Expanding our universe...looking beyond dopamine
 

Interesting interview with Jack Clark, neurologist out of University of Toronto, who seems to get that we need to move beyond dopamine replacement therapy. He even calls it "Parkinson's Diseases" we have different etiologies with same clinical features.

Highlight of what he has to say at The Dana Organization; there is also a fantastic visual that can be printed for reference.

...Parkinson’s disease is far more than a degeneration of the nigrostriatal dopamine system. Instead, it is a widespread process involving multiple brain systems, including those involving noradrenaline, serotonin, acetylcholine, and other neurotransmitters.

Moreover, as the disease progresses, patients develop a number of symptoms that respond poorly if at all to dopamine replacement therapy. These symptoms—now commonly believed to occur due to involvement of non-dopaminergic brain regions—account for a very large proportion of the disability seen in the later stages of the disease.

Just as man needed to move beyond the Ptolemaic belief that the earth was the center of the universe around which the sun and planets revolved, I feel that we now need to go beyond the belief that dopamine is the center of the Parkinson Universe

It/s Tony Lang!
 

Laura - I looked at the article and made the same mistake - then I looked closer - the interview is with Tony Lang who is the Jack Clark Chair of PD Research at U Toronto.

Dr. Lang is well known to us - a major foe in the GDNF wars; disdainful of patients (tell them about San Diego, Paula!), and a huge influence in PD research (past president of the Movement Disorder Society)

That said ........ I am so very encouraged by his words - I can barely believe they are coming from him!

Thanks for the correction, Carey. This is what happens when multitasking- do I dare say, "brain cramp"? ;)

I am; however, disappointed to hear he is our Lex Luther. Paula, maybe some day, you can add your Tony Lang story here?

I guess on the bright side, we should be encouraged that an old timer is actually "getting it". :) No matter what his faults, he seems to have the courage of his convictions, and I can respect that.

Laura

Across the universe - yeah, yeah, yeah!
 

Laura - exactly! If he is thinking this progressively, it is good that he is in a position of influence. Maybe he'll warm up to the presence of patients and our ideas as well. After all, patients have known for as long as we have lived with PD that what we are experiencing is not the small universe as described in the literature - it's much more expansive - glad the research is finally catching up!

more connections
 

oh where to begin? i met jack clark ...lol...he is [was? this was during plwp days] a patient and a millionaire in canada. he held a symposium at his mansion that we all attended on alternative therapies - reiki, etc. a different therapy in each room. his giant kitchen provided a wonderful huge dinner and we all ended up dancing, including the elderly jack and his wife to "We are Family". All arranged through lynda mckenzie's group [the gal in Freed's fetal cell study]

jack donated the money for the chair. Tony Lang is a bright guy and he is authoring some of this nondopaminergic thinking. He defended Amgen at the table that day for 3 hours in San Diego and authored much of the pro amgen arguments in the medical journals. Two things stand out for me about Tony Lang. One is that he wasn't glad about the halt of gdnf at first either. That;s the good stand out. The other is his statement to April, a participant, that day ,"do you want two hockey pucks in your stomach forever?"

well--yeah----some of the gdnf participants did...otherwise why were they inserted? were they ever really going to produce that treatment?

On the same day, the very same day, a new definition of pd appeared on the front page of the San Diego newspaper that redefined pd as having a non motor component.

Now the nondopaminergic movement.

But what is being created - a medicine or a market? in theory i am having no trouble with nondopaminergic - I'm living it. I agree with Dr. Lang in theory. Someone should write and ask him what he thinks about alzheimers drugs helping pd. Here we have a " consultant" and many 'conflicts of interest". What are they? just something listed at the end of articles....with no explanation.


paula

Paula - that is so funny! I've always heard from you veterans about the Canadian meetings, and have had the opportunity to meet Linda MacKenzie, but I have never heard the Jack Clark story! It's been soooooooo long!

Carey, Paula,
Because of your posts I have read and re-read the article, and I think there is a huge amount in it that needs discussion, there is a very revisionist quality to it. For instance there is a statement that many people in the pre-levodopa era died before exhibiting the non-dopaminergic symptoms, that they in other words died prematurely. This is not anything that I have seen expressed elsewhere, and I grew up with my untreated grandmother, who had PD and lived into her eighties, certainly over 30 years with PD, and it was my understanding that this was normal in untreated PD. She certainly had the non-motor symptoms. It was not an unusual condition in my community, in fact there are descriptions in modern writing that bear this out. So I don't quite buy the idea that the motor symptoms masked the non-motor in days before levodopa........, or that the differences between non-motor, non-dopaminergic and dopaminergic symptoms were not evident and visible - ignored, not considered, or regarded as untreatable maybe...

