January 3, 2012 at 8:52am
As more and more MS reseachers come forward and explain how MS appears to be a disease of the gray matter first---before white matter lesions appear---it is vital that we look at gray matter structures in the MS brain, to see what is different in the MS brain when compared to normal brains.
This post will be long, but I believe it's important to understand MS research as it stands today, the beginning of 2012.
Last month, University of Texas researchers published in the Journal of Neuroscience--reporting that the thalamus, the deep gray matter of the brain, is smaller and atrophied in people with MS when compared to normal brains, and that this loss of deep gray matter tissue happens at the beginning of the disease, early on and before any white matter lesions are detected.
+++++++++++++++++++++++++++++++++
A recent paper from Hubbard, Haacke, et al shows how stenotic veins creates slowed jugular return of blood in pwMS. Blood flow thru the brains of pwMS is much less than those with non-stenotic veins. This may be an indication of hypoperfusion and decreased oxygenation, and we'll be hearing more about that from the Hubbard Foundation later this year.
Dr. E. Haacke has also noted an early change in the gray matter of MS brains--abnormally high iron content.
Dr. E. Mark Haacke has been looking at the gray matter in MS brains for almost a decade. He is one of the inventors of SWI technology, an imagery system that can visualize iron deposed into brain tissue.
This is from his new paper is published in the American Journal of Neuroradiology--
Fifty-two patients with MS were recruited to assess abnormal iron content in their basal ganglia and thalamas (THA) structures. One hundred twenty-two healthy subjects were recruited to establish a baseline of normal iron content in deep gray matter (GM) structures.
RESULTS: A clear separation between iron content in healthy subjects versus patients with MS was seen. For healthy subjects 13% and for patients with MS 65% showed an iron-weighting factor.
The results for those patients younger than 40 years are even more impressive. In these cases, only 1% of healthy subjects and 67% of patients with RRMS showed abnormally high iron content.
Currently, there is an increased interest in studying how GM is affected and particularly deep GM involvement in MS when iron deposition has been observed.
Brain iron accumulation in neurodegenerative diseases, including MS, is not new and has been shown histologically in the past. In MS, its source is likely due to myelin or oligodendrocyte debris, concentrated iron in the macrophages, or as a product of local microhemorrhages following venule wall damage. As the wall breaks down, free iron may escape outside the vessel. This process has typically been seen in the basal ganglia, neurons, oligodendrocytes, macrophages, and microglia.6 Generally, free iron is known to lead to the formation of highly reactive hydroxyl radicals that can trigger cell membrane dysfunction and chronic microglial activation. Thus, iron from any of the above-mentioned sources could lead to inflammation and a further buildup of iron, causing the system to be self-sustainable.
+++++++++++++++++++++++++
What Dr. Haacke is explaining is that we've known about iron in gray matter tissue in MS brains and other neurodegenerative diseases for awhile. This is not new information. Dr. Haacke explains that there are three possible causes of this iron in the MS brain. The iron could come from one, two, or all three of these sources.
1. When myelin and oligodendrocytes die, they leave behind iron. This happens in a hypoxic, or low oxygen state or inflammatory state.
2. Macrophages, the white blood cells from our immune system, are iron rich and could be the source. This happens in an inflammatory or immune activated state.
3. The walls of blood vessels (called the endothelium) could be damaged, and leak blood particles into brain tissue---called "microhemorrages". This could be caused by refluxive blood flow, venous stasis, or CCSVI.
+++++++++++++++++++++++++++++++++
Now, we enter the area of the chicken and egg debate between MS specialists and other scientists.
This is going to be the place where researchers could stay mired in arguments for years. Which is NOT good for pwMS today.
The debate is--
There is some unknown, mystery source of neurodegeneration or cellular inflammation that is killing off brain cells, and iron deposed into gray matter is secondary
vs.
Iron deposition into gray matter is the very first step in MS
Here's what Dr. Zivadinov says about this chicken vs. egg debate.....
Recently, it was proposed in a pilot study that iron deposits in MS may be related to chronic cerebrospinal venous insufficiency (CCSVI), a vascular condition characterized by anomalies of the main extra-cranial cerebrospinal venous routes that interfere with normal blood outflow of brain parenchyma in patients with MS .
The peculiarity of CCSVI-related cerebral venous blood flow disturbances, together with the histology of the perivenous spaces, leads to the hypothesis that iron deposits in MS may be a consequence of chronic insufficient venous drainage According to this hypothesis, an excessive amount of iron, due to altered cerebrospinal venous return, may cause damage to the blood-brain-barrier and consequent disturbed microcirculation, leading to erythrocyte extravasation as a primary source of iron deposition in the form of micro bleeds.
In fact, histological and MRI studies confirm erythrocyte extravasation in a subset of brain plaques of MS patients, and the presence of iron-laden macrophages at the perivenular level, with lesion progression occurring along the venous vasculature. It has been observed that the cell involved in iron overload with the greatest effect on immunity is the macrophage, and there is a close relationship between iron and the major cells of adaptive immunity, the T lymphocytes, since they are major players in recycling the iron from hemoglobin.
Therefore, iron may be a powerful chemotactic stimulus that attracts macrophages and contributes to or causes initial activation of T-cell autoimmunity in patients with MS. On the other hand, an alternative hypothesis could be that decreased blood flow in brain parenchyma of MS patients could result from vessel congestion or occlusion due to inflammatory cells, fibrin deposits, or other factors. In this case, iron deposits could develop as a consequence of inflammatory reactions rather than causing them.
+++++++++++++++++++++++++++++++++++
Now, onto Dr. Zamboni and Dr. Zivadinov's actual study in people (not an EAE mouse model) where they looked at patients with MS/CCSVI, and tried to find some correlation between gray matter atrophy, disability, CCSVI and iron deposition in gray matter--and they found it.
Sixteen (16) consecutive relapsing-remitting MS patients and 8 age- and sex-matched healthy controls (HC) were scanned on a GE 3T scanner, using SWI.
Results. All 16 MS patients fulfilled the diagnosis of CCSVI, compared to none of the HC. In MS patients, the higher iron concentration in the pulvinar nucleus of the thalamus, thalamus, globus pallidus, and hippocampus was related to a higher number of venous hemodynamic (VH) criteria . There was also a significant association between a higher number of VH criteria and higher iron concentration of over- lapping T2 (r=-0.64, P=0.007) and T1 (r=-0.56, P=0.023) phase lesions. Iron concentration measures were related to longer disease duration and increased disability as measured by EDSS and MSFC, and to increased MRI lesion burden and decreased brain volume.
Conclusion. The findings from this pilot study suggest that CCSVI may be an important mechanism related to iron deposition in the brain parenchyma of MS patients. In turn, iron deposition, as measured by SWI, is a modest-to-strong predictor of disability progression, lesion volume accumulation and atrophy development in patients with MS.
To summarize-
Dr. Zamboni and Dr. Zivadinov found a direct correlation between
1. severity of CCSVI--or altered venous hemodynamics
2. amount of iron deposited into gray matter
3. disability
4. gray matter atrophy
5. disease duration
Again, that is a direct, in vivo correlation between the level of altered venous blood flow, gray matter atrophy, iron deposited into gray matter and MS disability.
And that is not a mysterious, unknown disease mechanism, proposed by some neurologists and modeled inaccurately in mice.
It's a quantifiable correlation between blood flow and iron, found in living people with MS.
More will be reported on at the International Society of Neurovascular Diseases meeting in February.
Joan
Thankyou Joan
ReplyDeleteyou're welcome, Lynne! Thanks for your advocacy in the UK.
Delete