Disease Modification in Parkinson's Disea... - Cure Parkinson's

Cure Parkinson's

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Disease Modification in Parkinson's Disease: Current Approaches, Challenges, and Future Considerations. (Wiley Online Library)

MBAnderson
MBAnderson

IMHO, I think the jury can be brought in that Parkinson's is not one disease, but that there are many subsets.

" ... can we justify further large and expensive trials of single putative, disease‐modifying therapies in our current state of ignorance? Considering the many potential explanations for past failures (Table 1), it is very difficult to justify continuing to utilize existing disease‐modifying treatment paradigms in the absence of major advances in a number of areas particularly biomarkers, especially those that successfully subtype patients into categories that predict response to specific mechanistic interventions."

"In this article, we review the concept of “disease modification,” the reasons for past failures, the approaches that are currently being explored or that will be explored in patients in the near future, and how the field should proceed over the short‐ and medium‐term future."

"Beyond the current phase 2 or 3 studies underway evaluating treatments directed at oxidative stress (inosine), cytosolic Ca2+ (isradipine), iron (deferiprone), and extracellular α‐synuclein (passive immunization), and upcoming trials of interventions affecting c‐Abl, glucagon‐like peptide‐1, and glucocerebrosidase, it might be argued that further trials in populations not enriched for the targeted pathogenic process are doomed to repeat the failures of the past."

Conclusions

The answer as to “Which therapeutic developments are more likely to modify progression in PD?” may depend, at a basic level, on the understanding of what PD means from the standpoint of therapeutic development. We would argue that our emphasis should not be about the tools of warfare (the design of clinical trials, the sensitivity of the endpoints, the therapeutic interventions) but about the reconfiguration of warfare itself. The who/what we are fighting (based on disease model of pathogenicity) is as important as how we fight. The face of our “enemy” has undergone relatively few changes ever since we evaluated whether vitamin E and selegiline could have neuroprotective effects using a 2 × 2 factorial design. During the subsequent 3 decades, we have tested ever more interesting potential treatments but have used the same enemy, “early, drug naïve PD,” with features only cosmetically more attractive than those originally described over 200 years ago. Our overall tools have been refined, but the who/what targets with those tools have not. We have excused ourselves for therapeutic failures with a variety of cogent reasons (Table 1), but have only tangentially included in the list our definition of the target as a problem.

onlinelibrary.wiley.com/doi...

26 Replies

I agree that there is not one form of Pd, in fact there maybe as many forms as there are patients.

In my view it is useless trying to find treatments for symptoms we should be trying to find a CURE.

While we are trying to find a cure, why are we not trying to find a way to get our brains to produce more GDNF, which repairs damaged brain cells and thereby e=helps us to get better. GDNF has been artificially manufactured and inserted into the brain with mixed results but WHY DON'T WE LOOK FOR A WAY OF GETTING THE BRAIN TO PRODUCE MORE?

The answer to that is quite obvious. It would cost money to find the answer and if found it would reduce the amount of money being made on existing medications, that don't work anyway.

Unfortunately the neuro sciences are still in their infancy. I think we should have an international NASA style approach to upgrade the assault on and defeat of neurological disease.

rideabike
rideabike in reply to etterus

From everything I've been reading it seems pesticide usage all over the world is a huge contributing factor and what kind we've been exposed to, how much, how long and each of our DNA reaction might be a consideration. Loss of function from dopamine and how each tiny area in or connected to the substantia nigra may be like a neuron map with each deletion causing different dysfunction. Can scientists really know that much about the human brain? DNA is still in it's infancy but studies come up with some basic stuff on Parkinson's and it's always interesting so I keep reading even if it is so complex. Thankfully had some physiology courses to try and decipher them. If nothing else I'm getting a good science lesson and the mechanics of life are amazing....when things aren't going sideways, that is.

etterus
etterus in reply to rideabike

Since no two of us are the same genetically plus the phenomena of neuroplasticity the neuro mapping is one of a kind... yes the challenge of knowing all of the intricacies is hugely phenomenal. It’s on par with outer space challenges. Hence the NASA model of research but enhanced to international participation .

M_rosew
M_rosew in reply to etterus

If you like the idea of international co-operation, book yourself a place at the 2019 World Parkinson Congress. I went to the 2016 WPC in Portland OR, and found it inspiring. The networking was both international and multi-discipline, and everything included pwp and their carers.

