gray matter affected in earliest stages of MS

If it's on your mind and it has to do with multiple sclerosis in any way, post it here.

Postby OddDuck » Fri Nov 19, 2004 5:40 am

Yes, yes, and yes! Personally, there is not a doggoned thing either of you have just posted that I haven't also found!

Gee....where to start today!

Robin:

I have spent more time trying to disprove what I believe than I have trying to prove it. So far I have been unable to do so. I personally would welcome any input that would cast doubt on these findings.


Same here! So far, not a soul has been able to cast ONE doubt. From a couple of the top neuros, to a geneticist (PCP), to the NMSS. So.........If you trust what I'm saying here, don't worry, we've at least put a lot of the pieces together allright. I've tried for months for somebody.......anybody........to poke holes. As I said.......so far.......nada.

Wesley: I'll be darned again! Last night I found what you just wrote. Desferal, it was called (i.e. deferoxamine). The thing is, they DID attempt this on MSers back in 1989, with little success. And my thought on why that was, I swear, was exactly what you pointed out. How to get it out of the cells, not just the blood.

http://www.fedem.org/revista/n8/progresioning.htm

In 1989, a trial with an iron chelating agent (Desferal) in 12 SP MS patients with a severe disability was well tolerated, but no long-term clinical benefit was mentioned.34


So, believe it or not, I concluded the same as Robin. Another "piece" but unfortunately, not the WHOLE story. And the more I looked into iron and gray matter, it turned into Parkinson's disease and Alzheimers. All neurological, of course, but........you see the slightly different slant it took. Right away from MS. So....ok....I circled back.

BUT...I was left with some interesting, but TOTALLY unanswerable questions about it. This you both might find interesting....hence, I think the iron "element" of this is worth a second look and should probably be kept in mind as perhaps one of the "triggers" (?), and here's why I was left with that thought (I'll highlight - the highlights are what you may find interesting, as I did). Now the OTHER interesting thing about this hypothesis is how it fits into that previous article I posted that I had no immediate thoughts about (and it was regarding the timing of children being provided iron at specific times in their lives.) Again, no conclusions, but it's sort of left hanging in the back of my mind. All I can say is "hmmmmmmmm", right now:

Ann. N.Y. Acad. Sci. 1012: 224–236 (2004). doi: 10.1196/annals.1306.019
Copyright © 2004 by the New York Academy of Sciences

Brain Ferritin Iron as a Risk Factor for Age at Onset in Neurodegenerative Diseases


GEORGE BARTZOKISa,b,c,d, TODD A. TISHLERc,e, IL-SEON SHINa,f, PO H. LUa,g and JEFFREY L. CUMMINGSa,g

aDepartment of Neurology, UCLA, Los Angeles, California, USA
bLaboratory of Neuroimaging, Department of Neurology, Division of Brain Mapping, UCLA, Los Angeles, California, USA
cGreater Los Angeles VA Healthcare System, Department of Psychiatry, West Los Angeles, California, USA
dDepartment of Psychiatry, Charles R. Drew University of Medicine and Science, Los Angeles, California, USA
eNeuroscience Interdepartmental Graduate Program, UCLA, Los Angeles, California, USA
fDepartment of Psychiatry, Chonnam National University Medical School, Kwangju, Korea
gDepartment of Psychiatry and Biobehavioral Sciences, UCLA, Los Angeles, California, USA

Address for correspondence: George Bartzokis, M.D., UCLA Alzheimer's Disease Center, 710 Westwood Plaza, Room 2-238, Los Angeles, CA 90095-1769. Fax: 310-268-3266. gbar@ucla.edu
Ann N.Y. Acad. Sci. 1012: 224-236 (2004).

Tissue iron can promote oxidative damage. Brain iron increases with age and is abnormally elevated early in the disease process in several neurodegenerative disorders, including Alzheimer's disease (AD) and Parkinson's disease (PD). Higher iron levels in males may contribute to higher risk for younger-onset PD and recent studies have linked the presence of the hemochromatosis gene with a younger age at onset of AD. We examined whether age at onset of PD and AD was associated with increased brain ferritin iron. Ferritin iron can be measured with specificity in vivo with MRI utilizing the field-dependent relaxation rate increase (FDRI) method. FDRI was assessed in three basal ganglia regions (caudate, putamen, and globus pallidus) and frontal lobe white matter for younger- and older-onset male PD and AD patients and healthy controls. Significant increases in basal ganglia FDRI levels were observed in the younger-onset groups of both diseases compared to their respective control groups, but were absent in the older-onset patients. The results support the suggestion that elevated ferritin iron and its associated toxicity is a risk factor for age at onset of neurodegenerative diseases such as AD and PD. Clinical phenomena such as gender-associated risk of developing neurodegenerative diseases and the age at onset of such diseases may be associated with brain iron levels. In vivo MRI can measure and track brain ferritin iron levels and provides an opportunity to design therapeutic interventions that target high-risk populations early in the course of illness, possibly even before symptoms appear.


