Is Parkinson death rate increasing?

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Here is a report that more than twice as many Americans dying from Parkinson disease in 2019 (35,311) compared with 1999 (14,593). The study was published in the November 16, 2021, issue of Neurology.

Using data obtained from the National Vital Statistics System of the National Center for Health Statistics, the researchers calculated a total of 479,059 U.S. deaths from Parkinson disease between 1999 and 2019.

The age-adjusted death rate nearly double in 20 years, from 1999 to 2019. There was an average annual increase of 2.4% over the two decades.

Parkinson disease mortality increased significantly in all age groups, sexes, and racial and ethnic groups, as well as in urban and rural locations. There were, however, several notable differences within these categories. Mortality rates for men were twice those for women throughout the study period. Also, White individuals had higher mortality rates than people from other racial or ethnic groups which implies there is some genetic aspect.

The scientists speculate that that increased exposure to pesticides, herbicides, heavy metals, and air pollution, could raise Parkinson disease risk. However a doubling death rate would mean a rather obvious change in environment The scientists speculate that as people are living longer, thereby contributing to higher Parkinson disease incidence and mortality. Yet in US the life expectancy didn't increase during that period.

Most patients die with Parkinson’s Disease and not from it. The illnesses that kill most people are the same as those that kill people with PD. These are heart conditions, stroke and cancer. As we age we become increasingly aware that more than one bad thing can happen to our bodies.

Why L-dopa, the drug used for treating Parkinson's disease, loses efficacy and causes dyskinesia as treatment progresses.

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Paradoxically, the therapy that improves the quality of life of patients with Parkinson's disease is the one that later contributes to the decline in their quality of life. Indeed over time, L-dopa (l-3,4-Dihydroxyphenylalanine), the main treatment for Parkinson's disease, loses its effectiveness and causes involuntary muscle movements and erratic movements and sometimes hallucinations. Although this effect is well identified, scientists did not understand why L-dopa accelerates the progression of the disease.

L-dopa and other pharmacological treatments for Parkinson's disease are designed to replace lost dopamine caused by degenerating nerve cells in the brain. Although dopamine cannot cross the blood-brain barrier, which allows substances such as water and oxygen to pass into the brain, L-dopa can. However, 99% of L-dopa is metabolized outside the brain, so it is given in combination with an enzyme inhibitor to prevent side effects such as nausea and heart problems, and allow more of the drug remains in the blood so as to be percolated through the blood-brain barrier. In this case, 5 to 10% of the ingested dose reaches the brain.

A team of researchers from the University of California, Irvine studied the molecular binding characteristics of L-dopa and related compounds using an optical technology called surface plasmon resonance to measure interactions between the drug and the target proteins. The results of the study were recently published in ACS Chemical Neuroscience. enter image description here

Their studies aimed to test whether continuous administration of L-dopa in animal models of Parkinson's disease is associated with increased iron accumulation in dopaminergic neurons in the brain and whether this accumulation depends on the binding of L-dopa to siderocalin.

The researchers also wanted to determine whether the complex can be detected in the blood of patients with Parkinson's disease. The relative amount of this complex would then serve as a biomarker to determine when it becomes appropriate to switch to new treatments for the disease.

Indeed l-DOPA chelates iron through its catechol group, is forming the l-DOPA:Fe complex. Siderophore-like catechol compounds are known to bind siderocalin (Scn)/lipocalin-2 to form stable siderophore:Fe:Scn complexes. Scn is up-regulated in the substantia nigra of PD patients and may play a role in the pathophysiology of PD.

Their results demonstrate that L-DOPA forms a stable complex with Scn in the presence of Fe3+.

Expressed more simply, this means that L-dopa and the protein siderocalin combine in the presence of iron to create a complex that can cause cellular iron overload, resulting in an imbalance between free radicals and antioxidants, as well as neuroinflammation.

The authors speculate that as Parkinson's disease progresses, this effect increases, inducing these negative side effects, while the dose needed to relieve disease symptoms increases, resulting in a window narrow therapy.

