Vascular Dysfunction in the Brain as an Initiating Event in Parkinson’s Disease

[JayPwP]

parkinsonsnewstoday.com/for...

The concept that Parkinson’s disease is essentially a vascular dysfunction disorder comes from the pioneering work of Dr. Berislav Zlokovic and his research team at the Keck School of Medicine at the University of Southern California. These USC researchers believe that a substantial proportion of neurogenerative diseases are wholly or partly due to age-related small vessel disease of the brain.

Here is a quote from one of Dr. Zlokovic’s papers published in the prestigious peer-reviewed journal, Cell: “aberrant angiogenesis, vessel regression, brain hypo-perfusion, and inflammatory responses, may initiate and/or contribute to a ‘vicious circle’ of the disease process, resulting in progressive synaptic and neuronal dysfunction and loss in disorders such as Alzheimer’s disease, Parkinson’s disease, amyotrophic lateral sclerosis, multiple sclerosis, and others.” (Cell, vol 163, pp 1064-1078, November 19, 2015).

[Smittybear7]

Thanks for sharing

[chartist]

Jay,

Thank you for the link!

I would think that what Dr. Zlokovic is describing are downstream/later events in the disease process from what takes place in the gut well before the processes he is describing. If his idea was 100% correct, FMT would not have worked as it did in the FMT/PwP studies nor would it have worked as fast as it did. Just my opinion of course. What he is describing does no doubt contribute to the disease process, but seems questionable as being the point of origin. If it were the point of origin, how could the FMT/PwP results have happened so quickly or at all. The two FMT studies were small and only preliminary, so hardly definitive, but if his idea is correct, the FMT results should have been nil over the study period of 12 weeks, again, imo. I don't think it would be possible to reverse the type of damage he is describing in just 3 months or less.

Art

[WinnieThePoo in reply to chartist]

I don't understand how something in the gut could cause a loss of blood vessels in the SN, and then within 3 months a regeneration of those blood vessels

In simple terms, how about the loss of blood vessels , poor waste clearance, poor oxygen supply, leaves neurons weak and vulnerable, and toxic processes from the gut brain axis then inflict the damage which shuts them down

The author of the quote by the OP is senior management with Zhitia - who are trying to get their angiogenesis protein FGF-1 approved to treat Parkinsons disease. They have finished recruitment for a human clinical trial in Mexico, which is due to start any day.

If if works for people like it works for Monkeys, it could be the big one. Isn't "IF" a big word?

[chartist in reply to WinnieThePoo]

Yes, that was my point. If he was correct about the origin and the amount of damage to blood vessels, then how can FMT in the gut start to cause recovery in three months, well actually less because improvement was seen well before the end of the FMT study. The type of damage he is describing could not possibly be repaired in such a short time frame as the FMT study took, yet the FMT study showed benefit early on.

Art

[sharoncrayn in reply to chartist]

"FMT would not have worked as it did in the FMT/PwP studies nor would it have worked as fast as it did...."

The 3 Chinese FMT/PwP studies were extremely weak due to the very small # of participants (1, 11, 15). Very high probability of non-existent statistical significance of any of the results due to a strictly tiny Chinese sample....proving almost nothing.

sharon

[chartist in reply to sharoncrayn]

What was useful about that data was that they showed that the colonoscopy delivery was superior to the nasointestinal delivery. Future studies should focus on the colonoscopy delivery or crapsule delivery of FMT as it has shown to be effective in other studies and is less invasive than the colonoscopy delivery.

Art

[sharoncrayn in reply to chartist]

For Chinese PwP I agree. I wouldn't expand your conclusion to everywhere until we see some results from some where else other than China. These were very weak studies.

[WinnieThePoo in reply to sharoncrayn]

I agree. I still think FMT and microbiome management are strong candidates for possible therapy, but these "trials" are too poor. And its disappointing that the Scandanavian and Belgian trials have not reported (Does that imply failed?)

12 weeks is the blink of an eye in PD. My condition, or individual symptoms, can fluctuate all over the place over that time frame. So placebo effects are a given. If anything, on the question of most interest to me considering an FMT, the first trial established that only 2/12 get a 2 year benefit, and 10/12 only benefit 6 months

If FMT works that would mean 2 15 day sessions a year at around £7000 a time or £14000pa for the benefit. Not very encouraging

[sharoncrayn in reply to WinnieThePoo]

When a CT doesn't publish within a reasonable time from closing, it is a strong indication the results did not meet their primary/secondary objectives.

I doubt your gut microbiome is similar to that of the Chinese in those 3 studies.

