As a newbie, I've been bringing myself up to date on Parkinson's research. There seem to be almost as many theories for the mechanism by which the disease develops as there are scientists working on it!
One paper which caught my eye reported in 2007 that drinkers of black tea (in Singapore) had about a quarter of the risk of non-drinkers of developing PD.
(http://aje.oxfordjournals.org/content/167/5/553.full#sec-6). This has probably been discussed in an earlier thread.
When I looked in Google Scholar for papers which followed this up I found there is some rationale being established experimentally to explain the protective effect of black tea. Apparently black tea contains theaflavins which are potent anti-oxidants. An Indian group has shown that theaflavins protect nigral dopaminergic neurons (in a test tube) against a neurotoxin known to induce Parkinson's like symptoms, a Japanese group that theaflavins stimulate autophagy (putting in the cell dustbin) of alpha-synuclein(a protein most suspected of being the initiator of cell death in PD) and a German/American group have shown (in the test tube again) that theaflavins stop alpha-synuclein from turning rogue.
What I am wondering out loud is, if these experiments really do demonstrate the molecular basis for the protective effect of black tea then surely the same effects should slow down progression of the disease too?
I'll make a cuppa and think about it...........
it depends whether the initial cause is the same as the ongoing cause. for example a virus could initiate an immune response which carries on after the virus has gone. if however the disease was simply caused by an external factor then the same action that reduced the chances of the disease starting could also reduce its ongoing activity.
my own belief is that pd has many initial causes but only one (or at most a handful) ongoing cause(s) in which case it is too late to shut the stable door as a self-perpetuating cycle has begun, and a spanner needs to be poked in its wheels.
my own belief is that pd has many initial causes but only one (or at most a handful) ongoing cause(s) in which case it is too late to shut the stable door as a self-perpetuating cycle has begun, and a spanner needs to be poked in its wheels.
Hi Bartobob
Interesting questions!
Quite a few lifestyle factors have been identified as reducing risk of Parkinson's including drinking tea or coffee, taking ibuprofen and smoking.
Earlier this month a small but interesting study was published that seemed to show that taking caffeine pills may slightly improve some of the movement symptoms of Parkinson's.
http://www.parkinsons.org.uk/about_us/news/news_items/all_news/a_coffee_a_day_for_parkinsons.aspx
But so far there's no evidence that any of these things can slow the course of Parkinson's in any significant way.
Best wishes
Claire
(Research team)
Interesting questions!
Quite a few lifestyle factors have been identified as reducing risk of Parkinson's including drinking tea or coffee, taking ibuprofen and smoking.
Earlier this month a small but interesting study was published that seemed to show that taking caffeine pills may slightly improve some of the movement symptoms of Parkinson's.
http://www.parkinsons.org.uk/about_us/news/news_items/all_news/a_coffee_a_day_for_parkinsons.aspx
But so far there's no evidence that any of these things can slow the course of Parkinson's in any significant way.
Best wishes
Claire
(Research team)
Several cups of black tea later.........
Yes, Turnip, there may be 2 phases to the disease, an initial conversion event and then a self propagating progression. A plausible sequence of events which is being shown experimentally is:
the transformation of alpha synuclein protein into a toxic form in the splanchnic nerve of the gut (no experimental evidence yet);
migration of the toxic alpha synuclein initially to the brain stem (experimental evidence);
propagation of toxic alpha synuclein in a progressive manner from the brain stem to several regions of the brain (experimental evidence). Experiment and neuroanatomical studies have shown that toxic alpha synuclein protein behaves like a prion (an agent of infection);
Once in the neuron the toxic form of alpha synuclein causes natural alpha synuclein present to convert to the more toxic form.(Experimental evidence)
The neuron's rubbish disposal systems cannot cope with the sudden build up of toxic protein and the cell dies.(experimental evidence?)
The toxic prion disrupts cellular membranes either by sitting in them or by switching off production of their components. Inability to make energy and maintain cell internal environment ensues and the cell dies. (experimental evidence)
Theaflavins have been shown to interfere with the transformation of natural alpha synuclein into other forms ans also to stimulate autophagy (rubbish disposal). So they could in theory be acting at the initial conversion event in the gut or on the progressing disease in the brain. However I suspect the concentration of thiaflavins achieved in the gut by a cup of black tea is more biologically relevant than that achieved in the brain. It would be interesting to see the effect of theaflavins (at the level found in the CSF) on infected neuronal cell systems like those used by Desplats et al. to test the possibile effects on cell death. (http://www.pnas.org/content/106/31/13010.full)
So yes, on reflection my gut feeling is tea is probably preventing the initial disease event..............
