Parkinson's Animal Studies: Do Pretreatment Success Stories Mask Posttreatment Failures?

[park_bear]

For most of us, by the time Parkinson's is diagnosed, something like 80 percent of the dopamine producing neurons have already perished. Likewise, for most of us, in retrospect we realize that Parkinson's symptoms had been building for some time prior to diagnosis, typically for years.

According to the current medical understanding, for which there is good evidence, Parkinson's is caused by accumulated aggregates of alpha synuclein that neurons are unable to dispose of.

In the title, "pretreatment" refers to the practice, in animal studies, of pretreating the animal with a test substance and then subsequently, or simultaneously, applying a toxicant that causes a Parkinson's like condition. In this case, if the test succeeds, that means the substance has prevented the aggregation of clumps of alpha synuclein. This has little to do with treating actual Parkinson's. That requires the dissolution of formed clumps of alpha synuclein. To test this, the animal must be treated with the toxicant first, time allowed for the alpha synuclein aggregates to form, and then treated with the test substance.

It is very frustrating to find that most animal studies are of pretreatment only. Based on the foregoing, this is not evidence of efficacy in treating Parkinson's.

Now let us consider that these animal trials typically have several arms, consisting of some or all of the following:

• The control arm of toxicant only

• Test substance plus toxicant, possibly more than one arm with different dosages, with simultaneous application or pretreatment with test substance

• Negative control of toxicant vehicle only

• Test substance only

With some or all of these arms going already, the cost of adding an additional arm of test substance applied after toxicant, rather than before, is insignificant. Why do investigators not do that? Maybe they do!

Let us suppose that they do and the posttreatment arm fails but the pretreatment arm succeeds. If this happens and they disclose the failure of the posttreatment arm, no one is going to be very interested in publishing a study with success in the pretreatment arm but failure in the posttreatment arm. What to do? Deep six the failed posttreatment arm and publish the success story. I do not know that this is happening, but I wonder.

These kinds of papers are mostly published by academic researchers. Before someone accuses me of hating on researchers, I do not. The academic model is "publish or perish". The pressure is intense as is the competition to get funding. I know of someone involved in academic research, not medical, and he has been in an ongoing state of stress for years. So if this is going on I would blame the system rather than the researchers.

Update – case in point of why pretreatment versus posttreatment matters. A lot: jstage.jst.go.jp/article/dd...

"Pre-treatment with eugenol reversed motor dysfunction caused by MPTP administration while post-treatment with eugenol at a high dose aggravated the symptoms of akinesia associated with MPTP administration."[Emphasis added]

Update – Investigators serious about treating Parkinson's they make sure the test animal has Parkinson's before applying treatment

Cases in point:

Inhibikase Therapeutics C-Abl inhibitor IkT-148009 science.org/doi/10.1126/sci...

"PD, IkT-148009 suppressed c-Abl activation to baseline and substantially protected dopaminergic neurons from degeneration when administered therapeutically by once daily oral gavage beginning 4 weeks after disease initiation. Recovery of motor function in PD mice occurred within 8 weeks of initiating treatment concomitantly with a reduction in α-synuclein pathology in the mouse brain." [emphasis added]

Inhibikase ran a phase 2 trial, which unfortunately failed. It was poorly designed - far too short to demonstrate efficacy.

Cinnamon

In this study: Reduction of Lewy Body Pathology by Oral Cinnamon link.springer.com/article/1...

Investigators used 10-month-old A53T mice. These mice are genetically modified to produce defective human Alpha synuclein with the A53T mutation. Regarding these mice: alzforum.org/research-model...

"Moreover, around 10 months of age they begin to develop severe motor impairments (Lee et al., 2002). Early signs of impairment include wobbling and posturing."

My report on Cinnamon here: healthunlocked.com/cure-par...

[kevowpd]

As bad as things look from the outside, they are probably worse on the inside. I have had the opportunity to look behind curtains that most people do not (not in medicine or research but in other fairly significant parts of society where joe main street would reasonably expect that everything would be done with great rgourous and clinical adherence to predetermined standards) and the reality is a fair portion of the people involved are basically winging it.

Society is laden with poor incentive structures, sadly.

[MarionP in reply to kevowpd]

Poor incentive structures, good description. But you know, everyone loves a winner, and nobody loves the goat.

