Dr. Ge at ISNVD

[Cece]

https://twitter.com/

Dr. Ge: Mitochondrial dysfunction is a form of metabolic hypoxia in MS

Dr. Ge: Venous structures in MR scans of MS patients are diminished nin advanced stages

Dr. Ge: Oxygen delivery and consumption are critical to neuronal health and critically under studied in MS

Dr. Ge being questioned about his data by Dr. Zamboni about cerebral blood flow...now Dr. Haacke weighs in. Fascinating!

Who is Dr. Ge? This is, as Nat'l CCSVI Society said first, fascinating.

Does the mitochondrial dysfunction and metabolic hypoxia remain after CCSVI is treated?

[Cece]

www.isnvd.org/files/ISNVD%20Abstract%20Book.pdf

Technology Insights of Oxygen Metabolic Abnormalities in MS (Yulin Ge, USA)

The role of vascular pathology in multiple sclerosis (MS) was suggested long ago by Ribbert (1882) and Putnam
(1933). With the invention and advances of imaging technology, now there is accumulating evidence in vivo of
primary vascular pathogenesis and hemodynamic impairment in MS. In particular, there is cerebral blood
perfusion changes in lesions and normal appearing brain tissues, suggesting there might be an ischemic and/or
hypoxic origin of MS disease. In this presentation, I am going to discuss the hemodynamic perfusion changes
and vascular abnormalities measured with several advanced MRI techniques and their pathophysiological
significance in MS. First, the close perivenous relationship of MS lesions associated with the underlying
vascular inflammatory changes can be evaluated with high resolution susceptibility-weighted imaging. Second,
cerebral blood perfusion changes including cerebral blood volume (CBV) and flow (CBF) have been evaluated
with dynamic susceptibility contrast-enhanced (DSC) and arterial spin labeling (ASL) MRI techniques. The
lesions showed different patterns of perfusion change despite that hypoperfusion is a general feature seen in
MS tissues. The perfusion changes in MS may provide additional information of microvascular abnormalities.
Third, the recent promising vascular ischemic / hypoxic hypothesis can be evaluated in vivo with several
techniques including perfusion- and diffusion- weighted imaging during the acute phase and oxygen
metabolic measures as well as functional MRI techniques. In summary, there is increased awareness from both
histopathologic and imaging studies of the role of microvascular and hemodynamic impairment in tissue injury
in MS; therefore, targeting hypoxic injury may be indicated in the new therapeutic strategy.

[cheerleader]

Dr. Ge has worked with Haacke on other studies, Cece.
He is at NYU, and is a researcher/radiologist.
http://www.med.nyu.edu/biosketch/gey01/publications

We've discussed him on the CCSVI forum originally, since he published on venous vasculature and MS in '09.
He has seen this reduced perfusion/ischemia in vivo.
http://onlinelibrary.wiley.com/doi/10.1 ... 8/abstract
cheer

[Cece]

As soon as I saw the name Yulin on the abstract, that helped me remember. Dr. Yulin Ge. This is my new improved post-treatment memory too. I remember after my 2006 relapse when I couldn't read a magazine because I'd forget it as I read. Really disturbing.

Thanks for the additional information on Dr. Ge!

[Cece]

Dr. Ge, at ISNVD 2014:

Nitric Oxide and a Vascular Hypothesis in Multiple Sclerosis
Yulin Ge, M.D., NYU Langone Medical Center, NY, USA

Multiple Sclerosis (MS) is considered an inflammatory demyelinating disease. One of the hallmarks, however, is the progressive neurodegeneration that plays a key role in the progression of neurological disabilities. Little is known of the link between neuroinflammation and neurodegeneration. Recent biochemical studies suggested a crucial role of nitric oxide (NO) over-production in neuronal/axonal injury. There is abundant evidence showing that the production of NO is significantly elevated in MS secondary to vascular inflammatory cascade. NO is an endogenously produced versatile signaling molecule. During an initial stage of acute inflammatory attack in MS, studies have shown diffusely activated T cells initiate the pro-inflammatory cascade and produce elevated levels of NO by upregulating inducible NO synthase (iNOS). It was found that the NO endproducts (i.e. nitrates and nitrates) levels were higher (approximately 2.5 times) in the CSF of MS patients with more clinical disease activity than those who were clinically stable (1.7-fold higher in relapses than in remission).

