Hi

With this post I seek neither to preach or teach but merely stimulate discussion.

Ever since I was diagnosed I've become increasingly convinced that not only are there undiscovered sub-sets of Parkinson's but that other Neurotransmitters are involved. My particular interest is stress as a causative factor in the development of the disease and therefore a possible role played by acetylcholine,serotonin,etc.
I was therefore both heartened and frustrated to discover that here in England Huw Morris stated that he now thinks early onset Parki is a separate disease related to serotonin, that MJF foundation has commissioned it's first research into stress and that the US Army has started researching Parkinson's and one of several areas interest is stress. (combat veterans sometimes manifest PTS as a movement disorder very Parkinsonian in appearance)
I say frustrated because I'm just a bloke with a laptop and average intelligence......so why only now are researchers starting to think outside the box.
General Anxiety Disorder and depression are separate conditions but both are assumed to be caused by low serotonin levels and as such are treated,mostly, with anti-depressants. These work, with varying degrees of success, for most people but not all. Further they are famous for initially making the problem worse (to the point of suicide in some cases) before the sufferer gets better.
Now in Sweden a team has mapped serotonin function in diagnosed GAD subjects and found they actually had too much serotonin which may explain the variable treatment results.
In our world I keep coming across folk who have been traditionally diagnosed, respond to dopa yet have a negative dat.scan. Whats the response ? Dat.scans are not foolproof/rely on operators skill. The usual. Maybe it's because dopamine ain't the 'main' problem ?
But levodopa works ! It's the 'Gold Std' ! Yes it does but it also slowly stops working.

Im not saying it's not dopamine,far from it. But since the last breakthrough was in the 1960's and its now 2015 and the last 50+ years of research have been focussed on dopamine cell death and we're no further on in this fight I feel it's time for a Paradigm shift.

Nigel

there are many neuros that state dopamine doesn't stop "working", but as you advance in the disease you have less neurons that can convert l-dopa to dopamine, less cells that control movement, etc. the brain is like an engine that is wearing out and leaking oil, the oil still lubricates but you have to keep adding more oil as it gradually leaks out faster. when you are first diagnosed, i imagine the healthy neurons compensate and produce more dopamine, more connections, more dopamine receptors but as you progress you reach a point where the rate limiting factor of how well l-dopa works is based on ........ dunno.

"Levodopa in combination with the dopa-decarboxylase inhibitor benserazide (co-beneldopa) or carbidopa (co-careldopa) remains the most efficacious treatment for the motor symptoms of PD.6 As PD progresses, most patients will develop motor complications, including ‘wearing off’ of the treatment response and levodopa-induced dyskinesias (LIDs). Risk factors for LIDs include younger age at onset, longer duration of treatment and higher dose of levodopa.6–8 Fear of these complications has promoted ‘levodopa phobia’, which has delayed the introduction of levodopa. To those clinicians and patients who worry about the ‘risks’ associated with levodopa therapy, I recommend a useful review by Vlaar et al, which dispels much of the mythology.9 As long as the diagnosis has not changed, levodopa should never ‘stop’ working, although the consistency of response declines over time. Moreover, the risk and severity of LIDs can be minimised by keeping the dose of levodopa low. Levodopa should therefore be considered as a potential first-line therapy in all age groups, although caution may be required in younger patients, particularly those younger than 50 years.

http://www.clinmed.rcpjournal.org/co...dicine;13/1/93


i only post this since l-dopa gets a bad rap it doesn't deserve. pd'ers suffered greatly and lifespans were a lot shorter before C/L became available.

if you want to see what was studied before C/L was commercialized in the 1970's, look at :

876 pages
starts discussing use of l-dopa p. 491
Beans, roots and leaves
A History of the Chemical Therapy
of Parkinsonism
by
Paul Bernard Foley
B.Sc. (Hons) (Macquarie), M.A. (Würzburg)
Doctoral dissertation submitted to the Bavarian Julius Maximilian University, Wurzberg, 2001
http://d-nb.info/96446392X/34

Niggs,

Thank you for posting this. I would agree with much of what you write: subgroups, dopamine not being the whole story, a role for stress as a causative agent (but, not THE causative agent), disappointing progress in the last 50 years. However, I would argue that much progress has been made: DBS, agonists, better symptom control techniques.

