Dr. Ge at ISNVD

A forum to discuss Chronic Cerebrospinal Venous Insufficiency and its relationship to Multiple Sclerosis.

Dr. Ge at ISNVD

Postby Cece » Mon Feb 20, 2012 10:18 am

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?
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Re: Dr. Ge at ISNVD

Postby Cece » Mon Feb 20, 2012 3:08 pm

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
.
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Re: Dr. Ge at ISNVD

Postby cheerleader » Mon Feb 20, 2012 7:52 pm

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
Husband dx RRMS 3/07
dx dual jugular vein stenosis (CCSVI) 4/09
http://ccsviinms.blogspot.com
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Re: Dr. Ge at ISNVD

Postby Cece » Mon Feb 20, 2012 8:08 pm

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!
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Re: Dr. Ge at ISNVD

Postby Cece » Tue Feb 11, 2014 6:32 pm

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.
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Re: Dr. Ge at ISNVD

Postby Cece » Tue Feb 11, 2014 6:33 pm

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).
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Re: Dr. Ge at ISNVD

Postby cheerleader » Tue Feb 11, 2014 8:31 pm

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 8O

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/Minagar%20BBB%20disruption%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
Husband dx RRMS 3/07
dx dual jugular vein stenosis (CCSVI) 4/09
http://ccsviinms.blogspot.com
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Re: Dr. Ge at ISNVD

Postby Cece » Sat Feb 22, 2014 7:56 pm

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!
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