The following has been shown in peer reviewed research (i.e. I'm not theorizing):
1) Exposure to bacterial toxins in the womb has three effects
a) lower density of dopaminergic neurons in the substantia nigra
b) changes to endocrine system that makes the stress response poorly controlled
c) changes to immune system that increases system inflammation and also sets up a hyper-reaction in the brain itself to future toxins of the same type

2) b and c above both tend to open the BBB particularly when stress or illness are a factor

3) the bacterial toxin (LPS) is always present in the body so when the BBB leaks LPS entere the brain and the hyper-reaction in c above is triggered and neurons are destroyed by the immune system

4) throughout all this the immune system is producing chemicals (cytokines) and so is the endocrine (corticoids) - both enter the brain and damage nerve tissue. Both are also neuroactive and interfere with brain function

after a few decades of this PD is born

Joop,
Dank U wel, Ik kan alleen een beetje Nederlands spreken.
First why are you surprised that substances like homocystine which damages the BBB, affects other illnesses besides PD? Most substances have one or more substantial effects on a particular illness, as well as lots of side effects on other illnesses.
For example, hypertension drugs which are normally used to lower blood pressure, also reduce the BBB permeabilty, and have been shown to be of value in PD.
Again, you say,
"Further heavy metals are known to interfere with the BBB. They are also associated with lots of neurological disorders."
This is what we would expect if the theory is correct. It goes for many other toxic compounds, like pesticides.
You say why does a PWP have a defective BBB? But why do some people have a defective heart, a defective lung , kidney etc. It is presumably the luck of the draw. Why are some people fair and others darK?
Normally with a healthy BBB, levodopa can pass, carbidopa can't.
This fits in with the fact that levodopa has the lower molecular weight. The solubility of the molecule is critical also. Low molecular weight molecules which are fat soluble can pass the BBB. The difference may be small, but carbidopa has a -NH-NH2 group that levodopa hasn't. This will make carbidopa more polar, less fat soluble, and less able to cross the BBB.
Hope this helps
Ron
PS THere is something we can do to put this theory to the test.
Take a group of PWP with ascending PD progression, and measure their BBB permeability (This can be done).
If the theory is correct, we should get a table where the newly diagnosed has the lowest BBB permeability, and the most advanced PWP has the highest.

Ron,
No I’m not surprised that homocysteine is associated with several neurological disorders. In fact it suggests that a common factor is behind all this. Such a factor could be the widening of the BBB. But homocysteine is correlated with more than just that. This gives rise to the idea that the course is some mechanism in homocysteine-metabolism.
Next heavy metals play the same role. They are associated with the BBB and with neurological disorders. You may conclude that damage of the BBB is the common factor, but that does not convince me yet. Both heavy metal intoxication and elevated homocysteine levels are associated with a large number of diseases that are not neurological.
What I’m looking for is fundamental process, a chemical reason that explains why the BBB is insulted by homocysteine or heavy metals or pesticides. There is a process that is involved in all this and it is called methylation. This is the attachment or substitution of a methyl group And the big difference between levodopa and carbidopa in this respect is not the -NH-NH2 group that levodopa hasn't, but the methylgroup that levodopa hasn’t.

Joop

Hi Joop,

Are you saying that methylation is the process which is involved in all the processes of degeneration or improvement of symptoms of PD?
I accept that carbidopa has a methyl group and levodopa hasn't, and this could be the reason why carbidopa can't pass a healthy BBB whilst levodopa can. I don't think that has any bearing on the BBB permeability theory however. How do you explain by methylation that whilst levodopa can pass a healthy BBB, dopamine can't. There is no methyl group involved here. The only difference is a molecule of carbon dioxide. The difference between the two compounds is very small, yet one can pass, the other can't.
What I am saying is substances or treatments which widen the permeability of the BBB cause an exacerbation of symptoms, such as stress or carbon monoxide etc. How can you explain it is due to methyl groups in cases such as these. Look at my list of questions and answers and try to give answers for all based on methyl groups.
Joop, you say, " You may conclude that damage of the BBB is the common factor, but that does not convince me yet."
I despair of convincing anyone, particularly the medical profession. How much evidence do people need.
1. Your Dutch professor Leenders has shown that PWP all have defective BBB's.
2. Every substance, or treatment I have examined that widens the permeability of the BBB causes an exacerbation of symptoms. Stress, carbon monoxide, pesticides, organophosphates, old age etc
3. Every substance or treatment that I have examined that reduces the permeability of the BBB causes an improvement in systems. curcumin, alpha lipoic acid, CDP choline, hypertension drugs etc.
4 The BBB is implicated in a number of neurological diseases, eg Alzheimers, MS and Chronic Fatigue Syndrome.
The medical profession could so easily and cheaply test this theory. The BBB permeability (BBBP) of a living person can be measured. So take a healthy person and measure his BBBP. Take a group of PWP with years since diagnosis of 1, 2,5, 8, 10, and 15 years, and measure their BBBP.
If you get a correlation, (the healthy person is lowest BBBP and the 15 year is highest, with the rest in ascending order), it is proven.
Then you also have a scientific method of diagnosing PD, instead of winding his arm around looking for cogwheel rigidity. This is the 21st century isn't it??? Then direct all your research to a way of repairing the BBB. Stop drilling holes in peoples heads!!
This project could surely be completed for below $0.5m. Yet hundreds of millions have been spent, and where are we?
There should be a film made in the "Carry on" series called "Carry on Suffering"!!!!
Joop, I am grateful for your input, and Rick and others, it feels as though I am not alone. At least you are putting thought into the matter, but I wish we could get somewhere. We are all getting older, and our BBBP is getting wider by the day.
Ron

