Friday, 1 February 2013

Atrophy: a picture tells a 1000 words




"As a follow-up to yesterday's post on brain atrophy; please study the MRIs above. These MRIs are from two MSers I met when I did my PhD from 1993 to 1996; they were participating in a phase 2 clinical trial of a biological  therapy that targeted CD4 T-cells (anti-CD4 therapy). Unfortunately, the anti-CD4 trial was negative. This trial still questions the role that CD4 cells play in the pathogenesis of MS; well at least in my mind. Most immunologists still believe MS is driven by CD4 T cells; but that is another story."

"What the serial MRIs on these MSers show is the extraordinary amount of brain atrophy that can occur over an 18 month period - look at the black spaces in the centre of the brain, the ventricles, and see how they enlarge over 18 months. Also look at the black spaces on  the surface of the brain, the sulci, and see how they open up over 18 months. This brain atrophy is partly due to loss of axons and neurones and is unequivocally linked to disability progression and cognitive impairment. This is why there is increasing emphasis on drugs that can prevent or at least slow the rate of brain atrophy down."

"Preventing atrophy completely is unlikely to happen as brain atrophy occurs as part of normal ageing; from the age of 35 our brains shrink - mine included. The aim therefore would be shift the brain atrophy rate in MSers to that which occurs in normal ageing. Can we do this? Not yet, although several DMTs are showing promise in this area. This is why we are keen to explore attitudes to incorporating brain atrophy into clinical practice."

21 comments:

  1. The CD4 trial was done in the age when AIDS had just arrived and people were worried about dropping the white cell count too low... so they didnt and the antibody did little, plus the antibody used did little to the primed T cell phenotype that you would think contains the disease causing cells. If Alemtuzumab only depleted to the extent in the CD4 trials would it not work either. We will never know the answer.

    It would be good to retry this approach in the age were marked depletion is achieved. If it still failed then the imunologists really do need a rethink

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  2. As MD says, the level of CD4 depletion was not great enough to influence disease due to fears raised by the AIDS epidemic. It's certainly rather a leap to question the role of CD4 T cells in MS. Anyway it's too late now as this will not be repeated.

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  3. Time to include brain atrophy as one of the Grand Challenges?

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    1. Definitely - I will include it on the ever expanding list!

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  4. This happens to every MSer after 18 months?

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    1. These are examples peoples disease can be very different, so I would say no not every MSer. I wonder if this person was progressive and so probably would not respond to CD4even if it was the best thing since sliced bread

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  5. These images make me feel ill(er). They are frightening. MS is truly a scary disease.

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    1. Before anyone gets too alarmed with the scary pics it is important to remember that there is a lot of spare capacity of nerves in the brain which means that many can be lost without having much effect. It's once the threashold is crossed that things get more problematic. We see this in our mice too.

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  6. Is this a PPMSer? Does a PPMS brain go through a similar decay? I thought that there was less in the way of lesions in PPMS?

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  7. These images are from MSers with very active RRMS and hence the degree of atrophy is greater than one usually sees over an 18 month period. Yes, atrophy does occur in PPMS but the rate of loss is relatively slower.

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    1. If that is the case then why is disability more of a feature of PPMS?

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  8. According to your statement, Prof. G, the phase II clinical trial run by Dr. Chataway et al. with Simvastatin for SPMS, and showing a 50% reduction in brain atrophy after a 2 year period is definitely positive and an empirical approach for an off-label use of statins (harmless in principle) could be envisaged, wouldn't it?

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    1. That is correct! You have to realise that the Simvastatin trial was a phase 2 study and needs to be done in a larger group of MSers. We alsoi need more safety data; 80mg is a large dose and may not be safe. Statins may also interact with interferon and hence should not be taken in combination. We need to make sure the findings are robust before prescribing the drug to all MSers. In other words we need the FDA and EMA to licence Simvastatin for progressive MS. The problem is who is going to pay for the studies?

