Did you ever wonder why diseases of the brain seem to perpetuate? A soldier has PTSD and is affected for life. Someone has a concussion, and years later, their brain is not right. A hockey player slams into the boards and misses half the season. Meanwhile, his/her knee was damaged, which is better in a month or two.
A couple of Australians shed light on the unique aspect of how the brain manages inflammation. The title of this article is among my top 5 favorites for its cleverness.
"The meteorology of cytokine storms and the clinical usefulness of this knowledge"
(My favorite title is "Living and Dying For Sex." I will discuss this paper's serious content by Dr. Craig Atwood shortly.)
Summary:
The term cytokine storm has become a popular descriptor of the dramatic harmful consequences of the rapid release of polypeptide mediators, or cytokines, that generate inflammatory responses. This occurs throughout the body in both
non-infectious (for instance, in gut sensitivities) and
infectious disease states, including the central nervous system.
It has become a useful concept to appreciate that most infectious disease is caused directly by a pathogen and/or by an overexuberant innate immune response by the host to its presence.
It is less widely known that in addition to these roles in disease pathogenesis, these same cytokines are also the basis of innate immunity and, in lower concentrations, have many essential physiological roles.
Here, we update this field, including what can be learned through the history of how these interlinking three aspects of biology and disease came to be appreciated.
Exuberant response to infection
Innate immunity
Essential physiological roles
We argue that understanding cytokine storms in their various degrees of acuteness, severity, and persistence is essential to grasp the pathophysiology of many diseases. This particularly applies to the neurodegenerative diseases.
In this section, I am focusing on cytokine storms in the brain.
Moderate but persistent cytokine storms are typical of chronic neurodegenerative states, including post-stroke, post-traumatic brain injury, and Alzheimer’s disease (AD).
In the weather analogy, cytokines are what water is to life. Light falls of rain, like low levels of TNF and IL-1, keep physiology ticking and the organisms alive.
Rain improves outcomes in moderate amounts, as does self-limiting innate immunity, but in acute excess or unrelenting moderate amounts, rain and cytokines can harm.
Both the acute and unrelenting patterns are valid cytokine storms.
Acute systemic cytokine excesses, ie those outside the central nervous system (CNS), typically arise from the effects from bacterial or viral pathogen-associated molecular patterns (PAMPs), and are, if not acutely fatal, generally transient or insidiously chronic.
In contrast, when excess cytokine is generated within the brain in sufficient quantities, as distinct from entering from outside, the usual type of cytokine storm is an unrelenting moderately raised activity that leads to non-resolving inflammation.
This non-resolving pattern of inflammation in the brain is consistent with the consequences of injecting LPS, the prototype TNF inducer, and a TLR4 agonist to generate neurodegenerative disease models in rodents [89].
LPS are dead bacterial remnants used in medical research to induce inflammation. Instead, they are inducing the byproduct of infection - a key difference.
Following a single systemic LPS injection, TNF production in the mouse brain remains high for at least ten months [90].
KEY POINT: Keep in mind, this LPS is NOT a replicating infection - it is a one-time "insult," yet it persists. Since the brain is generally recognized to elicit one type of immune response - microglial cell activation, in theory, anything that stimulates inflammation in the brain could be "non-resolving."
In contrast, serum TNF levels peaked at the expected nine hours. Why this difference?
These authors argue that acute systemic injection of LPS activates brain microglia through TNF receptors that initiate sustained activation of brain cytokine synthesis and neuroinflammation.
These studies are consistent with earlier work in which the TNF switch-off that occurs systemically after a second LPS injection, which demonstrates the presence of LPS tolerance, proved to be absent in the intracisternal space [91].
Evidently TNF generation is inhibited differently systemically and cerebrally, conceivably mediated either through failure of the anti-inflammatory cytokines IL-4 or IL-10 to increase as they do systemically, and, as noted above, LPS tolerance being weak or absent inside the blood brain barrier (BBB).
It is also consistent with the activated state of microglia many years after brain ischemia [92] or brain trauma events [93, 94], as well as with evidence for a positive feedback loop for microglial activation via TNF [95].
