Talk:Progress and Prospects in Parkinson's Research/Magazine Section/Draft article 1

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Comments on the Multi Hit Hypothesis draft article
First there is confusion as to what constitutes the 'Multi Hit Hypothesis'. For instance the Stein paper (http://en.wikiversity.org/wiki/PD_Magazine_Section/Draft_article_1#cite_note-0) describes it as a set of genetic and environmental risk factors which may vary in their timing and whose impact may be additive or synergistic. It is set within an essay on environmental effects and therefore is largely to do with the multiple hits from the environment that may be needed to induce Parkinson's in a particular individual.

On the other hand, the Sulzer paper is really talking about the various internal, interacting biopathological pathways and processes involved in Parkinson's.

I suggest that the title 'Multi Hit Hypothesis' is reserved for the first context - multiple hits from the environment which may be required to induce Parkinson's in a person with a genetic predisposition.

I suggest that the phenomenon referred to in the second, internal, biopathological context is referred to as 'Mulitfactorial'. I also suggest that the word 'hypothesis' is dropped in this context because it now appears to be well established that there multiple interrelating pathways are involved in Parkinson's biopathology and so is a developing theory.

There are many papers which cite the Sulzer paper. There is one review in particular which appeared in Nature Medicine in May 2010 and is noteworthy because its authors have been prominent in the Parkinson's research field for many years:  Obeso, Jose A., Maria C. Rodriguez-Oroz, Christopher G. Goetz, Concepcion Marin, Jeffrey H. Kordower, Manuel Rodriguez, Etienne C. Hirsch, Matthew Farrer, Anthony H. V. Schapira, and Glenda Halliday. “Missing Pieces in the Parkinson’s Disease Puzzle.” Nature Medicine 16, no. 6 (2010): 653–661. http://www.nature.com/nm/journal/v16/n6/full/nm.2165.html

Thus I think that we should have two articles here:
 * One which deals with multiple hits from the environment and can use the Stein paper as its starting point. (It would be worth looking for more recent papers and reviews that cite it and may indicate further advances.)
 * A second titled something like 'Parkinson's multifactorial pathogenesis'. The Nature Medicine review could be a springboard for that.

The Multiple Environmental Hits idea is something that is not talked about much so is worthy of a Magazine Section article. We must research more, though, on the LPS aspect. We must find out what has been done recently and whether the idea of pre-natal preconditioning has continued to receive support. We must also determine whether it is thought that LPS is the unique cause of early disposition towards PD or is merely an example of a toxin or infection that has this effect. Further, is it claimed that LPS simply reduces the count of SN neurons or does it set up a persistent inflammatory state?

The Multi-factorial pathogenesis idea is really at the heart of the topic in Section 1 on Pathogenesis - the Current Parkison's Paradigm. I suggest that these pages are developed rather than spending time on a Magazine Section article (although there could be a Magazine Section article which serves as an introduction and points to the pages in the main section).

Droflet (talk) 13:07, 1 November 2012 (UTC)

There is another comparatively recent paper that is relevant to the multifactorial basis for Parkinson's pathogenesis: Durrenberger, Pascal. F., Edna Grünblatt, Francesca S. Fernando, Camelia Maria Monoranu, Jordan Evans, Peter Riederer, Richard Reynolds, and David T. Dexter. “Inflammatory Pathways in Parkinson’s Disease; A BNE Microarray Study.” Parkinson’s Disease 2012 (2012). http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3324922/. The lead author is David Dexter, Imperial College and the Parkinson's UK Tissue Bank.

With regard to this (or these) articles, we must get in touch with researchers who are making (or have made) the running in this field and ask their views on the current state of play. The more specific the questions that we can ask them the better.

Following on from this (and in line with what I am writing below) I think we should attempt to start from the most up to date information and remove material that is more than a few years old - or attempt to replace it with more recent material. For an article like this in the Magazine section, people will not be interested in tracing a historical account of how the hypothesis developed. Understanding why a hypothesis is needed, yes. But a minimum of historical details.

Droflet (talk) 13:07, 1 November 2012 (UTC)

An approach to drafting articles - General points
For all articles there first needs to be a search for the most recent papers that address the topic. In PubMed when you are looking at an abstract you will find on the right a list of other papers which cite the one that is being looked at. This is invaluable for finding out not only which other papers referred to the current one, but also what significance subsequent researchers have given to the material in it. The principle here is that people are interested in reading about the latest results and they are not interested in tracing the historical development of the topic. We must ferret out the latest word on the topic.