It remains that the effects of the enzyme inhibitor used to mitigate L-Dopa side effects, are not trivial either, but this study does not address this subject.

Moreover L-Dopa is not a panacea either, indeed its therapeutic effectiveness is different for different types of symptoms. Bradykinesia and rigidity are the most sensitive symptoms to L-Dopa administration, while tremors are less sensitive. Speech disorders, speech and swallowing disorders, postural instability and frozen gait are the least reactive symptoms.

Entrepreneurial activism, mannitol and Parkinson's disease

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A new article in the journal BioSocieties, published by Drs. Shlomo Guzmen-Carmeli and David A. Rier, from the Department of Sociology and Anthropology at Bar-Ilan University, tell the story of CliniCrowd, an Israeli company established to test the effectiveness of nutritional supplements like mannitol, cinnamon or cherries in Parkinson's or Alzheimer's disease.

CliniCrowd's model emphasizes speed, efficiency and creativity in dealing with a particular kind of unfinished science, involving potential orphan drugs which, of natural origin, cannot be patented.

Indeed, scientific questions do not all have the same chances of being explored by officially accredited scientists.

The term “unfinished science” refers in sociology to areas of research identified by societal movements as having potentially important social impacts which are however not funded, or incomplete or even completely ignored. This research, although often initiated, is ultimately not carried out for financial, theoretical, ideological or even political reasons.

The classic model of Parsons (1951) of the patient's role as patient supposes that all the action lies with the doctor (the expert), who acts on the passive patients who themselves remain passive, because a priori incompetent.

However, this evolved towards the end of the 20th century, in particular with the fight against AIDS. In 1987, the Community Based Research Initiative, a partnership of physicians and community patients, began a pivotal clinical trial of a treatment for pneumocystis pneumonia, then the main threat to AIDS patients.

The trial provided important clinical data, quickly influenced clinical practice, and was even used by the United States Food and Drug Administration (FDA) in the approval process.

Activists have also formed groups to identify and obtain (sometimes, via smuggling) potential treatment not available in the United States. They criticized drug companies for their high prices and inability to study a wider range of compounds. They particularly attacked the FDA's reliance on very slow and expensive randomized clinical trials (the traditional “gold standard”).

In 2004, the PatientsLikeMe community site was started by two brothers and a friend of a patient with amyotrophic lateral sclerosis (ALS). It opened in 2006 as an online platform, allowing patients with ALS to share their downloaded and anonymized clinical data, assess their own progress, exchange advice and support. , and to contribute more generally to emerging clinical knowledge on the disease.

Finally, PatientsLikeMe is currently a for-profit company, as it was acquired in 2019 by a large healthcare management company. They sell aggregated and anonymized data to academic and professional customers such as pharmaceutical and medical device companies.

In Israel, defense elites and high-tech start-ups are often considered some of the brightest and most innovative in society, trained to think creatively, collaborate and take risks.

Dan Vesely, is a retired Israeli general and high tech entrepreneur. Here's how he describes his response to his terrifying Parkinson's diagnosis in 2013: "If there’s a problem, deal with it. No crying over spilled milk or grieving about my misfortune, about what I ‘won’ [said cynically]. Come on, what do we do next? We think of solutions. [interview, January 24, 2018]"

Vesely, obviously dissatisfied with the treatment options available to him, then turned to acquaintances for help. A small group of entrepreneurs have gathered around him to research the published research on Parkinson's disease.

They quickly noticed the published - and forgotten - study on the possible effect of mannitol on patients with Parkinson's disease. Vesely and some partners contacted Professor Dan Segal of Tel Aviv University, who had co-led the research team, and asked to meet with him:

"It had not yet been tested on humans. So I made an appointment .... Prof. Segal told us his story, described the experiment, and said it's all simply been shelved, there's no incentive for the pharmaceutical companies. at each other and said, 'So we'll take it!' The professor said, 'Who exactly are you? You brash Israelis, who are you?' But it was clear to us that if you can't go through the door , you go through the window. [Vesely interview, Jan. 24, 2018]"

The heartbreaking story of the abandonment of the study born affected the group of friends. Vesely then resolved to test the mannitol on himself. However, its partners dissuaded it from being ineffective for the community because it was totally inconclusive. Instead, together they decided to test mannitol on a number of patients with Parkinson's disease.