Now, I did find some information that showed how the oligodendrocytes are involved in iron regulation. Except that where that left me was again, where you two appear to be.

Perhaps the iron deposition in the brain cells is the result of the O's dying off and therefore unable to assist with iron metabolism? And that just brings us back to what, then, is causing the O's apoptosis? So......all in all, the iron deposition MOST LIKELY is an effect from a different cause and is probably happening later on in the cascade of events, not earlier. Which MIGHT, though, also perhaps HELP explain why it takes some time for MS to appear until later years. Again, notice the "age" factor in this. So, at the very least, PERHAPS this iron factor may be a part of what goes into determination of someone's "predisposition" to MS? Interesting..........

J Anat. 1995 Feb;186 ( Pt 1):165-73.



Transient expression of transferrin receptors and localisation of iron in amoeboid microglia in postnatal rats.


Kaur C, Ling EA.

Department of Anatomy, Faculty of Medicine, National University of Singapore.

The expression of transferrin receptors marked by the monoclonal antibody OX-26 and the localisation of iron were studied in amoeboid microglial cells in postnatal rats. Transferrin receptors were vigorously expressed in amoeboid microglia in rats ranging from 1 to 10 d of age but were undetectable in older rats. Thin serial sections showed that the OX-26 positive amoeboid microglial cells were also immunoreactive for OX-42 and ED1. Using Perls' medium, this study showed the presence of a considerable amount of iron in amoeboid microglial cells in 1-10 d rats. Most iron-containing cells were round but their number had diminished by 2 and 3 wk of age, when the iron was localised instead in some branched cells which were identified as either oligodendrocytes or ramified microglia cells. There has been much speculation on the functional significance of transferrin receptors on amoeboid microglia in postnatal rats. It is suggested that the receptors facilitate the acquisition of iron necessitated for various functions of amoeboid microglia in the developing brain. The presence of iron in some oligodendrocytes suggests their involvement in mediating iron mobilisation and storage. Its localisation in some ramified microglia in older rats indicates the possible role of these cells in sequestration and detoxification of iron in the central nervous system.
PMID: 7649811 [PubMed - indexed for MEDLINE]


I'm sure you guys ran across this same type of the next two abstracts that I'm going to post here, but I thought I'd just post them anyway.......strictly FYI. Not really to make any one "specific" point or anything. I personally have arrived at Robin's point. Interesting, iron MIGHT play a role (probably does), but just doesn't appear to be a HUGE "causal factor"....or at least not that I personally can see at this point. You can see, also, how I kept getting farther away from MS, and into Parkinson's and Alzheimers, which of course, are not to be made light of, but it just got too far away from MS and what we currently DO know is going on. Besides, (and Robin, I think you'll notice this........"), look where it starts to lead us back to again. The adrenals, huh? (Except, I will say again, though, that the focus that I have found in my earlier research on what may be exacerbating the problems in MS is norepinephrine, not dopamine. I'll post an abstract again that has been posted here previously, but perhaps it'll be easier to work it into this current scenario.) At that point, I said ok........enough of the iron research! :wink: At least for now. I've circled back around again. MY suggestion from all this? Everybody load up on antioxidants!

Exp Neurol. 1998 Aug;152(2):188-96.

Astrocyte mitochondria: a substrate for iron deposition in the aging rat substantia nigra.

Schipper HM, Vininsky R, Brull R, Small L, Brawer JR.

Lady Davis Institute for Medical Research, Sir Mortimer B. Davis Jewish General Hospital, Montreal, Quebec H3T 1E2, Canada.

Little is currently known concerning the cellular substrates for, and the mechanisms mediating the pathological deposition of, redox-active brain iron in Parkinson's disease. In various subcortical brain regions, populations of astroglia progressively accumulate peroxidase-positive cytoplasmic inclusions derived from effete, iron-laden mitochondria. In the present study, histochemical, ultrastructural, and elemental microanalytical techniques were used to demonstrate the existence of peroxidase-positive astroglia in the substantia nigra of adult rats. At 4 months of age and earlier, few GFAP-positive nigral astroglia contained small, electron-dense cytoplasmic inclusions which exhibited faint endogenous peroxidase activity (diaminobenzidine reaction product) and no detectable iron by microprobe analysis. In contrast, by 14-18 months of age, there was a significant, fourfold increase in numbers of peroxidase-positive astrocyte inclusions in the substantia nigra. The nigral gliosomes in the older animals were heterogeneously electron dense, immunoreactive for ubiquitin and a mitochondrial epitope, and often exhibited X-ray emission peaks for iron. Copper peaks were also detected in a minority of nigral gliosomes. Previous in vitro work indicated that the iron-mediated peroxidase activity in these cells promotes the bioactivation of dopamine and other catechols to neurotoxic free radical intermediates. Thus, mitochondrial sequestration of redox-active iron in aging nigral astroglia may be one factor predisposing the senescent nervous system to parkinsonism and other neurodegenerative disorders.
Copyright 1998 Academic Press.

