Iron and gray matter - What do we know?

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.

http://health.usnews.com/health-news/family-health/brain-and-behavior/articles/2011/12/30/multiple-sclerosis-may-cause-changes-in-thalamus-study

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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.  

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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.

A History Lesson- from Dr. Mark Haacke

January 9, 2010 at 12:24pm

We've been discussing the importance of knowing the history of MS. As MS patients and caregivers, it is vital that we understand why certain medical paradigms are discarded in preference for others. 

Doctors around the globe are digging into medical vaults and finding more on the venous vascular connection to MS. We will not let this moment pass unnoticed.

From Dr. Haacke:

A Brief History of the Early Venous Vascular Observations in MS

This section will be developing over time as we review the past and sometimes almost ancient literature related to MS. According to Putnam (1) who discussed vascular abnormalities in MS in 1936, the first observations related to abnormal vasculature or effects related to the vasculature appeared in Cruveilhier (2) in 1839, more than 170 years ago who compared areas of sclerosis with the results of embolism. Rindfleisch (3) noted in 1863 an engorged vessel in the center of a plaque and in the same year Charcot (4) described vascular obstruction in MS. These observations would be noted again and again over the next 135 years. What was missing was the advent of imaging as a tool to investigate the vascular system in three dimensions, something that ultrasound takes a step toward as used by Zamboni and more recently the use of magnetic resonance imaging in the study of cerebro-spinal vascular insufficiency or CCSVI.

But Putnam didn't stop there. With an ingenious idea, he proceeded to study the effects of obstructed venous flow in the cerebral veins of dogs. These animals developed a number of abnormalities many of them similar to encephalitis or multiple sclerosis. His comment at the end of his paper was as follows (5): "The later stages (up to ten months) of the lesions consist of plaques of demyelinization with practically complete preservation of the axis-cylinders and with dense fibrous gliosis confined to the white matter. The similarity between such lesions and many of those seen in cases of multiple sclerosis in man is so striking that the conclusion appears almost inevitable that venular obstruction is the essential immediate antecedent fo the formation of typical sclerotic plaques." Despite the wonderful immunological advances in the last 75 years, how can we ignore the early work that so clearly demonstrates the role of the venous system in MS? The precocious work of these early researchers today finds its laurels in the current extracranial obstructions proposed by and seen by Zamboni (6) and now others.

There are more intriguing connections as one reads these old papers. Venous blood is more prone to clot. And these micro-thrombi may rapidly disappear and so become unobservable. An increase in capillary density also seems to develop and this may well describe the "capillary recruitment for venous drainage hypothesis proposed by Haacke". In this hypothesis, the obstructed flow leads to endothelial damage (7) and iron build up (8) and the need to increase the outflow capacity in the venous system. The brain then recruits capillaries to become veins and these in turn are also damaged leading to further iron deposition. If this is the case, then the iron build up should take place backward along the venous drainage system, which appears to be the case (9).

The story continues with a reference to Borst who founded a theory on the occurrence of vascular obstruction where he mentions the process of significant narrowing to the point of complete obliteration, hyaline transformation, etc. Perivacular hemorrhages were also frequently described by many authors. Borst (10) also mentions the presence of pigments. Others describe the combination of all three: congestion, perivascular hemorrhage and pigments (possibly hemosiderin or iron related) in encephalitis post measles (11). Many noticed venous engorgement and one study showed that thrombi were visualized in nine of seventeen MS cases and all three encephalomyelitis cases.

(1) Putnam (1939). Evidences of vascular occlusion in multiple sclerosis and encephalomyelitis.
(2) Cruveilhier (1839).
(3) Rindfleisch (1863). Histologisches detail zu der grauen degeneration von gehirn und rueckenmark. Arch. Path. Anat. Physiol. Klin. Med. 26: 474.
(4) Charcot (1863).
(5) Putnam (1935). Studies in multiple sclerosis: encephalitis and sclerotic plaques produced by venular obstruction. Archives of Neurology and Psychiatry. 33: 929-940.
(6) Zamboni (2009). Chronic cerebrospinal venous insufficiency in patients with multiple sclerosis. J Neurol Neurosurg Psychiatry 80:392-399.
(7) Adams 1987. Periventricular lesions in MS. Neuropathol Appl Neurobiol. 13: 141.
(8) Singh and Zamboni (2009). Anomalous venous blood flow and iron deposition in multiple sclerosis Anomalous venous blood flow and iron deposition. JCBF 1-12.
(9) Haacke et al. Evidence of an increase in basal ganglia and thalamic iron content in multiple sclerosis and its vascular implications: An initial analysis with susceptibility weighted imaging. Submitted to Intern. Angiology.
(10) Borst Anatomica 9, 67, 1903 Die multiple sklerose des zentranervovensystems.
(11) F. Wohlwill. Ueber encephalomyelitis. Neurol and Psychiat, 112: 20, 1928.

Notes from CCSVI conference, 

Bologna, Italy --September 8, 2009

September 9, 2009 at 7:37pm

Notes from the CCSVI presentation
September 8, 2009


Dr. Ellliot Frohman, University of Texas Southwestern Medical Center Neurology, Dallas, Texas and Robert Zivadinov, Jacobs Neurological Institute, Buffalo, NY are chairs for the morning session:

Dr. Frohman makes the introduction. CCSVI is removed from how we think about MS or any other immune mediated diseases. Could other diseases we currently classify as autoimmune be related to venous disease? Autoimmune diseases share in common molecular adhesion molecules. Perhaps Crohn’s could be venous? Validating CCSVI in MS may affect the classification of other autoimmune disorders. This venous model has been overlooked.

Micrographs, histopath proficles, periventricular cuffs, red cells we see in post capillary venules. This is not new. In 1863 -before Charcot.- G.E. Rindfleisch writes of venous congestion in MS.

Could the immune system go anywhere blood goes? Is this why there is an inappropriate immune response? He notes the large crowd in the room (it’s packed) and says he hopes people will speak out. (they will!)

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Dr. Paolo Zamboni- Universita degli Studi di Ferrara, Italy director of vascular studies

The drama of CCSVI and MS is that of severe stenosis of the extracranial pathways. Everyone in this room can return home and establish a cooperation between vascular and neurology departments. A simple demonstration - he shows a video demonstration of doppler protocol to aid diagnosis. There is a blocked outflow of blood.

In the normal control groups, there is a monodirectional flow of blood. In MS the periventricular vein has a bidirectional flow. Substitute circles avoid intracranial hypertension. Mean transit time is increased.

Dr. Zamboni proposes a “Menu” for the day-

1. Entree- what is the origin of venous stenosis?
2. Pasta- May we assess consequences of CCSVI in the brain. Perhaps microbleeding is the source of lesions.  Just like CVI in other parts of the body- there is microcirculation
Cerebral spinal fluid ultrafiltration and reabsorption depends on transmural pressure.
TMP = IVP-EVP
In venography, there is much higher pressure in MS patients then controls.
Histology- research cited:
-red blood cell extravastion during relapse
-fibrin cuffs in venous hypertension
-iron laden macrophages
are ALL found in MS patients.

3. Main Course- Is CCSVI treatable?
measuring pressure before and after Liberation procedure is significantly changed.

4. Dessert- What are the effects of CCSVI treatment?

and for Today’s Special---Chronic fatigue as a symptom of CCSVI
(you have to love the Italians and their food analogies.)