A chronological model for the pathogenesis of PD

[wriga]

Hello everyone. This is work in progress. I invite you to download the Pdf file and give me your opinion of how easy this is to understand and any other comments you wish to make.

Parkinson’s disease is characterized by the loss of dopaminergic neurons in the substantia nigra in the midbrain and a deficit of dopamine in the terminal synapses in the striatum, but a simple model presenting the stages leading up to this condition has so far not been presented.

Here I proposes a simplified model that schematically represents the chronology of the major events that I believed are involved in the pathogenesis of Parkinson’s disease in a way designed to be accessible to patients. The model also proposes which steps may be subject to influence through medical or patient intervention, so that patients can make informed decisions about how to manage their own condition. The model covers the progression of Parkinson’s disease from benign redox imbalance in brain cells to chronic oxidative stress which initiates a cascade of two major events: (i) mitochondrial dysfunction, a condition which reduces the energy available to host cells and (ii) degeneration of vulnerable axons in the striatum region of SN neurons as a consequence of this energy loss. The model links these major events and draws attention to the considerable delays occurring between the beginning of the events and the observation of symptoms eventually produced by them, a situation which masks the true progression of the disease.

To build this model, evidence for the three major conditions already identified in the progression of Parkinson’s disease; age-related oxidative stress, mitochondrial damage and loss of dopaminergic SN neurons was investigated. There are convincing arguments for the processes that link these conditions and make up the basic version of the model. Each process has also been examined in more detail to consider the potential roles other factors having the capacity to modify or invalidate the primary model, such as α-synuclein, genetic variants, toxins or lifestyle. These additional factors add complexity to the model but help to understand how the pathogenesis and development of Parkinson’s disease is multifactorial. This article presents only the simplified model only.

This model has yet to be fully proven, but identifying the different processes opens up the possibility of researching appropriate therapy to slow the disease. Two particular processes that fit this condition are oxidative stress and mitochondrial dysfunction. Both of these work synergistically to create degeneration in axons of dopaminergic neuron in the striatum, far from the nucleus of these neurons which are located in the substantia nigra.

The main file is available via this link : patientresearcher.com/2021/...

[Turnipbarrow]

I will download and let you know how easy it is to understand . Thank you for sharing your work! Given the exponential increase in Parkinsons cases any possibility of intervening in the process is needed!

[wriga in reply to Turnipbarrow]

Thanks Turnip,

I realise from the lack of response that I've pitched this at a level that few non scientifics can readily understand. If any of you who does understand it, can you give a summary for the others. Thanks.

[Despe]

As usual, you have put your scientific background to work, trying to help yourself and fellowmen.

How are you doing in your personal journey? I hope your broccoli sprouts experiment is still producing the desired outcome! Please keep us posted.

THANK YOU, Albert!

[wriga in reply to Despe]

Hi Despe,I'm doing fine, better every day and every week.

I would just like to say this to everyone who follows what I do. This model that I present here is not something I just made up. I am convinced that it is pretty close to reality. What you have here is the short version of the simplified model. I have also written a longer version of the more complete model that takes account of pesticides, a-synuclein, obesity, exercise, mutated genes etc.. but much too long for here. It all fits with no serious contradictions that I can find.

All the hard work has been done by other very smart people. I only joined up the dots.

In summary, it means that PD is caused by oxidative stress from free radicals that are formed as a by-product when mitochondria make energy and the combined failure of 2 control systems simultaneously; the Nrf2 antioxidant defence system and the mitochondrial repair and maintenance system. Either one of them can stop it in the early stages. This double failure is a rare event, whereas temporary failure of any one is probably commonplace. What I mean by that is that it only happens in a very small number of cells (compared to all the cells in our body) of a small number of people, mostly when we get older.

The rare event occurs in only special sites where prevention is a problem. In PD this is in the very long and complex branches of axons of dopaminergic neurons the start in the substantia nigra and end up in the striatum. Each neuron starts with a single axon that branches into more than a million. To make energy, these have to be fed with glucose and oxygen from the nucleus into mitochondria all along the axons to the synapses. They make a lot of free radicals in a very closed space. These have to be removed in real time (milli secs) by antioxidants made by the Nrf2 system which is centralised far away in the nucleus. Mitochondria have a life cycle of about 2 weeks. When they get damaged by the free radicals, they get broken down and recycled. New proteins have to be ordered and delivered from the nucleus to repair the damaged mitochondria and the waste debris has to be taken back along the axon highway to the nucleus to be destroyed. It's a logistical nightmare. One traffic jam means lots of ROS pollution and both systems fail at the same time. That's stage 3.1. When that happens, it produces a power shortage and a storm of free radicals. The mitochondria retreat from and abandon the worst hit axons and regroup in others. The network is then less dense but still works. That's stage 3.2. Repeat 3.1 and 3.2 several times and you've got PD.

