Sunday, 18 September 2011

Why age is potentially very important for progressive MS

In response to your comments about ageing and disability.

It is well known that recovery from insults to the brain and spinal depend on age; the younger you are the better you recover. Young bodies are simply able to repair themselves better. This is no different in MS. There is increasing evidence that the ability to recover from relapses is age dependent. This is probably why children and young people with MS have a longer disease course before the become disabled.

The corollary to this is that progressive MS may be a manifestation of accelerated ageing. MS damages the brain and spinal cord which results in the repair mechanism becoming exhausted. This then allows premature age-related mechanisms to manifest earlier in life and are part of the progressive MS.

Why is this important? It means that if we found out how ageing affects repair we may be able to target the mechanisms to treat progressive MS.

In relation to this issue you may find the following article interesting:

Villeda et al. The ageing systemic milieu negatively regulates neurogenesis and cognitive function. Nature. 2011 Aug 31;477(7362):90-4. doi: 10.1038/nature10357.

In the central nervous system, ageing results in a precipitous decline in adult neural stem cells or progenitor cells and neurogenesis (formation of new neurons), with concomitant impairments in cognitive functions. Interestingly, such impairments can be ameliorated through systemic perturbations such as exercise.

This study uses a method called parabiosis; essentially you sew together two mice so that they share a common circulation. This the allows you to combine an old mouse with young mice and vice versa. 

"The following diagram illustrates this experimental technique. Another way of thinking about this is the artificial creation of "Siamese" or conjoined twins. We can do these experiments in mice because when use in-bred strains of mice, i.e. the mice are so inbred that the off-spring are genetically identical to their parents."

In this study the investigators show that blood-borne factors present in the systemic circulation can inhibit or promote adult neurogenesis in an age-dependent fashion in mice. 

Exposing a young mouse to an old systemic circulation from old mice decreased neurogenesis and impaired cognition (contextual fear conditioning and spatial learning and memory). 

The study identified signalling molecules that cells use called chemokines (CCL11) as the mediators of this process. Plasma or blood levels of these chemokines correlate with reduced neurogenesis in young mice linked to aged mice. Interestingly, the levels of these chemokines are increased in the plasma and cerebrospinal fluid of healthy ageing humans. 

Increasing peripheral chemokine levels in young mice decreased adult neurogenesis and impaired learning and memory. 

Together these data indicate that the decline in neurogenesis and cognitive impairments observed during ageing can be in part attributed to changes in blood-borne factors.

"Wouldn't this be interesting if it also correlated with the progressive phase of MS? We could then block these plasma or blood messages in the hope of delaying the onset of or preventing progressive MS. This may also prevent age-related decline in cognition."

"A real worry for me is that it appears stem cells from the peripheral blood are required to promote new neuron formation and to prevent age-related cognitive decline. Stem cells use the same molecules than inflammatory cells use to cross into the brain from the peripheral blood. Why is this important for MS'ers? It is very important because some of the therapeutic strategies we use to treat MS, block trafficking of inflammatory cells into the brain and spinal cord. This is how natalizumab or Tysabri works. As natalizumab blocks trafficking of stem cells into the brain it may accelerated progressive MS once it has become established and it may accelerate age-related cognitive decline. This is something we had better look as a potential long-term complication of natalizumab therapy."

6 comments:

  1. If this is proves to be true about Tysabri it is very worrying. How do you propose studying it?

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  2. A question for the Mouse Doctor; don't you think sewing mice together is unethical?

    Talk about Frankenstein science; despite having MS and potentially benefiting from science I have some sympathy for the anti-vivisectionists.

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  3. It's bad enough being on Tysabri with the fear of PML, and now when I turn progressive I amy progressive mauch faster. It's never easy with MS is it!

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  4. Re; "If this is proves to be true about Tysabri it is very worrying. How do you propose studying it?"

    I will need to think about this. The best way to do this is to use the same parabiosis model with a mouse form of natalizumab or similar drug to stop trafficking of stem cells into the brain.

    I note that somebody raised ethical concerns about this form of experiment. Lets's see if it generates some debate.

    Unfortunately, mouse natalizumab does not have the same effect in mice as it does in humans. So another strategy will be necessary.

    I will pop this question to Professor Robin Franklin and get back to you if he replies.

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  5. Re: "It's bad enough being on Tysabri with the fear of PML, and now when I turn progressive I amy progressive mauch faster. It's never easy with MS is it!"

    Please don't take the comment literally. This was a hypothetical argument and will need to studied formally to see if this is a possibility.

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  6. Dear Prof G, are male patients on Tysabri able to try for a family whilst on treatment or should they stop taking the medication?

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