Astrocytes and cerebral blood flow

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

Astrocytes and cerebral blood flow

Postby Crabby » Tue Sep 22, 2009 6:55 pm

Maybe I'm missing something, but I'm surprised that no one (as far as I can tell) has delved into the link between what Dignan has called the two biggest recent developments in MS -- CCSVI and the possibly integral role astrocytes play in the development of MS.

I've only quickly scanned a couple of abstracts, but it seems that there's a lot of research about astrocytes playing a critical role in cerebral blood flow. Could it be possible that the reflux from CCSVI stenoses somehow damages astrocytes and triggers a chain reaction that leads to inflammation and neurodegeneration?
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Postby cheerleader » Tue Sep 22, 2009 7:36 pm

Crabby-
You're right....Astrocytes are very important...they help maintain the endothelial lining of the blood brain barrier- but not to speak for everyone here- I personally feel that they are merely bystanders or victims in the CCSVI process, and we have a better understanding of their place in the chain of events thanks to Dr. Zamboni.

This is the order Dr. Zamboni puts forth in his latest paper on cerebral bloodflow-the abstract and charts are in the research sticky-

1. CCSVI - chronic cerebrospinal venous insufficiency- a cerebral venous outflow abnormality caused by a congenital venous malformation
2. iron deposition into and oxygen deprivation of brain tissue
3. hypoxia and cellular death
4. activation of immune system

I suppose the astrocytes would come into play at step 2, where the bloodbrain barrier is broken due to shear stress. But the astrocytes do not initiate this process....they are affected by the reflux created by stenosis- Step 1.

The ECTRIMS study just looked like another hyperfocusing on one small piece of the puzzle. Zamboni's work provides an over-arching explanation of the process- that's why I was not jumping up and down at the new research (but I do appreciate dig's posting and your mention- because they are obviously related.)
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Postby CureIous » Tue Sep 22, 2009 7:56 pm

:)
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Astrocytes and Ischemia

Postby Shayk » Wed Sep 23, 2009 8:11 pm

Just want to add that on the surface it seems the info about astrocytes and MS could be quite consistent with the info on CCSVI.

Per Hollie's (Accelerated Cure Project) 2009 Ectrims notes about Dr. Prineas' Charcot Award Lecture:
In MS, the connection of astrocyte "foot processes" with the glial limiting membrane is often gone (these foot processes form part of the blood-brain barrier .... perhaps MS is also a disease of astrocytes?

It seems possible that ischemia also induces reactive astrocytes. Per this abstract-- Acute astrocyte activation in brain detected by MRI: new insights into T(1) hypointensity
Increases in the T(1) of brain tissue, which give rise to dark or hypointense areas on T(1)-weighted images using magnetic resonance imaging (MRI), are common to a number of neuropathologies including multiple sclerosis (MS) and ischaemia

These findings suggest that an increase in T(1) relaxation may identify the acute development of reactive astrocytes within a central nervous system lesion.

Early changes in T(1) may, therefore, provide insight into acute and reversible injury processes in neurologic patients, such as those observed before contrast enhancement in MS.


I thought it was interesting anyway...Take care all

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Postby radeck » Thu Sep 24, 2009 8:59 am

cheerleader wrote:This is the order Dr. Zamboni puts forth in his latest paper on cerebral bloodflow-the abstract and charts are in the research sticky-

1. CCSVI - chronic cerebrospinal venous insufficiency- a cerebral venous outflow abnormality caused by a congenital venous malformation
2. iron deposition into and oxygen deprivation of brain tissue
3. hypoxia and cellular death
4. activation of immune system


A slightly off-topic question on this (I was pondering starting a new thread, or posting it in the "skeptics" thread, but since I don't consider myself skeptic this is perhaps the best place for it):

Could you cheer and/or others summarize what the evidence we have for the venous issue being generally congenital? I didn't see this clearly stated in the Zamboni article. There's been some discussion over in the antibiotics forum of the stenosis being caused by ulcers and Cpn involvement, etc.

