Nice to see some interest on PD :)

What are you calling "the cause of PD"? If you mean the cause of the main symptoms then the SN cell loss is a sexy hypothesis. if you are speaking of the cause of all symptoms then it does not apply at all. Review nicely in:

Braak,H., Ghebremedhin,E., Rüb,U., Bratzke,H. and Del Tredici,K. (2004) Stages in the development of Parkinson’s disease-related pathology. Cell Tissue Res., 318, 121–134.

By the way, their is still no clear demonstration of which molecular mechanisms lead to cell toxicity in PD. Lots of hypothesis but still no round shape story...

Thanks, Nicolas. I'm writing a review of what is known about the science of PD. According to Google there are more than 4 million publications on PD but ...... too much hypothesis and speculation and not enough facts.

It depends on what you mean by cause as suggested. I'm not sure of any neurodegenerative disease has a perfect 1:1 necessary and sufficient relationship with any cellular or molecular feature.

One line of evidence comes from the neurontoxins MPTP and 6-hydroxydopamine, which bind the dopamine receptor and lead to lesions in the SN in mice. These treatments recapitulate some, but not all, of the cardinal symptoms of Parkinson's.

see here:

Experimental models of Parkinson's disease

http://www.nature.com/nrn/journal/v2/n5/full/nrn0501_325a.html

Some other possibly useful links, although not a direct answer to your question:

1. Neurodegeneration possibly precedes lewy body formation and clinical parkninson's

Lewy pathology is not the first sign of degeneration in vulnerable neurons in Parkinson disease

http://www.neurology.org./content/79/24/2307.long

Neurodegeneration in Parkinson disease: Moving Lewy bodies out of focus

http://www.neurology.org.proxy.lib.umich.edu/content/79/24/2298.long

2. Direct link between an alpha-synuclein fiber injection, Lewy pathology, and loss of dopamine neurons in anatomically connected regions

Pathological α-Synuclein Transmission Initiates Parkinson-like Neurodegeneration in Nontransgenic Mice

http://www.sciencemag.org/content/338/6109/949

Jeffrey -

You make a good and important point. We are accustomed to think of PD, as we used to think of cancer, as one disease with many manifestations. We ought to get used to the possibility that it is several diseases whose symptoms overlap and sometimes converge - "Parkinsons' Diseases". Three weeks ago I had a 3 hour assessment as a subject in a research project and was told that I had "too few of the characteristic symptoms" and was "atypical". I'm sure a lot of cases are not diagnosed, in which case our view of the disease will be distorted.

Hi Jeffrey!

I like to see PD as a vicious loop in which the first insult may vary (for example mitochondrial dysfunction, protein degradation pathway impairment...) and leads to a generalized pathology and to a final condition which is reported as the clinical feature of PD.

However this critical pathological loop is still controversial as the importance of some elements (such as inflammation process) are disputable.

Hi, Stephen,

I'm not sure if there is agreement on the cause. Alexander's "Biology of Parkinson's disease: pathogenesis and pathophysiology of a multisystem neurodegenerative disorder" (http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3181806/) may be of interest to you.

He makes the point that motor symptoms are associated with dopamine depletion in only a small area of the ventrolateral SNc. He also clearly identifies other neurotransmitters besides dopamine, and other brain regions affected by PD. Plenty of midbrain-produced dopamine continues to innervate other brain regions besides the BG even in advanced PD. “PD is a disorder of multiple functional systems, not simply the motor system, and of multiple neurotransmitter systems, not merely that of DA. The characteristic pathology intraneuronal Lewy body inclusions and reduced numbers of surviving neurons—is similar in each of the targeted neuron groups, suggesting a common neurodegenerative process.”

He does call it a cell loss in the midbrain neurons, that "gives rise" to the motor symptoms rather than "causing" Parkinson's. I take it you view it as a dormancy in dopamine production, rather than cell loss? I have seen that view elsewhere.

