BBB update
 

The Role of the BBB in PD
We have a lot of facts that are generally not disputed, connected to PD, and the more of these facts which can be explained by a theory, adds credence to the theory.
Let us assume that a healthy person has a BBB permeability value of 100. Assume that it needs to be 150, to let in the first toxins, the
smaller ones, more fat soluble. The larger molecular weight toxins need 170. The largest molecules with a very low fat solubility need 190 permeability of the BBB to get past it. Completely ficticious figures to illustrate the ideas.
So between 100 and 150, a person can have mild BBB damage and not show PD. The BBB ages as we age, so does your heart, liver, skin etc.
Assume that when the figure goes over 200, it allows dopamine to leak out of your brain into the bloodstream. This could be the threshold for movement to be very inhibited. It also can let carbidopa from your sinemet leak in. This is very bad news since carbidopa is mixed with levodopa in your sinamet, to stop it forming dopamine by decarboxylation. When carbidopa gets into
your brain, it does not matter how much levodopa you pack into your brain, it won't form dopamine.
So can this idea give explanations for observed facts.
Qu.1. Why do symptoms vary so much in different PD sufferers.
A. Possibly because the toxins admitted at say 150 to 160 only cause a tremor. A permeability figure just above the 150 threshold may only attack one side of the brain also, giving an explanation for
Qu 2. Why is PD often initially one sided?
A. See above.
Qu 3. Why does stress cause a catastrophic increase in symptoms?
A. Because stress has been proven to open the floodgates of the BBB,
and you reach say over 200, where your tiny supply of dopamine is dumpted out of the brain into the bloodstream. Reason why you freeze.
Qu 4 Why does your heart pound when you are in a stressful situation.
A. Because of the dopamine dropped into your bloodstream, where it acts as a hormone, increasing your heart rate. Surgeons often add it in an operation if the heart starts to become sluggish.
Qu 5. Why do symptoms increase in type as the disease progresses,
eg, start with a mild tremor, then get trouble swallowing, then difficulty turning in bed, getting off a chair, eventually total immobility.
A, Again, as you progress up the permeability scale, it opens the door to ever more toxins, each with a different effect, and closer to the threshold where you lose dopamine.
Qu 6. Why is PD normally an old person's disease?
A. Because as explained above, all BBB's increase in permeability with age. A young person can be unfortunate to be born with a BBB higher than normal, and can reach the threshold sooner than normal. Just as my granddaughter was born with a defective heart and died at 6 months.
Qu 7. Why does curcumin alleviate symptoms ?
A Because it reduces BBB Permeability
Qu 8 Why does alpha lipoic acid get a good reputation as a PD supplement.
A Because it reduces the BBB permeability.
Qu 9 Why do pesticides like MCPA cause PD?
A. Because they widen the BBB permeability
Qu 10. Why is citicholine (CDP Choline) found to be a good supplement.
A. Because it reduces the BBB permeability.
Qu 11. In an advanced Parkie, medications frequently simply don't work. Why?
A. Duie to carbidopa getting into the brain and stopping conversion of
levodopa.

I asked Prof Al Lossinsky whether the BBB Permeability of a living person could be measured. He said yes, by putting radio-opaque tracers in the blood and use special scanners to measure permeability.
Could we therefore use this technique on a group of parkies with a spectrum of years with PD, and show a correlation.
The numbers are guesses, and the order of symptoms could be different, but you get the idea.
Years of PD BBB permeability Symptoms.
0 100 none
0 140 none
2 160 tremor
5 180 tremor, turning in bed, impaired walk
10 200 v. bad walking, largely imobile etc

If a correlation like this could be shown, we would have a method to warn of the impending approach of PD. We would have a scientific quantitative method of diagnosing PD, (instead of swinging their arm round!!).
We could follow the progression, we could note the effect of new drugs which reduce the permeability. We could evaluate drugs already approved for human use, such as hypertension drugs which have recently been found to improve PD. Why? because they reduce the BBB permeability.

