Blocked drains II

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When something lands on and penetrates your skin, it is drained down vessels called lymphatics into the lymph glands or is taken there by cells in the skin that gobble the stuff on your skin. In the lymph gland there are cells waiting to be activated in case the something is an infection. The cells then get activated and leave the lymph glands via lymphatic vessels which drain into your blood in the armpit. They can circulatd round lymph glands but can also go into tissues on a seek and destroy mission. This is called immunity. However it has been suggested that the central nervous system was special and that you could start an immune response from there because there was no lymphatic drainage pathways. We knew white blood cells enter the brain from the blood associated with disease. How could they be activated. We have come up with ideas such as a a lymphocyte that becomes sensitized to an infection that cross reacts to myelin. Of course you can ask is MS an autoimmune disease and it may well not be but it is probably seen as scientific-herecy to suggest otherwise.

Blausen 0623 LymphaticSystem Female.png

But when it was seen that there were lesions in the MS brain that did not have lymphocytes, then it had to start in the brain and the white blood cells were called in. However people started to find myelin in the lymph glands of the neck. Then they found the glymphatics and another explaination for how the lymphocytes becomes possible. Anything in the brain can now be sensed and immune responses can generated there. So it can be inside-outside-in and I always realised this, even if I didnt know how it happened this, so paid no attention to the outside-in and inside-out debate. It was a non-event.

During the day you spend all day making nerve connections (synapes) and you need to remember the important bits and forget the non-important bits. e.g. can you remeber the shape of the clouds outside today? I suspect not but if something was unusual you probably would remember it. So the synapes need to be clipped away,. These need to be cleared and it happens when you sleep notably during REM sleep. You brain gets a flush and the sewage tubes are called glymphatics. When you sleep the vessels in the brain being to pulse and it gets rid of the days brain waste. So dont sleep and you brain fills up with rubbish and you go abit loopy

Jessen NA, Munk AS, Lundgaard I, Nedergaard M. The Glymphatic System: A Beginner’s Guide. Neurochem Res. 2015; 40:2583-99. 

The glymphatic system is a recently discovered waste clearance system that utilizes a unique system of channels, formed by astroglial cells, to promote efficient elimination of soluble proteins and metabolites from the central nervous system. Besides waste elimination, the glymphatic system may also function to help distribute non-waste compounds, such as glucose, lipids, amino acids, and neurotransmitters in the brain. Intriguingly, the glymphatic system function mainly during sleep and is largely disengaged during wakefulness. The biological need for sleep across all species may therefore reflect that the brain must enter a state of activity that enables elimination of potentially neurotoxic waste products, including β-amyloid. Since the concept of the glymphatic system is relatively new, we will here review its basic structural elements, organization, regulation, and functions. We will also discuss recent studies indicating that glymphatic function is suppressed in various diseases and that failure of glymphatic function in turn might contribute to pathology in neurodegenerative disorders, traumatic brain injury and stroke.

Here we have a paper saving the drainage pathways in MS are blocked and this may influence progression.

I hadn’t realised it was a MRI paper when I first looked at it and I am sorry to say I have decided not to comment on these types of paper, in case someone gets upset. I am not sure what the MRI measures are really detecting and don’t have enough knowledge to comment. Maybe ProfK can say more. To get an impression of correlations read this

Glymphatic system impairment in multiple sclerosis: relation with brain damage and disability.Carotenuto A, Cacciaguerra L, Pagani E, Preziosa P, Filippi M, Rocca MA.Brain. 2021:awab454.

