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Radiological Society of North America

Multiple sclerosis damage found in 'normal' brain tissue

OAK BROOK, Ill. -- The effects of multiple sclerosis (MS) extend beyond visibly affected areas into large portions of the brain that outwardly appear normal, according to a study appearing in the September issue of Radiology.

"This disease process in the normal-appearing brain tissue affects the brain globally and has substantial clinical impact," said the study's lead author, Hugo Vrenken, Ph.D., from the Multiple Sclerosis Center at VU University Medical Center in Amsterdam, The Netherlands.

MS is a chronic, autoimmune disease characterized by the destruction of myelin, the protective layers that surround nerve cells. It can affect numerous body functions, and symptoms may include visual and speech impairment, memory loss, depression, muscle weakness, loss of coordination, numbness or pain, bowel and bladder problems and sexual dysfunction.

MS affects approximately 400,000 people in the United States and as many as 2.5 million worldwide, mostly women between the ages of 20 and 50, according to the National Multiple Sclerosis Society.

"The areas of demyelination, or lesions, in patients with MS can be visualized with magnetic resonance imaging (MRI). However, the volume of lesions visible at MRI only correlates moderately with clinical disability measurements," Dr. Vrenken said. "This may be due to disease activity outside the visible lesions."

To gain a better understanding of the effects of MS on the whole brain, Dr. Vrenken and colleagues studied T1 changes in normal-appearing white and gray brain matter in patients with MS.

T1 is a measurement of proton relaxation after exposure to a magnetic field and a radiofrequency (RF) pulse. Due to this RF pulse, protons in the body first reach an excited state and then relax back to a state of equilibrium by funneling the excess energy to the surrounding tissues. T1 refers to the time required for protons to relax to the equilibrium state in this particular manner.

The researchers investigated T1 changes in 67 patients with MS and 24 healthy control volunteers. T1 graphs of normal appearing white and gray matter were significantly different for patients with MS than for controls. Moreover, these graphs differed among patients with MS based on the type of disease: secondary progressive (SP), relapsing-remitting (RR) or primary progressive (PP). The results were most pronounced in patients with SP disease, where at least 31 percent of normal-appearing white matter and 20 percent of cortical normal-appearing gray matter were affected. In RR disease, 16 percent of normal-appearing white matter and 9 percent of cortical normal-appearing gray matter were affected. In PP disease, the normal-appearing white and gray matter affected were 11 percent and 8 percent, respectively. These changes were found throughout the brain, including areas remote from localized lesions that are typically associated with MS.

"These findings demonstrate that in MS, disease processes outside MR-visible lesions are not limited to a few sites but act throughout the brain and affect large fractions of normal-appearing white and gray matter," Dr. Vrenken said.

The researchers also explored correlations between the areas of the brain being analyzed in the patients with MS and the level of atrophy or clinical disability present.

"The results suggest that the damage to normal-appearing brain tissue plays a larger role in the progression of atrophy and clinical disability than do the visible lesions," Dr. Vrenken said.

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Journal attribution required.

Radiology is a monthly scientific journal devoted to clinical radiology and allied sciences. The journal is edited by Anthony V. Proto, M.D., School of Medicine, Virginia Commonwealth University, Richmond, Va. Radiology is owned and published by the Radiological Society of North America, Inc. (RSNA.org/radiologyjnl)

The Radiological Society of North America (RSNA) is an association of more than 38,000 radiologists, radiation oncologists, medical physicists and related scientists committed to promoting excellence in radiology through education and by fostering research, with the ultimate goal of improving patient care. The Society is based in Oak Brook, Ill. (RSNA.org)

"Whole-Brain T1 Mapping in Multiple Sclerosis: Global Changes of Normal-appearing Gray and White Matter." Collaborating with Dr. Vrenken on this paper were Jeroen J. G. Geurts, M.Sc., Ph.D., Dirk L. Knol, Ph.D., L. Noor van Dijk, M.D., Vincenzo Dattola, M.D., Bas Jasperse, M.D., Ronald A. van Schijndel, M.Sc., Chris H. Polman, M.D., Ph.D., Jonas A. Castelijns, M.D., Ph.D., Frederik Barkhof, M.D., Ph.D., and Petra J. W. Pouwels, Ph.D.