PMID: 9710517 [PubMed - indexed for MEDLINE]


Cysteamine pretreatment of the astroglial substratum (mitochondrial iron sequestration) enhances PC12 cell vulnerability to oxidative injury.-

Frankel D, Schipper HM

Exp Neurol 1999 Dec;160(2):376-85.

Much of the excess iron reported in the substantia nigra of subjects with Parkinson's disease (PD) implicates nonneuronal (glial) cellular compartments. Yet, the significance of these glial iron deposits vis-a-vis toxicity to indigent nigrostriatal dopaminergic neurons remains unclear. Cysteamine (CSH) induces the appearance of iron-rich (peroxidase-positive) cytoplasmic inclusions in cultured rat astroglia, which are identical to glial inclusions that progressively accumulate in substantia nigra and other subcortical brain regions with advancing age. We previously demonstrated that the iron-mediated peroxidase activity in these cells oxidizes dopamine and other catechols to potentially neurotoxic semiquinone radicals. In the present study, we cocultured catecholamine-secreting PC12 cells (as low-density dispersed cells or high-density colonies) atop monolayers of either CSH-pretreated (iron-enriched) or control rat astroglial substrata. In some experiments, the PC12 cells were differentiated with nerve growth factor (NGF). The nature of the glial substratum did not appreciably affect the growth characteristics of the PC12 cells. However, undifferentiated PC12 cells grown atop CSH-pretreated astrocytes (a senescent glial phenotype) were far more susceptible to dopamine(1 microM)-H2O2(1 microM)-related killing than PC12 cells cultured on control astroglia. Differentiated PC12 cells behaved similarly although the fraction killed was about half that seen with the undifferentiated PC12 cells. In the latter experiments, PC12 cell death was abrogated by coadministration of the antioxidants, ascorbate (200 microM), melatonin (100 microM), or resveratrol (50 microM) or the iron chelator, deferoxamine (400 microM), attesting to the role of oxidative stress and catalytic iron in the mechanism of PC12 cell death in this system. The aging-associated accumulation of redox-active iron in subcortical astrocytes may facilitate the bioactivation of dopamine to neuronotoxic free radical intermediates and thereby predispose the senescent nervous system to PD and other neurodegenerative disorders.


Neurobiol Dis. 2004 Mar;15(2):331-9.

Astrocytic beta2-adrenergic receptors and multiple sclerosis.

De Keyser J, Zeinstra E, Wilczak N.

Department of Neurology, University Hospital Groningen, Groningen, The Netherlands. j.h.a.de.keyser@neuro.azg.nl

Despite intensive research, the cause and a cure of multiple sclerosis (MS) have remained elusive and many aspects of the pathogenesis are not understood. Immunohistochemical experiments have shown that astrocytic beta(2)-adrenergic receptors are lost in MS. Because norepinephrine mediates important supportive and protective actions of astrocytes via activation of these beta(2)-adrenergic receptors, we postulate that this abnormality may play a prominent role in the pathogenesis of MS. First, it may allow astrocytes to act as facultative antigen-presenting cells, thereby initiating T-cell mediated inflammatory responses that lead to the characteristic demyelinated lesions. Second, it may contribute to inflammatory injury by stimulating the production of nitric oxide and proinflammatory cytokines, and reducing glutamate uptake. Third, it may lead to apoptosis of oligodendrocytes by reducing the astrocytic production of trophic factors, including neuregulin, nerve growth factor and brain-derived neurotrophic factor. Fourth, it may impair astrocytic glycogenolysis, which supplies energy to axons, and this may represent a mechanism underlying axonal degeneration that is hold responsible for the progressive chronic disability.

PMID: 15006703 [PubMed - indexed for MEDLINE]


Robin, note the word "astrocytes"..........there are your microglial connections.

And for those who aren't certain about astrocytes in layman's terms, here's a quick definition:

astrocytes
The largest and most numerous neuroglial cells in the brain and spinal cord. Astrocytes (from "star" cells) are irregularly shaped with many long processes, including those with "end feet" which form the glial (limiting) membrane and directly and indirectly contribute to the blood-brain barrier. They regulate the extracellular ionic and chemical environment, and "reactive astrocytes" (along with microglia) respond to injury. Astrocytes have high- affinity transmitter uptake systems, voltage-dependent and transmitter-gated ion channels, and can release transmitter, but their role in signaling (as in many other functions) is not well understood.


Although, I MIGHT beg to differ about how well "understood" they are these days. hehehe.........I think we're well on our way, don't you? :wink:

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Postby OddDuck » Fri Nov 19, 2004 5:55 am

Robin: And here I said I was trying to stay away from "epics".....hard, isn't it?

Wesley: I still say that the fact that females have different hormones going on, is what may play a big role in the gender ratio of MS. Add that in, also, with your epigenetics theories as Robin just pointed out, and I bet it works in there somehow.

What did I find and post earlier somewhere about possible factors that may help explain the gender ratio? I posted something somewhere here on this website (an older thread).

Was it something regarding progesterone, perhaps? Hmmmmmm......can't recall at the moment.