Thanks Claire for the info on other agents that affect Parkinson's symptons.
Yes, Turnip, there may be 2 phases to the disease, an initial conversion event and then a self propagating progression. A plausible sequence of events which is being shown experimentally is:
the transformation of alpha synuclein protein into a toxic form in the splanchnic nerve of the gut (no experimental evidence yet);
migration of the toxic alpha synuclein initially to the brain stem (experimental evidence);
propagation of toxic alpha synuclein in a progressive manner from the brain stem to several regions of the brain (experimental evidence). Experiment and neuroanatomical studies have shown that toxic alpha synuclein protein behaves like a prion (an agent of infection);
Once in the neuron the toxic form of alpha synuclein causes natural alpha synuclein present to convert to the more toxic form.(Experimental evidence)
The neuron's rubbish disposal systems cannot cope with the sudden build up of toxic protein and the cell dies.(experimental evidence?)
The toxic prion disrupts cellular membranes either by sitting in them or by switching off production of their components. Inability to make energy and maintain cell internal environment ensues and the cell dies. (experimental evidence)
Theaflavins have been shown to interfere with the transformation of natural alpha synuclein into other forms ans also to stimulate autophagy (rubbish disposal). So they could in theory be acting at the initial conversion event in the gut or on the progressing disease in the brain. However I suspect the concentration of thiaflavins achieved in the gut by a cup of black tea is more biologically relevant than that achieved in the brain. It would be interesting to see the effect of theaflavins (at the level found in the CSF) on infected neuronal cell systems like those used by Desplats et al. to test the possibile effects on cell death. (http://www.pnas.org/content/106/31/13010.full)
So yes, on reflection my gut feeling is tea is probably preventing the initial disease event..............
Thanks Claire for the info on other agents that affect Parkinson's symptons.
Continuing with my sudden interest in slowing down Parkinson's ..........
Zheng et al.(http://stm.sciencemag.org/content/2/52/52ra73.abstract) have identified PGC-1alpha, a master gene regulator protein which has been found at unnaturally low levels in the brains of PD patients. Fortunately a family of compounds in use to treat diabetes(such as Avandia or Actos) is known to switch up this regulator. These compounds were subsequently shown to protect cells (in the test tube) against a neurotoxin which causes PD symptoms (http://www.nature.com/news/2010/101006/full/news.2010.518.html#B1).
One of these compounds is in clinical trials to determine if it will slow down PD in people (http://www.bidmc.org/CentersandDepartments/Departments/Neurology/ParkinsonsDiseaseandMovementDisorders/ResearchandClinicalTrials.aspx)or if it will stop dyskinesia induced by L-Dopa (https://www.michaeljfox.org/foundation/grant-detail.php?grant_id=678). Results eagerly awaited!
.....Parkinson's UK is sponsoring research studying pGC-1alpha in fruit flies, looking for other compounds which turn it up. (http://www.parkinsons.org.uk/pdf/H-1105_Partridge_plain-english-summary.pdf)
Zheng et al.(http://stm.sciencemag.org/content/2/52/52ra73.abstract) have identified PGC-1alpha, a master gene regulator protein which has been found at unnaturally low levels in the brains of PD patients. Fortunately a family of compounds in use to treat diabetes(such as Avandia or Actos) is known to switch up this regulator. These compounds were subsequently shown to protect cells (in the test tube) against a neurotoxin which causes PD symptoms (http://www.nature.com/news/2010/101006/full/news.2010.518.html#B1).
One of these compounds is in clinical trials to determine if it will slow down PD in people (http://www.bidmc.org/CentersandDepartments/Departments/Neurology/ParkinsonsDiseaseandMovementDisorders/ResearchandClinicalTrials.aspx)or if it will stop dyskinesia induced by L-Dopa (https://www.michaeljfox.org/foundation/grant-detail.php?grant_id=678). Results eagerly awaited!