Like Heidi, I have been hoping to interest a professional researcher who would confirm or otherwise, the correlation between PD progression and BBB permeabilty, as in the table above. Surely no more than $5,000 to $10,000.

Ron

Thanks.
 

I have read a great deal about the importance of exercise for P.W.P(See,for example, interview with Lisa Shulman in Accelerating the Cure posted on this forum by Carolyn)Does exercise fit into the BB hyposisis or is something else at work?

Possibility
 

Chronic stress raises levels of cortisol and epinephrine. They, in turn, increase the BBB permeability. <I need to double check that part> Exercise, however, decreases the hormone secretion.

I think
 

you will find the research into Zonulin, also interesting...
http://www.sciencedaily.com/releases...0104065455.htm

Zonulin channels are also in the GI tract.
These are being testing with blocking agents now for Celiac/gluten intolerance.

http://www.medicalnewstoday.com/articles/52442.php
http://jccglutenfree.googlepages.com/zonulin

The BBB is critical as we age. One family of drugs...the H2 antagonists, actually cross the BBB more often in the elderly causing delerium.

Pressure differentials?
 

Ron-

In addition to permeability, it might be interesting to know what pressure and osmotic differences exist in the brain and the blood stream and how they fluctuate. A slight increase in BBB permeability could mean a lot more with a pressure behind it or an electrolyte differential.

-Rick

Blood pressure
 

Hi Rick,
You are quite right, blood pressure must be important, it is like volts and amps. a high voltage is the pressure component, and amps are the quantity. Higher blood pressure presumably helps push a larger molecule through.
It is significant that hypertension drugs improve matters, and in addition to reducing blood pressure, they reduce BBB porosity.
Mrsd,
This is the direction we need to examine. Zonulin is a signaling protein that transiently opens the BBB to let in a medication that can't normally pass.
This is of course is the opposite way we are interested in, we need such a protein or other compound which will cause a permanent reduction in permeability. I wonder do patients given zonulin suffer very transient freezing or movement side effects?? Maybe the increase in permeability is low eg 140 on my imaginary scale, so no PD symptoms occur.
Intersting about the H2 agonists crossing the highly permeable BBB's of the elderly and causing delirium. The medical profession has until recently never considered the dide effects caused by the BBB not remaining impervious to everything it normally won't pass. See the cause of Gulf War syndrome.
http://www.sciencenews.org/pages/pdf...4/15024-10.pdf

serving
in the Persian Gulf War suffered adverse side effects from the inoculation. These reactions
puzzled physicians, who had expected the blood-brain barrier to keep this drug—like many
other chemicals circulating in the blood—out of the brain.
Now, an Israeli study suggests that stress may have temporarily opened the blood-brain barrier.
“It was surprising—we saw quite large amounts of brain penetration,” says Hermona Soreq of
the Hebrew University in Jerusalem, a coauthor of the report in the December NATURE MEDICINE.
During the Gulf War, Soreq and her colleagues at Tel Aviv University studied a unit of soldiers
given pyridostigmine, a drug that attaches to receptors on nerves outside the central nervous
system. When chemical weapons invade the body, they can’t bind to the occupied receptors,
which limits their ability to cause damage.
Usually, only small amounts of pyridostigmine cross the blood-brain barrier. However, nearly
one-quarter of the inoculated soldiers complained of mild neurological side effects, such as
headaches and drowsiness. When the researchers inoculated another group of soldiers during
peacetime, only 8 percent reported symptoms. “Our suspicion was that the stress associated
with war made the difference,” says Soreq.
The physicians also injected the drug into mice that had been forced to swim for two 4-
minute intervals and into unstressed mice. The researchers found that it took over 100 times
more pyridostigmine to penetrate the brains of unstressed mice as the brains of stressed mice.
Tests using a larger molecule, a blue dye, showed a similar effect.
“The important thing is finding a drug that should not have crossed the blood-brain barrier
and apparently did, under conditions of stress,” comments Israel Hanin of Loyola University of
Chicago in Maywood, Ill., who advises physicians to consider reducing the drug dosages they
prescribe to stressed patients.