But, like Sharon points out often with her research, the hormonals seem to work right in there, also. I'm just not certain exactly where, but there are still big "gaps" in the MS cascade, so I'll bet anything it fits in there somewhere.

Perhaps Sharon can chime in here and refresh us on her thoughts! (We may want to consider starting a new thread now, too, but I'll leave that up to "vote" amongst everybody.)

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Postby raven » Fri Nov 19, 2004 7:57 am

Just a quickie as I'm kinda busy today..

Deb, I remember you posting about green tea somewhere. I couldn't see the thread to add to it so I thought I'd post here as it's relevant here as well.

Green tea contains high concentrations of flavinoids. According to the following article flavinoids inhibit MMP-2 and MMP-9.

<shortened url>

Guess who's off to buy some green tea later... :wink:

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Postby bromley » Fri Nov 19, 2004 2:28 pm

Dear all,

Most of what has been discussed has gone way above my head - I understood the green tea bit.

Some questions - lots of references to grey matter and brain atrophy. I assume that 'grey matter' means brain cells. Why do they not get replaced (like skin cells etc)? What replaces them - what fills the hole?

References to stem cell research always seems to refer to the myelin making cells. Is any research going on into how grey matter (brain cells) might be replaced?

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Postby OddDuck » Fri Nov 19, 2004 6:45 pm

Bromley,

I assume that 'grey matter' means brain cells.


No, not exactly. Every part of our body contains "cells". Using the term " brain cell" means nothing specific, it just means cells located in the brain. Grey matter is a term for a specific type of biological tissue (for lack of a better layman's description). The term "brain cells" is a very broad term.

If actual "cells" located within the brain die (which there are many types of cells), they usually aren't replaced on their own. (Remember when we were teens, how they drilled into our heads that every time we drank, we killed some brain cells, which couldn't be replaced?) Brain "cells" do not regenerate very well on their own when they are damaged. When they are lost, they are usually lost. NOW, having said that, there is VERY recent research that shows that it may be possible to help brain cells regenerate (i.e. stem cell research, for one). And it has been shown in recent years that the body does make an attempt to repair brain cells that are lost, but usually the cause of why they were lost in the first place is also what keeps preventing the body from repairing the cells. Also, remember, brain cells normally die irreversibly as a result of actual physical brain trauma, or stroke, for example.

What happens in MS is that myelin is destroyed, which eventually leads to axonal damage (and in some patterns of MS, it is now thought that axon destruction may also be happening without demyelination.) This "damage" is primarily happening in the "transmission" functions of our bodies (i.e. white matter portions). It all depends on where MS just happens to strike someone.

Here's an article that to me shows a more positive way of looking at MS:

Brain Produces New Cells in Multiple Sclerosis
For release: Tuesday, February 26, 2002

Overview The brain produces new cells to repair the damage from multiple sclerosis (MS) for years after symptoms of the disorder appear, according to a recent study. However, in most cases the cells are unable to complete the repairs. These findings suggest that an unknown factor limits the repair process and may lead to new ways of treating this disorder.

The brain produces new cells to repair the damage from multiple sclerosis (MS) for years after symptoms of the disorder appear, according to a recent study. However, in most cases the cells are unable to complete the repairs. These findings suggest that an unknown factor limits the repair process and may lead to new ways of treating this disorder.

"The brain is making a serious attempt to repair the damage," says Bruce D. Trapp, Ph.D., of the Cleveland Clinic Foundation in Ohio, who led the study. The findings are consistent with those of other recent studies showing that the adult brain has the capacity to replace cells, he adds. The study was supported by the National Institute of Neurological Disorders and Stroke (NINDS) and appears in the January 17, 2002, issue of The New England Journal of Medicine.

In patients with multiple sclerosis, brain inflammation in random patches, or lesions, leads to destruction of myelin, the fatty covering that insulates nerve cell fibers called axons in the brain and spinal cord and aids in transmission of signals to other neurons. This inflammation causes the myelin to deteriorate and leads to the symptoms of MS. Previous studies have shown that some brain lesions are repaired during the early years of multiple sclerosis. However, many other lesions are not repaired.

In the study, Dr. Trapp and colleagues examined brain tissue obtained during autopsies of 10 patients with MS to see if new myelin-producing cells, called oligodendrocytes, were being produced in the chronic MS lesions. They found that most of the lesions contained newly produced oligodendrocytes. The percentage of lesions from each brain that had these new cells decreased as the duration of the disease increased, but the decline was not related to the type of MS the patients had or to their ages at death. The new oligodendrocytes extended "arms" that produced myelin-related proteins and grew around the damaged axons as if they were trying to repair the myelin. However, in most cases the axons were not repaired.