.....Parkinson's UK is sponsoring research studying pGC-1alpha in fruit flies, looking for other compounds which turn it up. (http://www.parkinsons.org.uk/pdf/H-1105_Partridge_plain-english-summary.pdf)
The link in the second paragraph of my last post should read:
(http://www.bidmc.org/CentersandDepartments/Departments/Neurology/
ParkinsonsDiseaseandMovementDisorders/ResearchandClinicalTrials.aspx)
(http://www.bidmc.org/CentersandDepartments/Departments/Neurology/
ParkinsonsDiseaseandMovementDisorders/ResearchandClinicalTrials.aspx)
very interesting Bartobob
i had never come across the idea that the alpa-s could go toxic (misfolding?) outside the brain first. Personally i would bet on the nose rather than the gut, but i suppose there's no reason it can't be both?
one thing that is encouraging is how much more detail there is on the wikip page
http://en.wikipedia.org/wiki/Alpha-synuclein
the scientists are really getting a very detailed picture of the mechanisms, hopefully coming up with some way of stopping it.
i had never come across the idea that the alpa-s could go toxic (misfolding?) outside the brain first. Personally i would bet on the nose rather than the gut, but i suppose there's no reason it can't be both?
one thing that is encouraging is how much more detail there is on the wikip page
http://en.wikipedia.org/wiki/Alpha-synuclein
the scientists are really getting a very detailed picture of the mechanisms, hopefully coming up with some way of stopping it.
Yes Turnip, the nose, tongue or eye might be rich access points for a toxin to transform alpha-synuclein. If Parkinson's is a prion disease, do cannibals have a higher incidence?
Anyway, three exciting clinical studies looking at slowing down Parkinsons:
Actos(Pioglitazone) which switches up PGC-1alpha as described in my last post has a phase 2 clinical study (phase1-is it safe?,phase2 does it have the right effect?, phase3 what best dosage?)finishing at the end of this year.
Cogane, a plant derived compound which stimulates the growth of new nerve cells in the brain (http://www.phytopharm.com/index.php?option=com_content&view=article&id=45&Itemid=31) and is being tested for slowing the disease down,finishes its phase 2 study at the end of this year too.
Preladenant an adenosine 2A (A2A) receptor antagonist (shuts down those brain cells which stimulate the substantia nigra)developed by Schering-Plough is recruiting to test its efficacy to stop L-DOPA induced dyskinesia in a phase2 study.
I've seen a lot of clinical trials produce disappointing results but I am definitely faintly optimistic that one or more of the above will be successful!
Anyway, three exciting clinical studies looking at slowing down Parkinsons:
Actos(Pioglitazone) which switches up PGC-1alpha as described in my last post has a phase 2 clinical study (phase1-is it safe?,phase2 does it have the right effect?, phase3 what best dosage?)finishing at the end of this year.
Cogane, a plant derived compound which stimulates the growth of new nerve cells in the brain (http://www.phytopharm.com/index.php?option=com_content&view=article&id=45&Itemid=31) and is being tested for slowing the disease down,finishes its phase 2 study at the end of this year too.
Preladenant an adenosine 2A (A2A) receptor antagonist (shuts down those brain cells which stimulate the substantia nigra)developed by Schering-Plough is recruiting to test its efficacy to stop L-DOPA induced dyskinesia in a phase2 study.
I've seen a lot of clinical trials produce disappointing results but I am definitely faintly optimistic that one or more of the above will be successful!
Don't think there is any correlation between cannibalism and pd, or at least no-one on the forum has mentioned having partaken. There used to be cannibals in Guam where there is Lytico-Bodig disease but that might be from eating poisonous fruit bats. Or perhaps the old ways are still being practiced in secret!
Am I correct in thinking that these studies of the role of toxic alpha-synuclein (and hence the potential benefit of black tea in it's role as an anti-oxidant as opposed to something which stains your tea cup , as a preventative measure rather than a treatment for Parkinson's ) relates to familial or sporadic PD, and not the far more prevalent idiopathic PD?