Ron

:) 1,000 thanks

Is zinc the answer?
 

See

http://lpi.oregonstate.edu/ss03/zinc.html
We recently examined the role of zinc in maintaining the integrity of the blood brain barrier (BBB), which is the highly specialized blood vessel system of the CNS that serves to protect the brain by excluding toxic agents and other foreign compounds. Alterations or dysfunction of the BBB have been observed in many brain disorders. Free radicals may play an important role in damaging the BBB because it is especially sensitive to oxidative damage. This vulnerability may be due to the high polyunsaturated fatty acid content of the BBB membrane—fatty acids that are very susceptible to free radical attack—as well as the relatively low antioxidant capacity of the BBB. Oxidation of the membrane drastically compromises its barrier properties and may lead to subsequent brain tissue damage, resulting in a host of pathologies.
Ron
Our investigations have focused on the antioxidant function of zinc that may protect the BBB against oxidative damage. Using magnetic resonance imaging, or MRI, we have demonstrated that zinc deficiency in rats dramatically increases the permeability, or leakiness, of the BBB. Additionally, we have observed that when zinc deficiency is accompanied by oxidative stress, as might occur during a bacterial or viral infection, BBB permeability increases dramatically. These observations have led us to hypothesize that under normal conditions, zinc protects the BBB against oxidative stress through its antioxidant properties and in so doing, helps to maintain homeostasis within the brain and prevent the development of neurological disorders.

In our initial work we examined the consequences of the loss of BBB integrity during zinc deficiency. First, we noted significantly increased water content, or edema, of the brain as a result of zinc deficiency. Second, we observed increased protein oxidation within the brain. And third, we documented significant changes in brain energy metabolism. These observations led us to propose that these events may be pivotal in the development and pathogenesis of many brain disorders, and our laboratory will continue to define the important roles of zinc in disease prevention.

Blood pressure
 

I have had genetic low pressure all my life.In the range of 90/60 and yet I was diagnosed with PD 5 years ago.

I too have a normal blood pressure of 90/60 or lower. I ended up with PD anyway. But that doesn't contradict Ron's assertions.

I didn't know that stress can increase the permeability of the BBB. It can sure explain a lot. The idea of leakage of carbidopa and dopamine is also most enlightening. I have told my various doctors for years that stress impacts my symptoms.

Sometimes, I can feel my symptoms get worse as I experience stress. Last week while talking with my psychologist, I became upset about something and within minutes (maybe seconds) I could feel the pain and stiffness in my neck and shoulders increase. I even told the doctor. This is a case in point of the fact that stress has been a major part of my experience with PD.

Karl

KIbsen,

Your post keeps the percentage of people we have all talked to who say stress is a factor and affects symptoms at 100%.

paula:(

Stress is at the heart of it
 

Aside from theories about its role in causing PD, the hormones associated with stress (cortisol, epinephrine, and norepinephrine) are themselves neurotransmitters and so are their breakdown products. Neurologists dismiss the importance of stress because that is the province of endocrinologists. Furthermore, stress can trigger inflammation which involves chemicals called cytokines and they, too, are neuroactive. But they are the territory of the immunologists. We are stuck in the crack between these three disciplines.

And, lest anyone think this is off topic, both conditions open the BBB.

BBB permeability and Biblical considerations
 

Ron,
I so don’t have the background for your question so this may be way off base. I wonder if any of your BBB permeability questions have been answered in investigations of the Dopamine theories of Schizophrenia:

Neuroleptic drugs and the Blood Brain Barrier

http://www.metacrawler.com/info.meta...17/top/-/-/1/1

is a search that yields similar info on antipsychotic meds.

On the stress factor, I tremor to beat the band everytime I have to do any public speaking and my Grandfather, a brittle diabetic, ran the risk of insulin shock whenever he had to address an audience.