I can remember two arguments in favor of them being *often* congenital. One is that many patients treated by Dr. Dake had twisted jugulars or jugulars squeezed by surrounding material, like jawbone. Another is Zamboni re-visiting people (as far as I know it is not clear how many) in Sardinia after 20 or so years, who he had diagnosed with (some form of?) venous malformations in their childhood to find that now 90% of them had MS.

Also, an argument against auto-immune involvement in causing the stenosis (but maybe not an argument against them being caused by ulcers caused by an infection) was given at the conference following a detailed analysis of the vein walls (at least that's what I remember, I can't find it anymore).

One thing that puzzles me is that (as I read it) *azygos reflux* is seen more often in secondary progressive patients than in relapsing-remittent ones. *Azygos malformations* on the other side are (as I understand) not seen at all by Dr. Dake. This would mean that at least the azygos reflux is not congenital (except for, maybe, in primary progressive people), and caused by something else.
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Postby cheerleader » Thu Sep 24, 2009 9:21 am

Radeck-
please refer to the Bologna notes on Marie's 2nd post here at the top of the page:
http://www.thisisms.com/ftopict-7098.html
Dr. Byung B. Lee gave a presentation on congenital truncular venous malformations- associated with the Caucasian race and formed in utero. All of the discussion on the vein walls collagen I and collagen III are there, as well. If you would like to do more research on TVMs and start a new thread, go ahead!

Back to astrocytes....
Sharon- thank you for the study on ischemic changes to astrocytes- makes alot of sense in the CCSVI paradigm.
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Re: Astrocytes and cerebral blood flow

Postby MarkW » Sat Jun 23, 2012 9:27 am

Due to Cece's info on the two compartment model of cerebral model of blood flow I spotted this thread from Crabby in Sep 2009. For me astrocyctes are critical in the etiology of MS although I am not sure where they fit into the cascade, which leads to MS. For folks who like detail this needs revisiting.
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Mark's CCSVI Report 7-Mar-11:
http://www.telegraph.co.uk/health/8359854/MS-experts-in-Britain-have-to-open-their-minds.html
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Re: Astrocytes and Ischemia

Postby MarkW » Sat Jun 23, 2012 9:42 am

Putting Zamboni on CCSVI (not iron) and Prineas on Astrocyctes together would be a fascinating discussion. MarkW

Shayk wrote:Just want to add that on the surface it seems the info about astrocytes and MS could be quite consistent with the info on CCSVI.
Per Hollie's (Accelerated Cure Project) 2009 Ectrims notes about Dr. Prineas' Charcot Award Lecture:

Here are Hollie's notes:
Friday September 11, 2009
Plenary Session 2: Charcot Award Lecture
The pathogenesis of relapsing and remitting multiple sclerosis – versions one to five and counting
J. Prineas (Sydney, AU)
Dr. Prineas received this year's Charcot Award for his contributions to understanding the pathology of MS, based in particular on his extensive analysis of MS tissue. In his talk, he divided the historical conception of MS into five phases (actually, he added a sixth new one at the end):
•Charcot's era: MS is a disease of the myelin involving excess glial tissue that compresses and compacts myelin, leaving the axons intact.
•1870-1916: Myelin destruction in MS occurs acutely and begins around blood vessels.
•1950-1960: There are other diseases of the central and peripheral nervous system characterized by perivascular demyelination (such as EAE and Guillain-Barre).
•1960-1985: Myelin destruction in MS and EAE is caused by macrophages; he showed some neat pictures of macrophages squeezing their way into the outer layer of myelin around an axon. Remyelination can occur within a couple of weeks, indicating that the environment is no longer hostile to oligodendrocytes.
•2004: The myelin targeted by macrophages in MS may not be normal myelin -- rather, it displays markers that attract macrophages to destroy it. He has seen lesions with apoptotic ("suicidal") oligos outside the lesion, and myelin breakdown inside the lesion with no oligo cell bodies to be found. Lesions characterized by apoptotic oligos have few lymphocytes. In newly developing lesions, he views three zones: (1) outer zone with some apoptotic cells and activated microglia but no macrophages, (2) a phagocytic zone with macrophages, (3) a post-phagocytic zone with loss of myelin and higher number of T cells and plasma cells than in the other two zones. He does not know why the oligos become apoptotic and whether the activated microglia are a cause or an effect of that.
•He believes that neuromyelitis optica (NMO), which appears to be a disease of astrocytes, is the demyelinating disease that most closely resembles MS. In NMO, there is an even deposition of complement C9 neo along the glial limiting membrane outside the blood vessel, then there is a gathering of macrophages. Astrocytes are destroyed (they may come back but are abnormal), and myelin loss happens after the loss of astrocytes. Apoptotic oligos have been seen in NMO lesions too. In MS, the connection of astrocyte "foot processes" with the glial limiting membrane is often gone (these foot processes form part of the blood-brain barrier and are a prominent target in NMO). He feels that NMO and MS are so alike that they must have something in common -- perhaps MS is also a disease of astrocytes?
* * * * * * * * * * * * * * * *
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Mark's CCSVI Report 7-Mar-11:
http://www.telegraph.co.uk/health/8359854/MS-experts-in-Britain-have-to-open-their-minds.html
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Re: Astrocytes and cerebral blood flow

