Wednesday, 28 February 2018

Genes with progression show us it is inflammatory Start to Finish.

Ageing is part of the MS process.
If you are interested in what genes are turned on read here.

But it is very clear that inflammation is part of Advanced (progressive) MS



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Luchetti S, Fransen NL, van Eden CG, Ramaglia V, Mason M, Huitinga I. Progressive multiple sclerosis patients show substantial lesion activity that correlates with clinical disease severity and sex: a retrospective autopsy cohort analysis. Acta Neuropathol. 2018. doi: 10.1007/s00401-018-1818-y. [Epub ahead of print]

Multiple sclerosis (MS) is a highly heterogeneous disease with large inter-individual differences in disease course. MS lesion pathology shows considerable heterogeneity in localization, cellular content and degree of demyelination between patients.  In this study, we investigated pathological correlates of disease course in MS using the autopsy cohort of the Netherlands Brain Bank (NBB), containing 182 MS brain donors. 

Using a standardized autopsy procedure including systematic dissection from standard locations, 3188 tissue blocks containing 7562 MS lesions were dissected. Unbiased measurements of lesion load were made using the tissue from standard locations. Lesion demyelinating and innate inflammatory activity were visualized by immunohistochemistry for proteolipid protein and human leukocyte antigen. Lesions were classified into active, mixed active/inactive (also known as chronic active), inactive or remyelinated, while microglia/macrophage morphology was classified as ramified, amoeboid or foamy. The severity score was calculated from the time from first symptoms to EDSS-6. Lesion type prevalence and microglia/macrophage morphology were analyzed in relation to clinical course, disease severity, lesion load and sex, and in relation to each other. 

This analysis shows that 

(1) in progressive MS, with a mean disease duration of 28.6 ± 13.3 years (mean ± SD), there is substantial inflammatory lesion activity at time to death. 57% of all lesions were either active or mixed active/inactive and 78% of all patients had a mixed active/inactive lesion present; 

Therefore the suggestion of doing mono therapy neuroprotective trials without dealing with inflammation seems ill-advised.

(2) patients that had a more severe disease course show a higher proportion of mixed active/inactive lesions (p = 6e-06) and a higher lesion load (p = 2e-04) at the time of death, 

Therefore the suggestion of doing mono therapy neuroprotective trials without dealing with inflammation seems ill-advised.

(3) patients with a progressive disease course show a higher lesion load (p = 0.001), and a lower proportion of remyelinated lesions (p = 0.03) compared to patients with a relapsing disease course, 

Therefore the suggestion of doing mono therapy neuroprotective trials without dealing with inflammation seems ill-advised.

(4) males have a higher incidence of cortical grey matter lesions (p = 0.027) and a higher proportion of mixed active/inactive lesions compared to females across the whole cohort (p = 0.007). 


We confirm that there is a higher proportion of mixed active/inactive lesions (p = 0.006) in progressive MS compared to relapsing disease. Identification of mixed active/inactive lesions on MRI is necessary to determine whether they can be used as a prognostic tool in living MS patients.


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People with Advanced MS had more lesions, so stop lesions from occurring

People with relapsing remitting disease had more evidence of repair




In conclusion

"There is considerable heterogeneity in MS lesion pathology between pwMS, and lesion characteristics show strong correlations with clinical course, severity and sex. This study shows that inflammatory lesion activity is substantial at the time of death in progressive pwMS with long-standing disease. In addition, pwMS that have had a shorter time to EDSS-6 have a higher lesion load and proportion of mixed active/inactive (chronic active) lesions. Males have a higher cortical grey matter lesion incidence and proportion of mixed active/inactive lesions across the whole cohort. pwMS with a progressive disease course have a higher lesion load and less remyelinated lesions compared to relapsing rwMS. Mixed active/inactive lesions are increased in progressive pwMS."

PwMS need anti-inflammatory treatment in addition to neuroprotective/repair treatments so monotherapies targeting just the latter elements is not science based.

Prof Franklinstein indicated that young microglia promote repair. 

This study looks at genes being activated in old microglia. You can have a look if you like as it's open access

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Olah M, Patrick E, Villani AC, Xu J, White CC, Ryan KJ, Piehowski P, Kapasi A, Nejad P, Cimpean M, Connor S, Yung CJ, Frangieh M, McHenry A, Elyaman W, Petyuk V, Schneider JA, Bennett DA, De Jager PL, Bradshaw EM. A transcriptomic atlas of aged human microglia. Nat Commun. 2018; 9:539.

With a rapidly aging global human population, finding a cure for late onset neurodegenerative diseases has become an urgent enterprise. However, these efforts are hindered by the lack of understanding of what constitutes the phenotype of aged human microglia, the cell type that has been strongly implicated by genetic studies in the pathogenesis of age-related neurodegenerative disease. Here, we establish the set of genes that is preferentially expressed by microglia in the aged human brain. This HuMi_Aged gene set captures a unique phenotype, which we confirm at the protein level. Furthermore, we find this gene set to be enriched in susceptibility genes for Alzheimer’s disease and multiple sclerosis, to be increased with advancing age. These findings confirm the existence of an aging-related microglial phenotype in the aged human brain and its involvement in the pathological processes associated with brain aging.

The phenotype of aged human microglia. Functional annotation reveals that human microglia aging manifests itself as loss of function as well as gain of function changes in phenotype. a Volcano plot depicting the results of differential gene expression analysis between the Zhang et al. (middle aged microglia; N = 3) and our dataset (aged microglia; N = 10). One thousand sixty genes were found to be upregulated while 1174 genes were downregulated with aging.



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6 comments:

  1. Everytime you have tissue destruction you have inflamation

    If you have more damage(lesions) you have more inflamatory cascade

    Is the immune system trying to heal repair ? Or make matters worse?

    Nice find ,nice paper

    Obrigado
    Luis

    ReplyDelete
  2. On a side note, just want to make everyone aware of An Instinct for Kindness, which was broadcast on BBC Radio 4 this afternoon. (https://www.bbc.co.uk/programmes/b09snwmr)

    Now this is a heartbreaking but essential radio drama about the bravery of suffering with MS and the true story of a woman who makes the decision to go to Switzerland to end her life. It is a tough listen, but you'll be grateful you heard it. It is essential to hear this story for both sufferers and physicians working in MS.

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  3. The comment that monotherapy without tackling inflammation is a bad idea..... what medication are you implying should be used alongside the therapy...steroids?

    This surely explains why people with progressive MS who still have relapses often benefit from steroids. This is my experience of MS.
    With lesions predominantly on my spine MRI struggles to show any inflammation but steroids always helps following a relapse.

    ReplyDelete
    Replies
    1. One of the current DMT plus the repair agent.

      Steroids work as they tackle inflammation but their long-term use carries problems

      Delete
  4. They demonstrated that ALL repopulated microglia in the brain were derived from the proliferation of the few microglia surviving after pharmacological ablation (<1%), and the dividing microglia transiently expressed Nestin.
    The results provided solid evidence that repopulated microglia were solely derived from residual microglia rather than de novo progenitors, indicating the absence of microglial progenitor cells in the adult brain. In addition, through RNA sequencing, researchers found that the repopulated microglia may share similar functions as the resident microglia in homeostatic and diseased brains.

    Repopulated microglia are solely derived from the proliferation of residual microglia after acute depletion
    https://www.nature.com/articles/s41593-018-0090-8

    ReplyDelete

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