http://www.ncbi.nlm.nih.gov/pubmed/17437543

This paper states,
" We conclude that disruption of the BBB may be a causative factor for degeneration of nigral dopaminergic neurons"

I have enclosed my original post on the BBB. I don't understand why this is not given more attention by researchers.
Ron

THE ROLE OF THE BLOOD BRAIN BARRIER IN PARKINSON’S DISEASE.

SUMMARY

Could Parkinson’s Disease (PD), be caused by sufferers having a defective Blood Brain Barrier, (BBB), which has greater permeability than that of a normal person? Neurotoxins that circulate harmlessly in the bloodstream normally, are able to enter the brain, and damage neurons. At an increased permeability, dopamine could leak from the brain to the bloodstream. Dopamine does not pass through a healthy BBB, but could pass through a defective BBB. Dopamine is actually a smaller molecule than levodopa, which can pass the BBB. So the permeability od the BBB does not need to be much higher for dopamine to leak out. Also Carbidopa could now enter the brain, (this has now been shown to happen), and prevent the conversion of levodopa into dopamine. This would explain the catastrophic effect of stress when for example you are faced with trying to enter a crowded lift and freeze.


DISCUSSION
K.L.Leender’s group (ref 1) have shown that the BBB is defective in Parkinson’s patients, with all patient values of permeability of the BBB being higher than all controls. Also, he states,
. This is the first evidence supporting a dysfunctional blood-brain barrier as a causative mechanism in PD.

Treatments that increase the porosity of the BBB might therefore cause PD or may worsen the symptoms in a PWP.
(a.) Stress is well known for it’s detrimental effect on a person with PD, and has been shown to open the BBB. (ref 2),
(b) PD is predominantly an old person’s disease. The reason could be that ref 3 reports that “old age significantly increases BBB permeability”
(c). Pesticides. Recently shown by Aberdeen University that exposure to pesticides leads to an increased risk of contracting PD by 39%. (ref. 4)
Ref 5 states, “The pesticide MCPA, used as an ingredient in some lawn pesticides, has been found to damage a part of the brain known as the blood brain barrier .
serendip.brynmawr.edu/bb/neuro/neuro00/web2/Patel.html
states
In the CNS lead increases the permeability of the blood-brain barrier (BBB)

Blaylock states that a number of factors make the blood-brain barrier more porous, including exposure to pesticides, hypoglycaemia, all immune diseases (such as lupus and diabetes), Alzheimer's and Parkinson's, strokes (including silent strokes) and a whole range of medical drugs. .

Substances which are reported to ease the symptoms of PD, such as curcumin, alpha lipoic acid, CDP choline (citicoline) and GNDF also reduce the porosity of the BBB. (Ref 13), (Ref 15), (Ref 18).
Certain diverse anti hypertension drugs have been found to be beneficial in treating PD, and Losartan, (Ref 17), Captoprill, (an ACE inhibitor), and two calcium entry blockers Nifedipine (Ref 16) and Flunarizine, all reduce the permeability of the BBB.

TNF-alpha is a pro-inflammatory cytokine which increases BBB permeability, which is centrally involved in the pathogenesis of Alzheimer’s.
By treating Alzheimer’s patients with an anti TNF drug etanercept, resulted in resulted in rapid cognitive improvement within minutes!! (Ref 9).

E.A. van Vliet (Ref 10) reports “leakage of the BBB is associated with various neurological disorders.”.

COX inhibitors (Cyclooxygenase inhihitors) are reported to limit BBB disruption
(Ref 12) Non-steroidal anti-inflammatory drugs (NSAIDs). are the main COX inhibitors
In a prospective trial, regular use of nonaspirin nonsteroidal anti-inflammatory drugs was associated with a 45% lower risk of developing Parkinsons. (Ref 11).

I.Rite et al, (Ref 14) state “We conclude that disruption of the BBB may be a causative factor for degeneration of nigral dopaminergic neurons.” In a paper in which they employed intranigral injections of vascular endothelial growth factor (VEGF), the most potent inducer of blood-brain barrier (BBB) permeability.

Opinion is now changing regarding the involvement of the BBB in PD.
In http://www.nature.com/nrn/journal/v7...m/nrn1824.html (Ref 7.)
It states,
“There is increasing evidence that the function of the BBB is altered
in several neuropathologies, including brain oedema, epilepsy,
Alzheimer's disease and Parkinson's disease”

A recent report (Ref 8), “Blood-Brain Barrier Pathology in Alzheimer’s and Parkinson’s Disease,”
states,
"Though the BBB is thought to be intact during neurodegenerative diseases such as Alzheimer's (AD) and Parkinson's disease (PD), recent evidence argues otherwise."
The report goes on to say,
" Dysfunction of the BBB may be involved in disease progression,..........
Developing a better appreciation of BBB dysfunction in AD and PD may not only provide novel strategies in treatment, but will prove an interesting milestone in understanding neurodegenerative disease etiology and progression."