[MarionP]

Your concern has for a very long time been a concern of scientists and an endemic problem with the publish-or-perish nature of competitive research and competitive publishing, both of which actually function as competitive businesses in a capitalist model. The concern is of the effect of both a business and psychological problem, actually a positive bias, against publishing what are called negative findings or findings that are not in the hoped for direction of the powers who ultimately need to profit in a capitalist sense from the research in order to recoup the expense and also in order to simply earn a great living. That's a bias and the bias is carried into government or nonprofits which also are in the business of awarding funding research in hopes of the ultimate results becoming commercially applicable as well as applicable from a reputational standpoint on the scientist and the investors and the treatment business. It is an unfortunate byproduct and well known to be an inherent problem, if only a problem known to a very few insiders who understand what it takes to produce value and then to expend that value and need to recoup it in order to create professional justification of one's career, mercantile justification of one's investment, and simple ego which responds better to approval and positive success then it does appear scientific success of including negative results when they occur. It's not your imagination, it's very well known, all of it, just not commonly known among the 99.999% of the laity, which is 99.999% of everybody.

Nobody likes to appear failure, and nobody likes to lose. We all like to win. We like winners. Actually we love winners. We do not love losers. We reward winners in many areas of life, not least being financial reward, Fame reward, eagle reward, many other sorts of rewards and they are real. In fact actual research has established that anybody who we think of as a winner turns out actually as broad class to be a winner. Examples: tall people get more money, more girls, better careers, in all fields. People with unusually big heads tend to become stars in media, arts, movies and tv, other broadcast media. It's actually been established by the same scientific evidence that we have a right to question when it comes to "negative" results. Go back and look at all of the famous people you've seen and the greatest of the stars. It's actually true, their heads are freaking bigger, and if you see them in real life, their heads are way bigger in proportion to their bodies, than anybody else's. Freaky. But scientifically established. "I'm ready for my closeup Mr DeMille."

Winning in this case comprises only apparently "positive" results. Nobody really looks to fund failure and something that doesn't seem to on its face or in the common thought appear to "win" gets much future approval, accolades, money, or other forms of success. It's a bias. A horrible bias. A bias that produces error in an entire field.

Don't take my word, it's actually been established overtime in a number of areas of inquiry, by actual scientific research and well-designed experimental studies to try to tackle the question that you posed. Unfortunately, it's actually no longer new, and the concern that you have has been established as an actual effect.

And yes, sometimes arms that are inconsistent with one's natural need, and financial need, to produce "wins" can indeed be buried. Also, fail your to achieve a hoped for positive result can also be buried, by faking data after the fact. Many such scandal cases in fact exist, including people who made a career of doing so, sometimes after the researcher has died in cases of really famous people who managed to do it all of their career and achieve great Fame as a foremost researcher until after their death the frauds begin to accumulate and the collusion and the publishing industry also becomes apparent.

In fact, a career full of absolute fraud, blatant in fact, of fully lionized Peers (with a capital "P") in their field, does occur.

Case in point, Sir Cyril Burt, and he's only one of actually quite a few. Here's another (sorry to be hitting on Brits tonight, they just happened to spring to mind because they're both from my own profession and it pisses me off royally because they were practically the most published in each of their generations, the most lauded, the most successful at publishing, the most cited for significant work in several subfields of their professions... And both only caught after their death...Hans Eysenck. So Burt and Eysenck. And I was even very close personal friends with one of Eysenck's kids, whom I shared a year with at University as it happened...which pisses me off even more (no, of course she didn't know, she's as much a victim as anyone).

But believe me, they are not alone and their profession is not the only one, believe me believe me and believe me once again. It's why I pound so hard on people looking at such services as Retraction Watch and several other similar type efforts.

[Hidden in reply to MarionP]

This might be interesting to you, Open Science: scienceofparkinsons.com/202...

[Bolt_Upright in reply to Hidden]

Great are in that article:

Patent Troll

[MBAnderson in reply to MarionP]

"...their heads are freaking bigger, and if you see them in real life, their heads are way bigger in proportion to their bodies, than anybody else's. Freaky."

Whew what a relief to know this is actually a thing. I thought I was the only one who noticed.

[Bolt_Upright]

Don't blame the player, blame the game!

[cgreg]

There is more bad news even from the highest levels of academe:

Stanford President to Resign After Research Questioned - "But several of the papers "exhibit manipulation of research data," they found."

"In a letter announcing his resignation, the 63-year-old Tessier-Lavigne, whose research has focused on brain diseases such as Alzheimer's and Parkinson's, said the panel had "identified some areas where I should have done better."" news.yahoo.com/stanford-pre...

[MBAnderson]

excellent points