The increased NO competitively inhibits the binding of oxygen to mitochondrial respiratory complex (i.e. IV) and affects ATP synthesis, yielding a condition in which cells and tissues are unable to use O2 even if available. This phenomenon is called “histotoxic hypoxia” with potentially reduced oxygen consumption or cerebral metabolic rate of oxygen (CMRO2). A second consequence of NO over-production is the detrimental effect on brain vascular health. NO is a strong mediator of neurovascular coupling that is responsible for increased blood supply during transient neural activation. In MS, the presence of a tonically high NO level (even during resting) may alter endothelial function (vascular habituation) with a consequence of decreased vasodilatory capacity and limited blood supply when neurons perform a demanding task. This deficit in cerebral vascular reactivity (CVR) may in turn cause more neuronal damage (activity induced hypoxia) as a result of transient but frequent ischemic attacks during daily life, which is another result of excessive NO that cause damage to previously healthy neurons, thereby a progression of neurodegeneration.

These evidences together with our preliminary imaging results led us to propose that MS has significant abnormalities in CVR (oxygen delivery) and CMRO2 (oxygen consumption) that are consequential to cellular energy failure, and are predictive of disease progression. These alterations may be a significant underlying cause of the diffuse and progressive neurodegeneration in MS, but have been fundamentally under-investigated, especially in human subjects at early stage of disease.

This presentation will cover the use of several advanced metabolic/vascular MRI techniques to characterize the above-referenced deficits including a recently developed T2-Relaxation-Under-Spin- Tagging (TRUST) for the evaluation of global CMRO2 and a patient-comfortable CO2 inhalation paradigm to measure CVR. Some of our preliminary results of CMRO2 and CVR abnormalities will be presented in patients with relapsing-remitting and secondary progressive MS that are associated with clinical disability and disease progression. The hypothesis of our study is that there is significant abnormality of oxygen delivery (blood flow regulation) and oxygen metabolism (uptake), which may be key factors causing neuronal/axonal injury in MS.

Fundamentally under-investigated. Truer words were never typed.

[Cece]

http://www.isnvdconference.org/program/ ... -book.html

Also from Dr. Ge, at ISNVD 2014:

Hemodynamic Impairment in Multiple Sclerosis: Imaging Techniques and Perspectives

Yulin Ge, M.D., NYU Langone Medical Center, New York, NY, USA

Being the most common demyelinating disease of the central nervous system, multiple sclerosis (MS) MS has a significant microvascular pathological component as a consequence of the perivascular inflammation. The role of vascular pathology in MS was suggested long ago. Now there is accumulating evidence of a primary vascular pathogenesis in MS. In vivo studies of vascular and hemodynamic impairment in MS may provide insights into the etiology and pathophysiology of MS and offer the potential metrics for assessment of outcome of the disease.
In MS, vascular inflammation can induce several critical pathophysiological events including BBB breakdown, reactive vasodilatory, and hypoxia-like tissue injury. This presentation will review microvascular and hemodynamic abnormalities in MS. In particular, the following pathophysiological aspects will be highlighted with MR imaging evidence: (1) the classic and modern views of perivascular inflammation and MS lesion development; (2) the vulnerability of white matter to vascular compromise with blood-brain barrier (BBB) breakdown and monitoring disease activity; (3) Hemodynamic impairment in MS including the perfusion abnormalities of cerebral blood flow (CBF), cerebral blood volume (CBV), and vascular permeability in MS; (4) MRI techniques to measure vascular abnormalities and perfusion changes including Gd-enhanced T1 imaging, dynamic susceptibility contrast perfusion MRI (DSC-MRI), arterial spin labeling (ASL), MR angiographic imaging, and functional MRI.