Work is currently being conducted at the Michael J. Fox Foundation where in their June 30th 2005 report they state, “The Project will include PET imaging to compare the BBB of people with PD to those who do not have the disease. It is hypothesized that biochemical changes that occur in the BBB of people with PD could allow greater accumulation of environmental toxins in the brain.”

A recent paper confirming the role of the BBB is,
Neuropathol Appl Neurobiol. 2008 Dec 11. [Epub ahead of print] Links
Role of developmental inflammation and blood-brain barrier dysfunction in neurodevelopmental and neurodegenerative diseases.Stolp H, Dziegielewska K.
Department of Pharmacology, University of Melbourne, Parkville 3010, Australia.

Abstract The causes of most neurological disorders are not fully understood. Inflammation and blood-brain barrier dysfunction appear to play major roles in the pathology of these diseases. Inflammatory insults that occur during brain development may have widespread effects later in life for a spectrum of neurological disorders. In this review a new hypothesis suggesting a mechanistic link between inflammation and blood-brain barrier function (integrity), which is universally important in both neurodevelopmental and neurodegerative diseases, is proposed. The role of inflammation and the blood-brain barrier will be discussed in cerebral palsy, schizophrenia, Parkinson's disease, Alzheimer's disease and multiple sclerosis, conditions where both inflammation and blood-brain barrier dysfunction occur either during initiation and/or progression of the disease. We suggest that breakdown of normal blood-brain barrier function resulting in a short-lasting influx of blood born molecules, in particular plasma proteins, may cause local damage such as reduction of brain white matter observed in some newborn babies, but may also be the mechanism behind some neurodegenerative diseases related to underlying brain damage and long-term changes in barrier properties.

PMID: 19077110 [PubMed - as supplied by publisher

In a communication with Prof. Al Lossinsky, he confirmed that BBB permeability can be measured in a living person, stating,
“Yes, there are methods available in the clinic to measure BBB leakage in humans. The person would be given special radio-opaque tracers into their blood and any increased permeability would be measured in special scanners."
Therefore, the BBB permeability should be measured in a group of PD patients with a spectrum of progression, from slight to severe.
If a correlation can be established, ie if the slight person is close to the permeability of a normal person , then increasing severity of symptoms shows an increasing permeability figure, this will be a massive step foreward.
A simple measurement of the permeability would confirm the PD diagnosis or otherwise.
New drugs or treatments could be evaluated simply and cheaply by their ability to show a reduction in permeability, by the time and level of reduction.
A reduction in permeability to that below the threshold of dopamine leakage would constitute a cure.

CONCLUSIONS
There is much evidence to date showing a link between the BBB and the onset of PD, or an adverse effect on the symptoms of a sufferer, possibly due to a build up of toxins in the PD brain. In addition, the higher permeability of the BBB in PWP, may allow dopamine to pass out of the brain into the bloodstream, exacerbating the symptoms of PD.
By the same token, carbidopa could possibly now enter the brain, and prevent the conversion there of levodopa into dopamine. See ref. 6.
There is also the intriguing possibility that research into manipulating the permeability of the BBB may also benefit a series of neurological diseases, since evidence exists that the BBB is implicated in multiple sclerosis,. ALS, schizophrenia, Alzheimer’s disease, brain oedema and dementia.