I’d like to learn more about BBB theories. The appeal for me is they could address PD through the ages. I downloaded an e-text of the King James version of the Bible and found dozens of references to palsy which I accept as references to PD or similar diseases. I don’t think folks during the time of Christ had worries over pesticides or pollution, however the same virus that could invade the lining of the heart muscle may permeate and cause a bruising of the brain.

Bible, King James Version
14 matches.
________________________________________
1Mac.9
1. [55] And as he began to pull down, even at that time was Alcimus plagued, and his enterprizes hindered: for his mouth was stopped, and he was taken with a palsy, so that he could no more speak any thing, nor give order concerning his house.
Matt.4
1. [24] And his fame went throughout all Syria: and they brought unto him all sick people that were taken with divers diseases and torments, and those which were possessed with devils, and those which were lunatick, and those that had the palsy; and he healed them.
Matt.8
1. [6] And saying, Lord, my servant lieth at home sick of the palsy, grievously tormented.
Matt.9
1. [2] And, behold, they brought to him a man sick of the palsy, lying on a bed: and Jesus seeing their faith said unto the sick of the palsy; Son, be of good cheer; thy sins be forgiven thee.
2. [6] But that ye may know that the Son of man hath power on earth to forgive sins, (then saith he to the sick of the palsy,) Arise, take up thy bed, and go unto thine house.
Mark.2
1. [3] And they come unto him, bringing one sick of the palsy, which was borne of four.
2. [4] And when they could not come nigh unto him for the press, they uncovered the roof where he was: and when they had broken it up, they let down the bed wherein the sick of the palsy lay.
3. [5] When Jesus saw their faith, he said unto the sick of the palsy, Son, thy sins be forgiven thee.
4. [9] Whether is it easier to say to the sick of the palsy, Thy sins be forgiven thee; or to say, Arise, and take up thy bed, and walk?
5. [10] But that ye may know that the Son of man hath power on earth to forgive sins, (he saith to the sick of the palsy,)
Luke.5
1. [18] And, behold, men brought in a bed a man which was taken with a palsy: and they sought means to bring him in, and to lay him before him.
2. [24] But that ye may know that the Son of man hath power upon earth to forgive sins, (he said unto the sick of the palsy,) I say unto thee, Arise, and take up thy couch, and go into thine house.
Acts.9
1. [33] And there he found a certain man named Aeneas, which had kept his bed eight years, and was sick of the palsy.
________________________________________

Why?
 

I don't understand why doctors and scientists from the different disciplines aren't working together. It seems like they do in the study of other disorders. I'm pretty tired as I write this so it's hard to think... but this just seems so wrong.

I've learned more about how to cope with PD from this forum than from any other source. It's great that the forum is exists, but it's sad that there aren't other similarly valuable sources. Of course, I'm a newbie and haven't yet been able to go to one of the high-quality clinics.

I'd like to know if there are any people who are actively engaged in the study of PD who are lurking this forum. I understand why a professional wouldn't want to express an opinion. It sure would be valuable for them to monitor our writings. Perhaps we need to give the URL to our doctors and urge (or maybe coerce) them to browse the site.

BBB and expert help
 

Karl,
I am in contact with a professor in the UK who is an expert on the BBB and heads a group doing research into the BBB. She is very interested in the concept, and is starting work shortly on this topic. So the cavalry is coming in the form of professional help.
wwallyo,
I have not investigated neuroleptic drugs, not quite sure what you are suggesting. As far as I know , neuroleptic drugs can be tranquilisers, so do they fight stress by reducing permeability of the BBB. Try your search adding "permeability" to your search words.
Ron

MS, Epstein Barr Virus and the BBB
 

An interesting article on Epstein Barr Virus being the cause of MS and how the virus crosses the BBB.
Ashley

In the case of MS, EBV is carried across the blood-brain barrier by lymphocytes B - the cells of the immune system that make anti-bodies, Aloisi said.
"This is an extraordinary result," said ISS President Enrico Garaci.
"For the first time, the observation of a virus in the brain of MS patients has enabled researchers to explain both the characteristics and the mechanisms of the disease".

