The brain and the blood vessels. So intimately intertwined but so rarely studied together. In retrospect, that’s kind of strange as blood vessels may have more to do with brain functioning than anything else.
By weight, the brain is almost a non-entity – it takes up about 2% of our body weight – but blood flows are another story. The brain receives 15-20% of our blood supply; i.e. it may be the most blood vessel-rich and blood vessel-dependent organ in the body.
Given that we know the spike protein of the coronavirus triggers coagulation, and that several other things (platelet activation, endothelial dysfunction) have gone wrong with the blood vessels, it only seems to make sense to check out the impact blood vessel functioning might have on the brain in long COVID.
Of course, there’s the ME/CFS angle as well. We know that blood flows to the brain are impaired in ME/CFS, and there’s evidence of neuroinflammation, basal ganglia dysfunction, prefrontal cortex problems, etc., but until the coronavirus popped up – except for Ron Davis’s exploration of red blood cell deformability – there was almost no focus on blood factors.
In both illnesses, the brain imaging studies tend to be locked into the brain and only the brain. While blood flows within the brain are often assessed, anything outside of the brain is a no-no. Not so with this PolyBio Research Foundation-funded study.
That changed with the “Neuroinflammation in post-acute sequelae of COVID-19 (PASC) as assessed by [ 2 11C]PBR28 PET correlates with vascular disease measure” study (it’s currently a preprint) featuring Michael VanElzakker and Marco Loggia.
This study asked whether neuroinflammation in the brain and markers of blood vessel dysfunction in the plasma were correlated; i.e. it asked if people with higher levels of blood vessel dysfunction in the blood plasma also experienced more neuroinflammation in their brains.
A positive finding would putatively connect what’s going on in the blood vessels in the body to damage to the brain. We’ve heard of the gut-brain axis. Now we have the blood vessel-brain axis.
The researchers specifically looked at the activity of the glial cells in the brain. The innate immune cells found in the brain, the glial cells are composed of microglial cells and astrocytes.
These are the cells that produce the “sickness behavior” symptoms (flu-like symptoms such as fatigue, pain, etc.) we experience when we encounter a pathogen. In the short term, they play a vital role in clearing pathogens and the damage they’ve caused to our systems. If they remain in a chronically activated state, they may – besides producing a lot of symptoms – produce a lot of dysregulation that shows up in all sorts of neurological symptoms.
The study included 12 long-COVID patients and 43 pre-pandemic healthy controls. The authors used a second-generation ligand [32 11C]PBR28 that can pick up glial cell activation to assess neuroinflammation, and assessed the following factors in the plasma:
- Vascular health (α2- 238 macroglobulin, orosomucoid, CRP [C-reactive protein], fetuin A, fibrinogen, haptoglobin, 239 sL-selectin, PF4 [platelet factor 4], pentraxin-2)
- Cytokines (GM-CSF, IFNγ, IL-1β, IL-1RA, IL-2, IL-4, IL-5, IL-6, 241 IL-8, IL-10, IL-12(p40), IL-12(p70), IL-13, MCP-1, TNFα)
- Angiogenesis (angiopoietin-2, BMP-9, EGF, endoglin, endothelin 243 1, FGF-1, FGF-2, follistatin, G-CSF, HB-EGF, HGF, IL-8, leptin, PLGF, VEGF-A, VEGF 244 C, VEGF-D).
(The plasma is a light-colored fluid that contains what’s left over in the blood after the red blood cells are removed).
They also assessed symptoms using the Brief 252 Pain Inventory (BPI), and the Beck Depression Inventory (BDI). The patients were screened to fulfill a modified myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) International Consensus Criteria (ICC) criteria. Most of the long-COVID cases (10) had not been hospitalized for COVID-19.
“To our knowledge, ours is the first study to provide direct evidence that processes related to neuroinflammation and vascular dysfunction are directly related in PASC (long COVID).” the authors
They found evidence of neuroinflammation (activated glial cells) across a wide swath of the brain in the long-COVID patients. The inflamed areas included the midcingulate cortex, corpus callosum, thalamus, basal ganglia/striatum, subfornical organ, anterior cingulate cortex, medial frontal gyrus, and precentral gyrus.
They really hit the nail on the head with their blood vessel factors. With elevations in 7 of the 9 vascular factors (fibrinogen, α2-macroglobulin, orosomucoid (alpha-1-acid glycoprotein 427 or AGP), fetuin A, sL-selectin (soluble leukocyte 428 selectin, or sCD62L), pentraxin-2 (serum amyloid P component, or 429 SAP), haptoglobin), they found strong evidence of vascular dysfunction.
- Although the brain gets from 15-20% of the blood in the body and may be the most blood vessel-rich organ in the body, brain studies tend to focus on the brain alone. With ample evidence of blood vessel problems showing up in the long COVID, though, that’s changing. A recent PolyBio Research Foundation study assessed both neuroinflammation in the brain and factors associated with blood vessel damage.
