Blood Flow and white matter lesions

August 27, 2010 at 10:58pm

The idea that MS is related to hypoperfusion, or slowed blood flow, is not new.

Here's is Dr. Juurlink's proposal from 12 years ago--

http://www.ncbi.nlm.nih.gov/pubmed/9824835

Hypoperfusion in the MS brain explained:

"Hypo"; meaning under or sub-par and "perfusion"- meaning the delivery of blood to the capillary bed.

In MS brains, there is a below normal delivery of blood into brain tissue.  Neurologists have never given a good explanation as to why this happens.  Here's a great paper that looks at this phenomena.

(terms to know -NAWM  is normal appearing white matter, or healthy myelin.  

Ischemia means a lack of oxygen or hypoxia.)

http://www.nature.com/jcbfm/journal/v28/n10/full/jcbfm200872a.html

"Accumulating evidence indicates that there is a decreased perfusion throughout the NAWM (normal appearing white matter) in patients with MS. It occurs in both relapsing–remitting and primary progressive MS, strongly suggesting that it represents an integral part of the disease process. Ischemic changes might be involved in the development of a subtype of focal demyelinating lesions (type III lesions). There appears to be a relationship between reduced white matter perfusion and cognitive dysfunction in patients with MS.

Ge et al (2005) interpreted the hypoperfusion in NAWM as a vasculopathy in the context of the perivascular inflammations that occur in focal MS lesions. However, although inflammatory infiltrates in MS are typically located around small- or medium-sized veins (Adams, 1989) and in the perivascular spaces surrounding arterioles (Gay, 2006; Gay et al, 1997), microvessel thrombosis is only exceptionally being observed within these lesions (Aboul-Enein and Lassmann, 2005; Wakefield et al, 1994)."

So, this paper comes pretty close to saying that this slowed perfusion and white matter lesions could be created by slowed blood flow and a lack of oxygen in the brain.  This is exactly what Dr. Juurlink was proposing.

Here's a study that shows that white matter lesions in rats were formed when cerebral hypoperfusion was created in their brains.

http://www.ncbi.nlm.nih.gov/pubmed/13680276

"Cerebrovascular white matter lesions represent an age-related neurodegenerative condition that appears as a hyperintense signal on magnetic resonance images. These lesions are frequently observed in aging, hypertension and cerebrovascular disease, and are responsible for cognitive decline and gait disorders in the elderly population. In humans, cerebrovascular white matter lesions are accompanied by apoptosis of oligodendroglia, and have been thought to be caused by chronic cerebral ischemia. In the present study, we tested whether chronic cerebral hypoperfusion induces white matter lesions and apoptosis of oligodendroglia in the rat. Doppler flow meter analysis revealed an immediate reduction of cerebral blood flow ranging from 30% to 40% of that before operation; this remained at 52–64% between 7 and 30 days after operation. Transferrin-immunoreactive oligodendroglia decreased in number and the myelin became degenerated in the medial corpus callosum at 7 days and thereafter."

There is NO NEED for any auto- immune system activation to create white matter lesions or myelin destruction.  NONE.  Dr. Juurlink knew this.  Many doctors who study stroke know this.   All that is needed is slowed blood flow.  

Did you know that most elderly people have white matter lesions in their brains?  We don't see them, because they are not routinely given MRIs.  But it's a known fact that the aging brain has slower perfusion, slower circulation and decreased blood flow, resulting in less oxygenation.  Why has the correlation of circulation in MS and other neurodegenerative diseases been ignored?  This chaps my hide.

Here's a paper where they created white matter lesions in rats' brains by clamping their carotid arteries closed.  Remember, the arteries bring the blood in, the veins take it out.  Slowed perfusion can be created by slowed delivery of blood, or slowed removal.  It works both ways.

http://www.ncbi.nlm.nih.gov/pubmed/11743996

Notice in this study, the first areas of white matter lesions were on the optic nerve after only THREE DAYS of ligation.  This mimics the order of problems we see in pwMS. RRMS patients typically present with vision problems first and show white matter lesions.