In vivo characterization of vascular and hemodynamic impairment in MS will likely refine and improve our understanding of the pathogenesis of MS including the relationship between tissue hypoxia (an underappreciated phenomenon in MS) and other pathophysiological alterations (i.e. iron deposition, neurodegeneration).

[cheerleader]

Thanks for posting, Cece---
Dr. Ge's info was really dense, he is very knowledgable, and a GREAT asset to the ISNVD. Wow--he and Haacke are stars in the imaging world, and they are working together to understand the vascular connection to MS. He showed some 7T images that were really scary...micro-bleeds/lesions in the MS brain, that are not detectable by weaker machines, and show up prior to demylinating lesion formation.

Dr. Steven Alexander questioned Dr. Ge's reference to nitric oxide after his presentation--since there is a big difference between eNOS (endothelial-derived NO) and iNOS (inducible NO from cytokines). I was glad Dr. Alexander dug in a bit more and asked for clarification on this with Dr. Ge, since I've been singing the praises of NO, and here was a theory stating NO was behind the damage of MS and O2 utilization (eek!) I got a look from the Hubbards

eNOS controls perfusion, is vasodilating and strenghtens the BBB. It comes from a healthy endothelium, which has shear stress and good tight junctions.
iNOS is induced by cytokines, is inflammatory and damaging to the BBB.

Here's a recent paper from Dr. Alexander--
‎www.direct-ms.org/sites/default/files/M ... n%2003.pdf

Levels of NO+ and its metabolites are elevated in blood, urine, and CSF of MS patients,103 but it remains controversial whether NO+ plays a protective, an injurious, or both roles in pathogenesis of MS.103 In the BBB, CEC form NO+ via endothelial NO+ synthase (eNOS, NOSIII) and may decrease or increase BBB. CEC sense NO+ by a cGMP- pathway that may phosphorylate junction associated proteins (like VASP),104 which strengthen paraendothelial barrier and limits endothelial permeability. Although by scavenging oxidants NO may also serve as an important antioxidant defense in CEC,105 several reactions between oxidants and NO+ can lead to formation of highly reactive species, like peroxynitrite, which disintegrate the BBB.106 The induction of iNOS by cytokines in several cells within the BBB could release sufficient NO+ to form toxic levels of NO+ metabolites that disrupt the BBB.107

http://www.ncbi.nlm.nih.gov/pubmed/12399227

Our data demonstrate that iNOS and eNOS are differently regulated in physiologic conditions and in liver disease. While eNOS seems to be involved in the physiological regulation of hepatic perfusion, strong upregulation of iNOS might contribute to inflammatory processes in FHF.

So...endothelial health depends on the good NO.
eNOS is a sign of good brain health, BBB integrity. iNOS shows permeable BBB, unhealthy brain.
http://kuscholarworks.ku.edu/dspace/bit ... 0Oxide.pdf

hope that makes sense my brain is still crispy.
cheer

[Cece]

I came to reread this since looking at a slide from Dr. Ge's presentation left me unsure.
eNOS vs iNOS
The bad NO (iNOS) causes the mitochondrial dysfunction that causes decreased oxygen delivery or usage.
If that's a full paper you've linked, I'll have to come back and read it. There has not yet been enough time to digest all that's come out of ISNVD!

[1eye]

All this talk about iNOS, eNOS, etc., seems to me to point at people (including me) not knowin enough organic chemistry to understand this topic. From Wikipedia:

Nitric oxide synthases (EC 1.14.13.39) (NOSs) are a family of enzymes catalyzing the production of nitric oxide (NO) from L-arginine. NO is an important cellular signaling molecule. It helps modulate vascular tone, insulin secretion, airway tone, and peristalsis, and is involved in angiogenesis and neural development. It may function as a retrograde neurotransmitter. Nitric oxide is mediated in mammals by the calcium-calmodulin controlled isoenzymes eNOS (endothelial NOS) and nNOS (neuronal NOS). The inducible isoform, iNOS, is involved in immune response, binds calmodulin at physiologically relevant concentrations, and produces NO as an immune defense mechanism, as NO is a free radical with an unpaired electron. It is the proximate cause of septic shock and may function in autoimmune disease.