One of the central questions in MS research is how to promote myelin repair. Many researchers have concentrated on increasing the number of oligodendrocytes through stem cell transplantation or other means. However, this study suggests that problems with the axons or with the tissue that surrounds them may prevent remyelination. Many of the axons that were not remyelinated looked abnormal, whereas remyelinated axons appeared healthy. This suggests that therapies which prevent axon degeneration or help oligodendrocytes complete the repair process in other ways may be necessary. More research is needed to identify drugs that may be useful for this purpose, says Dr. Trapp. While the study shows that the brain's attempts to repair itself decrease over time, new cells were produced even in patients who had had MS for as long as 15 years, implying that there is a long window of opportunity for treatment.

Researchers must now determine how long the new oligodendrocytes survive in the brain and whether the brain can produce enough of them to repair all the damage from MS, says Dr. Trapp. If the brain produces enough new cells on its own, then transplantation of additional cells may not be necessary. Research using brain scanning or other techniques may help to identify patients who are most likely to benefit from these therapies.

Reference: Chang A, Tourtellotte WW, Rudick R, Trapp BD. "Premyelinating oligodendrocytes in chronic lesions of multiple sclerosis." The New England Journal of Medicine, Vol. 346, No. 3, January 17, 2002, pp. 165 - 173.

- By Natalie Frazin

Date Last Modified: Wednesday, November 10, 2004


NOTE: I only chose this particular abstract to post because it was written in pretty understandable terms, I thought. I personally have found over and over from many other researchers the same thoughts as is contained in the above article.

Basically, the answer to your question as to why the "myelin" is not replaced when destroyed in MS, is because the oligodendrocytes THEMSELVES are also being destroyed or are dying (i.e. apoptosis). And it's the O's that do the remyelination. (Of course, this is putting it very simply.)

There are different areas of the brain and spinal cord that consist of different types of tissue or matter......different consistencies, sort of, and they perform different functions. Those different types of matter (i.e. gray or grey, or white) do different things for us, and also their biological "makeup" is different.

Here's a description of gray matter:

Grey matter
From Wikipedia, the free encyclopedia.

Grey matter is a category of nervous tissue with many nerve cell bodies and few myelinated axons.


Grey matter looks reddish grey on a freshly removed brain. It forms the superficial parts of the brain and the deep parts of the spinal cord. It is composed of the bodies of the nerve cells (neuron) and the initial parts of its processes (axons and dendrites) just emerging from the neurons. Grey matter is the major part of the nervous system in which the nerve impulses for all kinds of mental functions are produced and then sent away to be carried to their target organs by white matter.

The cerebrum and the subcortical nuclei, such as the putamen and the caudate, are composed of grey matter.

Generally, grey matter can be understood as the parts of the brain responsible for information processing; whereas, white matter is responsible for information transmission.


Here's white matter (it's just a flip from the gray, of course):

White matter
From Wikipedia, the free encyclopedia.

White matter is one of two categories of tissue in the nervous system. It forms the deep parts of the brain and the superficial parts of the spinal cord. It is composed of nerve cells processes (axons and dendrites) that connect various parts of the brain to each other and carry nerve impulses to or from the bodies of nerve cells (neuron). It differs from gray matter in that its neurons are covered with myelin.

Generally, white matter can be understood as the parts of the brain responsible for information transmission; whereas, gray matter is responsible for information processing.


Your cerebellum (at the base of the back of your skull) is like the main "computer" for your body. It does most of the processing and sends messages to other parts of the brain. Those various parts of the brain then send messages (transmission) to other parts of your body.

Multiple sclerosis is primarily a demyelinating disease; therefore, existing mainly in the white matter (affecting "transmission" of information from the brain). What happens when the myelin has degraded is that the body tries to replace the myelin with what is called a "plaque" (i.e. hard tissue like a "scar") Sclerosis, of course, means "scarring". The problem with that is that the "plaque" does not transmit information like the myelin does. So anyway, you can think of the answer to your question of what replaces the dead brain cell is that the scar tissue replaces it.

Now, you will also hear some comments now and again about "black holes". That is a descriptive word that refers to the image that the MRI may pick up sometimes in some people. It simply means that at that particular spot on the brain, nothing shows there. That doesn't mean something isn't "there", they just don't know what is. It isn't picked up. Brain tissue is very "odd" in a way. The medical world has a strange sense of humor, I guess you could say. They tend to use analogies in relationship to astronomy. Did you know that they sometimes refer to a spot on a brain scan as a "UBO"? Meaning "unidentified bright object". (Odd people, those medical folks are. hehehe.......)

Now, atrophy is simply loss of "bulk" or size. Here's something that may ease your mind somewhat about worrying OVERLY much about brain atrophy:

Atrophy and cell loss
The relationship between atrophy and the loss of oligodendrocytes, axons and neurones may not be linear. One post-mortem study (Pakkenberg and Gundersen, 1997) in previously healthy subjects reported that an age-related 9.5% reduction in neurone number was associated with a 12.3% reduction in neocortex volume and 28.0% reduction in WM volume. Whereas such a reduction in WM volumes with age is not universally supported by in vivo MRI studies and fixation artefacts may modify in vitro findings (Miller et al., 1980), the study highlights that there may be tissue-specific differences in atrophy and that atrophy might not reflect truly the extent of axonal and neuronal loss: the degeneration of other cell types may also contribute to volume loss. In addition, as noted above, in multiple sclerosis volume loss may be masked by oedema, cellular infiltration and proliferation. Furthermore, axonal and neuronal atrophy associated with demyelination has been reported (Yin et al., 1998) and, given that remyelination occurs (Prineas and Connell, 1978; Kornek et al., 2000), this effect may be reversible. Serial studies would help to clarify the temporal variability in atrophy, including the degree of reversibility.