"Cerebral white matter (WM) lesions are observed frequently in human ischemic cerebrovascular disease and have been thought to contribute to cognitive impairment. This type of lesion can be experimentally induced in rat brains under chronic cerebral hypoperfusion by the permanent occlusion of both common carotid arteries. However, it remains uncertain whether chronic ischemia can damage both the gray and white matter, and whether it can induce demyelination with or without axonal damage. Therefore, we examined axonal damage using immunohistochemistry for the amyloid β/A4 precursor protein (APP), chromogranin A (CgA) and demyelination using immunohistochemistry for the encephalitogenic peptide (EP) in this model. Severe WM lesions such as vacuolation and the loss of nerve fibers appeared in the optic nerve and optic tract after 3 days of ligation, and less intense changes were observed in the corpus callosum, internal capsule, and fiber bundles of the caudoputamen after 7 days with Klüver–Barrera and Bielschowsky staining. These WM lesions persisted even after 30 days. The APP, CgA, and EP-immunopositive fibers increased in number from 1 to 30 days after the ligation in the following WM regions: the optic nerve, optic tract, corpus callosum, internal capsule, and fiber bundles of the caudoputamen. "

When neurologists say that Dr. Zamboni's research is not based on fact....give them a lecture on hypoperfusion and white matter lesions.  This is science, this is fact, this is real.

Joan

Hypoperfusion (decreased blood flow) in MS

December 31, 2009 at 10:53am

Before 2009 comes to a close, I'd like to share more research on the decrease of blood flow in the MS brain. There are many researchers around the globe using new MRI technology to study slowed perfusion in MS brains.

I would like to break down this one medical research paper for you, to show you how these researchers' findings can be linked what Dr. Zamboni has discovered.  I will quote sections from the paper- and then we will discuss.

Hypoperfusion of the cerebral white matter in multiple sclerosis: possible mechanisms and pathophysiological significance

This work was supported by MS Anders (Amsterdam, The Netherlands).

Jacques De Keyser1,2, Christel Steen2, Jop P Mostert2 and Marcus W Koch2

1Department of Neurology, Universitair Ziekenhuis Brussel, Vrije Universiteit Brussel,Brussels, Belgium

2Department of Neurology, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands

http://www.nature.com/jcbfm/journal/v28/n10/full/jcbfm200872a.html

from the abstract:

"A number of recent studies using perfusion magnetic resonance imaging in both relapsing and progressive forms of MS have shown a decreased perfusion of the NAWM, which does not appear to be secondary to axonal loss."

This means that in normal appearing white matter (NAWM) in MS brains, there is a slowing of blood flow which does not appear to be caused by axonal death. Something else is causing the slowed blood flow FIRST-because it shows up before we see lesions.

"The classic teaching is that MS is a T-cell-mediated autoimmune disorder of the central nervous system. However, a number of pathophysiological observations cannot be simply explained on the basis of autoimmune mechanisms. First, the progressive (neurodegenerative) component of the disease continues despite intense immunosuppressive interventions that effectively stop inflammatory disease activity (Coles et al, 1999; Metz et al, 2007; Roccatagliata et al, 2007; Samijn et al, 2006). Second, pathologic studies have shown that some demyelinating lesions develop without a preceding inflammatory reaction (Barnett and Prineas, 2004; Gay, 2007, 2006; Guseo and Jellinger, 1975; Lucchinetti et al, 2000). Third, another intriguing finding difficult to explain by autoimmune phenomena is the finding of a diffuse cerebral white matter hypoperfusion, which is the subject of this review."

The prior thought has been that MS is a t-cell mediated disease, autoimmune..we've all heard this. HOWEVER, the researchers wonder, how can the autoimmune hypothesis explain what we (many other researchers) are observing?

1. Even when suppressing the immune system, damage continues in the MS brain

2. Demyelinating lesions appear BEFORE inflammation

3, There is a slowing down of blood flow in cerebral white matter in MS brains