I was humbled to realise that, worldwide, so many people (neurologists, doctors, nurses, therapists, teachers, dietitians, carers, etc, etc, etc) spend their whole working lives trying to improve things for pwp

etterus
etterus in reply to M_rosew

I attended it and agree that it is a great venue to bring the pwp, research and clinical world together. I however had a different conclusion then you. I had high expectations that I would be impressed with the probability of a real breakthrough with a significant solution or cure. But I was disappointed and concluded that it is still in its infancy.

M_rosew
M_rosew in reply to etterus

We may have met! Interesting that our expectations were different.

I heard my diagnosis and 'incurable condition' on the same day. I had spent 60+ years not thinking anything about PD. Suddenly a cure was of immediate interest to me - but I realised that nothing had changed beyond the pd-circle.

I could trawl the Internet for ever looking answers. But if a cure is found I'm likely to be too old to benefit. So instead I chose make the best of my new reality.

I am grateful to have access to a lovely Neurologist (quote "We will look after you for the rest of your life"), and her Neuro-team.

There is growing consensus in the Parkinson's research community that is the opposite of what the report says and what everyone posting here is thinking. It has long been known that the mis-folding of proteins is at the heart of many neurodegenerative diseases including all polyglutamine disorders plus Alzheimer's. The latest research indicates that the mis-folding of alpha-synuclein is the common thread among all cases of Parkinson's. Mis-foldeded alpha-synuclein leads to cellular death, but because alpha-syn is so ubiquitous in the human brain the resulting damage is highly variable unlike polyQ disorders like Huntington's disease where the mutant protein is localized in specific regions of the brain. Also in other diseases involving the mis-folding of a protein the cause of mis-folding can be linked to a specific genetic mutation. Such is not the case in Parkinson's, but even though researchers have not identified the reasons alpha-synuclein mis-folds, it is becoming clear that alpha-syn mis-folding may be at the root of all cases of Parkinson's. That is the belief driving Roche's research at Prothena:

prothena.com/pipeline/prx002/

scienceofparkinsons.com/201...

The loss of GDNF and other cellular symptoms of Parkinson's are all secondary results of cellular death caused by the primary problem of mis-folded alpha-synuclein. Preventing mis-folding and cleaning out bad proteins holds the potential to stop or slow progression of all Parkinson's cases. That is what mannitol and EGCG and Trehalose may do and what PRX002 is doing.

healthunlocked.com/parkinso....

Click on my screen name and follow my posts for a wealth of additional links on this topic.

So, I agree Prothena's stuff is encouraging. I posted links about them 10 months ago saying I thought it was perhaps the most dramatic trial I had read about, but I'm not clear where you or the links you posted make the case that Parkinson's is not a subset of illnesses.

So you're response is "I didn't read your links, but explain to me why you think you are right because I still think I am right" . . .

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I have to be honest. I am becoming increasingly curmudgeonly and uncivil and un-Budda like in my old age, and so I apologize for being a jerk online, but . . .

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I have read literally hundreds of papers now on the topic of protein mis-folding and almost an equal amount of time on papers regarding PD and the correlation with alpha-synuclein, and I am not a scientist or a doctor but I have a strong background in science and graduated at the top of my class at Dartmouth. I'm very capable of reading and interpreting scientific papers. If you click on my screen name and follow the links and actually read the hundreds of papers I have linked I believe you will come to the same conclusion I have.

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The one and only commonality between all PD cases is alpha-synuclein mis-folding.

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In some cases the cause appears to be genetic and in others it appears to be environmental, but if you can find a way to first recognize a mutant form of alpha-synuclein, and then stop it from becoming an "oligomeric" protein then I believe you will have found a cure for all cases of Parkinson's.

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The trouble with words is that they communicate a tiny fraction of our intentions and real meanings. The term "Parkinson's" was born to describe a set of symptoms that were believed to be common. As our knowledge base grows it turns out there are other ailments that have similar symptoms. Yes, there are many forms of "Parkinson's" that may not be the same, but that does not change the science of what is known. It means there are some forms of "Parkinson's" that may not have been adequately categorized.

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My disease is Spinocerebellar Ataxia Type 1. Ataxia is a term meaning a strange gait. The Ataxia forum is full of people with "ataxia", but the cause of their strange gait is as diverse as the numbers of people posting, and in some cases it is idiopathic meaning "of unknown cause". That fact does not alter the remaining fact that there are about a dozen forms of ataxia that are caused by mis-folded mutant proteins, and any possible cure will have to find a way to remove those mutant proteins before they cause cellular death.