I've attached a chart that might interest some of you and just might make something fall into place. It is an attempt to list everything Anne Frobert and I have found linked to PD and to show the various relationships. Very incomplete but I'm open to suggested additions. Methylation isn't on it yet, for example.

The BBB has a role in a lot of it. All? Who knows.

Attached Thumbnails

 

Ron, Reverett,
it takes me a while to prepare an answer. The difference between l-dopa and dopamine is a carboxyl-group (COOH). Because of this group l-dopa can easily be methylated and transported through the BBB. I'm discussing this issue with a Dutch chemistry researcher. I'm still not sure how exactly this works. What I do know is that some Metals can be methylated (e.g., mercury, arsenic, lead, selenium, and tin) and that methylation enables them to cross the blood-brain barrier.
Joop

Given that inflammation opens the BBB, that PWP have an unusual immune response to LPS, and that metals play such a role in PD, this caught my eye,

1: Clin Exp Allergy. 2007 May;37(5):743-51.

Lipopolysaccharide promotes and augments metal allergies in mice, dependent on
innate immunity and histidine decarboxylase.

Sato N, Kinbara M, Kuroishi T, Kimura K, Iwakura Y, Ohtsu H, Sugawara S, Endo Y.

Department of Fixed Prosthodontics, Graduate School of Dentistry, Tohoku
University, Sendai, Japan.

BACKGROUND: Few adequate murine models exist for metal allergies, it being
especially difficult to induce Ni allergy in mice. OBJECTIVE: We examined the
effect of lipopolysaccharide (LPS) on allergies to Ni and other metals in mice.
METHODS: Ten days after sensitization with a metal salt and LPS, the ears were
challenged with the same metal salt. RESULTS: LPS+NiCl(2) (1 mM) was effective at
sensitizing mice to Ni, LPS being effective at very low concentrations whether
injected intradermally or intraperitoneally. The ear-swelling response to Ni was
more severe and more rapid in C57BL/6 mice than in BALB/c mice. In
mast-cell-deficient mice, TNF-alpha-deficient mice, and interestingly even in
nude (T cell deficient) mice, NiCl(2)+LPS induced a Ni allergy similar in degree
to that in the respective control mice, but it induced Ni allergy only weakly in
TLR4-mutant mice, macrophage-depleted mice, and IL-1-deficient mice. The activity
of the histamine-forming enzyme histidine decarboxylase (HDC) in the ears
increased in parallel with ear swelling, and HDC-deficient mice were resistant to
ear swelling. Challenge with NiCl(2)+LPS augmented ear swelling (vs. NiCl(2)
alone). LPS induced effective sensitization to other metals (Cr, Co, Pd, or Ag).
CONCLUSIONS: These results indicate that in mice, LPS is a very important inducer
of metal allergies, and potently promotes them (dependent on both innate immunity
and HDC induction in cells other than mast cells). We discussed the idea that the
bacterial environment is important for the establishment of metal allergies and
for their provocation, and that the current thinking (including the contribution
of T cells) should be reappraised in future studies.

PMID: 17456222 [PubMed - indexed for MEDLINE]

