Beating a dead horse: dopamine and PD - from Mayo Clinic, no less
 

Basically, he's saying, So let's get on with it! We need to study other things. I have gisted some of the medicalese in brackets to make it more comfortable to read.

Jaye

//begin quote//

Neurology. 2007 Oct 23;69(17):1701-11. Links
Beating a dead horse: dopamine and Parkinson disease.

Ahlskog JE.
Department of Neurology, Mayo Clinic

Our collective thinking about Parkinson disease (PD) has been heavily influenced by the dramatic response to dopamine replacement therapy. For progress to continue, however, we need to take a broad view of this disorder, which includes recognition of the following. First, substantial evidence now indicates that dopamine oxidation is unlikely to substantially contribute to the pathogenesis of PD [means roughly that the body's processing dopamine probably doesn't hurt you much]. Second, levodopa therapy is not associated with neurotoxicity [it doesn't damage the brain or nerve cells]. Third, the first neurons affected in PD are nondopaminergic [PD starts first in other places than the substantia nigra layer of the brain, where the dopamine-making cells are]; the substantia nigra and other dopaminergic nuclei are affected only later in the course. Thus, PD is much more than degeneration of the dopaminergic nigrostriatal system. Fourth, in the current era, most of the disability of advancing PD is from involvement of nondopaminergic [non-dopamine-making] systems, including levodopa-refractory motor symptoms, dementia, and dysautonomia [dyskinesia, dystonia, dementia, malfunction of the autonomic nervous system]. Motor complications associated with levodopa therapy can be problematic, but they can be controlled in most, using available medications and deep brain stimulation surgery. We have reached the point of diminishing therapeutic returns with drugs acting on dopamine systems; more dopaminergic medications will provide only modest incremental benefit over current therapies. Finally, the benefits from transplantation surgeries aimed at restoring dopaminergic neurotransmission will be limited because later-stage PD disability comes from nondopaminergic substrates. Scale.
PMID: 17954785 [PubMed - in process]

//end quote//

Jaye - this has to be one of the most significant / provocative journal articles ever about PD (IMHO!)!

The author's conclusion is why I think that stem cells are not the answer (or at least, not the complete answer) for PD.

I love that the science is finally catching up to patient experience. If only they had started listening to us earlier!

Thanks, Carey!
 

I was so excited when I saw it come in on the AMEDEO feed this morning! We and the generations before us have waited a long time for this.

Trying to remember what dancing shoes were,
Jaye

Sorry to rain on the parade. but...
 

...this should be old news to every researcher and doctor in the world as the paper below shows. Thirty dam*** years ago. My point is that people have to get noisy about this at every opportunity.

1: Natl Inst Drug Abuse Res Monogr Ser. 1975 Nov;(3):13-21.

Brain monoamines and parkinsonism.

Hornykiewicz O.

In Parkinson's disease there is a derangement of the metabolism of at least 3
major brain monoamines, namely, dopamine (DA), norepinephrine (NE) and serotonin
(5-HT). Of these alterations the severe deficiency of DA in the striatum is most
characteristic, being (a) found in Parkinsonian syndromes of any etiology and (b)
significantly correlated with the degree of cell loss in the substantia nigra,
and the severity of the main symptoms. On the basis of neurochemical-clinical
correlations Parkinson's disease may be subdivided into (a) an asymptomatic stage
during which the striatal DA deficiency may reach a marked degree but can be
compensated by the remaining DA neurons, and (b) the stage of decompensation
(i.e. clinically manifest disease) which ensues when the depetion of striatal DA
reaches 70% or more. L-Dopa's main feature as a specific antiparkinson drug may
be seen in its potential to revert the decompensated stage of the disease to the
stage of functional compensation. This is in many cases possible because (a) the
DA turnover in the remaining DA neurons is increased, providing for a high rate
of formation (from L-dopa) and release of DA; (b) the "denervated" striatal
receptors are supersensitive to DA; and (c) the newly-formed DA can be expected
to reach a wide area of the striatum due to the high degree of divergence of the
dopaminergic innervation. Compared with the striatal DA deficiency, the degree of
NE and 5-HT decrease in the Parkinsonian brain is moderate. The decrease in NE
may be due to the (moderate) cell loss in the locus coeruleus; at present no
morphological basis for the lowering of brain 5-HT is known. The functional
significance of the changes in brain NE may be an aggravation of akinesia. The
decrease in brain 5-HT may be related to aspects of Parkinson's disease in turn
related to affective behavior and mood.

PMID: 787796 [PubMed - indexed for MEDLINE]

That's just the point - it's not old news to most researchers. Or else it's known but they have chosen to ignore it. That's why I think it's so provocative - because it bucks the prevailing trend/wisdom of mainstream research. But a few voices are starting to speak up - Bill Langston from the Parkinson's Institute is one - he uses the Braak stages (another maverick) as the basis for the talks he gives lately. Hopefully it's an old theory that will take on a new life.

translational medicine
 

I just said this:

But now also wondering if it is a result of the long term failure of translating what basic research says into what the clinician does with the patient. There are a lot of docs out there who view PD and PD treatment as simply a matter of dopamine loss and replacement.

"Translational Medicine" is the new thing at the NIH - very much needed and over due!

Dear Jaye and Indigogo
 

This is Vicky from Minnesota who has heard Dr. Ahlkskog speak in person. I still have the handout from the event he spoke some years ago. At that time I had been trying to keep my amount of Sinemet to as low a doseage as I was able to stand. Dr. J. Eric Ahlskog presented his opinion of 10 myths that sabotage treatment of Parkinson's Disease:

Myth #1 - Levodopa stops working after a few years.