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Yes, some people with Parkinson's don't fit the "norm", but that shouldn't stop the majority from understanding and interpreting the latest science. The vast majority of Parkinson's cases are likely a direct result of alpha-synuclein oligomers. Fix that problem without stopping the normal function of the protein and you will have cured the disease.

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scienceofparkinsons.com/201...

ncbi.nlm.nih.gov/pmc/articl...

parkinsonsnewstoday.com/201...

scienceofparkinsons.com/alp...

journals.plos.org/plosone/a...

ncbi.nlm.nih.gov/pubmed/292...

Like I said there are hundreds if not thousands of related papers and articles. One big problem is that many if not most researchers read little of what other researchers have found and so they remain entrenched in their beliefs and science gets caught up on dead ends. If you research and thoroughly read through some of the papers I have linked and then come back with a cogent argument as to why alpha-synuclein shouldn't be deemed the primary culprit, then I will be thrilled to have found someone on this forum that actually understands and can discuss the science of Parkinson's.

GioCas
GioCas in reply to sunvox

emh... !

“Controversies associated with Alpha Synuclein

One of the mysteries about alpha synuclein and its role in Parkinson’s disease is that approximately 10-30% of people over the age of 70 years will have lewy bodies in their brain, but with no problems with motor ability or memory function.

In a large autopsy study that investigated 904 brain, alpha synuclein lesions were observed in only 11.3% (or 106 cases), and of these only 32 had been diagnosed with a neurodegenerative disorder.

Another study found that 8.3% of the aged control brains had alpha-synuclein lesions in them. This would suggest that alpha-synuclein aggregation can be present in both healthy and diseased brains.

In addition, alpha synuclein lesions are not specific to Parkinson’s disease – approximately 50% of people who die with Alzheimer’s disease have been found to have lewy bodies.

This raises the question of whether lewy bodies are a causative agent in the disease, or simply an attempt by the cells to deal with a terrible problem of too much protein (are Lewy bodies simply the rubbish can of the cell?).

A lot of research is being conducted in this area and we will keep you up to date as new data comes to hand.”

sunvox
sunvox in reply to GioCas

So it turns out that it's not the clumps that are the problem, and that is what a Lewy body is, but I linked that article to help people understand the whole story. They can be symptomatic but not always, and now we know they are not the cause and that was part of the mystery that was unraveled. Tragically this was actually uncovered in 2001 by Dr. Orr when he studied mis-folding versus aggregation in SCA1. It's the mis-folding that researchers are now beginning to realize is the issue . . . not the clumps. The studies you are quoting above are examples of researchers that had not yet figured out that clumping wasn't the issue. Also this is an example of not reading and understanding the latest research. Do you understand what it means to become an oligomer? Science grows and new information negates old hypotheses.

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MBAnderson
MBAnderson in reply to sunvox

Good grief, sunvox. I enjoyed reading the insights of your post above until I got to the last 2 sentences. Then you ruined it. Why add the personal invective? Why not let the substance stand on its own without the personal commentary? I, for one, enjoy all of GioCas's posts.

GioCas
GioCas in reply to sunvox

emh sorry Joe, but I just reported something I read in your link above, you put it.

scienceofparkinsons.com/alp...

sunvox
sunvox in reply to GioCas

Yes, and my reason for posting the link was to provide people with a "story" to follow that helps explain why I developed the conclusion I did. As I said the science is not static. It keeps moving.

MBAnderson
MBAnderson in reply to GioCas

Good point. I read the same study. Not all PWP have Lewy bodies and some people who don't have Parkinson's have Lewy bodies and they don't know if a/syn is a cause or symptom.

sunvox
sunvox in reply to MBAnderson

No. That is my primary point. I believe there are diseases that present with Parkinson's like symptoms, but they are a small subset of the population that has a diagnosis of Parkinson's. I believe the majority of Parkinson's diagnoses are correct, and I also believe that for that majority it is mis-folded alpha-synuclein proteins that are the single root cause of the disease. Alpha-synuclein is everywhere in the body so IF it mis-folds the damage could be in many places and what's more research in other diseases that stem from mis-folded proteins shows that the level of mis-folding changes the toxicity of the protein so in Parkinson's since the cause or likely potential causeS of the mutation are as yet unknown then the variability in the disease must be high.

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I thought you liked it when I was "snarky" :D -

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As I said, I'm becoming less Budda like in my old age and so just say what I think . . . for better or worse . . . usually worse

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Thanks again for discussing. Joe

P.S. Don't know if you saw this yet, but just so you can put a face to the "jerk" online here I am:

facebook.com/profile.php?id...