Public recognition is still primarily based on motor symptoms. Recent research is focusing more on nonmotor symptoms looking for earlier diagnosis, because they may appear decades earlier, and are quite diverse (Parkinson's Disease: Non-Motor and Non-Dopaminergic Features. Olanow CW, Stocchi F, and Lang AE, eds., 2011; and the Michael J. Fox Foundation initiatives). There may be plentiful support for your thesis that there are multiple causes.

This is a good question but, I think, easily answered. i'll avoid getting bogged down in semantics over the meaning of cause etc, and get to the evidence of dopaminergic deficits in PD.

Perhaps the best evidence that nigrostriatal dopamine neurons are lost in PD is the loss of tyrosine hydroxylase (TH) stained cell bodies. This is a marker for catecholamine-containing neurons (dopamine and noradrenaline) - if TH staining is lost, that implies that DA neurons are lost. Of course, it may be the cells are "dormant", although I think that cell counts of all neurons in the SN would suggest that they are truly lost. There certainly in no evidence for a reversibility that might be possible if the cells were merely dormant. The imaging evidence needs to be looked at critically - the resolution is probably inadequate to identify a real shrinkage of the SN, a structure of only a few mm3 surrounded by unaffected tissue.

The l-Dopa problem - "if the cells aren't there, how can they produce dopamine?" - is probably due to the fact that while TH is specific and rate-determining for DA synthesis, the next enzyme, dopa decarboxylase, is not, but found far more widely. The fact that DA is not necessarily acting as a classical "fast" neurotransmitter but has actions in the synapse over minutes rather than milliseconds, means that funtionally important increases in extracellular DA may be brought about from the synthesis of DA from l-Dopa in other cells.

The various pathophysiological processes proposed - synuclein etc. - all result in a more-or-less specific cell death of DA neurons in the SN.

Just some thoughts - others more expert will have more to say, I'm sure!

I believe it is a marker, but not the cause of the disease.

Same story is valid with AD and the beta amyloid plaques

Thanks, Gavin - this is very helpful. The half- lives of DA I have seen range from 0.2 millisecond to 2 sec. I find it had to believe that dopa is decarboxylated elsewhere and the DA somehow finds is way to where it's needed. Cytoplasm is pretty viscous stuff and I m sure here must be intracellular transport highways for l-dopa and DA. Do you have a reference for your explanation? IF so I'd appreciate the details.

There are several reports that non-motor (?non DOPA-responsive) symptoms precede motor symptoms by years (although not in my case) but I have little confidence in clinicians' categorisation of symptoms. "postural instability" (falling over) can be caused by: (1) tripping because the feet are not lifted sufficiently when walking (2) inability to move feet quickly when off balance (3) loss of ability to detect loss of balance in the absence of visual or tactile cues. Only 3 is or may be non-motor.

Similarly speech problems arise from (1) poor coordination of tongue and teeth causing slurring (2) Shallow breathing reduces the pressure of air passing over the vocal chords leading to a quiet voice that fades away. (3) festination which makes you try to speak too fast. This leads to inaccurate choice of spoken word compared with the one you intended to use. If this is a genuine symptom of PD it is non-motor.

I don't know the official criteria for distinguishing motor from non-motor symptoms but clinically the distinction seems to be meaningless. For example constipation is usually described as an NMS but it is caused by a failure of the muscles that push the food and residues down the intestinal tract - it is an autonomous reflex motor symptom.

The summary of this paper (http://www.pdf.org/en/science_news/release/pr_1379423617) is a little confusing but seems to suggest that dopaminergic neurons may lose their capacity to produce l-dopa but do not die. See also http://www.ncbi.nlm.nih.gov/pubmed/23884810.,

Stephen,

Thank you for posting these papers. This seems to indicate that if neuroprotective and/or neurorehabilitative strategies were found, the remaining cells could respond by producing dopamine, especially in the early years post-diagnosis, but even later.

I can't really buy the idea that dopamine production stops because the neurones die.

I'm sure that neurones do eventually die but this is at the later stages of the disease.