• It does not stop working except in some very advanced cases.
• Over 10 to 20 years:
  • The responses are not as dramatic as initially, but typically still beneficial
  • the response often fluctuates and no longer smooth.
• Excellent response sometimes sustained indefinitely

Myth #2 - Levodopa may be toxic

• Toxic if applied directly to cells in test tube, but improves cell health in other test tube experiments.
  
• megadoses administered to mice for up to 18 months not toxic
  
• Increased lifespan in PD patients treated with levodopa.
  
  • Clinical Studies: rate of PD progression the same after one year of levodopa compared to other treatments
  Drugs withdrawn and comparison to baseline.

Myth #3 - Almost everyone develops dyskinesias of levodopa

• The wiggly movements of Michael J. Fox.
  
• Reflects an excessive levodopa effect
  
• May never develop in many people taking levodopa

Myth #4 - Dyskinesias are worse than parkinsonism

Dyskinesias (excessive movement):

• Data just shown relates to dyskinesias appearing for the first time, of any severity
  
• Resolve with levodopa dose reduction
  
• Even when present are often mild
  
• Do not interfere with activities unless severe
  
• Are not painful

Myth #5 - Levodopa should be delayed

• Any decline in the levodopa benefit is related to how long you have had PD, not how long you have been treated.
  
• You can't save the best responses
  
• Delay it only if you don't need it.

Myth #6 - The levodopa dose should be limited

• No long- or short-term benefit to keeping doses low
  
• May result in poor control of PD symptoms if arbitrarily limited
  
• May be detrimental if dose so low that activities limited

Don't take more than you need but take what you need.


Myth #7 - The dopamine agonist are nearly as effective as levodopa

Dopanine agonist=synthetic form of dopamine

• Pramipexole (Mirapex)
• Ropinirole (Requip)

• My experience: not nearly as good as levodopa
  
• Clinical studies: few can get by with these alone after 2-4 years
  
• Additional side effects
  
• Useful to smooth levodopa responses

Myth #8 - The dopamine agonist drugs may slow the progression of PD

Suggested by Brain Imaging studies

• Controversial (confounded)
  
• Drugs may have affected the test (imaging) rather than the PD progression
  
• Parkinson scores actually worse with agonists, opposite to the imaging.
  
• No proof that any medications slow PD progression.

Myth #9 - Controlled-release carbidopa/levodopa is preferred (Sinemet CR)

Facts about the CT formulation:

• Effect only lasts 1 hour longer than regular carbidopa/levodopa
  
• It is slow to kick-in and more erratic
  
• It is more expensive for 100 tablets

Myth #10 - Levodopa disrupts sleep

Facts:

• insomnia is common in PD
  
• Usually it is due to the loss of the levodopa effect
  
• Although levodopa doesn't induce sleepiness, it reduces the inner restlessness and stiffness that prevent sleep
  
• Adequate levodopa is the best sleep aid for PD

I believe not one person on this forum can be in complete agreement with Dr. Ahlskog with all of his myths. PD comes in too many forms.

I agree with you Indigogo, it is good to revisit older theories.

I also agree with Jaye. But the patients have to bear some responsibility for the attempts to prove theories rather than learn more about the disease. The lobbying and pressure that advocates applied to congress for funding theories to find a quick cure rather than learning the etiologie of PD slowed down the scientific community's research efforts. By trying to appease the patient lobbyists, the pharmaceutical companies let the patients' (their market) determine the direction of research, not hard science.

Vicky

Vicky - not all advocates lobby exclusively for a cure. Some of us have been lobbying the lobbyists for years to broaden the message to include more research for better treatments, legislation for issues that improve quality of life (insurance, Social Security, prescription drug policy, etc), and engagement with federal agencies such as the FDA. They are finally beginning to get the message and respond. Especially as hope for a quick cure dissolves as we learn more about the complexity of this disease we face.

This is the real power of patient advocacy - the orgs, especially the Parkinson's Action Network, set the legislative agenda. They are finally (the last 18 months or so) making room for patients in the rooms where the decisions are being made (places for grassroots advocates on their board and on internal committees).

This has not happened on its own accord - we've had to PUSH HARD - it has been a difficult campaign, one with no small amount of anger, tears, bad feelings, and, hopefully, finally, healing progress.

chit chat
 

Vicky,

i was delighted to read all of the debunked myths. So far, I find them to be true but as my first neuro made very clear - a rapid drop is possible at any time

So, I am not holding anything back, am not going to b.s. anyone. And I reserve the right to laugh and joke around - my favorite thing to do. Some of us have a major need for laughter and humor.

There is a possible collaboration settling into place.
I think the orgs are going to communicate and work together - possibility of jumbo grant. Things have never been so connected - I am starting to think we could get something..for relief ..had given up on that -----now i am getting refired up....all we have to do is be ourselves, no playing personality traps. - one does try one's best...after all this is volunteer work.

Vicky - Two other quick points:

1. Lobbyists can influence the overall amount of money appropriated by Congress for the NIH, but they have no power, and neither does Congress, to influence how the NIH actually allocates and spends the money. That is because they believe in precisely the point you made - government should not interfere in the scientific process; it's up to the various NIH institutes to make budget and funding decisions based on the science, not politics. (Bush stymied this hands-off policy by stopping stem cell research by Executive Order).

2. Lobbyists would love to be able to move Big Pharma and Biotech to pay more attention to cures - but treatments that are never ending are much more lucrative. Why cure someone when we can keep them buying our drugs for their whole lives? is the drug company motto.