In the absence of the support of a pharmaceutical company ready to invest in clinical research, they then sought to test mannitol as if it were a military operation.

They adopted a model, marrying patient self-experimentation with crowdsourcing techniques. Inspired by similar crowdsourcing projects like PatientsLikeMe, the group then planned to create a website for patients with Parkinson's disease who would agree to take mannitol regularly for an extended period.

This alternative is not, however, a real substitute for “* classic *” clinical trials. The survey platform would indeed lack a control group and patient monitoring would be carried out on site on a voluntary and independent basis, and not by a doctor. Nevertheless, this survey platform would generate preliminary data to justify the need for more formal clinical research which would be a result of great value in itself.

The founders of CliniCrowd initially considered marketing mannitol directly, but decided not to, to avoid conflicts with their research. But the founders of CliniCrowd nonetheless chose to register it as a company rather than a non-profit organization. This reflected their primary motivation to “get the job done” as quickly and efficiently as possible, through entrepreneurial tactics, rather than adopting the identity and tactics of social activism. In addition, Israeli non-profit organizations are more regulated than commercial companies.

So they created the company in August 2016. They recruited qualified staff with experience in planning and conducting clinical trials to create the company's platform, and then started recruiting patients using patient forums and media exposure.

At the start of 2021, 2,480 patients had registered on the platform dedicated to the research of mannitol for Parkinson's disease. Of these, 1,364 (55%) had completed questionnaires more than once. The platform allows patients to record and track data related to their disease and (while maintaining anonymity) compare this data with that of other members of the community. It is also possible to share the stored data with the attending physician.

CliniCrowd's efforts have unfolded in several stages. As Parkinson's patients on the platform began taking mannitol and regularly filling out questionnaires about their symptoms, the next step was to attract accredited scientists to conduct larger trials.

CliniCrowd's initial data helped generate public pressure, which in turn led to a formal clinical study, launched in 2018 at the Hadassah Medical Center in Jerusalem. This study (https://clinicaltrials.gov/ct2/show/NCT03823638), conducted with public funding, examines the effects of mannitol on Parkinson's disease. As of June 2021, the study was continuing, but had slowed down somewhat due to the coronavirus and its severe impact on the medical system. Additional studies, at universities and medical centers in the UK and US, are expected to begin shortly. As far as the authors of this article are aware, at the time of writing, however, these are limited studies.

Nonetheless, there has already been a major shift in the way scientists view mannitol research. As Vesely, the patient-founder of CliniCrowd, noted:

"It gives me great satisfaction that the studies we are currently talking about [the clinical research underway in Jerusalem and expected further studies] would not have taken place, nor would they have received funding or the attention of the medical establishment and the public, without the buzz and especially the clinical indications that CliniCrowd achieved in the wake of the surveys. [interview, July 7, 2019"

Researchers involved in planning the clinical trial confirmed in interviews with the authors that without public pressure, it is unlikely that a trial would have been initiated.

In fact, CliniCrowd's position vis-à-vis the biomedical establishment has evolved over the course of its short history. In early interviews, founders sharply criticized the pharmaceutical industry. For example, in the first interview with CEO Amir Sadeh, he describes the decision to start the business as follows:

"The goal is to create something that cannot be ignored and make available to the public what the pharmaceutical companies are trying to hide from us. Because they [such 'ignored' compounds] do not generate income, they do not make a profit, so it's better not to know about them at all. But now we're exposing them, showing their nakedness in public, telling them it's inexpensive and accessible. It treats the cause rather than the symptoms, and that's why it's the worst thing for the pharmaceutical companies to find a solution to Parkinson's disease. Ten million people, five billion dollars a year — as far as they're concerned, let's just treat the symptoms. It's cynical but that's the way it is…. [T] he benefit of the patients is not the paramount interest of the companies or the doctors, because they are waiting for the next seminar in the Seychelles, courtesy of one company or another. [interview December 3, 2017]"

Yet this initial position of "rebels against the pharmaceutical industry" was created by elite members of the Israeli establishment,

With this approach, CliniCrowd obviously found it difficult to gain the trust and support of the medical establishment.

