Wanted to include this private message response from Ron when I asked him if he had any evidence to the contrary about his BBB theroy.[with his permission]. it has a little more information.

Ron said:
Really, I have not found a single thing which argues against this theory. Every chemical which is beneficial to Parkies, also closes the pores of the BBB.
curcumin, GDNF, folic acid, biberry extract, etc.
Every chemical or treatment which opens the pores, causes an intensification of symptoms, stress, old age, nitric oxide, carbon monoxide, organic phosphates,
High blood pressure will weaken the BBB, and it is
associated with a high incidence of PD.
PD people have been shown to have abnormally high levels of iron in their blood
In http://www.medicinenet.com/script/ma...ticlekey=62531
where it is shown that if a baby has an underdeveloped BBB, it can absorb high levels of iron, leading to PD in adulthood. If we have a
leaky BBB since birth, it would account for the high levels of iron,
I guess there must be arguments against the idea, but i have not found any yet.

Paula

People with Hereditary Hemochromatosis genetically accumulate iron, at levels way beyond any of those found in people with Parkinson's Disease. If iron accumulation caused Parkinson's Disease, then everyone that had Hereditary Hemochromatosis would also have Parkinson's Disease. Yet in a study carried out in Ireland, where HH is at it's worst, none of the people with Hereditary Hemochromatosis had Parkinson's Disease. How do you explain this worst case scenario of iron accumulation not resulting in any cases of Parkinson's Disease at all.

If the blood brain barrier deteriorates with age, and thereby makes Parkinson's Disease more likely, how do you explain the three year olds found to have Parkinson's Disease, and the fact that amongst the very oldest of people - those between 110 and 120 years old, Parkinson's Disease is virtually unknown. At their age, if the theory was right, it should be almost inevitable that they get it, but virtually none of them do.

I didn't post the above to argue your point Mr. Duck. I just posted it as a continuation of Ron's theory because it contained a little more info.

Paula

Ron I got the name wrong. But as dumb as I am I would like to ask a question of you. If this is a sugar and the BBB can be passed by nicotine and caffein etc do you think the usage of these products that came more into our lives in the last hundred years could have been carriers if associated with Mannitol and sugars especially the artificial ones.

Thanks

One current treatment option involves weakening the connection between the endothelial cells that comprise the BBB. This treatment is especially useful as chemotherapy to suppress the growth of a tumor in the brain.

An arterially injected sugar solution called Mannitol shrinks the individual endothelial cells by osmotic force. Chemotherapy drugs can then diffuse into the brain through the gaps between the cells.

A patient who has chosen this option must actually be admitted to the hospital during treatment. Vital signs must be carefully monitored in case an infection develops while the BBB is in a vulnerable state. Throughout this the patient remains alert with normal cognitive functioning for several hours. A typical patient would be in the hospital for three to five days depending on their treatment and individual needs. The BBB returns to its normal, tight state once the Mannitol has been re-absorbed into the blood stream.

Keith,
I did not say iron caused PD. It is not known whether iron causes PD or PD causes accumulation of iron. It is however known that people with PD have a large accumulation of iron in their brains.
Yes PD has been diagnosed at 3 and people have lived to 120 without contracting PD, but what does that prove? It simply means that the 3 year old has a very defective BBB, whilst the 120 year old has a perfect BBB which has not deteriorated much with age. If the average age of death is say 75, why isn't the 120 year old dead? One can use these fallacious arguments to confuse.
You put words in peoples mouths that they have not said, I also did not say that " Parkinson's Disease is due solely to a loss of function of the blood brain barrier.". I could not make such a wild claim, I am simply putting this forward as a possible cause, but there may be other causes. However, sticking to facts, it is very significant that Parkies have been found to have defective BBB's in the work by the Dutch group led by Prof. Leenders.
I am glad you feel your brew "is overcoming to some extent some deficiency of the blood brain barrier.", since you are agreeing the BBB is defective in PD. (Just quoting you out of context, as you do!!!) LOL.

