Wednesday, 11 September 2013

Clinic speak: cognitive decline is worse in males MSers

Is MS sexist? Cognitive decline is worse in males MSers. #MSBlog #MSResearch #ClinicSpeak

"A few weeks ago we a heated debated about whether, or not, we should refer to MS as the shredder and whether or not we should rebrand MS a dementia. It is hard to get away from both issues. The following article supports both adjectives."

"In this study of early MS (6 years post diagnosis) there was significant brain damage on MRI that correlated with cognitive impairment. It is worth pointing out that this was worse in men than women. This is not surprising as the prognosis of MS in men is worse than in women.  We are not sure why women do better, but it may relate to the effect of female hormones on the immune system and their effect on promoting recovery from damage or neuroprotection."

"Interestingly, damage to an important structure of the brain called the thalamus was particularly correlated with cognitive impairment. The thalamus is a large gray matter structure deep in the brain through which the cortex (surface of the brain) communicates with structures lower down (brain stem, cerebellum and spinal cord); my anatomy teacher in medical school referred to the thalamus as the great railway junction of the brain. It is therefore not surprising that damage to the thalamus is strongly linked to cognitive impairment. Imagine what would happens to London transport if you damaged a major junction, for example Clapham Junction."



"The MRI techniques used in this study assess the integrity of neuronal pathways and is not part of routine MS diagnostic MRI studies. Therefore, at present you can't ask your neurologist to order a diffusion scan to assess you so called functional anisotropy (FA) that assess the integrity of your neuronal pathways. You have to take this study at face value and assume that there is a high likelihood that your FA is abnormal. What is more important to focus on is the fact that even early in the disease course MS is causing problems and the damage that is largely irreversible. The reason why you cope with the damage is that the brain has a lot of reserve capacity and you use or co-opt other areas to help the damaged areas with completing the task. This process is called brain plasticity. Plasticity has a downside; using extra areas of brain to complete tasks previously undertaken by a smaller specialised area means you consume excessive amounts or mental energy. This then manifests as cognitive fatigue and difficulty with multi-tasking. MSers frequently recognise these symptoms when asked about them directly."

"Can anything be done about damage that is already happened in MS? Possibly. If we suppress ongoing damage with highly-effective DMTs we often see functional recovery and improvement in disability. In addition, some MSers describe their cognitive fatigue improving. This must indicate that some recovery is occurring. The ability to recover is age and time dependent; the younger you are the better your recovery and the sooner after the onset of MS you allow recovery to occur the better. The latter makes sense; if you wait too long your recovery mechanisms may be exhausted. This is why the concept of the "window of opportunity" is so important to grasp; it is present early in the course of the disease and gradually closes as  the disease advances so that by the time you have entered the secondary progressive phase of the disease it is too late."

"Does this mean that it is hopeless for MSers with progressive disease? No of course not; it simply means we cannot rely on the brain and spinal cord to repair themselves, we need treatments and strategies to promote repair. Unfortunately, at present we don't have any therapies that have been shown to do this in MSers. There are however promising treatments currently in clinical trial that may impact on these processes. The one that springs to mind is anti-LINGO. Lingo is a molecule that inhibits remyelination. If we can block LINGO we may be able to stimulate remyelination. Anti-LINGO is currently being tested in MSers with optic neuritis in a proof of principle study. If this is positive I am sure Biogen-Idec, the company that is developing the drug, will consider testing it in progressive MS. However, you have to remember that for a remyelination strategy to work you have to have sufficient surviving nerve cells and axons to remyelinate. Therefore, it is important to protect as many of these as possible, this is why we will still need anti-inflammatory drugs to switch of the shredder and neuroprotective drugs to keep nerves alive to allow  them to be remyelinated. Don't expect remyelination strategies to work on their own; they need to used in combination. Despite saying this many times on this blog and at meetings you will be surprised at how many scientists and clinicians subscribe to the monotherapy paradigm in progressive MS. It simply won't work unless the drug has a multiple mechanisms of actions."

Epub: Schoonheim et al. Sex-specific extent and severity of white matter damage in multiple sclerosis: Implications for cognitive decline. Hum Brain Mapp. 2013. doi: 10.1002/hbm.22332. 

Background: Cognitive dysfunction is common in MS. However, the relationship between white matter (WM) damage and cognition remains insufficiently clear. 

Objective: This study investigates the extent and severity of WM diffusion abnormalities in MSers and their relationship with cognition. 

Methods: Diffusion tensor imaging scans were obtained in 131 MSers (88 women, 6 years post-diagnosis) and 49 age-matched controls (29 women). MSers groups were equal in terms of disease duration, disability, and WM lesion volume. Fractional anisotropy (FA), mean diffusivity (MD), axial diffusivity (AD), and radial diffusivity (RD) were compared between groups. Post hoc analyses calculated the spatial extent and severity of diffusion abnormalities to relate these to cognitive performance. 

Results: In controls, 31% of WM voxels showed higher FA in men; therefore, all MSers analyses were within-sex. The extent of diffusion changes was higher in male MSers than in female MSers for all parameters (FA: 24% in women, 53% in men), as was the severity of changes (FA: Z = -0.18 in women, Z = -0.41 in men). Especially the extent of FA abnormalities was strongly related to cognitive performance in all MSers (r = -0.42, P < 0.0001). Regionally, thalamic decreases in FA were especially correlated with cognitive performance. 