NOS catalyzes the reaction:

L-arginine + 3/2 NADPH + H+ + 2 O2 \rightleftharpoons citrulline + nitric oxide + 3/2 NADP+

NOS isoforms catalyze other leak and side reactions, such as superoxide production at the expense of NADPH. As such, this stoichiometry is not generally observed, and reflects the three electrons supplied per NO by NADPH.

NOSs are unusual in that they require five cofactors. Eukaryotic NOS isozymes are catalytically self-sufficient. The electron flow in the NO synthase reaction is: NADPH → FAD → FMN → heme → O2. Tetrahydrobiopterin provides an additional electron during the catalytic cycle which is replaced during turnover. NOS is the only known enzyme that binds flavin adenine dinucleotide (FAD), flavin mononucleotide (FMN), heme, tetrahydrobiopterin (BH4) and calmodulin.

Classification
nNOS
iNOS
eNOS
bNOS

These are enzymes which catalyze the production of raw NO in complex reactions, none of which I understand. None of these synthases are NO. They are all catalysts.

For that matter, I don't understand the reaction which produces raw NO from stored food and UV. I remember that the paper I was referring to said that it was NO that was being overproduced, and interfered with oxygen uptake by the mitochondria. It seems the blood that was being measured with MRI was far from hypoxic itself. It had under-used, extra oxygen. It sounds to me as if this fact is key to neurodegeneration. The hypoxia that is the problem is more the inability to use abundantly available oxygen, leaving tissues oxygen-starved. Any agreement here? Anybody understand this stuff?

[cheerleader]

Ok...will try to explain better.
I'm certainly not a chemistry expert, 1 eye, but have been reading papers on NO for seven years now, trying to get a handle on endothelial dysfunction. eNOS has been my focus. Dr. John Cooke, author of The Cardiovascular Cure, has been my mentor/go to expert in this understanding, because I was looking at the vascular connection to MS--as evidenced by Jeff's serum numbers and hypercoagulation, etc. I was looking at ways to reverse endothelial dysfunction via eNOS. Oxidative stress and hypercoagulation were addressed in The Endothelial Health program:
http://ccsvi.org/index.php/helping-myse ... ial-health

Despite the generation of NO by the oxygen-independent conversion of nitrate and nitrite, there are three major enzyme isoforms producing the molecule. These so-called NO synthases (NOS) utilize L-arginine and molecular oxygen to provide the free radical gas NO.[10]

Neuronal NOS (nNOS or NOS1) was the first discovered isoform.[11] nNOS is not only specific for neurons, but was also detected in other cell types, such as cardiomyocytes and arterial smooth muscle cells.[12,13] Inducible NOS (iNOS or NOS2) was originally isolated from macrophages and is expressed in glial cells.[14] Endothelial NOS (eNOS; NOS3) was also found in neurons.[15] Recently, mitochondrial NOS (mtNOS, NOS4) was detected in the inner mitochondrial membrane of different tissues such as brain, liver and heart.[16] mtNOS seems to modulate redox status and is involved in brain development.[17]

As in all biological systems, detrimental and/or beneficial effects of a molecule depend on its concentration in the microenvironment, resulting in either physiological or pathological processes. eNOS, as well as nNOS, are regulated by changes in intracellular calcium and by direct phosphorylation, producing only nanomolar levels of NO.[18] By contrast, iNOS is induced independently of intracellular calcium by proinflammatory cytokines, leading to excessive NO release.[19] Generally, the enzyme activity of iNOS is not enhanced compared with nNOS and eNOS, but increased iNOS protein can transiently be induced.

http://www.medscape.com/viewarticle/580254_3


Again, I focused on eNOS to help Jeff's health, so that's what I know most about.
Why eNOS is important in vascular health:
http://circ.ahajournals.org/content/113/13/1708.full