Turnip..........as PD affects only 1 in 500 of the population, that might be at too low a frequency to establish itself as a prion mediated disease in those societies in the habit of eating grandad's brain when he passes on........
annebernadette.......my understanding (as a retired molecular biologist with no experience in PD research) is about 5% of PD cases have been linked to mutations in one of six genes. These are referred to as familial PD as their inheritance will predispose to development of disease. The other 95% of cases are idiopathic (meaning of no known cause). There is evidence that idiopathic PD is caused by the naturally occurring alpha synuclein protein misfolding to a toxic form. That toxic form then goes on to damage a structure or biosynthetic pathway in the brain cell causing the cell to die. The familial gene mutations are thought to act by giving rise to damaged proteins involved in the same pathways or structures that toxic alpha synuclein affects.
If black tea acts by slowing down PD progression (and I think that's a very big 'if') then it might affect all forms of PD. If black tea only prevents start of the disease then it probably is only effective against idiopathic PD. The other medicines I've described which are in clinical trials should, if they work, be effective against both types of PD. (More information on those trials from www.clinicaltrials.gov)
annebernadette.......my understanding (as a retired molecular biologist with no experience in PD research) is about 5% of PD cases have been linked to mutations in one of six genes. These are referred to as familial PD as their inheritance will predispose to development of disease. The other 95% of cases are idiopathic (meaning of no known cause). There is evidence that idiopathic PD is caused by the naturally occurring alpha synuclein protein misfolding to a toxic form. That toxic form then goes on to damage a structure or biosynthetic pathway in the brain cell causing the cell to die. The familial gene mutations are thought to act by giving rise to damaged proteins involved in the same pathways or structures that toxic alpha synuclein affects.
If black tea acts by slowing down PD progression (and I think that's a very big 'if') then it might affect all forms of PD. If black tea only prevents start of the disease then it probably is only effective against idiopathic PD. The other medicines I've described which are in clinical trials should, if they work, be effective against both types of PD. (More information on those trials from www.clinicaltrials.gov)
three things that seem of particular interest to me
1) why is pd always initially unilateral? the brain is fairly symmetrical and if an infection or toxic protein arrives at one side why not the other?
2) why only the subs. nigra? why are those cells so vulnerable and others resistant?
what is different about them? other cells produce and store dopamine but only these ones are killed off (at least initially).
3) why is it so slow? even prions are faster (unless there is a cjd disaster waiting in the wings). i know many of us believe it has taken 20 or 30 years for our condition to reach this stage. that seems an extraordinarily slow spread.
the reasons i pick the nose (puerile joke) as the main source of infection are
a) the very common loss of sense of smell/taste which often precedes other symptoms
b) the high occurrence of chronic rhinitis in pwp
c) the superhighway between the nose and roughly the area affected by pd which by-passes the blood brain barrier
d) large numbers of alpha-syn in the nose
1) why is pd always initially unilateral? the brain is fairly symmetrical and if an infection or toxic protein arrives at one side why not the other?
2) why only the subs. nigra? why are those cells so vulnerable and others resistant?
what is different about them? other cells produce and store dopamine but only these ones are killed off (at least initially).
3) why is it so slow? even prions are faster (unless there is a cjd disaster waiting in the wings). i know many of us believe it has taken 20 or 30 years for our condition to reach this stage. that seems an extraordinarily slow spread.
the reasons i pick the nose (puerile joke) as the main source of infection are
a) the very common loss of sense of smell/taste which often precedes other symptoms
b) the high occurrence of chronic rhinitis in pwp
c) the superhighway between the nose and roughly the area affected by pd which by-passes the blood brain barrier
d) large numbers of alpha-syn in the nose
If I was a mouse with PD
Indeed I should be happy to be
Injected with PGC-1a
If improving my scurry it may
And neither am I a fruit fly
In a student's Laboratoire
I happen to be a human
With a very complex genome
Whilst I wish all the very best
To those who are trying out to test
The cause and the cure of PD
I think I may just stick to black tea
(sorry - may have put this in the wrong place. Too late - I am not doing it again)
Indeed I should be happy to be
Injected with PGC-1a
If improving my scurry it may
And neither am I a fruit fly
In a student's Laboratoire
I happen to be a human
With a very complex genome
Whilst I wish all the very best
To those who are trying out to test
The cause and the cure of PD
I think I may just stick to black tea
(sorry - may have put this in the wrong place. Too late - I am not doing it again)
Hi Turnip,
I second all your queries. Also from the 23 and me genetic testing I have a slightly increased risk for PD (who knew?!) and the most significant marker amongst the four I have is the one concerned with alpha-synuclein.
