Welcome! This blog contains research & information on lifestyle, nutrition and health for those with MS, as well as continuing information on the understanding of the endothelium and heart-brain connection. This blog is informative only--all medical decisions should be discussed with your own physicians.The posts are searchable---simply type in your topic of interest in the search box at the top left.Almost all of MS research is initiated and funded by pharmaceutical companies. This maintains the EAE mouse model and the auto-immune paradigm of MS, and continues the 20 billion dollar a year MS treatment industry. But as we learn more about slowed blood flow, gray matter atrophy, and environmental links to MS progression and disability--all things the current drugs do not address--we're discovering more about how to help those with MS.To learn how this journey began, read my first post from August, 2009. Be well! Joan
Wednesday, December 7, 2011
New Research from Mayo, Cleveland and Yale--It's not about White Matter lesions, it's the Gray Matter
December 7, 2011 at 2:21pm
Readers of this page will know that we've discussed how white matter lesions are not really indicative of MS disease severity or progression. That's why someone with over 20 white matter lesions, like my husband, can mountain bike, while a progressive patient with one lesion might not be able to walk. It's not about the lesions.
But because this is what MRI technology could SEE, what EAE attempts to model, and what MS drugs could address---MS became a disease diagnosed and defined by white matter lesions.
Gray matter atrophy and degredation, noted in more refined MRI technology in research over the past decade, has provided a better biomarker of MS disease progression.
Before we get to the new research presented by the Mayo Clinic, Cleveland Clinic and Yale (spoiler alert--MS is not about white matter lesions)--let's get our terminology straight.
White matter--is called this because of the white-colored fatty protein covering of myelin that provides the insulation for axons.
White matter is found in the inner layer of the brain's cortex, the optic nerves, the brainstem and on the outside of the spinal cord.
Gray Matter-- is called this because it's actually grayish/pink-colored, since it carries the blood-rich capillaries. Gray matter is found on the surface of the cerebral cortex and in the cerebellum, as well as in the depths of the cerebrllum....the thalamus, hypothalamus, basal ganglia, etc. While the gray matter does have some myelinated axons, it does not have as much myelin as the white matter...thus, the difference in color.
Now, on to the press release.....
I have bolded some of the words, because the researchers have "framed" this research to assert that immune modulating drugs are still the way to go. We'll discuss after the press release.
From the Outside In: Mayo Clinic Collaboration Finds Multiple Sclerosis Often Starts in Brain’s Outer Layers
ROCHESTER, Minnesota -- Multiple sclerosis (MS) may progress from the outermost layers of the brain to its deep parts, and isn’t always an “inside-out” process as previously thought, reported a new collaborative study from researchers at the Mayo Clinic and the Cleveland Clinic. The traditional understanding is that the disease begins in the white matter that forms the bulk of the brain’s inside, and extends to involve the brain’s superficial layers, the cortex. Study findings support an opposite, outside-in process: from the cerebrospinal fluid-filled subarachnoid space, that cushions the outside of the brain and the cortex, into the white matter. The new findings will guide researchers as they seek to further understand and treat the disease. The study was published in the December issue of the New England Journal of Medicine.
Researchers do not know precisely what causes MS, but it is thought to be an autoimmune disease in which the body’s immune system attacks and destroys its own myelin. This fatty substance surrounds and protects axons, nerve cell projections that carry information, and its damage slows down or blocks messages between the brain and body, leading to MS symptoms, which can include blindness, numbness, paralysis, and thinking and memory problems.
“Our study shows the cortex is involved early in MS and may even be the initial target of disease,” says Claudia F. Lucchinetti, M.D., co-lead author of the study and Mayo Clinic neurologist. “Inflammation in the cortex must be considered when investigating the causes and progression of MS”, she says.
Study authors say current therapeutic options may not even address issues associated with the cortex. Understanding how the cortex is involved, therefore, is critical to creating new therapies for MS. “Measures of cortical damage will enhance enormously the power of clinical trials to determine if new medications address tissue changes of MS in all regions of the brain,” says co-lead author Richard Ransohoff, M.D., a Cleveland Clinic neurologist.
These measures are important because disease accumulates in the cortex over time, and inflammation in the cortex is a sign the disease has progressed.
The research is distinct because it studied brain tissues from patients in the earliest stages of MS. “What’s unique about the study is, and the reason the National MS Society funded this international team of researchers, is that it offers a rare view of MS early in the disease,” says Timothy Coetzee, Ph.D., Chief Research Officer at the National Multiple Sclerosis Society. “Collaborative studies like this, that deepen our understanding of the sequence of nervous system-damaging events, should offer new opportunities for stopping MS disease progression and improving quality of life for people with MS.”
The findings support the understanding that MS is primarily a disease of inflammation, not neurodegeneration, as some studies have recently suggested. Co-lead authors Drs. Lucchinetti and Ransohoff conclude that it is “overwhelmingly likely” that MS is fundamentally an inflammatory disease, and not a neurodegenerative Alzheimer-like disease.