- The study found evidence of widespread neuroinflammation in long COVID in several areas of particular interest for ME/CFS. The anterior cingulate cortex, basal ganglia, and thalamus have all shown up prominently in ME/CFS as well. Reduced activation of two of these regions – the ACC and the basal ganglia – has been associated with fatigue and other symptoms in ME/CFS.
- With 7 of the 9 blood vessel damage factors significantly increased in the long COVID patients, blood vessel damage showed up big time. More importantly, the blood vessel factors were positively correlated with the neuroinflammation found; i.e. the worse off the blood vessels appeared, the more neuroinflammation was found. That suggested that blood vessel damage may be contributing to the neuroinflammation in the brain and a wide raft of brain-derived symptoms such as fatigue, chronic pain, flu-like symptoms, and brain fog.
- The authors speculated that remaining reservoirs of the coronavirus were triggering clotting, which was then damaging the blood vessels, and opening up the brain to inflammatory factors via a leaky blood-brain barrier.
These upregulated vascular factors do things like trigger coagulation, glial cell activation, draw immune factors to the blood vessels, and increase the permeability of the blood vessels. Interestingly, the study found increased signs of neuroinflammation in some areas featuring small thin blood vessels such as the basal ganglia, which seem to be more susceptible to damage.
Similarly, parts of the brain called the circumventricular organs (CVOs) lack a complete blood-brain barrier and seem to be “particularly vulnerable to being activated by blood-borne factors.”
These blood-borne factors could be triggering inflammation, putting holes in the blood-brain barrier, activating glial cells (which promote more neuroinflammation and a leakier blood-brain barrier), and wreaking havoc on the blood vessels.
The Brain Regions
Back in 2004, Chaudhuri and Behan proposed that problems in the basal ganglia, thalamus, limbic system, and higher cortical centers were causing ‘central’ or brain-induced fatigue. These areas showed up in spades in this latest study.
Anterior cingulate cortex (ACC)
Of all the brain regions, the anterior cingulate cortex (ACC) and the basal ganglia/striatum stand out with regard to ME/CFS. The ACC appears to be kind of a favorite in ME/CFS. It’s been associated with fatigue in ME/CFS numerous times.
Like all brain regions, the ACC is involved in a number of functions including attention allocation, reward anticipation, decision-making, impulse control – each of which I, at least, have trouble with. The “reward anticipation” is interesting as low reward has been associated with fatigue in the basal ganglia. The ACC also processes a lot of stimuli and is involved with motor control. It appears to kick in when effort is needed to complete a task.
Reduced cerebral blood flow, reduced glutathione levels and perhaps energy production, altered metabolites, altered connectivity associated with increased fatigue, dysfunctional motor planning and reduced acetylcarnitine uptake in the anterior cingulate cortex have all been found in ME/CFS.
Found deep in the brain, the basal ganglia have connections to the brainstem, thalamus, and other regions. The dopamine-producing center of the brain and an important facilitator of movement, basal ganglia dysfunction has been associated with fatigue in both ME/CFS and multiple sclerosis.
Andrew Miller – whose CDC-funded study found evidence of significantly reduced activation throughout the basal ganglia – believes basal ganglia dysfunction may be impacting the movement problems in ME/CFS, as well as causing both physical and mental fatigue, increasing the effort needed to do anything, etc.
Some evidence suggests that the basal ganglia may be uniquely vulnerable to inflammation.
Located just above the brainstem, the thalamus’s role in relaying sensory and motor signals from the body to the brain would seem to make it a potentially key factor in multisymptomatic and fatiguing diseases like long COVID and ME/CFS. Another brain region that has cropped up several times in ME/CFS, both the thalamus and basal ganglia have strong connections to the brainstem.
This kind of study which attempts to connect multiple systems together is vitally needed in these complex illnesses. The study was small – but its findings – if validated – loom large. The large differences in neuroinflammation found (no inflammation in any the healthy controls) and the rather dramatic evidence of blood vessel dysfunction (7/9 factors elevated in long COVID) suggested that while the study was small, it was on the right track.
In other words, this was not one of those – if only we’d added another 100 people to the study, this borderline result might become ‘significant’ – type of study. The differences were glaring even with these few patients.
The linkage between blood vessel dysfunction (but not immune activation) and neuroinflammation suggests blood vessel problems could be playing a really major role in these diseases. That’s not exactly new – Klaus Wirth and his colleagues have been postulating that’s true in ME/CFS for quite a while now – but, as the authors noted, it’s the first direct evidence that this is so.
While no one thinks just one treatment is going to do the trick, the study suggests that improving blood vessel functioning might have a significant impact on brain functioning (fatigue, brain fog, pain, movement) and overall health. The cause of the blood vessel problems is unclear but could result when the remaining spike proteins from the coronavirus produce clots that damage the blood vessels.
The results need to be validated in a larger study, but it’s hard to imagine, given this study’s findings, that we won’t see those bigger studies.
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I am still behind in my tallies, but thanks to the many, many people who have supported Health Rising during our end-of-the-year drive.
This is the kind of study – one that links different systems together to provide more complete explanations of these complex illnesses – that I love to emphasize. If that floats your boat as well, please support us in a manner that works for you.