Is it time for a paradigm shift? I think there's still mileage in finding ways to stop alpha-synuclein folding, and this should be our number one target. But that said I don't think we should put all our eggs in one basket. Research should be done on many different fronts, encompassing both the immediate (e.g. exercise) and the long-term (e.g. epidemiology).

You say you have a "particular interest" in the role of stress. Until his death last year Rick Everett often posted on this subject. His posts were excellent. I'd encourage you to read them.

I would also encourage you to become a "citizen-scientist". If you can find no answer to your questions in the scientific literature, go answer them yourself.

John

Soccertese,John

Thanks for the replies, I feel I'v joined the right forum.

Soccertese, I find the piece on levodopa a perfect balance, I have'nt read it before . I am aware of the life changing/extending impact of levodopa in the 60's but feel it,with good reason, came to be regarded almost as a cure. It is also cheap and adds to a general attitude of entrenched views.

John,it was a post by Rick Everett that I came across years ago that inspired me with his phrase "the dark underbelly of Parkinson's"
Also I was a contact Lens Optician for 30 yr and came across stress induced blindness (hysterical blindness) where temporary blindness manifests due to stress without any other pathology.

I agree that alpha syn. protein looks promising but so do calcium blockers and faulty D receptor mitochondria and so on. I also feel there are plenty of obvious things that should be fully researched such as paradoxical kinesia and the pronounced placebo effect.
I can't regard agonists as an advancement a la L..dopa. DBS can be remarkable....but only if it works for you.

I'm all for positive and responsible paradigm shifts, I would suggest a couple of shifts currently at work in the research community that may qualify as good ones:
A. Areas of research..
1. Physical exercise. Dr. Jay Alberts work on the effects of cycling and PD. I've used his work to inform my exercising.
2. Leading mechanism work done at Columbia U. on sense of smell and PD. I was a research subject there in this area.
B. Approaches to research by MJF, a nuber of MJF Foundation projects act as multipliers or accelerators of OTHER peopl work..
1. Fox Trial Finder uses simple 21st century technology to link researchers with subjects.
2. PPMI works on progression markers. The better these are the more efficient the research.
3. MJF Foundation will assist researchorganizations whose projects contain an outsized risk component that would make the research infeasible without help.

Hooray for these examples of great thinking as well as so many others.

Nigel, I agree with what you wrote.

A couple of years ago I listened to a talk on PD at a scientific conference from a speaker with both a PhD and a medical degree (impressive!).

The speaker made the point that PD is probably not "one disease" in the same sense that cancer is not "one disease".

Rather, it is a multitude of conditions with clinical signs in common - the underlying molecular pathologies will differ from person to person, though there may be some overlap of them between different people.

Rempatterson

Thankyou for your input,

Another area, in line with your post, would be to have a group whose purpose would be to trawl, collate and re-evaluate all the research that has been done over the past 15-20 yrs. There are countless small snippets that have been ignored,passed over probably because they don't fit the established viewpoint.
eg
(someone may be able to tell me where to find this)
A few years back I came across a piece, by chance, about a micro- neurosurgeon who operated on a PWP suffering from terrible neuralgia. He basically moved vessels which were misplaced and pressing on nerves. He was expecting to cure the neuralgia but was surprised to be thanked by the px for dramatically improving his Parkinson's.
I can't remember figures but he went back and examined the existing scans of 10 PWP's but this time looking for vessel/nerve postioning. He found, I think, probably 3 out of the 10 who could possibly be helped like the neuralgia px.
Maybe this was not reported accurately, simply false or perhaps a significant find. The point is, this, along with countless others seems to be simply brushed aside and forgotten.
Nigel

Thankyou Kiwi33 for your input,

I guess from your experience there is actually a shift slowly taking place, this can only be good for us all.

http://parkinsonsmovement.com/on-the-move

Article by Peter Jenner, Edition 12 , p.35 - 38

Looks like a shift is on the way !

Nigel
Regarding neurotransmitters, is this useful info?

http://www.ncbi.nlm.nih.gov/pubmed/20050885

You may also find more of interest on the Parkinsons Movement site ( or its parent site cure Parkinsons Trust). Jon Stamford one of the founders of PM is a neuroscientist with Parkinsons.