How They Did It
The research did not at first focus on the ‘outside-in’ question, says Dr. Lucchinetti. Instead, the team initially wondered what tissue changes in the cortex of MS patients gave rise to indicators of cortical damage. For the last several years, researchers knew from MRI studies that the cortex was damaged very early after onset of MS, and they knew from autopsy studies that the cortex was demyelinated, as was white matter. What researchers were unable to determine, until completion of the present study, was whether findings at autopsy (usually after 30-50 years of disease) accurately reflected the indicators of cortical damage from MRI images taken after only a few months of disease. In autopsy MS tissues, cortical lesions show demyelination, but without inflammation-raising the possibility that MS cortex degenerates due to intrinsic tissue defects. Such a process would not be treatable by current MS therapies and could not be explained by present concepts of the causes of MS.
Drs. Lucchinetti and Ransohoff determined to see if early-MS cortical lesions were, or were not, inflammatory. To do so, they studied the Mayo resource of white-matter biopsies taken largely from patients with suspected tumors, but eventually proving to have MS. About one-fourth of the biopsies also included tiny fragments of cortex, which formed the focus of study. The primary question was quickly answered: cortical demyelinating lesions of early-MS patients resembled those found at autopsy in every way but one -- the early lesions were highly inflammatory. These findings were reassuring because they indicated that treatments targeting inflammation in the disease may ameliorate MS effects on both the cortex as well as the white matter.
While investigating the cortical changes in the biopsies, researchers were struck by the high frequency of cortical demyelinating lesions. Furthermore, in the white matter biopsies, which contained miniscule cortical fragments, about 20% showed inflammatory demyelination was contained entirely in the cortex.
Researchers also noted inflammation was present in the meninges, the protective membranes that cover the surface of the brain and demarcate the subarachnoid space. Meningeal inflammation and cortical demyelination were highly-associated. Looking at implications of their data, Drs. Lucchinetti and Ransohoff could weave together a proposed pathway for lesion initiation, along with known experimental data from MS animal models, and term this pathway the “outside-in” theory. The research findings also lend urgency to efforts to use MRI to “see” more deeply into the cortical lesions of MS, particularly given that cortical damage is an important correlate of progressive disability and cognitive dysfunction in MS.
This study was funded by the National MS Society’s MS Lesion Project, led by Dr. Lucchinetti, as well as the National Institutes of Health.
Other Mayo Clinic study authors include: Bogdan Popescu, M.D.; Reem Bunyan, M.D.; Shanu Roemer, M.D.; Joseph Parisi, M.D.; Bernd Scheithauer, M.D.; Caterina Giannini, M.D.; Stephen Weigand, M.S.; Jay Mandrekar, Ph.D.
Additional authors included Hans Lassmann, M.D. from the Center for Brain Research, Medical University of Vienna, Austria; Wolfgang Bruck, M.D. from the Department of Neuropathology, University Medical Center and Institute for MS Research in Gottingen, Germany; and Natalia Moll, M.D, Ph.D. from the Neuroinflammation ResearchCenter and Department of Neurosciences Lerner Research Institute, Cleveland Clinic.
Here's a paper from Yale on the same topic-- Cortical Injury in MS--the role of the Immune System
The Yale researchers call this an "emerging" picture of immune-associated cortical demyelination. One might think they had coordinated the release of their paper at the same time as the Mayo Clinic and Cleveland Clinic.
Future work is necessary to more clearly define the emerging picture of immune-associated cortical demyelination that occurs in MS. Understanding the relationship between the profound inflammation commonly seen in the white matter and that of the cortex, which seems to be less consistently observed, is certainly a priority. Many other questions remain: From where do the meningeal infiltrates arise? Do the cells that populate these structures emerge from the periphery then migrate to this compartment or do pioneer naïve cells experience antigen in the CNS then proliferate exclusively within this compartment? How exactly do they affect tissue damage? Are these cells autoreactive? The antigen(s), whether they are self, environmental or unique to individuals, unquestionably need to be defined. While important recent findings have strengthened our understanding of MS cortical tissue damage they also highlight the critical need to further understand cortical pathology and pathogenesis
So. Although the researchers don't mention these points in the cheery press release, it might be good to state:
1. White matter lesions are not MS.
2. The classic EAE model is not MS, since the effect of EAE on the cortex is not well known.
3. We do not know for sure how current disease modulating drugs, created to ameliorate EAE, will affect the cortex, or even if they have any impact on disease progression at all.
4. Although the science is not in yet, it is "overwhelmingly likely" that this cortical damage is due to the immune system. Really? Researchers can "weave together" their theory using animal models? Really?
5. How do we account for the high levels of iron deposition in deep gray matter as noted on SWI technology? Venous reflux and stasis, anyone? Iron deposition would most certainly create inflammation in the brain. Perhaps the researchers might want to look at Dr. Haacke and Dr. Zivadinov's research before deciding that it's just aberrant inflammation.
6. Ischemic injury and reperfusion is known to create inflammation in the cortex.
7. Cortical demyelination and inflammation is noted in dementia in the elderly, and stroke
8. And finally, and importantly, I found many other studies asserting that cortical demyelination in MS is not immune modulated.
I am consistently amazed at how MS specialists and researchers are able to make the "reassuring" leap that MS is immune modulated, even when everything they thought they knew about the disease turns out to be wrong.