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What Causes Parkinson’s Disease?

J. Eric Ahlskog, M.D., is a Professor of Neurology at the Mayo Medical School, and Chair of the Mayo Section of Movement Disorders, Mayo Clinic, Rochester, Minnesota.  He has two OUP books on Parkinson’s Disease, The Parkinson’s Disease Treatment Book: Partnering With Your Doctor to Get the Most From Your Medications, which we have excerpted below and the new, Parkinson’s Disease Treatment Guide, For Physicians, which we will look at more closely next Monday.  In the excerpt below, from Ahlskog’s patient orientated book, we learn about the obscure origins of Parkinson’s Disease.

…Parkinson’s disease (PD) is a neurodegenerative disorder, one of a variety of such conditions.  To date, we have not identified the cause for any of them, despite major research efforts in laboratories and clinics around the world.

For decades, theories have been proposed for the cause of PD, but with little support from hard facts.  Blame has been placed on everything from viruses and bacteria to the food we eat.  Each hypothesis has had enough supporting evidence to stimulate research, mostly leading to dead ends.  We need credible clues to point us in the right direction.  Clues are slowly accumulating, although some may be red herrings.  However, the answer is probably buried in what we already know.  The trick is to figure out which of the many pieces of evidence will lead us to the cause of PD.  Let’s first review two areas of investigation that have been a central focus in the past ten to twenty years-the MPTP story and the oxidative stress hypothesis.

The MPTP Story

About twenty years ago, a number of young illicit drug users in California were diagnosed with parkinsonism, which developed over a few days to weeks.  The cause was found to be a street drug they injected for a high: a substance with chemical similarity to certain narcotics, MPTP (1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine).  We now know that this substance accumulates inside the sustantia nigra neurons in the brain and kills them.  MPTP was subjected to intense study in hopes that this might provide clues to PD in the general population.  Multiple investigators have looked for evidence that this or similar toxins might be present in either the environment or the body.  Despite enormous research, toxins of this type have not surfaced as a cause of PD.  At present, this appears to have been an isolated event.  No similar epidemics of parkinsonism have occurred.  This discovery, however, led to the development of animal models of PD.  MPTP injected into mice or monkeys makes them parkinsonian, which allows drugs to be tested for treatment.

Oxidative Stress as the Cause of PD

The most popular theory for PD in the past decade has been the oxidative stress hypothesis.  Oxidation is a natural chemical reaction that occurs in all of our cells.  It is necessary for life.  However, like too much of anything, too much oxidation is bad for cells.  Why do the substantia nigra cells degenerate in PD?  Perhaps it relates to the oxidation of dopamine inside those cells.  Specifically investigators noted that dopamine is metabolized by way of oxidation reactions.  This led to the proposal that excessive oxidation may damage substantia nigra neurons.  Thus dopamine-generated oxidative stress was hypothesized to cause PD.

In fact, a myriad of oxidation reactions continuously occur in every cell of the body and are essential for life.  There are many natural safeguards in all cells that control and counterbalance oxidation reactions.  Although indirect evidence suggested dopamine oxidation reactions as a possible culprit, direct evidence has not surfaced, and enthusiasm for this hypothesis is waning.  The most compelling argument against this theory relates to the fact that dopamine-containing cells are not the only neurons that degenerate in PD.  They are the most visible, since their loss results in such prominent symptoms.  However, the PD degenerative process similarly affects numerous other brain cells.  In fact, recent pathologic studies suggest that nondopaminergic neurons in the lower brain stem may be the first affected in PD, rather than the dopaminergic substantia nigra cells.  Thus scientists are looking in other directions.

PD researchers are like detectives trying to solve a crime.  Further insight into the cause surfaces with each new clue…

Recent Comments

  1. Ron Hutton



    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, and carbidopa could now enter the brain, (this has now been shown to happen), and prevent the conversion of levodopa into dopamine.

    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 .
    In the CNS lead increases the permeability of the blood-brain barrier (BBB)

    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,”
    “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.

    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

    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.

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