Brain FADE syndrome: the final common pathway of chronic inflammation in neurological disease, 2024, Khalid A. Hanafy

Importance: While the understanding of inflammation in the pathogenesis of many neurological diseases is now accepted, this special commentary addresses the need to study chronic inflammation in the propagation of cognitive Fog, Asthenia, and Depression Related to Inflammation which we name Brain FADE syndrome. Patients with Brain FADE syndrome fall in the void between neurology and psychiatry because the depression, fatigue, and fog seen in these patients are not idiopathic, but instead due to organic, inflammation involved in neurological disease initiation.

Observations: A review of randomized clinical trials in stroke, multiple sclerosis, Parkinson’s disease, COVID, traumatic brain injury, and Alzheimer’s disease reveal a paucity of studies with any component of Brain FADE syndrome as a primary endpoint. Furthermore, despite the relatively well-accepted notion that inflammation is a critical driving factor in these disease pathologies, none have connected chronic inflammation to depression, fatigue, or fog despite over half of the patients suffering from them.

Conclusions and relevance: Brain FADE Syndrome is important and prevalent in the neurological diseases we examined. Classical “psychiatric medications” are insufficient to address Brain FADE Syndrome and a novel approach that utilizes sequential targeting of innate and adaptive immune responses should be studied.
https://www.frontiersin.org/articles/10.3389/fimmu.2024.1332776/full

 

Long Covid:

Besides the visceral sickness mediated by the vagus nerve that can lead to PASC or Brain FADE, a more direct pathophysiology exists based on spike protein binding affinity for amyloid, synuclein, and tau proteins. These protein inclusions in neurons and the cerebral interstitial fluid are thought to be involved in Alzheimer’s and Parkinson’s and Traumatic Brain Injury. Lending credence to this hypothesis, one group found that the incidence of new onset of Alzheimer’s diagnoses was significantly increased in older adults in the year following COVID infection Another autopsy found increased amyloid accumulation in brains of patients with severe COVID illness younger than 60 years old (78, 79).

 

Amyloid deposits was also found in brains of people with severe Covid.

Is this similar to amyloid deposits in muscles that Wurt found recently?

 

FADE is composed of three symptoms that are not simply unquantifiable, but also very poorly defined. It doesn't apply to my ME, since I never considered "depression" as a symptom for me. Brainfog, yes. My weakness is perceived weakness (lack of will to exert myself).

I suppose if your definitions are vague enough, you can come up with a study showing that your wonderful psychiatric technique treats the symptoms, and any subject who doesn't report improvements is culled from the study because they don't fit the vague definitions just the way you want them to.

 

Allow me to add chronic inflammation from stress to the pathogenesis. Overtraining, in particular, has been one of the more common causes MECFS. Training without letting your body recover sufficiently will lead to chronic inflammation, which in turn can lead to overtraining syndrome which is similar to MECFS, and eventually MECFS. Jamison Hill is still suffering while I'm coming out of it after 15 years.

 

I would think inflammation's roll in depression and weakness is now well understood and accepted. And the emotional change accompanying PEM is rather palpable for some MECFS patients. How to quantify it? I have no idea. I suppose the change is as quantifiable as any depression/weakness. If depression is not quantifiable, then you can't study depression. I personally measure by how much dishes pile up and how much I yell at my partner during PEM (shitty fatigue), compared to equivalent post-exercise fatigue (happy fatigue).

 

No, nothing like, if indeed the staining in muscle is amyloid.

 

I suspect that this concept will FADE from everyone's brain soon enough.

 

Paroxetine for the Prevention of Depression Induced by High-Dose Interferon Alfa | NEJM, metioned in Inflammation of the body may explain depression in the brain - The Washington Post makes rather clear inflammation's role in depression.

Just to be clear, it is about the role of inflammation in depression, not as the pathogenesis of FADE or MECFS. I'm just making a connection between the two via overtraining syndrome, which is a FADE syndrome associated with chronic inflammation from over-exercise.