MBAnderson
MBAnderson in reply to sunvox

As much as you try to put me off, I will keep reading your stuff and keep liking you. So, I read your protocol when you 1st posted it and I've reviewed it a couple times. I hope you'd agree it's comparable to what a lot of PWP do who do a lot of research, so answer this 1 question for me. How to you/we know that it isn't 99% your exercise routine that has you so healthy and that the rest of the stuff may help but only marginally?

sunvox
sunvox in reply to MBAnderson

I TOTALLY think the exercise is the number one component. Each time I run on the treadmill I can feel my balance being off initially, and by the time I get to the 5 minutes of walking I notice that I can walk quickly with no roll in my gait at all, BUT that happens at the end EVERY DAY. However, I ran my whole life. Hard. 2 years ago, no matter how hard I exercised I could not recover, and I found myself unable to stand on one foot or easily walk downstairs in the morning. I exercised like a fiend both running and lifting weights. Not until I started taking supplements was I able to return to the normal process of gaining strength and endurance and recovering each day. I felt real changes in my legs in terms of heaviness and stiffness. That is why I believe it is the combination that is important. Is every supplement I take critical? I have no idea. I know the group I take right now is working, and I intend to refine that group as "scientifically" as I can hence at the moment I am in a period of 6 months of not changing anything. I think at the end of that period I will try to eliminate one or two items.

MBAnderson
MBAnderson in reply to sunvox

I was a long-distance runner my whole life too. I ran 10, 7 minute miles 25 days/month for 30 years -- and a year after I stop my PD symptoms started to show up. Do you think that's a coincidence?

If my post sometimes turn into gibberish it's because I use voice recognition software and don't always go back and edit

sunvox
sunvox in reply to MBAnderson

No worries. I know we discussed earlier, and I remember well that I know you deserve enormous credit and respect. I think it is a genuine travesty of science that they are not investigating individuals like yourself to find out why a person with a serious disease is doing better than others so late into their illness. I, for one, believe your early athleticism was neuroprotective, and I am certain that if you were running like that you were not eating Fritos and Coke for lunch. Again, thank you for your posts and willingness to forgive my terseness.

GioCas
GioCas in reply to sunvox

:-)

I'm sure that progress will solve these diseases and for ... future there will not be problems that we have. With all respect and friendship ciao and goodnight. Gio

Sunvox, calm down.

"If you research and thoroughly read through some of the papers I have linked and then come back with a cogent argument as to why alpha-synuclein shouldn't be deemed the primary culprit, then I will be thrilled to have found someone on this forum that actually understands and can discuss the science of Parkinson's."

Really?

All that because I said I thought Parkinson's might be a subset of illnesses??

sunvox,

I like you. You do a lot of in-depth research and post a lot of high-quality content. Almost as important, your snarkiness adds a little color to the place - and Lord knows reading these abstracts can get pretty boring.

Therefore, I’d like to try and lift the burden off your shoulders. This isn’t a contest. You don’t get relieved of your illness if you know more than the rest of us. You’re a smart guy. We all know that. If your research leads you to material that we would otherwise not know about, we appreciate you for that.

Brain chemistry is complex. It’s well above my pay grade, that’s for sure. I’ve learned more on this forum than I have from all the doctors, combined, in my life and I am healthier for it. If it were not for this forum I would be a basket case by now.

So, I hope you’ll keep sharing.

sunvox
sunvox in reply to MBAnderson

Thank you.

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As I said I'm getting old and curmudgeonly, but I hope everyone believes my heart is in the right place. I have a serious disease that by rights should have me in a wheel chair, but I am leading a 100% normal life.

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Let me say that again . . . I am leading a 100% normal life, and I have a genetic disorder that should have me in a wheel chair. Why am I not in a wheel chair? I'll tell you why . . . because I understand the chemistry of what is happening in my body, and I have found a way to counteract the problem. Will it stop the progression? I don't know, but for the moment it is slowing it enough for me to consider it stopped.

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I do not have Parkinson's, but I found the research linked to Parkinson's to be invaluable to my situation, and now I want to help educate the Parkinson's community.

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I made lifestyle choices earlier in life that turned out to be neuroprotective and probably gave me the head start to gain the upper hand on my illness, but I now have a small group of followers around the world including family members and people with Parkinson's, and those that are following my protocol are realizing the same results I am getting. My protocol is only for those early in diagnosis and those still able to exercise vigorously, but I just want as many folks as possible to give it a try, and I want people to understand the WHY of each item I chose.

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healthunlocked.com/ataxia-u....

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