I know there are a select number of decent researchers on this site.... those who read their fair share of medical papers and journal publications. I need some help with research...I simply don't have time to read everything on my own. The problem I'm interested in needs to be tackled because it very significantly determines whether a fair share of PD patients will deteriorate or not.
The subject I'm referring to is about maintaining adequate blood flow to the brain. The fancy term for this is cerebral hypoperfusion. It's related to dysfunction of the nervous system, and it's rather common in PD, and very common in LBD and MSA.
With PD, the more autonomic symptoms you have, the more likely you are to experience a faster progression of your disease, and the more likely you are to convert to lewy body dementia. The autonomic function issues i'm referring to include blood pressure issues, urinary dysfunction, and to a lesser extent constipation.
This problem is REALLY nasty. Inadequate blood flow to the brain causes an oxygen deprived brain and this causes alpha synuclein to be PRODUCED (phosphorylate) and SPREAD to cognitive areas of the brain like the cortex. YIKES!!! Yeah, you read that right. It basically causes lewy body dementia in those who already have PD or pre-PD.
The causes of neuronal orthostatic hypotension are very complex, and that's where I want the research community to identify what causes the underlying dysfunction. I'd also like to identify meaningful neuroprotective treatments for this... Can we please work toward a solution to this problem?
For one thing, the whole peripheral nervous system seems to slowly fail in synuclein disorders. A big part of this is that misfolded alpha-synuclein travels down the peripheral nervous system, gumming up the nerves throughout your body. This means that your brain can no longer effectively send a message to your vascular muscles to contract or expand, so when you sit up or stand, all the blood pools at your legs and an insufficient amount makes it to the brain, resulting in cerebral hypoperfusion. Also, this misfolded synuclein throughout the peripheral nerves causes them to downregulate their phenotype, undergo apoptosis, and die. If that sounds scary, it is. I should mention that peripheral nerves can regenerate quite nicely, but not if they have the burden of misfolded alpha synuclein.
Another part of this is that the brain's production of the important neurotransmitter norepinephrine is massively downregulated in PD and related disorders. Is there any way you can boost the health of this lagging norepinephrine-brain axis? What/where are these areas in the brain and what are the neurotrophic factors that are responsible for ensuring the health of such circuits? Obviously some folks are heavily effected by these autonomic issues while others escape relatively unscathed. This makes me wonder, are there any insults or other contributions involved here that are unique to the destruction of the brain's autonomic circuits?
Yeah I know you can boost norepinephrine by taking droxidopa. But wouldn't that result in negative effects, kinda similar to the idea of 'artificially' boosting dopamine by taking l-dopa? That is to say, taking l-dopa to boost dopamine eventually results in very negative side effects and cellular changes. Would the same concept apply with using droxidopa to boost norepinephrine?
And yes you can possibly take midocrine for symptomatic benefit. But doesn't it simply jack up blood pressure in a fashion that is separate from neuronal function? And does such a drug have any negative long-term side effects, vascular wise, such as long-term supine hypertension? (This has been hinted in some literature)
To those who do research out there, I appreciate your thoughts. Even if it is simply just reading TONS of journal articles and connecting the dots..... sometimes this is all that is needed to come up with new and innovative methods to protect the nervous system and treat this disease! Such an approach is exactly what Dr. Rhonda Patrick does by surveying the vast mountains of scientific literature, and she often comes back with meaningful results. I am a fan of hers!
Feedback from a PD research scientist in the department of Clinical Neuroscience at the University of Cambridge (UK), on PASADENA Trial...
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