How eNOS is released by the sun's UV rays, into our skin and circulatory systems via dietary nitrates stored in our flesh--
Dr. Richard Weller is the expert studying this mechanism.
http://www.nature.com/jid/journal/v134/ ... 1427a.html
Here's a 10 minute TED talk that explains it in (witty) layman's terms:


How eNOS is released by exercise:
http://www.sciencedaily.com/releases/20 ... 103948.htm

How eNOS is activated by dietary isoflavones:
http://cardiovascres.oxfordjournals.org ... t/75/2/261

This is going to get convoluted, but hang on.
After a stroke, iNOS and nNOS are activated in the brain, because ischemia induces an overproduction of NO, which is damaging.

But eNOS looks to be protective:

Indeed, in certain circumstances, NO confers protection against stroke because mice deficient in eNOS suffer greater damage than control mice after reversible ischemia (Huang et al., 1996). One explanation is that NO is not toxic in itself but becomes toxic only when it reacts with superoxide and is converted to peroxynitrite (Beckman and Koppenol, 1996) and that the likelihood that this will occur is dependent on where NO is being produced.

http://www.jneurosci.org/content/19/14/5910.full.pdf

Endothelial NO preserves collateral blood flow during ischemia, thereby reducing acute neuronal damage. Thrombocyte function is influenced by NO that is produced by endothelial cells and by platelet-derived NO. Therefore, targeting eNOS as a regulating molecule of vascular hemostasis could open new strategies for prophylactic and acute stroke treatment. Furthermore, eNOS-derived NO promotes angiogenesis as well as neurogenesis offering a tool to support post-stroke regeneration. In addition, inflammatory processes after cerebral ischemia are modulated by endothelial NO, but pro- and anti-inflammatory effects of eNOS have been described. With regard to this, more insights into the relation of eNOS to post-stroke inflammation are needed.

http://www.medscape.com/viewarticle/580254

There are many reasons oxygen may be under utilized, as I said on the other thread. Brain injury, neuronal loss, mitochondrial disease, increased iNOS and nNOS making O2 unavailable....pick your mechanism. Dr. Ge is still trying to figure it out.

One challenge from the current data is to answer the question of what is exactly the underlying cause of the changes of Yv and CMRO2 in MS. Although NO hypothesis of competitive inhibition of oxygen uptake in mitochondrial respiratory process was proposed, we could not exclude the contribution from neuronal tissue loss or cell death, which had a decreased oxygen demand and decreased oxygen utilization, based on these imaging data

https://files.nyu.edu/hr18/public/Ge_JCBFM_2012.pdf
And Dr. Alexander had a lot of great points at ISNVD as to why NO wouldn't be the culprit...but too tired to add now....going for walk,

cheer

[cheerleader]

OK, great walk.
Here's Dr. Alexander, who I met on this forum in 2007- http://www.shreveportphysiology.com/fac ... xander.htm
He was at ISNVD, asking questions of Ge, as to whether he considered eNOS separately in his NO theory of O2 metabolism (which he didn't)---here's some of Dr. Alexander's research into eNOS as a protective in inflammatory disease, including MS and bowel disease:
http://www.biomedcentral.com/1741-7015/11/219
http://www.sciencedirect.com/science/ar ... 4903006440
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3040330/
OK...hope that helps a bit! I'm not a scientist---but I've been lucky enough to get to hang out with them and learn.
cheer

[1eye]

I thought maybe I had slipped on another thread...

Anyway one of the skills imparted to us in technology school was the ability to ball-park. That means to say whether an answer is in the right ballpark. A gut-feel kind of thinking based on orders of magnitude (each one is separated by a factor of 1000) and based partly on whether a relationship is linear, squared, cubed, quadratic, etc... (exponents of 1,2,3,4, etc., or even -1, -2, -3, -4,...). This way we get a gut feel, especially when an answer is in the wrong ballpark.

That is why statements about concentrations in the microenvironment, and "producing only nanomolar levels of NO." (x 10 ^-9, or x .0000000001) are very informative.