Recent evidence show the existence of a central nervous system ‘waste clearance’ system, defined as glymphatic system. Glymphatic abnormalities have been described in several neurodegenerative conditions, including Alzheimer’s and Parkinson’s disease. Glymphatic function has not been thoroughly explored in multiple sclerosis, where neurodegenerative processes are intermingled with inflammatory processes. We aimed to investigate glymphatic system function in multiple sclerosis and to evaluate its association with clinical disability, disease course, demyelination and neurodegeneration, quantified using different MRI techniques. In this retrospective study, we enrolled 71 multiple sclerosis patients (49 relapsing-remitting and 22 progressive multiple sclerosis) and 32 age- and sex- matched healthy controls. All subjects underwent neurological and MRI assessment including high-resolution T1, T2 and double inversion recovery sequences, diffusion- and susceptibility weighted imaging. We calculated the diffusion along perivascular space index, a proxy for glymphatic function, cortical and deep gray matter volume, white and cortical gray matter lesion volume and normal appearing white matter microstructural damage. Multiple sclerosis patients showed an overall lower diffusion along perivascular space index vs healthy controls (estimated mean difference: -0.09, P = 0.01). Both relapsing-remitting and progressive multiple sclerosis patients had lower diffusion along perivascular space index vs healthy controls (estimated mean difference: -0.06, P = 0.04 for relapsing-remitting and -0.19, P = 0.001 for progressive multiple sclerosis patients). Progressive multiple sclerosis patients showed lower diffusion along perivascular space index vs relapsing-remitting multiple sclerosis patients (estimated mean difference: -0.09, P = 0.03). In multiple sclerosis patients, lower diffusion along perivascular space index was associated with more severe clinical disability (r = -0.45, P = 0.001) and longer disease duration (r = -0.37, P = 0.002). Interestingly, we detected a negative association between diffusion along perivascular space index and disease duration in the first 4.13 years of the disease course (r = -0.38, P = 0.04) without any association thereafter (up to 34 years of disease duration). Lower diffusion along perivascular space index was associated with higher white (r = -0.36, P = 0.003) and cortical (r = -0.41, P = 0.001) lesion volume, more severe cortical (r = 0.30, P = 0.007) and deep (r = 0.42, P = 0.001) gray matter atrophy, reduced fractional anisotropy (r = 0.42, P = 0.001) and increased mean diffusivity (r = -0.45, P = 0.001) in the normal-appearing white matter. Our results suggest that the glymphatic system is impaired in multiple sclerosis, especially in progressive stages. Impaired glymphatic function was associated with measures of both demyelination and neurodegeneration and reflects a more severe clinical disability. These findings suggest that glymphatic impairment may be a pathological mechanism underpinning multiple sclerosis. The dynamic interplay with other pathological substrates of the disease deserves further investigation.

So whilst you digest the stuff above we can go back to the question outside-in, inside-out? if below is right its outside-in and not lymphocytes but toxins from the gut.

Achilles Ntranos et al, Bacterial neurotoxic metabolites in multiple sclerosis cerebrospinal fluid and plasma, Brain (2021). DOI: 10.1093/brain/awab320

The identification of intestinal dysbiosis in patients with neurological and psychiatric disorders has highlighted the importance of gut-brain communication and yet, the question regarding the identity of the components responsible for this cross talk remains open. We previously reported that relapsing remitting multiple sclerosis patients (RRMS) treated with dimethyl fumarate have a prominent depletion of the gut microbiota, thereby suggesting that studying the composition of plasma and cerebrospinal fluid (CSF) samples from these patients may help to identify microbially derived metabolites. We used a functional xenogeneic assay consisting of cultured rat neurons exposed to CSF samples collected from multiple sclerosis patients before and after dimethyl fumarate treatment to assess neurotoxicity and then conducted a metabolomic analysis of plasma and CSF samples to identify metabolites with differential abundance. A weighted correlation network analysis, allowed us to identify groups of metabolites, present in plasma and CSF samples, whose abundance correlated with the neurotoxic potential of the CSF. This analysis identified the presence of phenol and indole group metabolites of bacterial origin (e.g. p-cresol-sulfate, indoxyl-sulfate and N-phenylacetylglutamine) as potentially neurotoxic and decreased by treatment. Chronic exposure of cultured neurons to these metabolites impaired their firing rate and induced axonal damage, independent from mitochondrial dysfunction and oxidative stress, thereby identifying a novel pathway of neurotoxicity. Clinical, radiological and cognitive test metrics were also collected in treated patients at follow-up visits. Improved MRI metrics, disability and cognition were only detected in dimethyl fumarate -treated RRMS patients. The levels of the identified metabolites of bacterial origin (p-cresol-sulfate, indoxyl-sulfate and N-phenyl-acetyl-glutamine) were inversely correlated to MRI measurements of cortical volume and directly correlated to the levels of neurofilament light chain, an established biomarker of neurodegeneration. Our data suggest that phenol and indole derivatives from the catabolism of tryptophan and phenylalanine are microbially derived metabolites, which may mediate gut-brain communication and induce neurotoxicity in multiple sclerosis.

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MouseDoctor

6 comments

  • Where do we do from here then?

    EBV can’t really be taken up as a theory as the cause of MS by the MS community

    It just seams like the more time passes, more theory’s come out and the water get muddier with the cause of MS.

    I don’t know if we are getting closer or further away from the cause, way to much time spent on immunosuppressants and not actual health I.e sleep
    Diet/sleep/gut, all these issues get swerved

      • Sorry I worded that wrong, EBV clearly plays a role, and is most likely the cause or a huge player

        I mean it’s like there are more theory’s all the time that dont really lead us to the cause of MS.

        Or maybe these findings do.

      • Sorry I worded that wrong. What I ment is EBV hasn’t yet been taken up as a valid cause of MS

        All these theory’s just add to the pool of theory’s and it’s seams to make it further and more complicated.

        Sleep and diet should be a priority if this theory is to be taken seriously. However no one want to really talk about valid issues like sleep and diet as little research is ever done on such issues that effect our lives every day. Health care is frustratingly geared towards money than health.

        That’s not a dog at you by the way. Brilliant research and information yet again.

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