Ron

Hi Thelma,
I had forgotten about the research using mannitol (which is a sugar), to temporarilly open the pores of the BBB. This is used as a method of drug delivery for drugs which normally will not get through the barrier. I think you have to distinguish between a short temporary opening of the BBB, and the permanently open BBB we Parkies suffer from. We have probably had a defective BBB since childhood, with continuing toxin entry into the brain, until 80% of the dopamine neurons are either dead or dormant, and we then show symptoms of PD.
Ron

I have been without my computer for two days...moving my home ALONE...ugh...not a pretty picture. Well, I did have two guys and a truck...nice guys...move it all from point A to point B. But now that I have it here...

I just want to say that it is mighty refreshing to see this thread alive and filled with such a lively discussion. All threads should have this kind of discussion.

Keep it moving!!

Ron, as you know there are a lot of toxic causes of Parkinson's Disease :



The nearest I can get to you on this one is that deficiencies in the blood brain barrier, or reduced function of the blood brain barrier with age, could make Parkinson's Disease that is due to toxicity more likely.

What I can not reconcile is how all of the dozens of other cell types are not also adversely affected.

Daffy

...regarding why, once past the BBB, the damage varies from region to region and between individuals. (That "weighty tome" has some interesting stuff in it, guys. )

For example-
1: J Neurosci. 2000 Aug 15;20(16):6309-16.

Regional difference in susceptibility to lipopolysaccharide-induced
neurotoxicity in the rat brain: role of microglia.

Kim WG, Mohney RP, Wilson B, Jeohn GH, Liu B, Hong JS.

Neuropharmacology Section, Laboratory of Pharmacology and Chemistry, National
Institute of Environmental Health Sciences, Research Triangle Park, North
Carolina 27709, USA.

Inflammation in the brain has been increasingly associated with the development
of a number of neurological diseases. The hallmark of neuroinflammation is the
activation of microglia, the resident brain immune cells. Injection of bacterial
endotoxin lipopolysaccharide (LPS) into the hippocampus, cortex, or substantia
nigra of adult rats produced neurodegeneration only in the substantia nigra.
Although LPS appeared to impact upon mesencephalic neurons in general, an
extensive loss of dopaminergic neurons was observed. Analysis of the abundance
of microglia revealed that the substantia nigra had the highest density of
microglia. When mixed neuron-glia cultures derived from the rat hippocampus,
cortex, or mesencephalon were treated with LPS, mesencephalic cultures became
sensitive to LPS at a concentration as low as 10 ng/ml and responded in a
dose-dependent manner with the production of inflammatory factors and a loss of
dopaminergic and other neurons. In contrast, hippocampal or cortical cultures
remained insensitive to LPS treatment at concentrations as high as 10 microg/ml.
Consistent with in vivo observations, mesencephalic cultures had fourfold to
eightfold more microglia than cultures from other regions. The positive
correlation between abundance of microglia and sensitivity to LPS-induced
neurotoxicity was further supported by the observation that supplementation with
enriched microglia derived from mesencephalon or cortex rendered LPS-insensitive
cortical neuron-glia cultures sensitive to LPS-induced neurotoxicity. These data
indicate that the region-specific differential susceptibility of neurons to LPS
is attributable to differences in the number of microglia present within the
system and may reflect levels of inflammation-related factors produced by these
cells.

PMID: 10934283 [PubMed - indexed for MEDLINE]

As for why the variance between individuals (the essential "why doesn't everyone get it?" test:

1: Neuroscience. 2004;124(3):619-28.

Combined toxicity of prenatal bacterial endotoxin exposure and postnatal
6-hydroxydopamine in the adult rat midbrain.

Ling ZD, Chang Q, Lipton JW, Tong CW, Landers TM, Carvey PM.