Conclusion: Cognitively impaired MSers showed greater extent and severity on all diffusion parameters compared to cognitively preserved patients. The WM of male MSers was both more extensively and also more severely affected than that of female MSers . The extent of WM FA changes, especially in the thalamus, was associated with cognitive performance in this cohort of early MS MSers.

"Before you fire off comments about me referring to MS as a dementia, please reflect on this post, and previous posts, and the preliminary results of the survey that are still live."


Other posts of interest:

12 Jun 2013
"For me the best thing about going to conferences is that it allows you thinking time, and time to interact with like minded colleagues. After my platform presentation on early aggressive treatment several European neurologists ...
20 Jun 2013
Survey results on MS as a dementing illness. #MSBlog #MSResearch "Next to my posts on CCSVI the 'Rebranding MS a Dementia' post caused quite a stir in the blogosphere. It is clear from the comments in relation to this ...
05 Jul 2013
Epub: Hofstetter et al. Progression in disability and regional grey matter atrophy in relapsing-remitting multiple sclerosis. Mult Scler. 2013 Jun 26. BACKGROUND: In multiple sclerosis (MS) regional grey matter (GM) atrophy ...
03 Jul 2013
"In general neurologists would agree that a minority of dementing illnesses are reversible; in particular those that occur in the context of a progressive neurodegenerative disease such as MS. Therefore it is not surprising to ...

17 Jun 2013
Cognitive impairment may begin before the first attack of MS. #MSBlog #MSResearch "This is an old post that needs more air time. It shows that over 25% of RISers, i.e. people who are asymptomatic and are found to have ...
14 Jun 2013
Disclaimer: This animation is part of a series of animations on a MSer website, called "MS and Our Story"; I note the site is sponsored by Novartis. Novartis are a Pharma Company that produce and market a drug called ...

11 comments:

  1. I wonder...is there more evidence, that men respond different in MS than women?

    E.g. men are more likely to have progressive MS or NMO?

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  2. Personal experience of friends who developed MS after me. The men seemed to fair worse. The old joke of men being unable to multitask may have something to do with women's brain being able to compensate for the damage. Scientists must have done some research.

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    1. We see the same sort of thing in our mice. Males tend to develop disability quicker than females. Must be due to female hormones such as oestrogen. Other studies have shown that pre-menopausal women do much better after a stroke than men.

      Delete
  3. "Does this mean that it is hopeless for MSers with progressive disease? No of course not; it simply means we cannot rely on the brain and spinal cord to repair themselves, we need treatments and strategies to promote repair. Unfortunately, at present we don't have any therapies that have been shown to do this in MSers."

    Erm, aren't you, like, contradicting yourself there? You state the situation isn't hopeless for PwPMS, and then proclaim that there is nothing that can provide hope right now other than preliminary experiments which are merely pipedreams at this present moment. Do you not see the absurdity in what you've just said?

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    Replies
    1. No absurdity. Team G is running clinical trials for neuroprotectants for MS as we speak based on results from our "pipedream" experimental studies. Also looks like laquinimod has a neuroprotective mechanism of action too.

      Delete
    2. Anon 3:03:00 pm

      Hope is not about the present, but the future. There is nothing absurd about Prof. G's post. I suspect all of the current treatments for RRMS started out as a pipedream to become a reality. At least they are doing something about it.

      Regards

      Full-of-Hope

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    3. Yes, and some day we will live on mars and feast on moon pies. It's almost offensive for Prof G to say there is so much hopefulness to aid progressive MSers, only to then say there isn't really anything right now.

      You know, some day the human race may figure a way to live forever. I suppose that is a hopeful ideal we can all take solace in.

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  4. Where is the monotherapy paradigm coming from? Is it related to the first cases of PML in Tysabri-treated patients who also happened to be on other DMT (and subsequent re-introduction of Tysabri as a monotherapy)? If this is the case, one can argue that PML is due to Tysabri itself rather than its use in combination with other agents (as many patient-years of real-world treatment seem to show). Are there liability issues with combination therapies when/if a particular drug was only tested as a monotherapy in clinical trials?

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    Replies
    1. The monotherapy paradigm in MS is the belief that stopping inflammation in the brain with effective DMT therapy is the complete answer for MS.
      Whilst stopping lesions is undoubtedly a good thing, it may not be the whole story.

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    2. Are there liability issues with combination therapies when/if a particular drug was only tested as a monotherapy in clinical trials?

      This may be so, there is always the possibilities of drug-drug interactions.

      PML is due to the lack of survellience of the CNS, and Tysabri increases ths risk. If you have prior immunosuppression it can increase this risk, probably because you are more immunosuppresed than if you have a monotherapy.

      When you use immunosuppressive drugs the effects on the immune system can be profound and may last many years, the most extreme example a the moment is with Alemtuzumab where T cells numbers go for many mnay years.

      Delete
  5. For those not familiar with London

    By the way Kings Cross is a Rail Terminus and not a Junction, Clapham Junction would have been a better choice of a train station and closer to home.

    ReplyDelete

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