http://www.ansa.it/site/notizie/awnp...105142211.html

Re: stress

Damage to the dorsal motor nucleus occurs in PWP. However it is not involved with heart rate and stress response, that is located in the nucleus ambiguus of the vagus.
PWP also show massive loss of hypocretin/orexin neurons in the hypothalamus (pdf). I propose this is a likely mechanism by which the stress response in PWP is amplified:

Hypocretin-1 (Orexin-A) Facilitates Inhibitory and Diminishes Excitatory Synaptic Pathways to Cardiac Vagal Neurons in the Nucleus Ambiguus

Hypocretin-1 is a neuropeptide recently shown to be involved in autonomic regulation. Hypocretin-1 is expressed by hypothalamic neurons, which project to many regions of the central nervous system, including the nucleus ambiguus. One possible site of action of hypocretin-1 could be cardioinhibitory parasympathetic vagal neurons within the nucleus ambiguus. This study examines whether hypocretin-1 modulates inhibitory and excitatory postsynaptic currents in cardiac vagal neurons in the rat nucleus ambiguus. GABAergic, glycinergic, and glutamatergic activity to cardiac vagal neurons was examined using whole-cell patch-clamp recordings in an in vitro brain slice preparation. Hypocretin-1 (1 µM) produced a significant increase in the frequency and amplitude of both GABAergic and glycinergic inhibitory postsynaptic currents and a significant decrease in the frequency of glutamatergic excitatory postsynaptic currents. Application of tetrodotoxin (0.5 µM) blocked all of the responses to hypocretin-1, indicating the changes in neurotransmission with hypocretin-1 do not occur at presynaptic terminals but rather occur at the preceding GABAergic, glycinergic, and glutamatergic neurons that project to cardiac vagal neurons. The increase in GABAergic and glycinergic inhibitory postsynaptic currents, and the decrease in glutamatergic excitatory postsynaptic currents, could be mechanisms by which hypocretin-1 affects heart rate and cardiac function.

(I have never been able to speak in public. My heart would race and my vision would constrict and I was unable to see my notes. Until recently I couldn't even post on online forums, the stress would give me tics for days.)

Schizophrenia and PD - not strange bedfellows
 

Ron;
15 years ago, I did a lot of reading on theories of the causes of Schizophrenia and why standard antipsychotic medications are suspected to work. Crudely put, the broad thought was that too much dopamine leads to auditory and visual hallucinations and psychosis. These major antipsychotic medications inhibit or slow down the processing of dopamine. The drugs used to control schizophrenia may share similar problems with Parkinson’s Disease treatment i.e. trying to regulate dopamine and ending up with too much dopamine or not enough. Look at, for example how many PD meds cause symptoms related to psychosis/ depression or how many things go wrong when we get too much dopamine. Chlorpromazine came out in the 50’s so surely the BBB must have been examined in Chlorpromazine’s development and subsequent decades of use. The discussion below ties Schizophrenia and Parkinson’s Disease on a few points. It is also interesting to note that prolonged use of anti-psychotic medications causes tardive dyskenesia and other parkinsonian features. These medications inhibit dopamine. Your discussion on BBB and permeability may be enlightened by examining Schizophrenia and the ways antipsychotic drugs work.

I pulled the following from:
http://www.benbest.com/science/anatmind/anatmd10.html