Of course, the preferable thing to do is prevent any of this damage from happening in the first place. And yes, that's what ALL of the research that is going on right now is doing. There is research going on from all perspectives and at all points during the MS "cascade" of events.

That's why you will see me refer to the "front end", the middle, or the "back end" of the MS cascade. Wesley is primarily interested in what the causal relationships may be that causes MS in the first place (the front end). Robin and Sharon and I all tend to find research of interest that helps to clarify what is happening once the MS process has started (the middle). Then the "back end" as I refer to it, is the therapy or treatment part. That's where I usually end up concentrating on. That's the pharmacology part. (But of course, you'll see us all jump around all over the place....sometimes we'll speculate on cause - such as viruses, toxins, etc. - sometimes we'll research and hypothesize on the process itself to see if there are any areas where the "domino effect" can be interrupted before too much damage has been done, and sometimes we'll touch on treatments.)

Believe me, research is going on regarding ALL of our, and your, concerns. The problem is so much is unknown.

Well, anyway, I'm sorry this got so lengthy. Does it help at all, or did I only make it worse? :?

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Postby BioDocFL » Fri Nov 19, 2004 7:03 pm

Bromley,

What we are arguing, and modeling, with our discussions of hypotheses is that there should be open discussion by everyone who has knowledge or a stake in the study of MS. There are probably plenty of people 'lurking' out there, reading these posts, who could contribute in some way. If we can put a new thought into someone's head, someone who can do research on it or fund the research on a particular aspect, then good. There are classes taught now at some universities (UNC for one I think, Bio165?) where they teach advanced courses on how to develop hypotheses on medical problems and then to come up with the experiments to test the hypotheses. I think it will put the 'fear of God' into some future MD's and PhD's to see what some of the 'laymen' (and women!) can come up without the glorious 'white coats'. What we are doing here is somewhat similar except that we have people who are more motivated and have more knowledge (personal and literature based) to develop hypotheses. And it is a dynamic process. We aren't going to turn it in at the end of the semester and walk away from it. I can speak for myself and perhaps others, my ego isn't in this but my interest and compassion are. (Well, maybe a little ego, but I can overlook it if someone questions my theory 3 threads over, 57 posts back, line 7. I'm bigger than that.)
I have made comments in previous posts, somewhat aimed at you, to get you involved in researching some ideas and learning. I hope you aren't offended but I have always found that doing something, anything, is best when confronted with uncertainty. You have actually contributed quite a bit already by representing so many of those lurkers who feel this has gone over their heads, or they are perhaps overwhelmed (temporarily) by a recent diagnosis of MS. It is the uncertainty that is the biggest problem I think. The aches and pains, the memory problems, the depression, are not solely MS problems. We are going to get some of those with age even without MS, perhaps not as severe, perhaps more so. It is the uncertainty that is the biggest problem with MS I think. So join us and work on it.

Keep asking us questions though because it helps us think better when we realize there are vague points we need to explain better. Thanks,

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Postby OddDuck » Fri Nov 19, 2004 7:14 pm

Oh, and Robin!

Yea....You have probably seen many posts of mine where I mention green tea here and there. HAH!

Be sure to get the green tea without all that added stuff in it, like lemon grass and stuff. I personally found that the best grade pure green tea bags are supposed to have the most "whatcha-ma-jiggers" in it....you know the polyphenols or whatever they are called.

:wink:

I swear, also........since I've been drinking green tea, which has been a few years now, I have not had ONE cold NOR picked up a flu bug since! I swear it's the green tea! :D

Deb

EDIT: Oh, yea.............and personally, I again support everything Wesley just posted. Great post, Wesley!
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Postby Sharon » Fri Nov 19, 2004 9:54 pm

Great information! Thanks to all of you.

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Postby JFH » Sat Nov 20, 2004 2:11 am

Well guys when I took the "Show me posts since your last visit" option and saw still more activity on this thread I very nearly skipped it - so much of the bio-talk flys past me - but clearly I came back, I'm nothing if not persistent! And so well rewarded!!! :D A fantastic posting Deb well done and thankyou. You got in there all and more of what I've started to learn about since my dx in July in language accessible but not patronising (should that be matronising ??). I even know now what an oligodendrocyte is.

Aaron how about copying Deb's posting to the FAQ area?

[EDIT:: Isnt oligodendrocyte a cool word :) ]

[2nd EDIT:: Decaffinated green tea doesnt taste any different to its insomnial relative - to me anyway. Anyone know if it has different beneficial properties?]
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Postby raven » Sat Nov 20, 2004 3:44 am

JFH,

Stay with us! If there's something that you don't understand or want explained in simpler terms then please ask. I, and I'm sure the others will be more than happy to go back over things. It will help us to put our own thoughts in order as well as expaining things.

