (acute/post 24 h.). Acute ketamine administration was associated with higher perfusion in interior frontal gyrus (IFG) and dorsolateral prefrontal cortex (DLPFC), but no other investigated brain region. Inhibition of glutamate release by pretreatment with lamotrigine abolished ketamine's effect on perfusion. At the delayed time point, pretreatment with lamotrigine was associated with lower perfusion in IFG.”

https://pubmed.ncbi.nlm.nih.gov/37231079/

Perhaps the increased glutamate relates to the lower CBF seen in pwME

 

[SWAlexander]

increased glutamate relates to the lower CBF

According to my reading, yes, increased levels of glutamate can be related to lower cerebral blood flow (CBF).
Excessive glutamate release or impaired uptake can lead to neurotoxicity, a condition known as excitotoxicity, which can harm neural tissue and lead to cell death.

Not finished reading yet. Is very complex. Will write a summary tomorrow.

 

[SlamDancin]

@SWAlexander Indeed it is complex but it would appear to my dumb ass that Glutamate actually increases perfusion and so maybe the reason it’s elevated is some compensatory mechanism to existing low CBF in pwME

 

[SWAlexander]

compensatory mechanism to existing low CBF in pwME

The more I read about it: Here is the summary of some of my search, although I believe not complete yet.

Elevated glutamate levels can potentially lead to lower CBF:

1. Excitotoxicity and Neuronal Damage: High levels of glutamate can overactivate glutamate receptors, leading to an excessive influx of calcium ions into neurons. This can trigger a cascade of events leading to cell damage, inflammation, and death (neuronal death). As neurons are damaged, there can be a disruption in the normal function of the brain, including the mechanisms that regulate CBF.
2. Vasodilation and Vasoconstriction: Glutamate has been shown to affect the blood vessels in the brain directly. Its effect on cerebral blood vessels can vary under different conditions, potentially causing either vasodilation or vasoconstriction. While glutamate-induced vasodilation could theoretically increase CBF, in the context of excitotoxicity and the resulting cellular stress and inflammation, the overall effect might lead to impaired vasodilation or enhanced vasoconstriction, thus reducing CBF.
3. Inflammatory Response: The neuronal damage caused by high glutamate levels can trigger an inflammatory response, which can further affect cerebral blood vessels and potentially reduce CBF. Inflammation can lead to changes in the blood-brain barrier, affect the smooth muscle cells of the vessels, and ultimately influence blood flow.
4. Energy Metabolism: Elevated glutamate and the subsequent cellular stress can disrupt the energy metabolism in neurons and astrocytes. This disruption can affect the production of vasodilators such as nitric oxide, which play a critical role in regulating CBF. Reduced availability of these vasodilators can lead to decreased CBF.

To manage conditions associated with excitotoxicity often aim to regulate glutamate levels, protect neurons from glutamate-induced damage, and ensure adequate CBF to affected regions of the brain.
Still looking for the exact relationship between glutamate levels and CBF in specific contexts (e.g., ischemic stroke, traumatic brain injury, or neurodegenerative diseases). Waiting for Danielle Beckman paper.