From interviews the authors conducted with patients who started taking mannitol between 2016 and 2018, it appears that those who saw their doctors have encountered substantial resistance to adopting mannitol as a remedy. The doctors' objections included comments such as, "this is a good woman's medicine" and "you had better get a rabbi's blessing."

At a conference of neurologists in early 2017, CliniCrowd delegates had only a few minutes to present their action, and most conference attendees ignored their speech. Such contempt is reminiscent of the opposition to the community production of knowledge about AIDS more than a generation ago.

The interviews clearly showed that the choice to adopt terms such as "dietary supplements" and "functional foods" reflects CliniCrowd's tactical decision to redefine mannitol as a new substance in the food supplement market.

Here's how CEO Sadeh described the change, in a follow-up interview: "We started out thinking we would call the venture Ampha, as opposed to Pharma. But the more we got into it, the more we realized that was not the point. Like Netflix doesn’t mean all movie theatres are closed, and Airbnb hasn’t replaced hotels, and Uber hasn’t replaced taxis, so CliniCrowd won’t replace the pharmaceutical companies. We fill a void and add something extra. If we started out by setting ourselves against the pharmaceutical companies, now we’re not against them, we’ll be in favour. We’ll complement them. Let’s shift the playing field. Instead of acting on the fiery and aggressive pharmaceutical playing field, let’s move the field elsewhere....And as long as the whole world of medicine doesn’t dance according to the interests of the pharmaceutical companies, we’ve done something great. [interview July 7, 2019]"

The rebranding of mannitol as a functional food proved to be a valuable maneuver, enabling CliniCrowd. This has helped promote acceptance of mannitol among physicians and patients.

Indeed, in the second half of 2018, the authors observed a change in attitude among doctors. Three doctors interviewed for the study told us that once they realized it was a dietary supplement, they stopped protesting: “It’s a dietary supplement. It may not help, but it is not harmful”.

As one neurologist explains: "I think no doctor likes it when the patient comes and says, 'Listen, I've found a treatment.' Most of the time I have to make sure his feet are on the ground, and I must explain why, most probably , in his case it won't work. This was also my initial response to mannitol, complete resistance, not wanting them to take it .... The attitude changes when there is already information and a mass of patients who have collated and documented its use in an orderly manner. Moreover, they didn't come and say this is a magic drug, but rather that it may help with some of the symptoms .... I suggest to patients, especially at the beginning, that they should read about mannitol. I definitely don't exclude it, in fact quite the opposite."

To understand how the patients themselves experienced this, consider Menachem [pseudonym], 68, diagnosed four years earlier. Asked about the experience of taking mannitol and participating in the online questionnaire, he replied: "My participation in the experiment has turned my world around. I come to the doctor and update him, see? I, Menachem, taught the neurologist that there is such a thing as mannitol, and that I am taking part in an experiment with other patients. When I go to see him, he immediately stands up! "Welcome", he says, "tell me how you are getting on". There is a sense that we are colleagues, and that I am doing something incredibly important. There is something in [mannitol] that helps, it’s not a magical cure, or maybe I no longer suffer. But there is an improvement in my sleep, my sense of smell, and also my difficulty in movement. [interview Oct. 30, 2019]"

Note the ease Menachem describes in his relationship with the doctor, his feeling of being an expert, his delight and agency he feels about being involved. These are all so important to him that he mentions them even before his improved health, which he attributes to taking mannitol on a regular basis.