The article does however define different aspects of PD well, and moves us into this unknown potentiality of a post-dopaminergic phase of PD - though I do not think we are anywhere near resolving the dopaminergic stage yet. I am not the expert, just a patient, yet I find this article both hugely hope-making from one type of reading, and rather disconcerting from another.

I am really glad that Laura brought it to our attention, not the least because it expresses some things that patients have been discussing for all of the time that I have been on the forums! As though these things are fresh and new.........

The history notwithstanding, I would like to see more opinion on the content of the interview.............

Lindy

devil's advocate
 

Lindy are you thinking that when dopamine stops working we get these symptoms? It's really the l-dopa addiction and just running out of dopamine?
Are you thinking it' still dopamine we need?

it's another way to look at this. we wouldn't have the nondopaminergic symptoms if we did not have the lack of dopamine and the dopamine replacement eventually stops working and causes serious problems. dopamine now doesn't help, because we have no more dopamine cells.

Yet Dr. lang in this interview and with others in other articles specifically states that cell replacement is not the answer. i'm soo in over my head here.

lindy is this what you meant?
paula

Paula,
I just think that all these symptoms have been there to be seen traditionally in PD, with the exception of those that are clearly side-effects and not symptoms.

So to talk about them as though they were not always there and visible is to re-write history. For instance it is not for nothing that once PD was treated in elderly patients who had it for a long time as a psychiatric disorder. In other words, there were always non motor symptoms, before levodopa, but neuros did not know what to do with them so they were passed on to the other variety of 'head' doctors, the psychiatrists, just as now if we manifest with bladder symptoms we are passed on to a urologist.

So to state that these symptoms only came into evidence in the 'dopamine era' is bending the truth.

So now patients are demanding, as they are more able and better informed, that these same symptoms be taken into consideration, and perhaps these same doctors who have always erred on the side ignoring these same symptoms can see that perhaps they can be treated....... but they have not yet really got a handle on dopamine treatments yet, We are better at this than they are. Look at the patients who have managed many years on dopamine, keeping their doses very low and ensuring that their brains have an even dose, or as much as possible, and have fewer side effects. But also consider those whose neuros do not really understand dopamine, and who willy-nilly encourage patients to up their dosage, or add other drugs, create huge cocktails of medication, and no-one professional really understands these complex interactions. In fact in the very elderly, because their brains by that time are very fragile, often drugs are reduced to the very minimum or in other words, dopamine only. Because the rest is too much for their bodies to cope with.

Obviously the best informed doctors are better, but we have seen many people come on the forums under-medicated, overmedicated, under-informed about their medication, and not knowing whether they were suffering from PD or side-effects, or whether they were progressing rapidly, and in a state of acute anxiety.

So I say that dopamine as a treatment has not really been properly understood. So how can we be at a stage called 'post-dopamine' era ? And if that is where we are heading, along with the industry that has accumulated around our condition, where are we going?? That is what I am asking about.

I do not know the answers, but I do think that when we are on a minimum of medication, and our non motor issues have been addressed, then we are likely to have the best quality of life.

It is making that happen, and making it work for us that is the real question. And I do believe that some of these things can happen without drug interventions, too. The multi-faceted approaches we have discussed here are surely part of the answer......

There has always been a minority of researchers who express doubts about ldopa. In particular, I wonder about the metabolites and waste products that go with it.

Lang is trying to cover his *****. He knows what the truth is; the fact is that the major researchers have done a great job ignoring facts about PD that didn't fit into their paradigm of the disease. They were wrong; it is good that they now recognize it, but they are never going to admit they were wrong.

The ultimate reason for the patient to be part of the research discussion. We know the disease; they don't.

post-dopa era? from the heart and not the head.......
 