Department of Pharmacology, 1735 West Harrison Street, Room 410, Rush University
Medical Center, Chicago, IL 60612, USA. zling@rush.edu

We previously reported that injection of the Gram (-) bacteriotoxin,
lipopolysaccharide (LPS), into gravid females at embryonic day 10.5 led to the
birth of animals with fewer than normal dopamine (DA) neurons when assessed at
postnatal days (P) 10 and 21. To determine if these changes continued into
adulthood, we have now assessed animals at P120. As part of the previous
studies, we also observed that the pro-inflammatory cytokine tumor necrosis
factor alpha (TNFalpha) was elevated in the striatum, suggesting that these
animals would be more susceptible to subsequent DA neurotoxin exposure. In order
to test this hypothesis, we injected (at P99) 6-hydroxydopamine (6OHDA) or
saline into animals exposed to LPS or saline prenatally. The results showed that
animals exposed to prenatal LPS or postnatal 6OHDA alone had 33% and 46%,
respectively, fewer DA neurons than controls, while the two toxins combined
produced a less than additive 62% loss. Alterations in striatal DA were similar
to, and significantly correlated with (r(2)=0.833) the DA cell losses. Prenatal
LPS produced a 31% increase in striatal TNFalpha, and combined exposure with
6OHDA led to an 82% increase. We conclude that prenatal exposure to LPS produces
a long-lived THir cell loss that is accompanied by an inflammatory state that
leads to further DA neuron loss following subsequent neurotoxin exposure. The
results suggest that individuals exposed to LPS prenatally, as might occur had
their mother had bacterial vaginosis, would be at increased risk for Parkinson's
disease.

PMID: 14980732 [PubMed - indexed for MEDLINE]

And finally-

1: In Vitro Cell Dev Biol. 1991 Feb;27A(2):113-20.

Blood-brain barrier alterations in bacterial meningitis: development of an in
vitro model and observations on the effects of lipopolysaccharide.

Tunkel AR, Rosser SW, Hansen EJ, Scheld WM.

Department of Internal Medicine, University of Virginia School of Medicine,
Charlottesville.

To further examine the effects of purified Haemophilus influenzae type b
lipopolysaccharide (LPS) on blood-brain barrier permeability, we have developed
an in vitro model of the BBB. Microvascular endothelial cells were isolated from
rat cerebral cortices by enzymatic digestion, dextran centrifugation, and
separation on percoll gradients. The cells were determined to be endothelial in
origin by positive fluorescent staining for Factor VIII-related antigen and the
ability to take up acetylated low density lipoproteins, and their cerebral
origin by the formation of junctional complexes in vitro. Cells were seeded onto
semipermeable polycarbonate filters and permeability assessed by measuring
traversal of radioactive albumin across the monolayer. Treatment of the cells
with LPS at concentrations of 1.0 microgram/ml and 0.1 microgram/ml for 4 h led
to statistically significant increases in albumin permeability of 4.6% (P =
0.001) and 5.6% (P less than 0.001), respectively, without evidence of cell
death as assessed by release of lactate dehydrogenase into the media. These
results indicate that LPS significantly increases albumin permeability across a
monolayer of cerebral microvascular endothelial cells in the absence of host
inflammatory cells. Future studies on the effects of LPS on intracellular
regulation will determine the mechanisms responsible for these alterations.

PMID: 1826902 [PubMed - indexed for MEDLINE]

For those that don't want to wade through the verbage:

1- The bacterial toxin LPS (it's everywhere by the way) can open the BBB;
2- Once inside it makes your microglial defenders go berserk and attack your own tissues;
3- with the help of the excess dopamine we are flooding our brains with?

oooooo!

And here lie the "hopefulls", whom after 20 or more years of quietly sufffering the effects of a still unelucidated etiology of parkinsonism have all but no interst left in talking about it. Some of us early onsets will just keep living this nightmare for decades, with very little help and very few resources; for the lucky ones of us who are still able to function for part of the day, consider yourself "lucky". There has been very litttle progress toward drugs that could at least make us be more able to tolerate the horrors of stage 4. I used to have hope, when i ws dxed in 1997. I looked around most corners for knowledge, but found a host of well meaning researchers who did a lot of work, but have not cracked the nut yet. God help us all..................cs