Joop,
I am not convinced that methylation has anything to do with the BBB theory that I have outlined. I have pointed out that levodopa can pass the BBB, whilst dopamine can't, and no methyl group is involved.
" How do you explain by methylation that whilst levodopa can pass a healthy BBB, dopamine can't. There is no methyl group involved here. The only difference is a molecule of carbon dioxide. The difference between the two compounds is very small, yet one can pass, the other can't."
You replied, "The difference between l-dopa and dopamine is a carboxyl-group (COOH)." However this is just repeating what I said, with no reference to methylation. There is no methyl group involved, levodopa is converted to dopamine by decarboxylation, ie losing a molecule of carbon dioxide, and this simple act is enough to convert the levodopa into a molecule, (dopamine), incapable of crossing the BBB.
I agree metals can be methylated, but have you references to show this enables them to cross the BBB. If when methylated, they can be proved to increase the permeability of the BBB, as well as exacerbating the symptoms of PD, then this will be relevant to what I am proposing. They can be added to the list of things which do this, eg pesticides, carbon monoxide, organophosphates, old age and stress.
It would be helpful if you if you could show your Dutch researcher this complete thread, and get his opinion on the possible correlation between BBB permeability and PD. Also, thanks again for your input, it is only by questioning an idea that we can progress.
Rick,
Thanks for your input also. There is a link with inflammation, and our favourite supplement(s) eg curcumin are also anti inflammatory in addition to reducing BBB permeability.
Most of the common supplements main function is as antioxidants, curcumin, alpha lipoic acid, glutathione etc., and I wondered by what mechanism they could be beneficial in reducing BBB permeability.
Then I read that the BBB is composed of molecules high in unsaturation and therefore susceptible to oxidation. The antioxidant supplements therefore probably protect the membrane from oxidation, since oxidation of the BBB increases its permeability. It all fits in.
I then found this paper.
http://www.msrc.co.uk/index.cfm?fuse...TOKEN=33116710

Experiments with animals have shown that there are three related chemicals, anthocyanosides, proanthocyanidins and procyanidolic oligomers, which strengthen the [Blood-Brain Barrier] BBB (Robert et al., 1977; Detre et al., 1986). These chemicals are found in blueberries, cherries, blackberries, grapes and the bark and needles of certain pine trees. They are currently available as encapsulated supplements called bilberry, grape seed extract and pycnogenol.

These supplements and/or substantial quantities of the above fruits should be ingested daily to help strengthen the BBB. The anthocyanosides and proanthocyanidins act as very powerful anti-oxidants, block enzyme actions and bind with the BBB and it is these properties which likely result in their beneficial effect on the BBB (see Stout essay for details).

The 3 related chemicals mentioned, anthocyanosides, proanthocyanidins and procyanidolic oligomers, are all strong antioxidants.
Ron

Thank you for this discussion. Please, please continue these types of discussions - they are very important. If nothing else, trying to understand the biochemistry keeps my brain active.

My mother, who lived to 96, had a stroke in her final years, and I remember her left side was severely disabled, very much like advanced PD.
I did a search and found that indeed, there is a temporary loss of BBB protection following a stroke, see
http://www.neurologyreviews.com/jul0...inbarrier.html
"it is becoming evident that the barrier itself may be subject to loss, perhaps underlying the initiation of chronic disease. In stroke, for example, there is a transient loss of blood-brain barrier function that happens within minutes or hours of the event, he said. In other settings, there appears instead to be a "leakage" across the barrier that may be protracted over time, leading to chronic diseases such as multiple sclerosis or Alzheimer's disease. "There's plenty of evidence … that if you lose blood-brain barrier function—even a low fraction of its function but for an extended period of time—you may allow entry into the brain, [of] molecules or cells that cause the development of pathology," he said."
The paper also says,
""How … [many] of these changes that are seen in pathological situations really relate to the loss of barrier function, and how early can we detect these changes in chronic neurological disease?" Dr. Janigro asked. The answers may make it possible to aggressively treat the blood-brain barrier disease, thereby preventing the cascade of events that lead to full-blown pathology."
I looked up the symptoms of a stroke,
numbness, weakness or inability to move the face, arm or leg on one side of the body
trouble with vision - sudden loss of sight in one eye, blind spots or double vision
confusion or difficulty understanding
difficulty speaking (this is called dysphasia or aphasia)
difficulty swallowing (this is called dysphagia)
problems walking, loss of balance or co-ordination
Sounds familiar!
- Weakness, arm or leg, One side of the body
- Problems walking, loss of balance, coordination.
- Difficulty swallowing,
These are my symptoms exactly, particularly walking and loss of balance. (Remember my fall into the greenhouse).
I should have realised this earlier, before I was diagnosed with PD, my wife told friends she thought I had had a stroke!!
Recently, we went to a restaurant, and the man in front of me was walking to the door with a walking stick. I followed him with my walking stick, and we all laughed. It seemed as though I was imitating him, our walk was so similar. I said to him, "Parkinson's???" No, he said, A stroke.
Take care of your BBB. Take curcumin with bioperine and you may stop a stroke as well as slowing your PD progression. Try adding anything that reduces BBB permeability, CDP choline, alpha lipoic acid, etc. Can we find anything that has such a strong effect in reducing permeability, that it switches us from off to on? (Totally stopping leakage of dopamine out of the BBB, and stopping leakage in of toxins.) Preferably a natural compound, like curcumin, or one already in the body, but probaly deficient, like CDP choline.
By the way, CDP choline is prescribed by doctors, to aid recovery after a stroke!!
Ron