.... how can there be a post dopamine era without a post dopamine treatment? my radar is not picking up on this....

l-dopa is not a perfect diamond
but it has not yet been surpassed
it's failings have not been addressed

neither have the failings in thinking,
like, when the cascade of events in our brains happens
why do people think the lack of neuromelanin in our p/m brains
is the most important sign of pd
when there are living specimens
ready and willing to be questioned
examined
at all stages of this condition
and show what PD
ACTUALLY IS

moreover
why do they have to prove it in creatures that cannot speak
when there are millions of creatures who can!

and again
all the non human models of pd
are not for us
not to prove what our condition IS
we are the proof of what our condition is....

our positions as stakeholders are different..........

may i add to your thoughts?
 

Why are we expected to get dementia?
Will these assigned by others expectations determine our outcome?
I reject the notion that we will get dementia;
Different doesn't mean dementia.
Just like it doesn't mean retarded.

paula

dementia
 

we probably won't ................

http://emedicine.medscape.com/article/289595-overview

but look at what's wrong with the end of this article, only a patient could understand!

Dopamine Dogma
 

Carey,

How very true this is in regard to patient involvement; in essence, we should drive the direction of research. What I find most troubling about all this is that much of the research I have unearthed on other areas of the brain and other neurotransmitters at play in PD dates back to 2000 if not earlier. It's not like this is newly discovered or anything. Clinicians have known since treatment for PD began with levodopa that it is by no means treats all our symptoms; it just plain cannot do it, given the complexity of the disorder and possibly the existence of sub-types.

In other words, researchers for the most part have been running in place looking for levodopa adjuncts or extenders or whatever- they have been playing it safe for at least a decade! It's like no one dare push levodopa off its throne. Like you said, largely this happened because the patient is so disconnected from the research process other than as guinea pigs at clinical trial time. Still, it is appalling to me that we have non-dopa things happening that result in disability and research never rose up to meet that need- why?
I think I read a researcher express that dopamine has become dogma in neurology and movement disorder treatment- it's an absolute truth that no one dare question or touch- and as such it's held us back for far too long.

Lindy,

There are some promising new treatments on the horizon. I've been working on reviewing treatments on the PD Pipeline and ran across this extremely promising new therapy targeting other neurotransmitters. The Addex ADX48621 is a glutamate inhibitor that they describe as a dimmer switch between neurotransmissions- it fine tunes everything and doesn't directly control any one chemical. While pharma is often very generous in their claims...I can't help but get excited when I read this at the Addex site:

Recent preclinical research in rodent and primate models of PD show that mGluR5 inhibition alleviates PD-LID. The clinical and preclinical evidence suggest that mGluR5 inhibition also may prove to be a dopamine sparing drug, or even a standalone alternative to levodopa, the long-standing gold standard therapy for PD.

mGluR5 is found in regions of the brain considered to be key control points in the neuronal movement circuits thought to be responsible for the abnormal signaling by the neurotransmitter glutamate. Perturbations in glutamate signaling (along with disruptions in dopaminergic signaling) is believed to be an underlying cause of movement disorders like Parkinson's disease. As such, inhibiting mGluR5 could act to re-establish normal movement via a non-dopaminergic mechanism, thereby offering a dopamine sparing therapy.

Separately, preclinical findings also suggest that mGluR5 inhibitors may be neuroprotective and may, therefore, hold potential to treat disease progression.


I was happy just to hear we may have an alternative in our lifetime let alone it may be neuroprotective (don't they all try to stake that claim!) I find this really exciting and hope it gets fast tracked. MJFF has thrown 4.5 million to research into the glutamate receptor, so I'm thinking that Addex may be onto something.

How is it delivered? Fortunately, no brain rewiring or hockey pucks in the gut- it's an oral suspension...more pill popping, but if it can take the place of levodopa and have a longer effect than 2 hours, hey, I'm all for it!

If we can all hang in there a little longer!

Laura

Laura, we are still all holding our breath -
when the theory results in a treatment -
it's a therapy when it gets into the hands of patients
a treatment when it is prescribed -
i am not being negative
just realistic, there have been so many
promising things sitting just out of reach
on our horizon......

Here's a good article about new targets, in PDF form. Let me know if you can't see it:

Novel pharmacological targets for the treatment of Parkinson's disease


AH Schapira, E Bezard, J Brotchie, F Calon … - Nature Reviews Drug …, 2006

http://www1.tu-darmstadt.de/fb/ch/Fa...en/nrd2087.pdf