As for the suspicion that one has it for a long time I first went to the GP about a change in my balance - nothing much but definite - in my mid thirties, forty years ago.
I have had tendency to a set expression for longer than I care to remember which I have to consciously counteract. My PE teacher commented that I was slow to get going. The list is endless. Like Spike Milligan had written on his gravestone
I told them I was ill. Actually I didn't because these symptoms were so vague but I did harbour the notion that I had a slow growing non-malignant brain tumour which I mostly put down to hypochondria
I second all your queries. Also from the 23 and me genetic testing I have a slightly increased risk for PD (who knew?!) and the most significant marker amongst the four I have is the one concerned with alpha-synuclein.
As for the suspicion that one has it for a long time I first went to the GP about a change in my balance - nothing much but definite - in my mid thirties, forty years ago.
I have had tendency to a set expression for longer than I care to remember which I have to consciously counteract. My PE teacher commented that I was slow to get going. The list is endless. Like Spike Milligan had written on his gravestone
I told them I was ill. Actually I didn't because these symptoms were so vague but I did harbour the notion that I had a slow growing non-malignant brain tumour which I mostly put down to hypochondria
Whilst I can't begin to understand the complexities of alpha-synuclein and misfolding proteins, the second paragraph of Turnip's message seems to tie in with the latest thinking on the antihistamine drug, latrepiridine. (Or is that too simplistic?)
Since last Thursday i started taking one 200mg Ibuprofen tablet per day. I'm surprised at what a difference its made to my parkinsons symptoms. Even to the extent that yesterday i was able top cut back on my normal intake of sinemet, and without any noticeable impact to my PD symptoms. I know its early days, but for me taking Ibubrofen seems to have really made a difference. Also I'm only taking one 200mg tablet each morning, which is just about the lowest recommended daily dosage.
I would be interested to know if anyone else has tried Ibuprofen or do you have a view on using it?
Regards
bluey
I would be interested to know if anyone else has tried Ibuprofen or do you have a view on using it?
Regards
bluey
i've been interested in trying ibuprofen but i believe it interferes with my high blood pressure meds so need to get bp down first but exercise is difficult because of pd problems ...
Thank you very much Bartobob for prviding the links re alpha-synuclein. I have been following the links for most of last night and this a.m. ( I had to keep looking up unfamiliar medical terms and of course one link leads to another.) I have learned more about PD and updated my knowledge of biochemistry (such as it was) without dwelling on my PD - if you see what I mean. Whether or not I retain any of it remains to be seen
I think I shall have to give it a rest for a while -my head is spinning. Having just read an article that concludes PD is the result of a faulty fight/flight response ( the susgestion being that the emotional make -up of individuals who develop PD is such that they "freeze" rather than do something more appropriate and this becomes a trace memory) and then to discover that things I have been taught were not good for me (smoking and too much caffiene) may revent the onset of PD, I think a little Mozart is called for.
Despite all the hours I have spent looking at different sites, I have not come across anything that answers Turnips excellent 3 Q's. But I will not give up. I did however find a few articles about the use of some histamines in the treatment of PD, specifically diphenhydramine for dyskinesia and Rivastigine having a significant (+ive) effect on cognitive functions and behavioural problems associated with PD dementia.
Eileenpatricia - some of the articles I read stated as many as 20 years for PD symtoms to be present but not recognised as such. You reminded me of a school report some 40+ years ago which suggested I might approach my work with a little less attentin to detail but with more energy. And it was not a PE report
I think I shall have to give it a rest for a while -my head is spinning. Having just read an article that concludes PD is the result of a faulty fight/flight response ( the susgestion being that the emotional make -up of individuals who develop PD is such that they "freeze" rather than do something more appropriate and this becomes a trace memory) and then to discover that things I have been taught were not good for me (smoking and too much caffiene) may revent the onset of PD, I think a little Mozart is called for.
Despite all the hours I have spent looking at different sites, I have not come across anything that answers Turnips excellent 3 Q's. But I will not give up. I did however find a few articles about the use of some histamines in the treatment of PD, specifically diphenhydramine for dyskinesia and Rivastigine having a significant (+ive) effect on cognitive functions and behavioural problems associated with PD dementia.