In conclusion, CliniCrowd demonstrated a new way of approaching "* unfinished science *", using participatory research to generate public pressure and influence with which to formally attract scientists to test low potential compounds. profit. CliniCrowd represents an intersection of scientific knowledge, technologies, practices, it is also the product of a sustained process of dissemination and decentralization of expertise.

Activisme entrepreneurial, mannitol et la maladie de Parkinson

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Un nouvel article dans la revue BioSocieties, publié par les Drs. Shlomo Guzmen-Carmeli et David A. Rier, du département de sociologie et d'anthropologie de l'Université Bar-Ilan, raconte l'histoire de CliniCrowd, une société israélienne créée pour tester l'efficacité de suppléments nutritionnels comme le mannitol, la cannelle ou les cerises dans les maladies de Parkinson ou d'Alzheimer.

Le modèle de CliniCrowd met l'accent sur la vitesse, l'efficacité et la créativité pour traiter un type particulier de science inachevée, impliquant des médicaments orphelins potentiels qui, d'origine naturelle, ne peuvent pas être brevetés.

En effet les questions scientifiques n'ont pas toutes les mêmes chances d'être explorées par les scientifiques officiellement accrédités.

Le terme de « science inachevée » fait référence en sociologie aux domaines de recherche identifiés par les mouvements sociétaux comme ayant des impacts sociaux potentiellement importants qui ne sont pourtant pas financés, ou incomplets ou encore complètement ignorés. Ces recherches, bien que souvent initiées ne sont finalement pas réalisées pour des raisons financières, théoriques, idéologiques, ou encore politiques.

Le modèle classique de Parsons (1951) du rôle de malade du patient suppose que toute l'action réside chez le médecin (l'expert), qui agit sur les patients passifs qui restent eux-même passifs, car à priori incompétents.

Cependant cela a évolué vers la fin du XX siècle, en particulier avec la lutte contre le SIDA. En 1987, l'Initiative de recherche communautaire, un partenariat de médecins et de patients communautaires, a commencé un essai clinique de base sur la pentamidine en aérosol comme traitement de la pneumonie à pneumocystis, alors la principale menace pour les patients atteints du SIDA.

L'essai a fourni des données cliniques importantes, a rapidement influencé la pratique clinique et a même été utilisé par la Food and Drug Administration (FDA) des États-Unis dans le processus d'approbation.

Les militants ont également formé des groupes pour identifier et obtenir (parfois, via la contrebande) des traitements potentiels non disponibles aux États-Unis. Ils ont critiqué les sociétés pharmaceutiques pour leurs prix élevés et leur incapacité à étudier une gamme plus large de composés. Ils ont particulièrement attaqué la dépendance de la FDA à des essais cliniques randomisés très lents et coûteux (le «gold standard» traditionnel).

En 2004, Le site communautaire PatientsLikeMe avait été lancé par deux frères et un ami d'un patient atteint de sclérose latérale amyotrophique (SLA). Il a ouvert ses portes en 2006 en tant que plate-forme en ligne, permettant aux patients atteints de SLA de mettre en commun leurs données cliniques téléchargées et anonymisées, d'évaluer leurs propres progrès, d'échanger des conseils et de l'assistance, et de contribuer plus généralement aux connaissances cliniques émergentes sur la maladie.

Finalement, PatientsLikeMe est actuellement une entreprise à but lucratif, car rachetée en 2019 par une grande société de gestion des soins. Ils vendent des données agrégées et anonymisées à des clients universitaires et professionnels tels que des sociétés pharmaceutiques et de dispositifs médicaux.

En Israël, les élites de la défense et des start-up high-tech sont souvent considérées parmi les plus brillantes et les plus innovantes de la société, car formées pour penser de manière créative, collaborer et prendre des risques.