Phenothiazine derivatives
Phenothiazine: One of a group of tranquilizing drugs with antipsychotic actions thought to act by blocking dopaminergic transmission (messages sent using the substance dopamine) within the brain.
Schizophrenia is thought to be due to an overstimulation of D2 receptors in the mesolimbic and mesocortical systems. Evidence for the "excess dopamine" theory of schizophrenia comes largely from the fact that D2 antagonist drugs alleviate the symptoms, whereas substances which increase D2 stimulation, such as amphetamines, can induce psychotic symptoms (which are reversible with D2 antagonists). About 10% of Parkinsonian patients given DOPA treatment will develop psychotic symptoms resembling schizophrenia.
The major classes of antipsychotic drugs are the phenothiazines (e.g., chlorpromazine), the butyrophenones (e.g., haloperidol) and the thioxanthenes (e.g., chlorprothixene). Butyrophenones are 100 times more potent against D2 receptors than against D1 receptors. The similarity in shape between a portion of the chlorpromazine molecule and dopamine indicates how chlorpromazine could bind to a dopamine receptor without triggering a response.
The mesolimbic & mesocortical dopaminergic systems are thought to play an important role in motivation, by attaching cognition of incentive significance to stimuli. In experiments on animals that are motivated to electrically self-stimulate themselves with electrodes implanted in their brains, dopamine is the mediating neurotransmitter for the locus ceruleus, lateral hypothalamus, ventral tegmental area and sulcal prefrontal cortex (but not the nucleus accumbens or substantia nigra).
Cocaine particularly increases dopaminergic activity in the mesolimbic areas of the brain by inhibiting dopamine re-uptake in the ventral tegmental area and the nucleus accumbens. Amphetamine seems more generalized in its action, not only by inhibiting re-uptake, but by releasing dopamine from most brain regions. Both cocaine & amphetamine produce feelings of psychological energy & arousal, associated with diminished appetite & need for sleep. Both cocaine & amphetamine can lead to visual & tactile hallucinations as well as paranoid thinking, although the psychotic effects of amphetamine may also be mediated by increased serotonin release. Chronic amphetamine users seem to lose a capacity for normal pleasure -- which has been correlated with neuron degeneration in the mesolimbic area.
Perception of time-intervals is believed to be mediated by spiny neurons located in the striatum of the basal ganglia. Timing begins with a burst of dopamine and ends with a recognized signal. Marijuana slows subjective time by lowering dopamine available, whereas cocaine and methamphetamine accelerates the sense of time by increasing dopamine availability. (Adrenaline and stress hormones can also "make seconds feel like hours".)
There is no answer required to what I’ve written here, but I believe it would be a service to your UK professor to consider Manic Depression, Schizophrenia, theories re: Dopamine, theories of the disease and tardive dyskenesia and parkinsonian damage from long term use of phenothiazines. She may find some of the leg work already done. Wish I knew more. When God creates a 48 hour day . ... Guy

Bbb
 

wwallyo,
Thanks, I will pass your information to the Prof. I am excited to get professional help on the BBB concept at last.
Ron

Ron, here's one to think about
 

1: Neurobiol Dis. 2000 Aug;7(4):429-47.

The single intranigral injection of LPS as a new model for studying the
selective effects of inflammatory reactions on dopaminergic system.

Herrera AJ, Castano A, Venero JL, Cano J, Machado A.

Departamento de Bioquimica, Bromatologia, Toxicologia, y Medicina Legal,
Universidad de Sevilla, Calle Prof., Garcia Gonzalez s/n, Sevilla, 41012, Spain.

We have injected lipopolysaccharide (LPS) into the nigrostriatal pathway of rats
in order to address the role of inflammation in Parkinson's disease (PD). LPS
induced a strong macrophage/microglial reaction in Substantia nigra (SN), with a
characteristic clustering of macrophage cells around blood-vessels. The SN was
far more sensitive than the striatum to the inflammatory stimulus. Moreover,
only the dopaminergic neurons of the SN were affected, with no detectable damage
to either the GABAergic or the serotoninergic neurons. The damage to the DA
neurons in the SN was permanent, as observed 1 year postinjection. Unlike the
direct death of dopaminergic neurons caused by agents as MPP(+) or 6-OHDA, LPS
seems to cause indirect death due to inflammatory reaction. Therefore, we
suggest that the injection of a single dose of LPS within the SN is an
interesting model for studying the selective effects of inflammatory reaction on
dopaminergic system and also potentially useful for studying PD. Copyright 2000
Academic Press.

PMID: 10964613 [PubMed - indexed for MEDLINE]


So the immune response to the presence of the bacterial toxin is to surround the blood vessels (i.e. the BBB) ? Interesting, no?