I'm quite ready to be proved wrong but proof will be hard to find. This was the explanation given to me by my neurologist in a confident self-satisfied voice. It sound facile and easy then but I didn't know enough (or have the heart) to argue with him. I don't blame consultants - most of their patients have dementia and they have no time to read all the papers published on PD. But research is always on high tech sophisticated hypotheses and we've lost sight of the simple questions and some of the simple answers.

To continue the discussion on dopamine synthesis in PD, Stephen, I could make two points. You draw attention, in one of the papers you link to, that loss of cell bodies in the SN lags behind loss of dopaminergic fibres in the putamen. This demonstrates that cell death is a slow degenerative process and not an all-or-nothing event. Thus cell bodies may still be relatively intact and still contain neuromelanin perhaps, but their afferents to the striatum are atrophying, with a reduction in synapses and a loss in the ability to deliver DA adequately. It would be extremely hard to provide an alternative to cell death for the case of loss of neuromelanin, a pretty inert substance that cannot be readily metabolised away in the neuron, and presumably is only removed by phagocytic glia when the cell membrane is no longer intact.

And yet a substantial increase in the extracellular concentration of DA in the striatum can be brought about by l-Dopa treatment, by-passing the rate-limiting tyrosine hydroxylase, through decarboxylation in the remaining functioning and part-functioning nigrostriatal neurons, but also by the Dopa Decarboxylase (i.e. AAAD) containing neurons which are found in the human striatum (Ikemoto et al, 1997).

This is hypothesis, of course, since absolute proof is difficult to get, but I can't think of better explanations that fit the data we have.

In further support the notion that L-DOPA can be converted to dopamine and released in other cells than the dopaminergic cells is that in rats in which the striatal dopamine system has been lesioned by 6-OH-dopamine, L-DOPA treatment still results in dopamine release.

Gavin, Karl - This is a very useful discussion and, as a biochemist who qualified in the early nineteen sixties I'm, learning a whole lot of new words. Now I must find a diagram to see what they mean! But I accept your calm arguments. Incidentally my own motor symptoms don't respond to l-dopa at all but I have no tremor, just bradykinesia and some autonomous system effects. I think I am atypical because I still have a perfectly good sense of smell, whereas Haehner et al in "Olfactory Dysfunction as a Diagnostic Marker for Parkinson's Disease" Antje Haehner, Thomas Hummel, Heinz Reichmann, Expert Rev Neurother. 2009;9(12):1773-1779, say that >95% of patients with confirmed PD have lost their sense of smell. The usual alternative is MSA but I haven't got that or I would be dead by now! Anyway .... I'm hooked on trying to understand PD now.

I notice that you commented on α-synuclein misfolded proteins under other questions. What do you think of the hypothesis that PD might develop from the α-syn misfolded proteins as a prion-like disorder? Especially the line of reasoning in 2.?

1. Olanow, McNaught. Parkinson's disease and alpha synuclein: is Parkinson's disease a prion-like disorder? http://www.ncbi.nlm.nih.gov/pubmed/23390095

2. Dunning, George, Brundin. What’s to like about the prion-like hypothesis for the spreading of aggregated α-synuclein in Parkinson disease?

http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3609056/

3. King, Gitler and Shorter. The tip of the iceberg: RNA-binding proteins with prion-like domains in neurodegenerative disease.

http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3372647/

I don't think it has been proved beyond all doubt that α-synuclein misfolding is infectious but it's hard to believe that α-synuclein starts misfolding spontaneously and simultaneously throughout the sub. nigra. Of course the cause of the misfolding (whatever it is) may spread gradually but your reference 2 provides evidence that α-synuclein misfolding spreads from cell to cell. This would be prion-like behaviour and I have remarked elsewhere that this has negative implications, for example, for the long term effectiveness of stem cell therapy for PD.