Review papers are better at summarising the current views on a topic. Individual papers that report on the results of only one set of experiments need to be treated with caution. All experimental results ought to be replicated by others before they can be fully relied upon. Review articles take results from many sources and often point out inconsistencies that need to be resolved. Articles in this wiki are essentially 'reviewing the reviews', especially for results and progress that seem particularly interesting and significant.

Articles in the Magazine section ought to be geared at explaining topics well in accessible language. Thus their style must be narrative, clear and interesting. This implies that their emphasis should be on bringing out the main points of interest and significance; systematically documenting the topic should take second place. (References should, of course, be given but they should not be centre stage.) The author should be encouraged to raise issues and discuss their pros and cons (so long as a personal view is not put over as an established fact). Discussion of the issues is often what makes the article interesting.

Look at the 6 principles for this wiki: Portal:The_Science_Behind_Parkinson's/Section_1/more

As we research issues, we should identify the researchers who are doing the most significant work in the field. We should then contact them to get them to clarify particular points or to answer questions that arise. We should cite their papers and ask what further work has been done. We are writing in public about their work and so they should be interested. If we can demonstrate that we are engaged in a serious undertaking they should be happy to cooperate and even to write material direct to the wiki itself. We must demonstrate that we are have done our homework on the topic in question and that we are not floating half-baked 'pet theories'. In this way researchers should appreciate the virtue in what we are doing.

Droflet (talk) 13:07, 1 November 2012 (UTC)

The Evolution of PD Hypotheses
I think that this introductory section is now very good.

I am not, however, fully happy with the last paragraph because I would not apply the term Multi Factor Hypothesis to the LPS thing. (See the discussion on Multi-factorial pathogenesis above.) I think what this final paragraph might be trying to say is that in some case the intitial 'hit' is prenatal exposure to LPS. What has not been established is whether this is a real effect in humans and, if so, how prevalent is it in practice. The paragraph reads rather as if all PD cases and especially all early onset cases are causes by prenatal LPS. Without spending a lot of time looking through the references I don't know whether the authors are suggesting this but I suspect they are not.

Brain Reserves
I think this is a misleading term. We are really talking about significant redundancy of neurons in a particular location, the substantia nigra pars compactor.

But I also think that reduction in the number of neurons is not necessarily the key factor. The evidence is that Parkinson's is a biopathological process and that there are a variety of triggers that might start it up. The MHH suggests that the first (or second) 'hit' might not fully start up the process but does in some way make the body more susceptible to future hits. The susceptibility towards the PD disease process starting up may possibly not be because there are fewer SNc neurons; it could be because the immune system has been sensitised to pro-inflammatory influences. But to look at it the other way round, if the disease process starts up in a person who has a reduced complement of SNc neurons, the motor symptoms will appear sooner than for a person starting with the full complement of neurons even though the disease process started at the same time. Also, from a third point of view, why should the deficit of SNc neurons in itself make a person more vulnerable to a second disease-process-promoting hit? A possible answer might be that after the first hit the body managed merely to slow the disease process but a subsequent hit aggravated it again. We need to find research that addresses these issues.

The MHH diagram
What is the origin and copyright status of the diagram? Also I am not keen on the 'fictional examples'. The specificity of each case gives the impression that these are proven rather than hypothetical scenarios.

Lipopolysaccharide (LPS)
Please remove the Telford/Hardwick section. It is too old and should be covered by subsequent work. If the questions have not been satisfactorily answered, the article itself could raise them again in a rephrased form.

The article needs more on what recent work on LPS (and other pro-inflammatory agents) and PD has been done. There then should be a concluding section which discusses the issues and questions why some are still outstanding and why there has not been recent follow up. Does it suggest that the whole idea is now discredited? Or what? Maybe people reading the article could help clarify this. Maybe it is time to write to some of the researchers to ask about the up to date position. The 2006 Carvey link (currently ref 12) no longer works.

I think the page structure where parts of papers are quoted and little comment is given is OK for the main part of Section 1. But in the Magazine section there should be a definite discussion/conclusions section where the relevance and significance of the quoted extracts are brought out from the author's point of view. This is the part of the wiki where hypotheses can be humbly aired and the views of others deliberately solicited!

Droflet (talk) 12:58, 26 November 2012 (UTC)