Immune response
 

Rick,
The paper is interesting, but I can't connect it with the concept of the BBB widening as we age or through chemical insult, causing leakage out of dopamine and leakage in of carbidopa and toxins, which are normally kept out.
Every time I see something that improves PD, I do a search to see if I can find a reference showing it reduces BBB permeability. However, this week, I did searches on NSAIDS and also osteopontin, but could not find anything.
Ron

ron
 

how about iv glutathione? there is evidennce that it improves symptoms and is neuroprotective. not being patentable, iv glutathione hasn't generated much n the way of research money.

Glutathione & BBB permeability
 

Oyster,
To see how glutathione fits in with the concept that anything that reduces BBB dysfunction is good news for PD symptoms, you need to do a search to find what effect glutathione has on BBB permeability. Glutathione is well known for its positive effect in improving symptoms, so we would expect it reduces permeability.
I did a quick search and sure enough, found that it does reduce dysfunction of the BBB.

http://www.springerlink.com/content/n6166473240wr556/

"It was also shown that observed BBB permeability dysfunction was associated with brain GSH depletion."

Also see

http://www.meao-cfs.on.ca/about_me/res_bloodbrain.shtml
"Certain deficiencies such as glutathione and essential fatty acids can lead to the barrier becoming more permeable, as can acute and chronic stress."
meaning as your level of glutathione drops, the BBB becomes more permeable.

Ron

Same theory, 2001
 

A paper proposing permeability of the BBB is the cause of many CNS disorders. Why are these papers ignored by big pharma.?
A. Because they have 5 million captive customers for life, that they don't want cured.
Ron

Med Hypotheses. 2001 Aug;57(2):231-7.

Chronic fatigue syndrome: neurological findings may be related to blood--brain
barrier permeability.

Bested AC, Saunders PR, Logan AC.

Environmental Health Clinic, Sunnybrook and Women's College, Health Sciences
Centre, Toronto, Canada.

Despite volumes of international research, the etiology of chronic fatigue
syndrome (CFS) remains elusive. There is, however, considerable evidence that CFS
is a disorder involving the central nervous system (CNS). It is our hypothesis
that altered permeability of the blood-brain barrier (BBB) may contribute to
ongoing signs and symptoms found in CFS. To support this hypothesis we have
examined agents that can increase the blood-brain barrier permeability (BBBP) and
those that may be involved in CFS. The factors which can compromise the normal
BBBP in CFS include viruses, cytokines, 5-hydroxytryptamine, peroxynitrite,
nitric oxide, stress, glutathione depletion, essential fatty acid deficiency, and
N-methyl-D-aspartate overactivity. It is possible that breakdown of normal BBBP
leads to CNS cellular dysfunction and disruptions of neuronal transmission in
CFS. Abnormal changes in BBBP have been linked to a number of disorders involving
the CNS; based on review of the literature we conclude that the BBB integrity in
CFS warrants investigation.

PMID: 11461179

------------------------------------------------------------------------

flouride neurotoxicity and the BBB
 

Damaged BBB
 

In the paper above on "chronic fatigue syndrome," you can substitute PD for CFS totally, and you get exactly what I have been proposing for PD. Fatigue is commonly associated with PD, does this mean that we all have CFS as well as PD???
However, this set me thinking (again)!
No-one would listen to BArry Marshall's assertions on helicobacter pilori and ulcers, so he infected himself with HP, got ulcers then erradicated the HP with antibiotics. Then they listened and gave him the Nobel prize!!
So what if we find a volunteer, give him some of the substances in the CSF reference above that damages the BBB, and show that he gets PD!!!
Then all we have to do to cure him, is find out how to repair his BBB such that the permeability is back to that of a healthy person. Easy Eh....
Ron

Chronic fatigue may be a gluten related immune disorder in the narcolepsy spectrum. I believe fibromyalgia is related too, an inordinate amount of people with narcolepsy have fibro. I believe they probably incur more peripheral lewy bodies thus the muscle fatigue/pain vs sleep or motor symptoms. I wrote to the leading Lewy body researcher in the UK asking her to consider looking for LB in fibro patients.