To fight back, you have to protect both systems; Nrf2 and mitochondrial maintenance.

2 systems = 2 therapies simultaneously.

Probably only 3.1 is reversible, but if you stop 3.1 you slso stop 3.2.

I've been doing that for 2 months and I'm much better than before.

So read the paper ten times if that's what it takes.

[Missy0202 in reply to wriga]

So encouraging! Thanks so much for taking the time to explain and doing your write up! Amazing!!!

[DJJD3 in reply to wriga]

Thank you for your work on this. I am not a scientist but I have read your paper twice and I think I grasp the outline, if not the details.Can you please share what actions you are taking to stop 3.1? In what symptoms do you find you are seeing improvement over the last two months?

Thank you,

James

[MarionP in reply to wriga]

"mitochondria retreat from and abandon the worst hit axons and regroup in others."

So you say that somehow mitochondria migrate and co-locate.

[chartist]

Albert, I wish there were more science minded people like you in current PD research because you are very dedicated and remain focused! Admittedly, I can see where you would be highly motivated, but you remain focused in your approach despite the frustration you run into.

I will follow your link in a moment and thank you very much for what you are doing here!

Art

[chartist]

I just finished the linked to page, Albert and it makes sense to me and seems to be in line with the studies I have read. I had unexpected company and had to stop , but I got back and finished reading your article. I think you did a very good job of clarifying things with what you wrote in an easy to follow process to go along with your staging model chart. As always, thank you for all of your time, hard work, reading, experimenting, testing and writing that went into what you are doing, that is dedication on your part and sharing your results with this forum is simply awesome!

Art

[chartist]

Albert,

I was just reading this article which I thought might be of interest to you. Here is a link to that article :

jci.org/articles/view/135026

Here is a link to the corrections to the original article:

jci.org/articles/view/150328

Art

[wriga in reply to chartist]

Thanks Art, as you have said before, melatonin is also a good Nrf2 activator. I don't have time to become fully informed about melatonin. I hope I can call on you to fill in the empty spaces when we come to discuss the subject of Nrf2 activators ....

[LAJ12345]

Just got this. Will read tonight!

[LAJ12345]

Ok, I have read through this. Firstly it is a very interesting theory. I don’t think though that it is very easy to read for the average Parkinson’s patient unless they have a scientific background. I have a background in chemistry from years back but the added genetic components of it are only familiar to me as I have done a lot of reading in the last year few years on Parkinson’s and genetics/ health. I think you will have a very limited audience but that doesn’t necessarily matter. It depends what the purpose of your paper is.

If it is to educate or help non scientific types I would say you have lost them. It is better for them to just have a light fluffy article on take broccoli seed extract and it will improve symptoms and here is how you do it with a recipe.

But if it is to try and get funding or interest in running more trials then I would say it is set at the right level.

I think one criticism you will get is that a sample of 8 is quite small, and also that there was no placebo given to any of them so it is possible people who bothered to carry out your method weren’t representative of Parkinson patients as they had the motivation and ability to carry out a complicated method, and just the enjoyment of being part of a trial may have improved say their mood. You may have more success in being listened to if you can recruit a greater number of subjects and have some of them take a placebo. To be representative you may need to have it administered to a group but prepared by a non participating member so you can have some people with worse symptoms included (or were some of the patients highly symptomatic but treated by more able and motivated spouses or caregivers ?)

Also I am not convinced that a chemical reason is necessarily the sole cause of PD. I have an alternative theory that lack of movement and poor posture causes fascia to become immobile and the lymphatic and glymphatic systems to stop working properly. This might be due to lack of exercise, injury, anxiety causing shallow breathing and tightening of the throat and neck muscles. The brain is then unable to carry away waste products so they begin to create the misfolded proteins seen in PD patients. These in turn create damage to the brain due to the brain being unable to transmit information as freely in those areas, and which causes different symptoms in different people depending on where the damage has occurred in the brain. Products like mannitol might help dissolve the proteins but without exercise freeing up fascia and glymphatic system drainage these waste products cannot be cleared away. Stretching exercises like qigong and yoga help with this. Exercise helps in that it facilitates the pumping of lymph fluid around the body clearing away waste.

Pharmaceutical drugs given to relieve symptoms cause new side effects and leads to a cascade of new symptoms each treated with a new drug and the number of symptoms increase. Most likely at least in part by the chemical methods you mention.

If the part of the brain where dopamine is produced is irreparably damaged this may be replaced chemically by levodopa drugs to mimic natural production of dopamine in the same way as antidepressants can mimic natural seratonin which may help some people if that is the part of the brain most affected. I think depression may also be caused by the same factors which is why it is associated with Parkinson’s.