Dan Vesely, est un général israélien à la retraite et un entrepreneur en haute technologie. Voici comment il décrit sa réponse à son terrifiant diagnostic de maladie de Parkinson en 2013 : "If there’s a problem, deal with it. No crying over spilled milk or grieving about my misfortune, about what I ‘won’ [said cynically]. Come on, what do we do next? We think of solutions. [interview, January 24, 2018]"

Vesely, évidemment insatisfait des options de traitement qui lui était proposées, a alors demandé de l'aide à des connaissances. Un petit groupe d'entrepreneurs s'est réuni autour de lui pour rechercher les recherches publiées sur la maladie de Parkinson.

Ils ont rapidement remarqué l'étude publiée - et oubliée - sur l'effet possible du mannitol sur les patients atteints de la maladie de Parkinson. Vesely et certains partenaires ont contacté le professeur Dan Segal de l'Université de Tel-Aviv, qui avait co-dirigé l'équipe de recherche, et ont demandé à le rencontrer :

"It had not yet been tested on humans. So I made an appointment....Prof. Segal told us his story, described the experiment, and said it's all simply been shelved, there’s no incentive for the pharmaceutical companies. We looked at each other and said, ’So we’ll take it!’ The professor said, ’Who exactly are you? You brash Israelis, who are you?’ But it was clear to us that if you can’t go through the door, you go through the window. [Vesely interview, Jan. 24, 2018]"

L'histoire navrante de l'étude abandonnée a affecté le groupe d'amis. Vesely a résolu alors de tester le mannitol sur lui-même. Cependant, ses partenaires l'en ont dissuadé comme étant inefficace pour la communauté car totalement inconcluant. Au lieu de cela, ensemble ils ont décidé de tester le mannitol sur un certain nombre de patients atteints de la maladie de Parkinson.

Faute de l'appui d'une entreprise pharmaceutique prête à investir dans la recherche clinique, ils ont alors cherché à tester le mannitol comme s'il s'agissait d'une opération militaire.

Ils ont adopté un modèle, mariant l'auto-expérimentation du patient avec des techniques de crowdsourcing. Inspiré par des projets de crowdsourcing similaires comme PatientsLikeMe, le groupe a alors projeté de créer un site Web pour les patients atteints de la maladie de Parkinson qui accepteraient de prendre régulièrement du mannitol pendant une période prolongée.

Cette alternative n'est cependant pas un véritable substitut aux essais cliniques « classiques ». La plate-forme d'enquête manquerait en effet d'un groupe de contrôle et la surveillance des patients serait effectuée sur le site de manière volontaire et indépendante, et non par un médecin. Néanmoins, cette plate-forme d'enquête générerait des données préliminaires permettant de justifier la nécessité d'une recherche clinique plus formelle ce qui serait un résultat d'une grande valeur en soi.

Les fondateurs de CliniCrowd ont initialement envisagé de commercialiser directement le mannitol, mais ont décidé de ne pas le faire, pour éviter les conflits avec leurs recherches. Mais les fondateurs de CliniCrowd ont néanmoins choisi de l'enregistrer en tant que société plutôt qu'en tant qu'organisation à but non lucratif. Cela reflétait leur motivation principale de « faire le travail » aussi rapidement et efficacement que possible, via des tactiques entrepreneuriales, plutôt que d'adopter l'identité et les tactiques de l'activisme social. Par ailleurs, les organisations à but non lucratif israéliennes sont davantage réglementées que les sociétés commerciales.

Ils ont donc créé la société en août 2016. Ils ont recruté du personnel qualifié expérimenté dans la planification et la conduite d'essais cliniques pour créer la plate-forme de l'entreprise, puis ont commencé à recruter des patients à l'aide de forums de patients et d'une exposition médiatique.

Début 2021, 2 480 patients s'étaient inscrits sur la plateforme dédiée à la recherche de mannitol pour la maladie de Parkinson. Parmi ceux-ci, 1 364 (55 %) avaient rempli des questionnaires à plusieurs reprises. La plateforme permet aux patients d'enregistrer et de suivre les données liées à leur maladie et (tout en préservant l'anonymat) de comparer ces données avec celles d'autres membres de la communauté. Il est également possible de partager les données stockées avec le médecin traitant.