Nonetheless, I'm still with you on the leaky membrane Ron!

I got my parents to donate some money, I'm going to the conference tomorrow armed with enough for 20 blood tests. Wish me luck in finding a researcher willing to do a preliminary study... H.

Ron and others,

I’ve been puzzled for a while by the correlation between Parkinson’s disease, low levels of B12 vitamin and high levels of Homocysteine.

There is for example a clinical trial going on by the American institute of health to investigate the effect of b12 supplementation in PD on homocysteine levels.

Levodopa is metabolized by COMT to 3-O-methyldopa. This conversion requires the methyl-donor S-adenosylmethionine. After S-adenosylmethionine donates its methyl- group, it is converted to S-adenosylhomocysteine and then to homocysteine.

There is research going on at the American Society of Hematology about elevated levels of homocysteine being responsible for damage to the blood-brain barrier integrity in mice

Elevated levels of plasma homocysteine are known to correlate with increased risk of cardiovascular and Alzheimer diseases.

On a hyperhomocysteinemic diet, cystathionine beta-synthase (Cbs)–heterozygous mice develop hyperhomocysteinemia. BBB permeability was measured and was found to be 25% greater.

Joop Oele (Netherlands)

Homocysteine & BBB
 

Hi Joopoele,
Hoe gaat U?
"Homocysteine increases the BBB permeability", see
http://bloodjournal.hematologylibrar.../107/2/591.pdf
and "Elevated levels of homocysteine have been observed in Parkinson's disease (PD) patients treated with levodopa." see

http://www.sciencedirect.com/science...eca28b1d018ad2

Isn't this what we would expect, accoding to the theory. It is yet another example of substances that increase the BBB permeability, are associted with PD.
"Vitamin B12-B6-folate. treatment improves blood-brain barrier function"
so low levels would be expected to worsen PD symptoms.
You can only do a literature search and you will find ever more examples of the 2 classes of substance, those that widen the pores of the BBB cause worsening of symptoms. whilst those that reduce the porosity
improve symptoms.
Ron

Dank je Ron, het gaat best lekker. Ik wist niet dat je zo goed nederlands sprak, maar als ik er niet meer uit kom in het engels is het goed dat te weten.

But you really have an interesting theory Ron. I wish there was something to put this theory to a test. This may all well be true, but still there are so many things I cannot explain. For example homocysteine, which is supposed to injure the BBB is associated with Parkinson’s disease, Alzheimer, Addison Biermer, restless legs and many other brain disorders, so far so good, but also with heart disease and other cardiovascular conditions. Further heavy metals are known to interfere with the BBB. They are also associated with lots of neurological disorders. There are theories that methylisation has something to do with that. Methyl groups seem to play a crucial role.

What do you think the mechanism is that widens the BBB? Do you have a theory why some people have a damaged BBB and others do not. Why is it that b12 shortage causes homocysteine levels to raise which in turn damages the BBB. How is this damage done. Does the damage consist of one big opening or many smaller holes. Do you have a picture of the size of the molecules that once couldn’t pass, and now can. For example levodopa can pass any BBB but carbidopa normally cannot.

Carbidopa, has a molecular weight of 244.3. It is designated chemically as (---)-L-a-hydrazino-a-methyl-ß-(3,4-dihydroxybenzene) propanoic acid monohydrate. Its empirical formula is C10H14N2O4•H2O,
Levodopa, has a molecular weight of 197.2. It is designated chemically as (---)-L-a-amino-ß-(3,4-dihydroxybenzene) propanoic acid. Its empirical formula is C9H11NO4.

The difference doesn’t seem too big to me.

Joop

toxins in the brain
 

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

homocystine etc
 

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

Methylation
 

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

Might be a clue
 

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.

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

metal allergies
 

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]

Methylation.
 

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

BBB update
 

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.

PD and strokes
 

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