For another example of prion like behavior in a-synuclein, look at the one below for evidence of a direct link between an alpha-synuclein fiber injection, Lewy pathology, and loss of dopamine neurons in anatomically connected regions

Thanks for the reference, Jeff. But we're still a long way from understanding how the huge range of, and variation in, symptoms arise. We tentatively concluded that PD is most likely not a single illness but several related conditions. It amazes me that there has been no systematic analysis of symptoms or of the effects of l-dopa on symptoms. My impression is that l-dopa mainly improves the tremor but has little direct effect on anything else. In my case this is true but if I reduce the dose I become increasingly withdrawn after 2-3 days but recover within an hour of restoring the dose. Despite the evidence clinicians still seem to obsess about dopamine and the dopaminergic neurons. There is still a wish, or even a determined effort, to fit patients into clinical stereotypes rather than using patterns of symptoms to develop a classification system.

The clinical stereo type is really sad, I have worked with people with PD over the last 10 years, as a neuroanthropologist (applied) and fitness therapist, each person is very different, and contrary to the segmentation of body parts from Pd there is a connection in the overall functioning of all organs and systems in the body. I encourage increase in precision, volume and rate of movement and, increased supplementation by 10-25%; especially creatine, glutamine, taurine mix, selenium , Omega 3. Am working with an 82 year old member (chiropractor himself) who has not walked in 2 years, after the traditional PT recommended for PD. After 3X week for 16 weeks he can with walker go across the house, get up from chair. The increase in muscle strength was so dramatic that his wife started taking the creatine, glutamine taurine mix also. I am 74myself and reversed osteo-perosis by 70% in a 2 year period by taking creatine, glutamine, taurine, etc. it makes the muscles work harder.

Couldn't stand the way clients were treated and got BA 2010, 1 semester MA in Public Health.

I had a 2 week course of prednsiolone (30mg.day) last September for an unretated condition and am now on an 8 week course of budesonide (9 mg/day) these abolish all joint stiffness and pain and I can now climb stairs easily, turn over in bed without having to plan it and gather strength, leap out of chairs and look over my shoulder. I still walk slowly and stil fall over more than I used to and my speech is no better but I'm not mildly incontinent any more!!

I was for a week taking 5-amino salicylic acid and this was, I think, just as effective.

It looks as if some PD symptoms are caused by inflammation and may be easily and safely treatable.

Absolutely get 2nd diagnosis with DAT scan most reliable at this time for PD

Prednisone or similar pharmaceuticals add energy and aggressive behaviors some times.

Stephen, I was going to provide a more in depth answer but i see many others have beaten me to it! I think your question should be answered in two ways- firstly..."death" of the DA neurons is not the cause of PD, but is the cause of some of the symptoms of PD. Secondly, the cause (apart from familial PD) is unknown- the most recent data suggests that alpha-synuclein may become "pathogenic" and is hyper-phosphorylated. At this point, we hypothesise that the normal "state" of the protein, be it a monomer, dimer or trimer, is altered so that oligomers are formed. Following this oligomerization, larger fibrils are formed and are deposited as Lewy bodys or Lewy neurites in the brain. This process appears to behave in a prion-like manner...that is, it spreads from one region of the brain to another, or from one cell to another. This data is very new and current, I'm sure in the next ten years we'll see a much more clearer picture, as was the case for the prion field following the "proof" of the protein-only hypothesis.

Melanin is an electronically-active polyacetylene, chemically-similar to the compounds that make up the OLED's in your cell phone. E.g., it acts as a voltage-controlled bistable switch (our device, now in the Smithsonian electronics collection-- smithsonianchips.si.edu/proctor ) and as a combined electronic/ionic conductor. . E.g., See: http://www.pnas.org/content/109/23/8943.long .

There is even research underway to use it in digital memories. So, may play some role in neuronal function or perhaps as an antioxidant or trap for neurotoxins. Hard to explain its presence in numerous brain tracts otherwise.

Interestingly, the discoverer of levodopa for Parkinsons, GC Cotzias, once commented that " I can't believe God put melanin in the central nervous system for nothing. It must be doing something important, Something that is going to win me a Nobel prize" (quoted from memory, but you get the drift).

Very interesting chat. I think this is the very first paper describing the neuronal damage in the substantia nigra (locus niger) in Parkinson’s disease.

Tretiakoff C (1919) Contribution à l‘étude de l‘anatomie pathologique du locus niger de Soemmering avec quelques deductions relatives à la pathologie des troubles musculaires et de la maladie de Parkinson. These, Paris

I am afraid, I could not find the proper paper to read it.