Eileenpatricia - some of the articles I read stated as many as 20 years for PD symtoms to be present but not recognised as such. You reminded me of a school report some 40+ years ago which suggested I might approach my work with a little less attentin to detail but with more energy. And it was not a PE report
re Ibuprofen - I am delighted that you find it helpful Blue-eyes. I have read there is a correlation between the use of this and a lower risk of developing PD, but not (yet) that it may reduce the need for levodopa medicines.
From a personal point of view, I will not give this a try. Apparently the reason I am intolerant to PD medication is that my liver does not funtion all that well, possibly due to a childhood illnes, and NSAID's are contraindicated.
From a personal point of view, I will not give this a try. Apparently the reason I am intolerant to PD medication is that my liver does not funtion all that well, possibly due to a childhood illnes, and NSAID's are contraindicated.
Turnip......
1) why is pd always initially unilateral? If PD (along with Alzheimers and Dementia with Lewy Bodies as argued recently (http://211.144.68.84:9998/91keshi/Public/File/41/336-6088/pdf/1511.full.pdf)
is a prion disease then most probably the reason it doesn't start up until late in life is because the cell manages to bin the prion before it reaches sufficiently high concentration to cause trouble. In familial cases the cell manages to identify and dispose of mutant proteins. In the 1 in 500 of us the rubbish disposal system in one of the billions of brain cells gets less efficient as we get older or gets simply overwhemed by toxins, the cell gets unhealthy and alpha synuclein prion form builds up to levels sufficient to infect the neighbouring cells. So in this scenario, PD starts somewhere in the brain and spreads by cell to cell contact. If it is unilateral (do you mean in one hemisphere?)maybe that's because of the geography of the brain's neronal or vascular connections.
2) why only the subs. nigra? why are those cells so vulnerable and others resistant?
Areas of Lewy body inclusions are found elsewhere in the PD brain but the substantia nigra seems particularly susceptible. Some experimental evidence suggests there is more oxidative stress in the subs. nigra due to its high rate of dopamine biosynthesis which facilitates the build up of prion....
(http://www.springerlink.com/content/r6701k82p8462827/)
3) why is it so slow? even prions are faster (unless there is a cjd disaster waiting in the wings). i know many of us believe it has taken 20 or 30 years for our condition to reach this stage. that seems an extraordinarily slow spread.
.....see the answer to 1. PD onset is presumably controlled by the brain's error eradicating mechanisms (autophagy, ubiquitin tagging, apoptosis) but for 1 in 500 of us in one of our billions of brain cells that mechanism falters one day....
Bernadette............loved the poem !
1) why is pd always initially unilateral? If PD (along with Alzheimers and Dementia with Lewy Bodies as argued recently (http://211.144.68.84:9998/91keshi/Public/File/41/336-6088/pdf/1511.full.pdf)
is a prion disease then most probably the reason it doesn't start up until late in life is because the cell manages to bin the prion before it reaches sufficiently high concentration to cause trouble. In familial cases the cell manages to identify and dispose of mutant proteins. In the 1 in 500 of us the rubbish disposal system in one of the billions of brain cells gets less efficient as we get older or gets simply overwhemed by toxins, the cell gets unhealthy and alpha synuclein prion form builds up to levels sufficient to infect the neighbouring cells. So in this scenario, PD starts somewhere in the brain and spreads by cell to cell contact. If it is unilateral (do you mean in one hemisphere?)maybe that's because of the geography of the brain's neronal or vascular connections.
2) why only the subs. nigra? why are those cells so vulnerable and others resistant?
Areas of Lewy body inclusions are found elsewhere in the PD brain but the substantia nigra seems particularly susceptible. Some experimental evidence suggests there is more oxidative stress in the subs. nigra due to its high rate of dopamine biosynthesis which facilitates the build up of prion....
(http://www.springerlink.com/content/r6701k82p8462827/)
3) why is it so slow? even prions are faster (unless there is a cjd disaster waiting in the wings). i know many of us believe it has taken 20 or 30 years for our condition to reach this stage. that seems an extraordinarily slow spread.
.....see the answer to 1. PD onset is presumably controlled by the brain's error eradicating mechanisms (autophagy, ubiquitin tagging, apoptosis) but for 1 in 500 of us in one of our billions of brain cells that mechanism falters one day....
Bernadette............loved the poem !