Quote:
Originally Posted by johnt
Rick,
Thanks for starting a debate on this topic: you can't get anything more important for us than the aetiology of PD.
Where I agree with your theory:
I can buy into the importance of neuroinflammation.
I think you're right to say that anti-inflammatories are inversely associated with PD, and inflammatories are positively associated with PD.
I think that your no one cause theory of PD is correct. This leads to a scoring system, a bit of this plus a bit of that, which builds up to something that leads to real damage.
But, all of that is insufficient to show direct causality.
GerryW's question is a good one: many people have exceptionally stressful lives, flu, h.pylori etc., but don't get PD; many people with PD haven't had noticeably stressful lives.
Where I disagree with your theory:
I think what's missing is the role of genetics and the role of alpha-synuclein.
I believe that the true significance of inflammation is that it increases the chance of misfolding, aggregation and clumping of alpha-synuclein. This leads to the death of neurones and the collection of symptoms that we see in PwP.
(I've written this post without references, but references to most of the post's assertations can be found by searching for the string johnt:alpha-synuclein .)
John
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John-
First, let me make it clear that this portion of the hypothesis is not "mine" other than in the sense that I champion it because I find it to be the best out there. The part that I posted should be credited to Carvey at Rush and Bin Liu and others at NIH. Later parts of the hypothesis are the work of myself in collaboration with Anne Frobert, MD of Lyon, France and a still later part is indeed my work. It is quite involved but thus far holds water. I will dust it off and start posting it for comment. So much work has gone into it (three years with Dr. Frobert for example) that I need to get it out while I still can.
Briefly-
It is known that a fetus can be programmed by a number of chance events including exposure to LPS and a similar exposure to maternal stress hormones. Both of these can have a dramatic effect on the immune and endocrine systems if they occur at critical times of development. These effects may not manifest until the chemical changes of puberty.
In the case of the immune system the observed changes include the decreased neuronal density noted above but also a overly vigorous response by the primitive innate part of the system called the microglia. In short, the microglia fail to respond to shut down instructions as they should. As a result it has been observed that a response that should have been over within a few hours was still going strong ten *months* later. While the microglia do not seem to attack the nervous system directly, there is collateral damage and waste of resources.
Most importantly, at least to me, is the role of the immune system's communication chemicals, the cytokines. Like their corresponding "cousins" in the CNS (the neurotransmitters) and in the endocrine system (the hormones), the cytokines are neuroactive and impact our behavior on various levels. It is here, BTW, that I enter new territory so your thoughts would be of considerable interest. And I have barely started on the endocrine system....
There is a lot more than dopamine at work, as we have long known. But I think that once we know just how far reaching it is that we will be suprised. -Rick