Stephen, I agree with you when you mention the inflammatory process. According to that, it has been described that alpha-synuclein promote an inflammatory reaction when it is excreted out of the cell by exocytosis, damaging the local neurons, activating the microglia and being reuptaked by astroglia.

“Direct transfer of alpha-synuclein from neuron to astroglia causes inflammatory responses in synucleinopathies”

Lee HJ1, Suk JE, Patrick C, Bae EJ, Cho JH, Rho S, Hwang D, Masliah E, Lee SJ.

J Biol Chem. 2010 Mar 19;285(12):9262-72. doi: 10.1074/jbc.M109.081125. Epub 2010 Jan 13.

Also, anti-inflammatory drugs could help according to this paper.

“Anti-inflammatory drugs and risk of Parkinson disease

A meta-analysis”

Joshua J. Gagne, PharmD, MS and Melinda C. Power, BA

doi: 10.1212/WNL.0b013e3181d5a4a3 Neurology March 23, 2010 vol. 74 no. 12 995-1002

There may be a protective effect of nonaspirin nonsteroidal anti-inflammatory drug use on risk of Parkinson disease (PD) consistent with a possible neuroinflammatory pathway in PD pathogenesis.

Interestingly, elevating the naturally-occurring antioxidant and antiexcitotoxin uric acid with inosine is currently in clinical trials for Parkinsons. See: http://www.medscape.com/viewarticle/818634

Stephen, in your initial question you were looking for a technique to demonstrate the loss of the pigment of the Substantia Nigra (neuromelanin). We work on such a technique using 3T magnetic resonance imaging sequences which emphasize the contrast between the pigment and the background tissue. You might be interested in looking at:

Article: T1-Weighted MRI shows stage-dependent substantia nigra signal loss in Parkinson's disease

MRCP Stefan T. Schwarz MD, Timothy Rittman BMedSci, BMBS, PGCertMedEd, MRCP, Vamsi Gontu MRCP, Paul S. Morgan PhD, Nin Bajaj PhD, Dorothee P. Auer PhD

link:

https://www.researchgate.net/publication/227722425_T1-Weighted_MRI_shows_stage-dependent_substantia_nigra_signal_loss_in_Parkinson's_disease?ev=prf_pub

Which is available on researchgate. We demonstrate that there is disease severity dependent signal loss which is presumably related to the atrophy of dopaminergic neurons and associated reduction in pigmentation.

We have also made recent progress in using iron dependent 3T magnetic resonance sequences demonstrating substantia nigra changes looking at a somewhat inverse kind of image of the pigmentation at the level of the Substantia Nigra. Hopefully the newly introduced swallow tail sign will help to advance MRI as a valid biomarker of PD even if the value of this marker in early disease still needs to be established.

Link to paper:

https://www.researchgate.net/publication/261403877_The_Swallow_Tail_Appearance_of_the_Healthy_Nigrosome__A_New_Accurate_Test_of_Parkinson's_Disease_A_Case-Control_and_Retrospective_Cross-Sectional_MRI_Study_at_3T?ev=prf_pub

Article T1-Weighted MRI Shows Stage-Dependent Substantia Nigra Signa...

Article The 'Swallow Tail' Appearance of the Healthy Nigrosome - A N...

Peter Proctor (21 Feb) very interestingly mentions an intriguing aspect of melanin function. However, I'd like to take issue with a couple of things he mentions in his statement:

"Interestingly, the discoverer of levodopa for Parkinsons, GC Cotzias, once commented that " I can't believe God put melanin in the central nervous system for nothing. It must be doing something important, Something that is going to win me a Nobel prize" (quoted from memory, but you get the drift)."

Firstly, Cotzias was not the discoverer of levodopa's action in PD; that was the Austrian Neurologist Walter Birkmayer with Pharmacologist Oleh Hornykiewicz - publishing their work a full 7 years (1961) before Cotzias. Hornykiewicz, with Ehringer, was also responsible for the original identification of the dopamine deficit in PD. Although at much the same time similar findings were being made in parallel in Japan.

