Fatigue in primary Sjögren's syndrome: A proteomic pilot study of cerebrospinal fluid

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SAGE Open Med. 2019 May 13;7:2050312119850390. doi: 10.1177/2050312119850390. eCollection 2019.
Fatigue in primary Sjögren's syndrome: A proteomic pilot study of cerebrospinal fluid.
Larssen E1,2, Brede C3, Hjelle A1, Tjensvoll AB4, Norheim KB5, Bårdsen K1, Jonsdottir K6, Ruoff P7, Omdal R5,8, Nilsen MM1,2.
Author information

Abstract
Objectives:
Fatigue is a frequent and often disabling phenomenon that occurs in patients with chronic inflammatory and immunological diseases, and the underlying biological mechanisms are largely unknown. Because fatigue is generated in the brain, we aimed to investigate cerebrospinal fluid and search for molecules that participate in the pathophysiology of fatigue processes.
Methods:
A label-free shotgun proteomics approach was applied to analyze the cerebrospinal fluid proteome of 20 patients with primary Sjögren's syndrome. Fatigue was measured with the fatigue visual analog scale.
Results:
A total of 828 proteins were identified and the 15 top discriminatory proteins between patients with high and low fatigue were selected. Among these were apolipoprotein A4, hemopexin, pigment epithelium-derived factor, secretogranin-1, secretogranin-3, selenium-binding protein 1, and complement factor B.
Conclusion:
Most of the discriminatory proteins have important roles in regulation of innate immunity, cellular stress defense, and/or functions in the central nervous system. These proteins and their interacting protein networks may therefore have central roles in the generation and regulation of fatigue, and the findings contribute with evidence to the concept of fatigue as a biological phenomenon signaled through specific molecular pathways.
KEYWORDS:
Brain; Sjögren’s syndrome; cerebrospinal fluid; fatigue; proteomics; sickness behavior
PMID: 31205695 PMCID: PMC6537061 DOI: 10.1177/2050312119850390
 

pattismith

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ljimbo423

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That seems surprising to me.
I get the sense that most of my symptoms are from my brain. I have mild noise and light sensitivity, a mild to very mild, headache, fatigue and mild to very mild flu-like symptoms fairly consistently.

All of which get much worse during PEM. I think all of these symptoms can be explained by the low grade brain inflammation and sickness response Jarred Younger is so focused on. Sometimes I get full blown symptoms from PEM, which feels just like a flu but never last more than 24 hours.

I get the same symptoms as above but they are 10 times worse. My feeling is, these flu-like flares are my "sensitized" microglia in my brain being fully triggered (by immune activation from my body) and pumping out all kinds of inflammatory cytokines into my brain, causing inflammation and horrendous flu-like symptoms.

EDIT- My hunch is, when my sensitized microglia are not fully activated, I just have mild chronic symptoms. The degree of microglial activation, I feel, determines the degree of my symptoms, fatigue being the worst.
 

ScottTriGuy

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I get the sense that most of my symptoms are from my brain. I have mild noise and light sensitivity, a mild to very mild, headache, fatigue and mild to very mild flu-like symptoms fairly consistently.

All of which get much worse during PEM. I think all of these symptoms can be explained by the low grade brain inflammation and sickness response Jarred Younger is so focused on...

EDIT- My hunch is, when my sensitized microglia are not fully activated, I just have mild chronic symptoms. The degree of microglial activation, I feel, determines the degree of my symptoms, fatigue being the worst.
That makes sense to me too.

I guess I was thinking about healthy people, and what came to mind was when I was doing triathlons (or any sport) the fatigue was due to exhausted muscles / calories / etc, so I'd say that kind of fatigue is different (in quality and location source) then the fatigue we feel from ME.
 

ljimbo423

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I guess I was thinking about healthy people, and what came to mind was when I was doing triathlons (or any sport) the fatigue was due to exhausted muscles / calories / etc, so I'd say that kind of fatigue is different (in quality and location source) then the fatigue we feel from ME.

Fatigue seems to be a very complicated process. This abstract is mainly talking about fatigue in healthy people but also mentions how "Many diseases speed up the depletion of the energy stocks within the body". From what I could understand, the body sends signals to the brain, because the the things you mention(muscle exhaustion, energy depletion, etc.) which are perceived as fatigue.

Abstract
Physical exercise affects the equilibrium of the internal environment. During exercise the contracting muscles generate force or power and heat. So physical exercise is in fact a form of mechanical energy. This generated energy will deplete the energy stocks within the body.

During exercise, metabolites and heat are generated, which affect the steady state of the internal environment. Depending on the form of exercise, sooner or later sensations of fatigue and exhaustion will occur. The physiological role of these sensations is protection of the exercising subject from the deleterious effects of exercise.

Because of these sensations the subject will adapt his or her exercise strategy. The relationship between physical exercise and fatigue has been the scope of interest of many researchers for more than a century and is very complex. The exercise intensity, exercise endurance time and type of exercise are all variables that cause different effects within the body systems, which in turn create different types of sensation within the subject's mind during the exercise.

Physical exercise affects the biochemical equilibrium within the exercising muscle cells. Among others, inorganic phosphate, protons, lactate and free Mg2+ accumulate within these cells. They directly affect the mechanical machinery of the muscle cell. Furthermore, they negatively affect the different muscle cell organelles that are involved in the transmission of neuronal signals.

The muscle metabolites produced and the generated heat of muscle contraction are released into the internal environment, putting stress on its steady state. The tremendous increase in muscle metabolism compared with rest conditions induces an immense increase in muscle blood supply, causing an increase in the blood circulatory system and gas exchange.

Nutrients have to be supplied to the exercising muscle, emptying the energy stocks elsewhere in body. Furthermore, the contracting muscle fibres release cytokines, which in their turn create many effects in other organs, including the brain. All these different mechanisms sooner or later create sensations of fatigue and exhaustion in the mind of the exercising subject.

The final effect is a reduction or complete cessation of the exercise. Many diseases speed up the depletion of the energy stocks within the body. So diseases amplify the effect of energy stock depletion that accompanies exercise. In addition, many diseases produce a change of mind-set before exercise.

These changes of mind-set can create sensations of fatigue and exercise-avoiding behavior at the onset of an exercise. One might consider these sensations during disease as a feed-forward mechanism to protect the subject from an excessive depletion of their energy stocks, to enhance the survival of the individual during disease.
link to paper
 
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I agree with everyone in this thread: Saying fatigue comes from the brain is simplistic.

Science knows very little about fatigue. There's at least four kinds I can think of, even in 'normal' people: sickness behaviour, nightly sleepiness, systemic exhaustion, specific muscle fatigue. Each is a complex mix of metabolism, autonomic nervous, immune, circadian and hormonal systems.

I'd say maybe the first three kinds of fatigue of those come "from" the brain. But of course the brain makes its decisions on when to feel tired by monitoring the body.

A whole branch of medicine to study fatigue would be useful.