 

Checking the definition, and the sickness response, also called sickness behavior, already well covers this set of broad symptoms. It is not discussed in the paper, so makes it feel a lot redundant to add another name for the same thing. I don't agree that psychiatry has anything to do with this, and not just for the complete mess of things they've done with psychosomatic ideology. This is especially problematic considering how depression covers most of this, but without an underlying illness, which is probably wrong as well, and is even more redundant, in a drugs and alcohol kind of way.

I'm not really convinced this is for neurology as well. ME has been technically categorized under neurology and it doesn't appear that they have much to do here, they only deal with broken nerves and this ain't it. This is really about the immune system, and it doesn't appear that any specialty of medicine can handle the systemic impacts. Closest remains rheumatology, but there are too many missing components. There is a need for an entire systems medicine specialty.

As for inflammation being recognized as a driver of depression: meh. The modern definition of depression is 99% psychosocial, and the only factor inflammation seems to play in that definition is the undying belief that any and all stress and life adversity can cause inflammation, thus covering the whole role of inflammation in the useless generic biopsychosocial construct. Which may be true, but is very likely to be secondary to the presence of immune factors in almost all cases. At best it can be seen as a dry weather makes it more likely for forest fires to break out, but you still need a spark. Or maybe the other way around. Analogies break down here.

This is not going to be figured out in this scattershot way. The only way to really understand illness is to make a long-term commitment in an AIDS-like moonshot program, including a proper dedicated specialty. And it needs to involve patients, no one understands illness unless they live it here and now. Doctors have not figured out how to do that, and probably never will. Maybe AI will, for sure it's far more likely to achieve that than human doctors, whose performance has peaked a long time ago.

 

Does it?
Interferon alpha is not a particularly pro-inflammatory cytokine as far as I know and giving it therapeutically does not produce inflammation.

Inflammation isn't cytokines. It is a form of vascular pathology that can be induced by certain cytokines released locally in tissue, not systemically. Signalling molecules that call white cells out into a tissue cannot do that if they are present in the circulation because the white cells are not being called out of the circulation. It is a very common misconception though.

 

Next to viral infection, overtraining appears to be. Julie (Meyer or something), an Olympic rower. Dean Anderson, competitive cross-country skier. Jamison, a gym rat. (And me who got sick while competing in Judo tournaments). One of the common refrain among MECFS patients seems to be "I used to be a competitive athlete, now I can barely walk". I'm not aware of any study that tabulated and ranked the trigger though.

 

Depression as part of sickness behavior, yes. FADE is not. One can debate FADE is real or not, but overtraining syndrome is real. And OTS appears to be a FADE by all acounts.

 

Is it fair to say inflammatory cytokines are inflammatory agents? The thesis, afaik, is that the inflammatory agents cause breaching BBB causing neurological pathology.

 

No it doesn't. I just threw it in there.

That has been the common question whenever overtraining is mentioned as a cause. One of the speculations is a dormant infection reactivated by the stress. Well, I can't say for other athletes, though Julie "Meyers" was indeed diagnosed for OTS first and then reclassified as MECFS after 6 mo, I can tell you that my case wasn't. I religiously documented and all my OTS cases, 7 in total I think, has been on Friday, exactly synchronized with my practice schedule. Sure, still not a smoking gun. But no infection can be that precise. At least I'm not aware of.

 

It's quite likely that they wouldn't be able to say. As we've learnt during the pandemic, a not insignificant proportion of people are infected but acutely asymptomatic. Some go on to LC/ME.

 

It actually goes both ways for MECFS. Some people with sudden onset just assume that it is an infection without diagnosis. Bruce Campell and his doctor, for example, assumed that he had a viral infection when he struggled with sudden unexplained fatigue. But he had several bouts with unexplained fatigue prior to the onset. His unexplained fatigues went away when he cut back on his activities, according to his writing.

 

I don’t know how far the evidence base has gotten on this, but CRP could be a potential biomarker of depression severity and worse treatment response. I guess though CRP is really nonspecific