The more people who participate in this discussion and ones like it, the better.

I'm afraid I can't answer your question about green tea. The only times I have drunk it are when I was in Japan. I'm sure Deb will have some info though...

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Postby JFH » Sat Nov 20, 2004 4:31 am

Kind thoughts Robin thankyou.

This might go a little off topic from this thread, apols in advance.

What is the proportion of grey matter to white matter in the brain? I ask because one thing in particular has niggled away and I cant seem to find the answer. There are, I am told, about 11,000,000,000,000 neurons in my head (I might have got the 000 count wrong but its shed loads anyway) each of which makes an average about 10,000 connections with other neurons. MRI scans count lesions in ones and twos, tiny by comparison. [Does a lesion span 00s or 000s of neurons, if so why clustering?] So why then does MS exhibt symptoms of such similarity across the range of us that have it? :? If the damage to the brain was random with respect to the area effected then one would expect quite a wide diversity of visible effects, or not? I asked this question of my neurologist in an early visit when we hadnt quite got the measure of each other and he gave me a short answer that said somehing like "it's all in the white matter". But unless the proportion of grey to white is huge surely the same question still applies. From any one neuron's viewpoint the white matter must seem universally big - so why do I and 000's of others have bladder, bowel, erectile, motor, optical, aural etc etc dysfunction. (Ok its a longish list but not comprehensive in coverage of human activity, or is it?)

Apols again if this is a really dumb bio-question, but pointers to the solution to this conumdrum for me much appreciated.
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Postby raven » Sat Nov 20, 2004 5:33 am

John,
An excellent question! There are many more neurons in the brain then there are axons within the white matter. I don't have the exact proportion but will try and find it for you later. Neurons make many connections amongst themselves. This is the processing center of the brain. In order to 'talk' to the rest of the body nerve impulses travel along the axons and down the spinal cord. Because these connections are disproportionately long compared to neuron-neuron connections the axons are insulated with myelin. This insulation helps to maintain and speed up the nerve impulses.

A lesion may involve many axons. The reason for this clustering is lesions appear around blood vessels within the brain. Breakdown of the blood-brain barrier at these points causes the inflammation and demyelinisation seen on MRI scans.

What has become apparent, and the reason for this whole thread is that damage is not confined solely to these lesions but also affects neurons and axons which under MRI appear normal.

As to why MS affects bladder, bowel, erectile, motor etc. function. these functions are controlled from the brain vis axons through the spinal cord (lesions also appear in the spinal cord). As such they are the most likely functions to be affected. The autonomic functions (breathing, heartbeat etc.) are controlled by a different mechanism and are extremely rarely affected. The optic nerve is also affected as it is also myelin coated.

What I have written is very simplified. I will attempt to find a more complete explanation when I have time and post it here.

Robin

EDIT: There is a 1:1 relationship between neurons and axons. The axon is a part of the neuron that is it's 'output mechanism' I might have been a bit misleading in the beginning of this post. What I meant to point out is that not all axons are myelinated.
Last edited by raven on Sat Nov 20, 2004 8:23 am, edited 1 time in total.
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Postby bromley » Sat Nov 20, 2004 5:44 am

OddDuck and co,

Thanks for the info on grey matter. My concern - as you probably guessed - is how much can we lose. We hear about memory loss and I'm not sure how this relates to grey matter loss.

On a different point - how does ms relate to other diseases eg Altzeimers and Parkinsons (and MND). In the case of Altzeimers I've read than plaques are involved. In the case of Parkinsons I seen reference to pre-programmed cell death - of a particular cell. Are the researchers on these diseases looking for links? Can MS lead to the death of the cells involved in Parkinsons - I've seen tremor listed as an MS symptom. Also- I've seen dementia mentioned in some ms articles - the classic Alzeimers symptom.

Sorry I cannot help out with the more scientific discussion (history and accountancy are my specialisms) - but I hope that some of the simple questions I ask will be of benefit to those like me.

Another quick point - minocycline seems to offer all sorts of benefits - maybe nero-protective; anti-inflammatory and possibly useful if bacteria is involved at the outset. So why isn't a larger trial taking place (I see that it is being trialled with Avonex)? Do we not need to start petitioning the ms societies to fund such work and to pick up on the work set out above? Many of you must rank alongside the best ms researchers in terms of knowledge and willingness to come at this from a different angle (Edward de Bono would be proud of you). But we need to make sure that the ideas above are not forgotten - I would have thought that a professor of neurology looking for a Nobel prize would do well to pull together the excellent ideas exchanged above.

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Postby OddDuck » Sat Nov 20, 2004 5:57 am

Good morning!

John, thank you for your kind words!

First off, decaffeinated green tea has the same properties. My understanding is that removing the caffeine doesn't affect its benefits.

And those are good questions, John!