Les efforts de CliniCrowd se sont déployés en plusieurs étapes. Alors que les patients atteints de la maladie de Parkinson sur la plate-forme commençaient à prendre du mannitol et à remplir régulièrement des questionnaires sur leurs symptômes, l'étape suivante était d'attirer des scientifiques accrédités pour mener des essais plus importants.

Les données initiales de CliniCrowd ont permis de susciter une pression publique, menant à son tour à une étude clinique formelle, lancée en 2018 au centre médical Hadassah à Jérusalem. Cette étude (https://clinicaltrials.gov/ct2/show/NCT03823638), menée avec un financement public, examine les effets du mannitol sur la maladie de Parkinson. En juin 2021, l'étude se poursuivait, mais avait quelque peu ralenti en raison du coronavirus et de son grave impact sur le système médical. Des études supplémentaires, dans des universités et des centres médicaux au Royaume-Uni et aux États-Unis, devraient commencer sous peu. Pour autant que les auteurs de cet article le sachent, au moment de la rédaction, il s'agit cependant d'études limitées.

Néanmoins, il y a déjà eu un revirement important concernant la façon dont les scientifiques considèrent la recherche sur le mannitol. Comme l'a fait remarquer Vesely, le patient-fondateur de CliniCrowd :

"It gives me great satisfaction that the studies we are currently talking about [the clinical research underway in Jerusalem and expected further studies] would not have taken place, nor would they have received funding or the attention of the medical establishment and the public, without the buzz and especially the clinical indications that CliniCrowd achieved in the wake of the surveys. [interview, July 7, 2019"

Les chercheurs impliqués dans la planification de l'essai clinique ont confirmé lors d'entretiens avec les auteurs que, sans la pression exercée par le public, il est peu probable qu'un essai ait été initié.

En fait, la position de CliniCrowd vis-à-vis de l'establishment biomédical a évolué au cours de sa courte histoire. Dans les premiers entretiens, les fondateurs ont vivement critiqué l'industrie pharmaceutique. Par exemple, dans le premier entretien avec le PDG Amir Sadeh, il décrit ainsi la décision de créer l'entreprise :

"The goal is to create something that cannot be ignored and make available to the public what the pharmaceutical companies are trying to hide from us. Because they [such ‘ignored’ compounds] do not generate income, they do not make a profit, so it’s better not to know about them at all. But now we’re exposing them, showing their nakedness in public, telling them it's inexpensive and accessible. It treats the cause rather than the symptoms, and that’s why it’s the worst thing for the pharmaceutical companies to find a solution to Parkinson's disease. Ten million people, five billion dollars a year—as far as they’re concerned, let's just treat the symptoms. It's cynical but that's the way it is…. [T]he benefit of the patients is not the paramount interest of the companies or the doctors, because they are waiting for the next seminar in the Seychelles, courtesy of one company or another. [interview December 3, 2017]"

Pourtant, cette position initiale de « rebelles contre l'industrie pharmaceutique" a été créée par des membres d'élite de l'establishment israélien,

Avec cette approche, CliniCrowd a évidemment éprouvé des difficultés à obtenir la confiance et le soutien de l'establishment médical.

D'après les entretiens que les auteurs ont menés avec des patients qui ont commencé à prendre du mannitol entre 2016 et 2018, il apparaît que ceux qui ont consulté leur médecin ont rencontré une résistance substantielle à l'adoption du mannitol comme remède. Les objections des médecins comprenaient des commentaires tels que : « c'est un remède de bonne femme » et « vous feriez mieux d'obtenir la bénédiction d'un rabbin ».

Lors d'une conférence de neurologues au début de 2017, les délégués de CliniCrowd n'ont eu que quelques minutes pour présenter leur action, et la plupart des participants à la conférence ont ignorés leur discours. Un tel mépris rappelle l'opposition contre la production communautaire de connaissances sur le SIDA il y a plus d'une génération.