Secondly, if you were to substitute "the appendix in the human abdomen" or "bilirubin in the blood" for "melanin in the central nervous system", then we can see how fallacious Cotzias' argument was! That is not to say that Peter's implicit point is wrong - melanin may well be of some value, despite it being a by-product of dopamine (and noradrenaline) synthesis.

Thanks for the reminder. The original discovers definitely deserve full credit. IIRC, Birkmeyer and Hornyliewicz had the idea and first tried levodopa, but dropped the study because of cost. Cotzias et al used gram-amounts for long periods of time. First for manganese poisoning and eventually for Parkinsons. So present-day therapy dates from their work. Cotzias also noted that toxin-induced Parkinson's mainly happens in species with visible neuromelanin.

Nobody really knows what neuromelanin does, other than it is all over the CNS. In addition to its solid-state properties, it is also a superoxide dismutase and traps toxins. So maybe it is a neuroprotectant.

@Cotzias also noted that toxin-induced Parkinson's mainly happens in species with visible neuromelanin.

Some idle speculation:

Melanosomes outside the CNS contain a substantial amount of a functional amyloid protein involved in melanin synthesis called Pmel. If a similar protein is involved in neuromelanin synthesis, there could be a cross -amyloid interaction between alpha-synuclein and the neuromelainin amyloid protein.

Alpha-synuclein aggregation is primarily extra-cellular but there may be a role for intracellular aggregation.

http://www.plosbiology.org/article/info%3Adoi%2F10.1371%2Fjournal.pbio.0040008

Peter - an elaboration and a question:

Birkmayer and Hornykiewicz had already investigated using an l-Dopa and dopa decarboxylase inhibitor combination when Cotzias started his high dose work, I think. It is this combination that has remained the basis of anti-parkinson therapy for almost half a century. But I am biased in kicking against a US-centric view of medical progress! ;)

Do you think the same properties are shared by skin melanin pigment, or is there something special about neuromelanin? I thought there wasn't...

There is a lot of beautiful work by Zecca L et al from Milano about the function and mis-function of neuromelanin in the Substantia Nigra of patients with Parkinson's disease.

I personally believe that there is some sort of interplay between neuromelanin, iron and the mitochondria that goes wrong in parkinson's disease. I am still not convinced about the primary role of alpha-synuclein, lewy-bodies, neurofibrillary tangles or amyloid as causative agents from the outset of all neurodegenerative diseases. They might make things worse along the way but I think there is still an essential step in the parthenogenesis missing.

Gavin: Skin and CNS melanin packaging is significantly different. However, at least electronically, one melanin is pretty much the same as any other. Interestingly, all polyacetylenes are melanins and vice versa. Some fungal melanis are even pure polyacetylene.

Various polyacetylenes constitute what we now call "organic electronics". The best applied example is the organic LEDs used In cell phone displays. Interestingly, dopamelanin is also electroluminescent. All of this leads to wide speculation about what all that neuromelanin is doing.

Interestingly, three years after our 1974 paper, other workers reported permanent high conductivity in a similar polyacetylene. They later won the 2000 Nobel Prize in chemistry for this, actually a rediscovery of something reported in 1964 by some Aussies, followed by several similar reports. The subject of an entire chapter in a classic textbook on electrochemistry.

Stefan - great typo - parthenogenesis instead of pathogenesis!

Peter - just seen your post:

Interestingly, elevating the naturally-occurring antioxidant and antiexcitotoxin uric acid with inosine is currently in clinical trials for Parkinsons. See: http://www.medscape.com/viewarticle/818634

No doubt someone has thought of this before, but wouldn't this approach imply that there is a lower than expected co-incidence of PD and gout? Do we know if this is true?

@Gavin "wouldn't this approach imply that there is a lower than expected co-incidence of PD and gout"

possibly so

http://www.ncbi.nlm.nih.gov/pubmed/18975349

Urate is also thought to be neuroprotective in ALS, and MS. There is even a phase-2 trial showing efficacy of uric acid infusion in acute ischemic stroke. Uniquely-high (200-400 mcm) urate levels in humans may even explain why antioxidant and antiexcitotoxic neurportectants that work in animal models crash and burn in human trials...

