This Is MS Multiple Sclerosis Knowledge & Support Community

Chronically reduced Cerebrovascular Reactivity (CVR) is suspected to be the cause of neurodegeneration in MS, due to a chronic overabundance of NO, which habituates the blood vessels to being continuously expanded. The excess of NO is thought to be the result of inflammation making immune cells to release iNOS, which results in catalysis of NO. The NO overload could also result in energy loss. It may be competing with O2 absorption by mitochondria, with the result that not enough ATP is produced. This is the topic of a paper by Dr. Ge which uses a state of hypercapnia (breathing air with enhanced CO2 content) to induce an increase in bloodflow, and measure the reactivity with MRI.

It is called Impaired Cerebrovascular Reactivity in Multiple Sclerosis by
Olga Marshall, MS; Hanzhang Lu, PhD; Jean-Christophe Brisset, PhD; Feng Xu, PhD; Peiying Liu, PhD;
Joseph Herbert, MD; Robert I. Grossman, MD; Yulin Ge, MD

It appears in JAMA Neurol. 2014;71(10):1275-1281. doi:10.1001/jamaneurol.2014.1668
Published online August 18, 2014

It shows how CVR is related statistically to EDSS and lesion load.

Personally, I suspect that the inability to use oxygen and produce ATP is a global problem, also resulting in muscle weakness and temperature sensitivity. I think it's a very heat-sensitive biochemical reaction.

Hey 1eye---Ge's conclusion was that CVR was related to the vasculature, perhaps endothelial dysfunction. Nothing about overabundance of NO or blood vessels chronically expanded. That's simply not true. All this paper showed was that the CVR response of pwMS is impaired-- here's more:

The study looks at cerebrovascular reactivity, or CVR. CVR is how the brain reacts or responds with blood flow when there is vasodilation. This function is extremely important, as neurons need adequate blood flow to provide glucose and oxygenation. Without this response of adequate cerebral bloodflow (CBF), the brain will not function properly, and neurons can potentially die.

http://archneur.jamanetwork.com/article ... id=1893478

What this new study did to measure CVR was to look at how healthy controls and pwMS responded to a hypercapnia (too much carbon dioxide), which the researchers created by using 5% carbon dioxide gas. This gas increases cerebral blood flow by creating vasodilation--or a widening of blood vessels. A healthy endothelium (lining of the blood vessels) would normally respond to hypercapnia by widening vessels and allowing for more blood to flow to the brain.

Patients with MS had a significant decrease of cerebrovascular reactivity compared with controls. This decrease in CRV correlated to gray matter atrophy, but did not correlate with white matter lesions.

Their conclusion was that there is an impairment in the cerebrovascular pathophysiology in pwMS, and that inadequate blood flow to neurons may indeed be the cause of neurodegeneration in MS. And that this was a vascular problem, NOT a problem initiated by white matter lesions.


We know that impaired CVR is related to arterial stenosis and occlusion of the blood vessels in the neck. http://www.hindawi.com/journals/rrp/2012/268483/

Note that this new study did not hypothesize why this is happening in people with MS. But this study could well be related to what the Columbia researchers saw when they damaged the vascular endothelial cells outside the brain.

The Columbia University study, which was published earlier this summer, found that when researchers damaged the vascular endothelial cells lining the blood vessels outside the brain using lasers to cause oxidative stress, they could disrupt blood flow to the brain and affect neurovascular coupling. http://ccsviinms.blogspot.com/2014/06/c ... e-new.html

Dr. Zamboni has noted that there is a derangement of the endothelial cell layer in the jugular veins and valves in people with CCSVI/MS. This loss of endothelial cell integrity could well be causing the decrease in cerebrovascular reactivity seen in people with MS.
http://phl.sagepub.com/content/early/20 ... 0.abstract

http://ccsviinms.blogspot.com/2014/08/i ... ty-in.html
cheer

Their results showed (my emphasis):

A significant decrease of mean (SD) global gray matter CVR was found in patients
with MS (3.56 [0.81]) compared with healthy controls (5.08 [1.56]; P = .001). Voxel-by-voxel
analysis showed diffuse reduction of CVR in multiple regions of patients with MS. There was a
significant negative correlation between gray matter CVR and lesion volume (R = 0.6,
P = .004) and a significant positive correlation between global gray matter CVR and gray
matter atrophy index (R = 0.5, P = .03)

Maybe I'm wrong there, but neither the grey matter atrophy nor lesion volume had been because of the hypercapnia. They were already there. I am not a statistician, but I think a significant correlation suggests either one is caused by the other (not the case), or that they are both caused by the same thing, whether the significant correlation is positive or negative. The confusion in my mind is that one could take a negative correlation to mean that there was no correlation. I took it to mean negative in the arithmetic sense, i.e. as grey matter CVR goes down, lesion volume goes up, but as I said, I'm not a statistician. The fact that it is grey matter CVR and not white matter suggest in my mind the same cause ("MS"). If this is the case it is the first time the two symptoms of "MS" have been significantly related to the same thing, other than with "MS". That suggests "MS" and CVR are significantly related also, however indirect that may sound.

Now what causes the CVR?

As you say, it could be eNOS, caused by a response to a vascular injury. The diffuseness (if there is such a word -- the spellcheck passed it, but it didn't pass "spellcheck") seems to show it is not localized like it would be if it were caused by a single or few veins being stenosed. I would go back to my words on "ballparking", and back to the study on cooling, both of which point to iNOS, not eNOS -- it is a massive thing, not microscopically small, or very localized.

I'm not making this up:

From the paper:

However, for patients with MS, chronically high
levels of nitric oxide may have detrimental effects on the vascular
health of the brain; its overproduction may desensitize
endothelial and smooth muscle function (vascular habituation),
causing decreased vasodilatory capacity and limited
blood supply for neurons that perform demanding tasks;
thus, this overproduction may create neuronal activity–
induced hypoxia.

and

Previous biochemical
studies1,2 have shown elevated levels of nitric oxide in
patients with MS produced by the activation of nitric oxide synthase
secondary to repetitive proinflammatory cascades.

from Wikipedia:

iNOS produces large quantities of NO upon stimulation, such as by proinflammatory cytokines (e.g. Interleukin-1, Tumor necrosis factor alpha and Interferon gamma).[12]

TNF and gamma interferon are associated with "MS" exacerbations.
The quantity, for me, is the kicker. The cooling paper said the immune cells reduced iNOS by 40%!

The mitochondria statement was from the first references in the paper.

When I said "this is the topic", I was referring to CVR. That much might have been ambiguous.

That's simply not true.

is simply not true. If anyone is interested they can read the paper itself, if they get over the paywall somehow.

I'm not saying eNOS or jugular problems are not involved. In fact, I still think immune cells are likely secondary to the venous problems. The microbleeds and BBB permeability allow immune cells that should not be there to get into the brain. Endothelial health is still required. But I think we have a better idea of the cause of "MS". That's all.

From the paper:

Conclusions
In conclusion, the direct measure of CVR with hypercapnia perfusion
MRI reveals important characteristics of vascular hemodynamic function,
and its impairment in patients with MS is usually
only detectable in in vivo studies. This technique allows for
a better understanding of the underlying mechanism of neurodegeneration
and the worsening of symptoms in MS.