I would like to add my own experience to that. I think, in contrast to nanomolar levels of anything, what is happening to me, in my low-energy state, and in the inability to use my muscles for any length of time, is massive. It affects my whole body. If it is being caused by some enzyme in my blood, it is there in high concentration.

The other fact I know about this pathological state is that it is definitely, without a doubt, affected by heat. I had thought heat must be affecting the viscosity of my blood, but another thing that might be happening is that heat (also inflammation, which includes heating) speeds up chemical reactions. The fact that iNOS can come from inflammation may be very meaningful. Perhaps the effect of a hot bath in "MS" is to increase iNOS and prevent mitochondrial respiration, a process which seems to be greatly accelerated by temperature.

If a chemical reaction can be identified it should be simple to test for it.

It seems the culprit may well not be NO itself, but one of those NOS's.

-Chris

[cheerleader]

The other fact I know about this pathological state is that it is definitely, without a doubt, affected by heat. I had thought heat must be affecting the viscosity of my blood, but another thing that might be happening is that heat (also inflammation, which includes heating) speeds up chemical reactions. The fact that iNOS can come from inflammation may be very meaningful. Perhaps the effect of a hot bath in "MS" is to increase iNOS and prevent mitochondrial respiration, a process which seems to be greatly accelerated by temperature.

If a chemical reaction can be identified it should be simple to test for it. It seems the culprit may well not be NO itself, but one of those NOS's.

-Chris

Sure could be, Chris. I dunno. Looks like cooling pwMS reduces iNOS production (leukocytes create inducible NO) Seems like cooling garments would help.

http://www.ncbi.nlm.nih.gov/pubmed/11552024

Neurology. 2001 Sep 11;57(5):892-4.
Cooling garment treatment in MS: clinical improvement and decrease in leukocyte NO production.
Beenakker EA, Oparina TI, Hartgring A, Teelken A, Arutjunyan AV, De Keyser J.

Ten heat-sensitive patients with MS were randomly allocated in a cross-over study to wear a cooling garment for 60 minutes at 7 degrees C (active cooling) and 26 degrees C (sham cooling). In contrast to sham cooling, active cooling improved fatigue and postural stability with eyes closed and muscle strength. There was no decrease in tympanic temperature, but active cooling was associated with a 41% decrease in mean leukocyte nitric oxide (NO) production This effect on NO could be relevant because it blocks conduction in demyelinated axons.

Anecdotal--Jeff had terrible heat intolerence (couldn't move when hot, fell asleep) which completely went away after stenting of dural sinus and jugular veins. We've thought it was due to brain cooling affect....but honestly, who the hell knows? Here's the upright doctor on heat intolerence in MS and the "radiator theory."
http://www.upright-health.com/brain-cooling.html

wish the way was clearer for you, Chris.
cheer

[1eye]

In the meanwhile, I proceed on the theory that a) heat and inflammation are both bad for me on account of leukocyte iNOS production. It would be really nice to have a ballpark figure for this. One thing I know is that heat intolerance seems universal in "MS'. The other is that this effect is massive, completely shutting down large parts of normal function. It could be secondary to heat problems caused by inadequate CCSVI venous drainage, since the heat seems to bring its own iNOS production by leukocytes. It could also be connected with the well-known fact that heat generally speeds up most chemical reactions.

It would also be nice to know if this is directly some effect of raw NO, or the NOS that catalyses production of it. Anyway, it seems to make the most sense to me, given there is a clear abundance of unused O2, that there is something preventing use of it. With an environment high in O2, there may also be bad oxide by-products floating around.

Something is messing up oxygen consumption. Due to the fatigue, I would blame mitochondria.

[Cece]

Dr. Ge: Oxygen delivery and consumption are critical to neuronal health and critically under studied in MS

One of the things I like about Dr. Ge's work is that this can be studied without reference to CCSVI. There is funding for MS research and not enough for CCSVI research so if this falls under the first category, it has a greater chance of going from understudied to fully studied.