I think a combination of your chemical explanation alongside the physical explanation might be a more complete theory.

[wriga in reply to LAJ12345]

LAJ, thanks for your point of view. I agree about losing PwP with no scientific background. I will write a summary people can understand. This was initially written for scientists which is why there are lots of references to back up the arguments. It is not at all dependent on the results of the broccoli seed tea experiment, but those results are consistent with it. Substantial evidence comes from peer reviewed research, hence the references. I'm not familiar with your other arguments, but we agree that failure of waste disposal may be a factor.

[Rhyothemis in reply to wriga]

Waste disposal in terms of autophagy / proteostatis is a huge factor for both PD and aging in general. Rapamycin has been found to extend life consistently in many animal models. An Nrf2 inducer complex (Protandim) was found to increase lifespan in male mice in the ITP study, but results were inconsistent across study cites (it's a multi-center project). However, Nrf2 also increases proteostasis(*), so it is hard to know how much of the benefit is from induction of antioxidant enzyme expression or from increased proteostasis (and rapa may also act through Nrf2, though mTOR inhibition is generally considered to be its main mechanism). Results from antioxidant enzyme overexpression in genetically engineered mice have been inconsistent, and supplementation with direct antioxidants including the mitochondrial targeted antioxidant, MitoQ, have not been found to increase lifespan in models.

Certainly I'm a fan of reducing excess ROS and minding my mitochondria (kinda have to since I have a fatty acid oxidation disorder), but it's not the whole story.

(*)

"Naked mole rats also have significantly elevated proteasome quality control mechanisms [25].The high breakdown and clearance of damaged proteins is suspected to be largely due to increased Nrf2 expression, as Nrf2 regulates the transcription of α and β subunits of the 26S proteasome, as well as the selective autophagy cargo protein p62 [48–50]." hindawi.com/journals/omcl/2...

Stuff on rapa and neurodegeneration towards the end of this post:rhyobrain.blogspot.com/2021...

[Rhyothemis in reply to Rhyothemis]

wanted to edit to include that rapa may also act through Nrf2, though not considered to be its main mechanism (which is mTOR inhibition). This site is very glitchy today.

[LAJ12345 in reply to wriga]

Yes of course. I didn’t look at all the papers at the end. Sorry.

[ryzlot in reply to LAJ12345]

Re "Sample of 8 is quite small" People ought to understand that the Pfizer "Vax" clinical trial that gave them emergency approval was based on EIGHT patients out of the 35,000 in the trial. Only 170 participants were exposed and got the flu - of these just 8 were deemed "saved" This is from their 52 page FDA application

[kevowpd in reply to ryzlot]

Does this intelligent discussion need derailing with COVID and vaccine arguments? Probably not?

8 people with no placebo is obviously very early stage for PD.

[Zella23]

Thank you for sharing this research with us. Both my husband and I are going to read through it and report back to you. John is still going on the broccoli extract, since I ve been less mobile since my operation, he has taken over the making of it so is experimenting keeping the amount low and taking it less times in a week to see what happens.

We re very grateful for all your expert help on this.

[Rhyothemis]

Prodromal symptoms of sleep loss and anxiety are most likely due to loss of noradrenergic neurons in locus coeruleus

healthunlocked.com/cure-par...

[wriga in reply to Rhyothemis]

Sure, the model includes the concept that other types of neurons are also likely to be affected by OS and mitochondrial dysfunction. I concentrate on Dopaminergic neurons to be coherent with current thinking and documented research and because distal axons of these neurons are extremely vulnerable.

[Canddy]

The stages are a little confusing as some may think they represent PD stages? Maybe call them something else? Otherwise - impressive!

[wriga in reply to Canddy]

I had also wondered about that problem. I may change stages to phases.

[faridaro]

Thank you Albert for such extensive work on the model of PD pathogenesis - how I wish I had a degree in biochemistry to understand intricacies of metabolic pathways which are mind boggling (at least for me) even in the simplified version.

Very much appreciate your effort to figure out etiology of PD which is the first step in development of an appropriate treatment and looking forward to your future article in which "the question of which therapeutic methods might be considered to address both oxidative stress and mitochondrial dysfunction will be discussed".

[wriga in reply to faridaro]

Start by looking here

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

[faridaro in reply to wriga]

Thank you for the link to the article - very informative! I already use most of the supplements mentioned there, but was quite surprised to see α-ketoglutaric acid - I was curious about it 2 years ago and posted a question on this forum but only one person responded and I assumed it was not worth pursuing : healthunlocked.com/cure-par... Now I am thinking of trying it.

Also, lately I've been looking into L-Carnosine which is supposedly to be critical for brain health and according to the included article "can revive mitochondria. And even rescue your brain cells if the mitochondria have stopped functioning", see nootropicsexpert.com/l-carn...