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  9. you are uploading private data from MS patients and there is no patients confidelity this is breaking rules and regulations

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    1. Not really; I simply published images from a scientific publication from 1996. The study subjects gave consent! You can download the images for yourself: the article is open access:

      http://brain.oxfordjournals.org/content/119/6/2009.full.pdf+html

      I am genuinely interested to know if you know the subjects?

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    2. To be accurate: Dr Nick Losseff, a colleague and friend of mine, gave me permission to use these images for educational purposes in 1996. They were part of his presentation on brain atrophy in MS. Both these subjects had consented to the study and to have their images published. The images are anonymous, therefore, I am not breaking any confidentiality rules.

      Losseff NA, Wang L, Lai HM, Yoo DS, Gawne-Cain ML, McDonald WI, Miller DH, Thompson AJ. Progressive cerebral atrophy in multiple sclerosis. A serial MRI study. Brain. 1996 Dec;119 ( Pt 6):2009-19.

      Recent studies of the spinal cord and cerebellum have highlighted the importance of atrophy in the development of neurological impairment in multiple sclerosis. We have therefore developed a technique to quantify the volume of another area commonly involved pathologically in multiple sclerosis: the cerebral white matter. The technique we describe extracts the brain from the skull on four contiguous 5 mm periventricular slices using an algorithm integrated in an image analysis package, and quantifies their volume. Intra-observer scan-rescan reproducibility was 0.56%. We have applied this technique serially to 29 patients with multiple sclerosis selected for an 18-month treatment trial with a monoclonal antibody against CD4+ lymphocytes (deemed clinically ineffective). A decrease in volume beyond the 95% confidence limits for measurement variation was seen in 16 patients by the end of the 18-month period. The rate of development of atrophy was significantly higher in those who had a sustained deterioration in their Kurtzke expanded disability status scale (EDSS) score compared with those who did not (respective means: -6.4 ml year-1 and -1.8 ml year-1, P < 0.05) but in both groups these changes differed significantly from baseline (P < 0.05). Baseline T2 lesion load, change in T2 lesion load over 18 months and the volume of new gadolinium enhancing lesions on monthly scans for the first 10 months showed no correlation with the development of atrophy. This study demonstrates that progressive cerebral atrophy can be detected in individual patients with multiple sclerosis, correlates with worsening disability and gives additional information to that obtained with conventional MRI. The effect of putative therapies aimed at preventing disability could be objectively assessed by this measure.

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  10. Sorry to be a pedant, but these images are not directly comparable.

    Images are generated by "slicing" a patient's brain in a particular direction, e.g. the above images have been taken front to back, perpendicular to the spine. Each slice generates one image. What is contained in that image depends on two main factors: the patient's head position and how the radiographer positions the slices. Because no one lies exactly the same way twice and because the radiographer typically has only a one dimensional image to position the slices on, it is impossible to have slices positioned in exactly the same way as previously. Moreover, even a small deviation in any of the three dimensions can lead to comparing apples and pears if one is not careful.

    As a result, it is unwise to simply look at the ventricles and assume that a different, larger shape means atrophy. (A pear sliced lengthways gives slices with a very much larger surface area than a pear sliced at right angles to this.)

    As a quick check of comparability, you need to look at ALL the sulci in the images to see that they are the same (atrophy is unlikely to leave them all unrecognisable). If you do this for these images, you can see that they are not the same.

    I don't doubt these patients had significant atrophy, but I have a suspicion that it would look a lot less shocking if the slices were exactly the same.

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    1. I agree that some of the images were not at the same level eg MSer1 baseline and 6 months, but I think the point is made that brains shrink I will ask DoctorLove for a picture that makes a similar point but is not MRI but you can look at the changes in the sulci, the folds in the brain. At the time of the study MRI technolgy was not as advances as it is now. In some programmes atrophy was based on changes against a consenus brain but others now compared to same brain.

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