Ok.....proportional relationships of grey matter and white matter. That varies between people due to genetics. There is a lot of research indicating that grey matter also has a relationship with IQ (i.e. the more grey matter someone happens to have, the likelihood of higher intelligence). That probably just goes along with what we have talked about earlier here. The fact that grey matter is where "processing" is done, whereas white matter is where "transmission" is done. There also appears to be some variation of grey matter between genders. Here's one abstract I found sort of interesting:

Neuroreport. 2002 Dec 3;13(17):2371-4. Related Articles, Links


Brain size and grey matter volume in the healthy human brain.

Luders E, Steinmetz H, Jancke L.

Department of Neurology, Johann-Wolfgang- Goethe University Frankfurt am Main, Germany.

Magnetic resonance imaging was used to evaluate the influence of sex and brain size on compartmental brain volumes (grey matter, white matter, CSF) in a large and well-matched sample of neurologically normal women (n = 50) and men (n = 50). As expected, we found a significant sex difference for the absolute volumes of total brain, grey matter, white matter and CSF, with greater volumes for men. Relating these compartmental volume measures to brain volume resulting in proportional volume measures revealed a higher proportion of grey matter in women. No significant sex differences were found for white matter and CSF proportions. However, when the influence of sex was partialized out by regression analyses, brain volume explained 40-81% of the variance of the absolute grey matter, white matter and CSF volumes. Performing these regression analyses for the proportional volume measures revealed that brain volume explained approximately 16% of the variance in grey matter proportion. Sex or the interaction between sex and brain volume revealed no additional predicitve values. Interestingly, the correlation between brain volume and grey matter proportion was negative, with larger brains exhibiting relatively smaller proportions of grey matter. Thus, sex is not the main variable explaining the variability in grey matter volume. Rather, we suggest that brain size is the main variable determining the proportion of grey matter.

PMID: 12488829 [PubMed - indexed for MEDLINE]


Proportionally, there is more white matter than grey matter. Here is a visual of the grey and white matter in the brain:

http://health.allrefer.com/health/white ... -info.html

Ok....now even though symptoms DO vary widely between people with MS, there is a tendency for symptoms associated with the disease to be of a certain group. The best explanation for that is because MS mainly is concentrated in the white matter and seems to mainly target myelin, axons and the oligodendrocytes (we'll leave it at that for simplicity). And even though MS "may" cause damage in other areas (hence you will find individuals with MS who have more rare types of symptoms now and again), the fact that MS seems to concentrate in specific areas of the white matter in the brain and spinal cord, MAIN symptoms of the disease tend to be identifiable and common between sufferers.

Now......the MRI. Again, the standard MRI, I hate to say, is not that good at creating a picture of the inside of the brain. You are correct in your mathematical musings about just how good of a snapshot are they getting with an MRI anyway? It's not the best, but it's better than anything we've had in the past. In layman's terms, all in all, it's still a pretty "fuzzy" picture. Think of it this way as a comparison of what the brain really looks like and what an MRI "snapshot" shows. We've all seen diagrams of the brain, and probably in science class have even seen the real thing. It's got all those ridges and bumps, and peaks and valleys. What do you see on an MRI film? It doesn't pick up a very "clear" picture of the true brain, does it? There is a LOT of guesswork going on by the person reviewing the films. That's why you can take your films to several different neuros, and they all might "see" or not see something different. That's also why it takes such "special" education to learn HOW to read them. If they were clear enough and showed excellent detail, anybody could read them and there wouldn't be so many differing opinions when interpreting them. But again, having said that, they still are the best we have in practical use right now. It wasn't that long ago when they couldn't see a THING inside the skull.

Which brings me back to my excitement earlier in this thread about the newer MRIs and MRS, etc. which apparently can now even pick up some details of the grey matter.

I hope this helps.

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Postby raven » Sat Nov 20, 2004 6:11 am

Hey, another excellent question! As I'm on UK time I'll attempt to give some answer to this as well. I'm sure the others will pile in later. Wakey wakey Deb! :lol:

Firstly the connection between MS and the other neurological disorders is unknown. In particular alzheimers syndrome seems to be fairly closely related to MS. Alzheimers also involves inflammation and plaques but seems to affect the grey matter much more than the white. Parkinsons involves neuron death within a particular part of the brain, the substantia nigra. All of these conditions appear to have a genetic component triggered by environmental factors.

Whilst the connection between the diseases is unknown, certain treatments appear to cross the boundaries and can be effective in more than one. For example minocycline is being investigated as a treatment for both parkinsons and alzheimers.

Why aren't there more trials for minocycline and some other drugs (desipramine perhaps :wink: ). The answer is money. Clinical trials are expensive. As these drugs are out of patent there is no real reward for the drug companies to pursue them. However Serono are working on a derivative of Minocycline because they will be able to patent it.

All we can do is, as you suggest, lobby as hard as we can for more trials of these cheap and effective treatments.

Robin

EDIT: It seems that while writing this Deb has surfaced! Good morning Deb! :D
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