Postby 1eye » Sat Jun 23, 2012 10:21 am

MarkW wrote:[in Neuromyelitis Optica] Astrocytes are destroyed (they may come back but are abnormal), and myelin loss happens after the loss of astrocytes.
Is this the same order of events in "MS"? In "MS" are astrocytes destroyed or abnormal?
MarkW wrote:...He does not know why the oligos become apoptotic and whether the activated microglia are a cause or an effect of that.
I have seen the term used a lot -- activated microglia. What are they? Good, bad, neither? What activates them?
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Re: Astrocytes and cerebral blood flow

Postby cheerleader » Sat Jun 23, 2012 11:58 am

Hi one eye---
Astrocytes are back in MS research, with a new paper--I wrote about it yesterday on FB.
Astrocytes are the most abundant cell in the human brain. One of the most important things astrocytes do is support the endothelial cells in our brain, and maintain the very important blood brain barrier. The blood brain barrier should have tight junctions, that don't allow blood particles into brain or spinal tissue. They are not bad guys....they are products of their environment, and they are regulators. They respond to an injurious situation, like hypoxia.

Here's the new paper link:
http://www.jci.org/articles/view/60842

Astrocyte-derived VEGF-A drives blood-brain barrier disruption in CNS inflammatory disease
Blood brain barrier (BBB) permeability is an early and prominent feature of inflammatory CNS conditions, including MS (13), viral encephalitis (14), and traumatic and hypoxic/ischemic injury (15). BBB disruption correlates with neurologic exacerbation, and MS patients with contrast-enhancing plaques are more likely to have irreversible pathology (13, 16). BBB breakdown leads to edema, metabolic imbalance, excitotoxicity, and ingress of factors that potentiate inflammation and inhibit repair (17–20) and facilitates infiltration of T and B lymphocytes, macrophages, and neutrophils (21). In diseases such as MS, current options to restrict relapse severity are limited, and patients may benefit from more selective agents (22).

Studies have identified astrocytes as regulators of BBB induction and maintenance (9–11) and have implicated astrogliosis, particularly induced by IL-1, as a driver of both BBB breakdown and repair (10, 12, 48). The mediators producing the effects of reactive astrocytes are incompletely characterized, and our data revealed VEGF-A as an important astrocyte-derived inducer of BBB disruption and pathology in vivo. Although VEGF-A–induced vascular permeability has previously been implicated in pathogenesis of disorders, including myocardial infarction, CNS hypoxia/reperfusion injury, and tumor growth and metastasis (49), and we and others have previously speculated on its role in BBB breakdown (12, 26), this study is the first to our knowledge to show the significance of astrocyte-derived VEGF-A in lesion pathogenesis and generation of clinical deficit in models of CNS inflammatory disease.



This is the first study that has noted the importance of astrocyte derived VEGF in the formation of lesions and brain damage in a model of MS.