I agree that evolution nearly always results in the elimination of waste and it would be prudent to assume (provisionally at least) that neuromelanin has some function rather than representing the accumulation of a useless waste product.

Referring back to an earlier comment of Peter Procter's, is it true that toxin induced Parkinsonism is associated with an absence of (or much reduced) bleaching of the S.Nigra? If so, is there any way of establishing the presence or absence of melanin in the SN in living patients or must they (we) be sacrificed to allow a post mortem? I confess to a personal interest because I have PD but lack several key symptom groups and do not respond to l-dopa. I also had, 4-5 years before the first symptoms appeared, a Birmingham hip resurfacing (50 mm metal on metal). This has worked well and still is still in perfect condition 11 years after implantation. Nevertheless these joints do produce very high serum levels of heavy metal ions. The UK recommendation is to measure serum metals every year in patients with m-o-m hip implants but no-one wants to spend money on a 75 year old when the result will not influence treatment or outcome .... and I don't blame them. I think I'll get some saliva metals done - it'll only cost about $30. Anyone interested in the result?

Serum metals do result in higher levels of metals in the saliva but I couldn't find any systematic study giving correlation coefficients. It is much easier and cheaper to screen saliva than blood samples.

Friends

I am sorry for the recent silence on my part. Our house was flooded (2 cm water in parts of the ground floor), we have had to move to temporary accommodation and our internet connection has been disrupted.

First of all I agree about my diagnosis. Two research workers each gave me a 2 hour set of tests and both said they didn't think I had PD. I think I probably have Parkinsonism but I don't know the cause - could be 20 years on atenolol or a hip resurfacing (metal on metal), which causes elevated serum metals. But a 75 year-old does not justify a lot of expenditure on diagnostics.

Can we agree that the source of the motor symptoms of PD arises from an inability to manufacture L-dopa. If L-dopa is supplied from an external source, in most patients it is rapidly converted to dopamine, which alleviates (some of) the symptoms. It is assumed that the breakdown in dopamine production is due to the death of dopaminergic neurons, an assumption for which there is supporting evidence.

It is further assumed that l-dopa is decarboxylated to dopamine either in the remaining neurons that still have the capability to do this or elsewhere.

Although this makes a plausible and superficially understandable story there are some questions that undermine my confidence in it.

1. Biochemical pathways are usually balanced so why do the surviving neurons have the capacity to decarboxylate dopa but not to make it?

2. It could be tyrosine (precursor of l-dopa) deficiency but the brain can make up for a deficiency of tyrosine by converting phenylalanine to tyrosine. The consequence of a loss of this capability is phenylketonuria. So …. Why no l-dopa?

3. L-dopa is, I think, primarily effective in eliminating tremor. It has no effect whatever on my own motor symptoms. Is the role of dopamine as a neurotransmitter specific and distinct (in function or location) for different motor functions?

4. Is this a side issue or is there something important to be learned here?

Dear Stephen,

My main interest is using changes in the substantia nigra pigment content to diagnose PD. Although we are finding more and more evidence that we can use Magnetic Resonance Imaging to demonstrate loss of neuromelanin pigment to help the diagnosis, we are still some way away from using MRI to routinely diagnose or excluded PD (the technique is just to complicated). However, we had some recent success in using MRI to help diagnosing PD which will hopefully help to replace DATscans at some point in the future.

With regards to different causes of parkinsonism unresponsive to dopaminergic medication the most likely one is vascular Parkinson's disease. Tiny ischaemic lesions/strokes are able to destroy the endings of the dopaminergic cells in the striatum of the brain. Less than half of the patients with vascular PD respond to treatment with dopamine replacement therapy. And small vessel ischaemic disease is a very common condition and associated to risk factors like hypertension, high cholesterol, diabetes mellitus, smoking and so on...