However, L-Carnosine is not mentioned in the "Mitochondrial Dysfunction and Chronic Disease: Treatment With Natural Supplements" article, do you think is it worth trying?

[wriga in reply to faridaro]

Hi faridaro,I haven't looked into l-carnosine at all, but the link you give to nootrppicsexpert.com is very interesting and full of useful information. Thanks

[Rhyothemis in reply to faridaro]

Carnosine is interesting since it can quench reactive carbonyl species such as acrolein. Acrolein can cause the formation of methemoglobin in red blood cells, which reduces oxygen delivery and can cause fatigue. Later stage PD patients have elevated levels of methemoglobin in RBCs. RBCs actually have a dopamine transporter and it may function to clear excess dopamine (maybe, not really known at this point). Oxidized dopamine can also interact with hemoglobin to form methemoglobin. Carnosine was found to reduce acrolein-induced methemoglobin in the following paper - which is unfortunately paywalled. The abstract says the carnosine had no effect on metHb formed by dopamine, but in the article it shows that the carnosine had an overall effect of greatly lowering the amount of metHb in the RBCs. The same group also put out a meeting abstract (so not peer -reviewed) that reported a lowering of the metHb caused by dopamine with spermidine. link.springer.com/article/1...

Acrolein is a very nasty substance and has been implicated in overall pathophysiology of PD: translationalneurodegenerat...

There is some controversy about oral bioavailability of carnosine vs. its pre-cursor, beta alanine. Beta alanine is taken by athletes to increase muscle carnosine stores and many in sports medicine say it is preferable since digestion breaks down carnosine anyway. I don't know what beta alanine would do for serum carnosine. Beta alanine can cause a weird side effect, some describe it as pins and needles - it felt to me like being poked with fine needles and it was not pleasant. Interestingly it is being used as a treatment for 'water allergy': reddit.com/r/aquagenicpruri...

There's a topical carnosine product, LactiGo, that apparently does get into muscles and improves athletic performance - but again I don't know if it has an effect on blood levels of carnosine. I've purchased some for my daughter to try - perhaps when her exams are over. She suffers from extreme fatigue and may be developing ME/CFS; people with ME/CFS have elevated metHb. She had central cyanosis (blue lips) during her bout of neuroleptic malignant syndrome from Reglan - I think it may have been due to methemobloginemia (of perhaps suflhemoglobinemia). She also had blue baby syndrome as an infant from eating spinach (was very brief episode, thank goodness). I may have her try oral carnosine or beta alanine at some point (I don't think she would like the 'pins and needles' from the beta alanine though).

[faridaro in reply to Rhyothemis]

Appreciate your input Rhyothemis, will look at the links over the weekend. Hope your daughter gets the right treatment and relief from fatigue. She is fortunate to have caring and supportive family. Happy Mother's Day!

[PalmSprings]

So interesting! I really appreciate your thorough research. I have the broccoli seeds and plan to try the tea soon. The article is so worth reading. I actually plan to read it a few more times to try and absorb all the information.

[Woofie123]

How it acts, yes. But why ? Why does that tiny particle, which isnt almost even alive, is driven to invade brains and destroy parts of them.

[ConnieD]

Hi Albert, thank you for your research! I can’t imagine the time you spend on it for the entire PD community. I’ve read through your research and at times being non scientific it is like trying to read a foreign language that I was never taught. I’m glad you continue to see improvements in your own PD symptoms. Is it correct that the broccoli seed tea only helps non motor symptoms?

[wriga in reply to ConnieD]

Hi ConnieD,No, the broccoli seed tea has a direct impact on non-motor symptoms because it helps stop the damage being done in step 3.1. I don't know if it is enough to stop it completely because 3.1 is the result of 2 processes, oxidative stress and mitochondrial failure. The broccoli seed tea deals with oxidative stress. Mitochondrial failure may need to be addressed separately although the 2 are intertwined because mitochondrial failure also causes oxidative stress. It's a vicious circle. If we can deal with both processes, then 3.1 can be reversed. There are green up arrows in the schema at 3.1.

If you stop 3.1, then 3.2 will go no further but the damage already done by 3.2 cannot be reversed. No up arrows at 3.2.

Broadly, I interpret 3.1 as causing non-motor symptoms and 3.2 as causing motor symptoms although there will probably be some overlap.

Even if 3.2 cannot be reversed because some axons or neurons are lost, if we stop only 3.2 but make the remaining neurons more healthy by reversing 3.1, they will function better than damaged ones, but over a longer timescale.

This should have a positive effect on motor symptoms also, but you have to be patient. This is my experience.

[ConnieD in reply to wriga]

Thank you Albert, very informative!