Ron Hutton

References,
1. E-MOVE reports from the 9th International Congress of Parkinson’s Disease and Movement Disorders, New Orleans 5-8 March, 2005. Pages and abstract numbers are from Movement Disorders 2005;20(suppl 10).
. Blood-brain barrier dysfunction in Parkinson's disease
KL Leenders, R Kortekaas, AL Bartels, J Oostrom, A Willemsen, J Bart
S77, P257
See also,
Kortekaas R, Leenders KL, van Oostrom JC, et al., Blood-brain barrier dysfunction in parkinsonian midbrain in vivo. Ann Neurol. 2005 Feb; 57(2):176-9. Comment in: Ann Neurol. 2005 Feb; 57(2):161-2.
2. Science News 1996 Dec. !4 vol. 150 No.24 p.375.
3. Molecular Medicine 7(12): 810–815, 2001
© 2001 The Picower Institute Press
ApoE Deficiency Compromises the Blood Brain Barrier
Especially After Injury
Nassia Methia,1,2* Patrick André,1,2* Ali Hafezi-Moghadam,1,2 Maria Economopoulos,1
Kennard L. Thomas,1 and Denisa D. Wagner1,2
4. http://www.news-medical.net/?id=25774
5. http://www.getipm.com/articles/bbb-lawn.htm
6. PMID 2753115 Experimental Neurology
Volume 105, Issue 2, August 1989, Pages 152-161 Ahlskog JE, et al.
7. N.Joan Abbott et al, Nature Reviews Neuroscience, 7, 41-43, Jan., 2000.
8. Desai, Brinda S.1; Monahan, Angela J.1; Carvey, Paul M.2; Hendey, Bill1
Cell Transplantation, Volume 16, Number 3, 2007 , pp. 285-299(15)
9. Edward L Tobinick and Hyman Gross
Journal of Neuroinflammation 2008, 5:2doi:10.1186/1742-2094-5-2 10. E.A.van Vliet et al, Brain, 2007, 130(2): 521-534, 11. Arch Neurol. 2003;60:1043-1044, 1059-1064 12. J. Pharmacol. Ext. Ther. 2007, Aug. 17, 17704356. 13. European J. of Pharmacology, April 2007, 561(1-3): 54-62. 14. I.Rite et al Journal of Neurochemistry, Volume 101, Number 6, June 2007 , pp. 1567-1582(16 !5. The J. of Immunology, 2006, 177, 2630-2637. 16. Int. J. Neuroscience Vol. 114, Issue 4, April 2004, 517-528. 17. Life Sci. 2003 Nov. 7, 73(25): 3235-44. 18. J.Neurosurg. 2003 Apr., 98(4):867-73.

An interesting paper showing a similar theory for MS was found by Rick in a previous thread.

"MS patients have been shown to have an abnormal blood-brain barrier, presumably as a result of excessive platelet adhesiveness and aggregation. Damage to the blood brain barrier may allow the influx to the cerebrospinal fluid of substances in the blood, such as bacteria, viruses, antibodies, toxic chemicals and other compounds, that are toxic to myelin. Lack of oxygen may also be a contributing factor in de-myelination, by promoting both the release of cellular enzymes and cellular suffocation (death)." (Encyclopedia of Natural Medicine, 1991, Michael T. Murray, N.D. & Joseph E. Pizzorno, N.D.)

http://www.opc.cc/opc-ms.html

A deficiency of Omega-3...alpha linolenic acid can be a factor here.

This is a long abstract, and very interesting discussing aging, and deficiency:
http://www.ncbi.nlm.nih.gov/pubmed/15129302?ordinalpos=1&itool=EntrezSystem2.PEntrez. Pubmed.Pubmed_ResultsPanel.Pubmed_DiscoveryPanel.P ubmed_Discovery_RA&linkpos=5&log$=relatedreviews&l ogdbfrom=pubmed

Some here may find this interesting.

Oh, the link did not bold... sometimes they don't. So a copy/paste is needed instead, sorry.

Terrific post, Ron. Thanks for your hard work in this arena. I think it's very important. There are researchers studying PD in my workplace. I'll try to discuss this with someone in the lab, though I don't really know them. Thanks!

We have seen several reports that coffee has a protective effect on warding off PD. For example http://www.gairrhydd.com/features/sc...ell-the-coffee
states, "Another study comparing heavy coffee drinkers (3.5 cups a day) with non-drinkers found that the coffee drinkers were significantly less likely to contract Parkinson’s Disease later in life. Likewise, a second study found an inverse relationship between the amount of coffee regularly drunk and the likelihood of developing Parkinson’s Disease."
This is another one to add to the list of beneficial substances which reduce the permeabilty of the BBB.
http://www.mombu.com/medicine/allerg...n-2470596.html
states, " A study in the open access publication, Journal of
Neuroinflammation revealed that caffeine equivalent to just one cup of
coffee a day could protect the blood-brain barrier (BBB) from damage
that occurred with a high-fat diet."
Also,
"In this study, researchers from the University of North Dakota School of
Medicine and Health Sciences gave rabbits 3 mg caffeine each day -- the
equivalent of a daily cup of coffee for an average-sized person. ...After 12 weeks a number of laboratory tests showed that the BBB was
significantly more intact in rabbits receiving a daily dose of caffeine."

Yet I can't interest any researchers or organisation to take seriously the involvement of a defective BBB in PD. How many more need we add to the list.
Ron