Another take on neuron death in Parkinson's is an autoimmune hypothesis:

http://nwpf.org/stay-informed/news/2014/04/is-parkinsons-an-autoimmune-disease-neurons-may-die-from-bodys-faulty-immune-system/

Jolanta - many thanks for your clear answer. It is very helpful indeed. I'm not sure why such a clear distinction is made between Parkinsonism and PD. PSP and MSA are separate and well documented conditions but PD and Pism are not. Would it not be better to consider Parkinson's as a spectrum of conditions? A first diagnosis would then be Parkinson's Spectrum Disorder (PSD), which could be refined into a more precise diagnosis later if and when the evidence justified it. I am afraid that clinicians like a clear diagnosis and,failing a good understanding of what goes wrong and why in PSD, they rely on arbitrary classification of symptoms. One website, for example, gave a list of 7or 8 common symptoms and claimed that a diagnosis of PD could be made only if patients had at least three of them. There is absolutely no science to justify this kind of rough and ready approach to diagnosis.

Running wheel activity restores MPTP-induced functional deficits.

Anders Fredriksson, Ingels Maria Stigsdotter, Anders Hurtig, Béatrice Ewalds-Kvist, Trevor Archer

Journal of Neural Transmission (Impact Factor: 3.05). 03/2011; 118(3):407-20. DOI:10.1007/s00702-010-0474-8

This may answer your questions and other research from Trevor Archer

Beatrice - this is an interesting article (I have others on the benefits of exercise). There are also articles (eg http://www.medscape.com/medline/abstract/21414422 and http://www.medscape.com/medline/abstract/22770766) on the similar benefits of ω-3 fatty acids in "theraeutic" doses. But...if the dopaminergic neurons are mostly dead, how is movement restored? There are several possibilities but is there any evidence to support a hypothetical mechanism - improved blood supply to the brain (I doubt if this is important), anti-inflammatory action of ω-3 fatty acids (plausible mechanism for reducing the rate of decline in dopaminergic neurons), induction of proteosomes (might reduce the rate of growth of protein tangles), induction of BDNF (could stimulate the re-growth of neurons)... etc.?

how does depletion of dopamine and reduction in DAT levels leads to neurodegeneration?? Is there anyone who read a paper about that?

Thanks

Dear Stephen, 

We did PD murine models by means of AMPT and then tested if the neurons could be restored by daily exercise in a running wheel. We find that also BDNF played its part. Also other papers by Trevor Archer and his co-authors deal with this problem. 

If you're still following, I would say that one strong line of evidence supporting SNc dopaminergic neuronal loss as the main driver of the core motor dysfunction of PD (as distinct from the nonmotor symptoms, which are fairly clearly not) is that so many different experimental models of SNc DA neuronal lesioning, with different mechanisms of DA neuronal death, all lead to motor impairments in experimental models, including MPTP/MPP+, 6-OHDA, knockout of the homeobox transcription factors Engrailed-1 and -2 http://www.pnas.org/content/103/41/15242.full , SNc-specific treatment with the proteasome inhibitor lactacystin, http://content.iospress.com/articles/journal-of-parkinsons-disease/jpd160921 https://www.ncbi.nlm.nih.gov/pubmed/21419185 , and SNc-specific transgenes for PD-associated mutant α-synuclein https://actaneurocomms.biomedcentral.com/articles/10.1186/s40478-017-0416-x .

Also, you asked: "Lack of dopamine causes motor symptoms but this can be alleviated by supplying ... (L-DOPA), which the brains of most PD patients are still clearly able to convert to dopamine. The cause of motor symptoms in PD is therefore not the inability to make dopamine but the inability to make L-DOPA. We can infer that the brain is capable of decarboxylating L-DOPA to dopamine ... Where is this done if most of the neurons are dead?"

It derives from elevated substrate-driven dopamine synthesis in the surviving neurons. Some of the side-effects of levoldopa therapy are presumably caused by the forced overproduction by the dwindling numbers, such as dyskinesias, impulse control disorders, and compulsive behaviors , or the psychotic delusions or hallucinations experienced with long-term levodopa therapy.