Please note the other diseases that have VEGF created "vascular permeability"--hypoxia and myocardial infarction. Vascular diseases. VEGF-a is activated in situations where there is low oxygen, and the organ begins to suffer the effects of low O2. Vascular endothelial growth factor (VEGF) is a chemical signal produced by cells that stimulates the growth of new blood vessels. It is part of the system that restores the oxygen supply to tissues when blood circulation is inadequate.
VEGF's normal function is to create new blood vessels during embryonic development, new blood vessels after injury, and new vessels (collateral circulation) to bypass blocked vessels.

sounds like CCSVI/slowed perfusion/could be linked to this new discovery. More research ahead.
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Re: Astrocytes and cerebral blood flow

Postby MarkW » Sat Jun 23, 2012 12:23 pm

I wish I could say such far reaching things after my research 1eye but these words are from Prof Prineas.
MarkW wrote:
Prineas wrote:[in Neuromyelitis Optica] Astrocytes are destroyed (they may come back but are abnormal), and myelin loss happens after the loss of astrocytesIs this the same order of events in "MS"? In "MS" are astrocytes destroyed or abnormal?
....He does not know why the oligos become apoptotic and whether the activated microglia are a cause or an effect of that.

1eye wrote:I have seen the term used a lot -- activated microglia. What are they? Good, bad, neither? What activates them?

When researchers answer those questions 1eye we will be closer to understanding the causes of MS.
MarkW
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Mark's CCSVI Report 7-Mar-11:
http://www.telegraph.co.uk/health/8359854/MS-experts-in-Britain-have-to-open-their-minds.html
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Re: Astrocytes and cerebral blood flow

Postby cheerleader » Sat Jun 23, 2012 1:05 pm

NMO is different than MS...astrocytes are destroyed in NMO by auto-antibodies. There are no autoantibodies in MS and no astrocyte destruction in MS.
here's the most recent Prineas and Barnett paper on that, from 2012---these researchers have now differentiated astrocytes in NMO and MS---
http://msj.sagepub.com/content/early/20 ... 5.abstract
Auto-antibody mediated astrocyte injury is implicated as a primary event in neuromyelitis optica (NMO) by biomarker, post-mortem and experimental studies that differentiate the condition from multiple sclerosis. .


In MS--astrocytes are a "product of their environment". They are not destroyed, but they are activated to perform a variety of functions in MS. Some are good, some not so helpful. Here's a great paper explaining what they do, one eye.
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2858316/

The paper I linked above shows how VEGF might be the reason astrocytes are activated in MS. To bring O2 to ischemic tissue, to reroute around blocked blood flow.
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Re: Astrocytes and cerebral blood flow

Postby 1eye » Sun Jun 24, 2012 2:38 am

Makes sense to me. I wonder about the O2-vein-genesis/VEGF connection. Maybe it's an automatic reaction programmed by DNA, to low O2?
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Re: Astrocytes and cerebral blood flow

Postby Bethr » Sun Jun 24, 2012 1:47 pm

double post - sorry :-D
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Re: Astrocytes and cerebral blood flow

Postby Bethr » Sun Jun 24, 2012 2:24 pm

How about this study http://www.jneurosci.org/content/32/14/4841.abstract . From what I can grasp FPN (ferroportin) was deleted from astrocytes and it hindered remyelination. This ties in with Genmati's gene study that highlighted the FPN gene in MS. Probably doesn't tie in with CCSVI?

Iron Efflux from Astrocytes Plays a Role in Remyelination
Katrin Schulz, Antje Kroner, and Samuel David+ Author Affiliations

Centre for Research in Neuroscience, The Research Institute of the McGill University Health Center, Montreal, Québec H3G 1A4, Canada
Author contributions: K.S. and S.D. designed research; K.S. and A.K. performed research; K.S. analyzed data; K.S. and S.D. wrote the paper.

Abstract
How iron is delivered to the CNS for myelination is not well understood. We assessed whether astrocytes can provide iron to cells in the CNS for remyelination. To study this we generated a conditional deletion of the iron efflux transporter ferroportin (Fpn) in astrocytes, and induced focal demyelination in the mouse spinal cord dorsal column by microinjection of lysophosphatidylcholine (LPC). Remyelination assessed by electron microscopy was reduced in astrocyte-specific Fpn knock-out mice compared with wild-type controls, as was proliferation of oligodendrocyte precursor cells (OPCs). Cell culture work showed that lack of iron reduces the ability of microglia to express cytokines (TNF-α and IL-1β) involved in remyelination.
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