Interesting issue Dunmann. This is one of the fields that could give a very useful information about the inexplicable relation between brain spots and physical problems and could lead us to know better that is happening between white and grey tissue, the most important part of MS, in my opinion.

oo

It just leaves me with the bitter realisation that my brain is all mushy

oo

Thanks Dunman--

Rita--I quite agree with you that this could help explain why there is little correlation between lesions on MRI and disability and why people experience problems even though they have no visible spots and vice versa, lots of lesions and no problems.

"The results suggest that the damage to normal-appearing brain tissue plays a larger role in the progression of atrophy and clinical disability than do the visible lesions," Dr. Vrenken said.

I also think like you do that the damage to the grey matter is an important consideration that seems to have been overlooked and neglected until recently.

Lyon--I think the study is already "holding true" to previous research on the association between atrophy (rather than lesions) and disability and that the answer to your question is yes. Permanent disability in MS is thought to be the result of the loss of axons and neurons so I definitely think recovery will probably take more than remyelination.

I also read the link you provided. I'm glad Dr. O'Looney recognized what I also think is important to MS patients.

"The ultimate hope for MS patients is to stop the neuro-degeneration that happens and causes disability," said O'Looney. Right now, though, science is still unraveling just how the disease manages to do its damage.

Carole--We're all in the same boat, unfortunately, but I do think research of this nature reflects progress in understanding the disease.

Take care all--

Sharon

I concur completely with Sharon. The degeneration of axons and neurons is the cause of disability. Re-myelination may save the axons and neurons which are still hanging on by providing the required support, but will do nothing for the ones that have perished. Stem cells / nerve growth factors may be the hope in terms of addressing the issue of lost axons and neurons.

I'm always amazed by how much of the research finds out that MS is actually much worse than first thought e.g. affects white matter (myelin) and grey matter; is likely to be a global disease of the CNS not just a focal disease etc etc. I suppose the positive from all this research is that a better understanding must lead to better treatments. As MRI and other technologies improve, it should be possible to monitor the damage / lesions that are currently difficult to see.

Ian

For now, I would settle for something that stops the disease.

It is my opinion that knowledge of the brain is still in the Dark Ages and I will be long dead before MS is eradicated from the hidden caverns of my brain matter.

Ian, have you seen any more about Neuren Pharmaceuticals research on brain trauma? This company's targets may be helpful with brain matter damage. I follow their research, but haven't seen anything about trials and lab reports in months.

gwa

GWA,

Neuren's work on brain trauma is being taken forward. I didn't realise that up to 70% of people who have heart surgery end up with some cognitive problems and Neuren seems to be focused on this market first (neuro-protection after brain surgery) and I imagine they will trial their products on MS some time in the future.

I think that it will be possible to stop the disease in the not to distant future, or I should say stop the processes that drive the disease on. These of course are different for the different disease types - inflammation is much more of a factor in RR than SP and PP. On current thinking, for the SP and PP types, it's the slow death of axons and neurons. That's why much research is focused on neuro-protection.

I was in Cambridge on Tuesday and Dr Coles told me that for the RR patients (quite a number now) who had received Campath 1-H since 1998, none had to date moved to the SP stage. This might point to a benefit of aggressive anti-inflammatory at and early stage to limit damage and prevent or radically delay the progressive stage. Of course, only time will tell.

A recent small trial combining Mitoxantrone and Copaxone showed stabilisation and in some cases improvements. Another small trial of Cytoxan involving those with RR and SP also resulted in stabilisation or improvements. So there is a sort of pattern emerging, but ony time will tell. I know HarryZ has expressed concern about the use of heavy duty cance drugs for MS, but if I had cancer I would take them and I consider MS to be on par with many cancers, particularly the latter stages of MS.

I have asked for the recording of the seminar which takes place with Profs Compston and Scolding on Stem Cells and the Future of MS Research which takes place next Wednesday and I will report back. At the end of September is the ECTRIMS conference. Lots of research is being presented and also some trial results.

But I think most of us would agree that stopping the disease in its tracks (whatever the stage / type) is the first step. Once stabilisation is achieved then the focus will shift more to repair of damage. If the neuros could figure out how to fill those holes then that would be a breakthrough.

Ian