The jury on FMT is still out as far as becoming a mainstream therapy is concerned.

sharon

[Nguflh58]

Head injuries cause vascular dysfunction in the brain.

[MarionP]

Hogwash as far as PD is concerned, the mechanisms are well enough described at the moment to be nowhere near what you're suggesting, which is probably why I see all these heavily weighted sales adjectives. Baloney.

[WinnieThePoo in reply to MarionP]

Don't throw the baby out with the bathwater

JayPWP's quote is a Zhittia staff responding to a blog about their companies proposed therapy

And it provides an erroneous reference to Dr Zlokovic's paper

And it takes it a bit out of context - although in another paper he said pretty much that about Alzheimers

But, albeit redacted, the quote is for real - this is the abstract from his 2008 paper

"The blood-brain barrier (BBB) is a highly specialized brain endothelial structure of the fully differentiated neurovascular system. In concert with pericytes, astrocytes, and microglia, the BBB separates components of the circulating blood from neurons. Moreover, the BBB maintains the chemical composition of the neuronal “milieu,” which is required for proper functioning of neuronal circuits, synaptic transmission, synaptic remodeling, angiogenesis, and neurogenesis in the adult brain. BBB breakdown, due to disruption of the tight junctions, altered transport of molecules between blood and brain and brain and blood, aberrant angiogenesis, vessel regression, brain hypoperfusion, and inflammatory responses, may initiate and/or contribute to a “vicious circle” of the disease process, resulting in progressive synaptic and neuronal dysfunction and loss in disorders such as Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis, multiple sclerosis, and others. These findings support developments of new therapeutic approaches for chronic neurodegenerative disorders directed at the BBB and other nonneuronal cells of the neurovascular unit."

[Despe]

". . . reduced blood flow and hypo-perfusion in the brains of patients with Parkinson’s disease."

That's for sure! Carotid artery stenosis one of the reasons, such as my husband suffered. Not enough blood flow and oxygen were the result of my husband's PD plus work-related stress.

[WinnieThePoo in reply to Despe]

I think you may have missed the point - as well as typing your own version (where does it say "reduced blood flow"??

I think you are confusing micro-vascular with cardiovascular.

[Despe in reply to WinnieThePoo]

Did you read the link Jay provided? The sentence in bold was copied/pasted from the link. Besides, his surgeon and the cardiologist mentioned that luck of adequate blood flow and oxygen most likely contributed to his diagnosis.

[WinnieThePoo in reply to Despe]

The quote in context is "In my next post, I will review the evidence for reduced blood flow and hypo-perfusion in the brains of patients with Parkinson’s disease."

Again context is a million dollars. This is about tiny blood vessels making the final supply of blood to neurons, not the pump that gets the blood there.

If a cardiovascular problem was the cause of your husbands PD, then, if you follow the logic, rectifying his heart problems should cure his PD.

If you restore the context, you realise it is specifically nothing to do with the heart - from the same post

"If vascular dysfunction occurs in the substantia nigra region of the brain that houses the dopamine-secreting neurons, it is our belief that this is the initiating event in Parkinson’s disease."

Obviously it meant to say "If vascular dysfunction occurs in the substantia nigra region of the brain, or carotid artery". They should have consulted with you before publishing

[JayPwP in reply to WinnieThePoo]

If a cardiovascular problem was the cause of your husbands PD, then, if you follow the logic, rectifying his heart problems should cure his PD.

Neurons that are dead are lost. I believe 'Vascular' refers to all blood vessels, major and micro

[WinnieThePoo in reply to JayPwP]

The text you quote is a forum posting by one of the senior team at Zhittia Genesis. They think they have a potential treatment because, even over 60 years of age , we can grow brand new original spec neurons. The old ones had died, and new ones aren't growing, because of restricted blood flow at the localised micro vessel level (capilliaries of veins). Restoring the blood flow allows brand new neurons to grow. Angiogenesis promotes neurogenesis. So whilst in absolute terms it may be true that neurons which are dead are lost, that doesnt mean they can't be replaced. Think of it as a sort of "grow your own stem cell transplant"

You guessed it - it works for rats and monkeys. Human trials are about to begin in Mexico (although phase 1 safety & tolerability, they will provide some clinical proof of concept in human situations).

But the concept only works at a microvascular level. Cardiovascular issues didn't cause the neurons to die, and cardiovascular interventions aren't going to promote the growth of new ones. Despe's post was about as relevant as suggesting ingrowing toe-nails were involved

[Despe in reply to JayPwP]

What is carotid artery?? I had two cardiologists telling me about the fact that blood and oxygen were not reaching his brain for a long time! I rest my case.