Thus the central nervous system is especially vulnerable to cytokine storms that arise when TNF is generated within the brain, from many cell types, particularly microglia and astrocytes but also including neurons [96], and leads to loss of homeostasis in such vulnerable sites as synapses.
One predictable consequence is the loss of the subtle homeostasis we depend on for learning, memory, and normal behavior, as seen in chronic neurodegenerative states.
As discussed below, severe changes include neuronal death through excitotoxicity.
Since brain function determines subtleties such as personality, behavior, executive function, mood, willpower, learning and memory, we can expect the effects of brain TNF excess to be much more nuanced than the same change in the rest of the bod
This is indeed what happens. For example, mice without certain TNF receptors do not become aggressive [97]. The origins of delirium, in which a seriously ill patient shows transient disorientation, confusion and memory loss as part of an exaggerated sickness behavior, remain controversial [98], but it is certainly part of a cytokine storm.
It is now considered to be best understood in terms of peripheral TNF being increased sufficiently for enough to cross the BBB for a limited period [99].
Dementia, in contrast, reflects continual TNF production within the brain. Likewise, the coma that is often part of an encephalopathy accompanying sepsis, influenza or malaria can also be rationalized in cytokine terms, with associated coma argued to arise through increased cerebral TNF reducing orexin levels [100]. See reference [101] for a review.
This next section is even more complicated. I will try my best to unpack the key points.
As we have noted [42], physiological roles of TNF and IL-1 inside the brain include their release during physiological neuronal activity and, as has been reviewed [102], playing a crucial role in regulating the strength of normal synaptic transmission. TNF, of itself rather than through the inflammatory cascade it can trigger, is also involved in normal transmission via modulating excitatory neurotransmission [103], trafficking of AMPA receptors [104], homeostatic synaptic scaling [105], long-term potentiation [106], and maintaining normal background levels of neurogenesis [107].
As noted earlier, and particularly relevant in the brain, which requires much oxygen, mitochondrial function depends on TNF [51]. So too does regulation of the neurotransmitter orexin [100], which, as we recently reviewed in a brain disease context [101], controls sleep, motor control, focused mental effort, appetite and water intake.
TNF also regulates neuronal type-1 inositol trisphosphate receptors (IP3R), which are central to neuronal Ca++ homeostasis, and thus the ionic signaling cascades on which normal function of these cells depends [108]. Likewise, glycine receptors, which are structurally related to γ-aminobutyric acid (GABA) receptors and have a similar inhibitory role, are influenced by proinflammatory cytokines [109].
Glycine supplementation is known to improve sleep quality - see the connection?
Treatment: Despite all the hand-waving, treating with a specific TNF inhibitor does not work. There are many such biological pharmaceuticals on the market, and no one has indicated they have benefits for dementia. Humaria is a TNF alpha inhibitor.
From the article regarding treatment:
In contrast, when someone is acutely ill from sepsis, the TNF that made them ill has largely come and gone, having set in train many harmful pathways. This is presumably what prevents specific anti-TNF neutralizing agents from being clinically useful in patients who are acutely ill from sepsis [134].
There is also the practical consideration of anti-TNF agents reducing the efficacy of innate immunity in acute infections, albeit first recognized in the treatment of RA patients harboring chronic infections such as tuberculosis, in which innate immunity is an important component [135].
And yet one of the golf dummies proudly promotes Humira.
"Unfortunately, this enthusiasm for treating the brain for excess TNF is, to date, largely restricted to neuroscientists and medical specialists with prior anti-TNF experience in their field [123, 137–139]. It has yet, it seems, to extend to neurologists [128], conceivably in part for commercial-in-confidence reasons [140]."
IMHO, this approach will not work. The authors state that TNF alpha inhibition is a great success in psoriasis - but nothing could be further from the truth compared to a functional approach.
Their conclusion:
In conclusion, we note that these recent implications of cytokine storms for understanding encephalopathies usefully allow disease pathogenesis to be appreciated as a single entity through bridging the gap between TNF in systemic disease and the brain, as well as encompassing infectious and non-infectious disease on both sides of the blood-brain barrier.
What to do? I published a blog and video titled "Dementia Considerations."
When it comes to dementias, some more aggressive treatments may be considered, including:
PEMF
Softwavetrt (if a provider will do this directly on the skull)
High-intensity light therapy.
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