Les interviews ont clairement montrés que le choix d'adopter des termes tels que « compléments alimentaires » et « aliments fonctionnels » reflète la décision tactique de CliniCrowd de redéfinir le mannitol comme une nouvelle substance dans l'alimentation marché des suppléments.

Voici comment le PDG Sadeh a décrit le changement, dans une interview de suivi : "We started out thinking we would call the venture Ampha, as opposed to Pharma. But the more we got into it, the more we realized that was not the point. Like Netflix doesn’t mean all movie theatres are closed, and Airbnb hasn’t replaced hotels, and Uber hasn’t replaced taxis, so CliniCrowd won’t replace the pharmaceutical companies. We fill a void and add something extra. If we started out by setting ourselves against the pharmaceutical companies, now we’re not against them, we’ll be in favour. We’ll complement them. Let’s shift the playing field. Instead of acting on the fiery and aggressive pharmaceutical playing field, let’s move the field elsewhere....And as long as the whole world of medicine doesn’t dance according to the interests of the pharmaceutical companies, we’ve done something great. [interview July 7, 2019]"

Le changement d’appellation du mannitol en tant qu'aliment fonctionnel s'est avéré une manœuvre précieuse, permettant à CliniCrowd. Cela a contribué à promouvoir l'acceptation du mannitol parmi les médecins et les patients.

En effet, au second semestre 2018, les auteurs ont constaté un changement d'attitude chez les médecins. Trois médecins interrogés pour l'étude nous ont dit qu'une fois qu'ils ont compris qu'il s'agissait d'un complément alimentaire, ils ont cessé de protester : « *C'est un complément alimentaire. Cela n'aide peut-être pas, mais ce n'est pas nocif » *.

Comme l'explique un neurologue : "I think no doctor likes it when the patient comes and says, ‘Listen, I’ve found a treatment.’ Most of the time I have to make sure his feet are on the ground, and I must explain why, most probably, in his case it won’t work. This was also my initial response to mannitol, complete resistance, not wanting them to take it....The attitude changes when there is already information and a mass of patients who have collated and documented its use in an orderly manner. Moreover, they didn’t come and say this is a magic drug, but rather that it may help with some of the symptoms....I suggest to patients, especially at the beginning, that they should read about mannitol. I definitely don’t exclude it, in fact quite the opposite."

Pour comprendre comment les patients eux-mêmes ont vécu cela, considérons Menachem [pseudonyme], 68 ans, diagnostiqué quatre ans plus tôt. Interrogé sur l'expérience de la prise de mannitol et de sa participation au questionnaire en ligne, il a répondu :

""My participation in the experiment has turned my world around. I come to the doctor and update him, see? I, Menachem, taught the neurologist that there is such a thing as mannitol, and that I am taking part in an experiment with other patients. When I go to see him, he immediately stands up! ‘Welcome’, he says, ‘tell me how you are getting on’. There is a sense that we are colleagues, and that I am doing something incredibly important. There is something in [mannitol] that helps, it’s not a magical cure, or maybe I no longer suffer. But there is an improvement in my sleep, my sense of smell, and also my difficulty in movement. [interview Oct. 30, 2019]"

Notez la facilité que Menachem décrit dans sa relation avec le médecin, son sentiment d'être un expert, son ravissement et l'agence qu'il ressent du fait de sa participation. Ceux-ci sont tous si importants pour lui qu'il les mentionne avant même son amélioration de la santé, qu'il attribue à la prise régulière de mannitol.

En conclusion, CliniCrowd a démontré une nouvelle façon d'aborder de la "science inachevée", en utilisant la recherche participative pour générer la pression et l'influence du public avec lesquelles attirer formellement les scientifiques pour tester des composés à faible potentiel de profit. CliniCrowd représente une intersection de connaissances scientifiques, de technologies, de pratiques,elle est aussi le produit d'un processus soutenu de diffusion et de décentralisation de l'expertise.

Deep sleep may slow the progression of Parkinson's disease

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In people with Parkinson's disease, dementia with Lewy bodies, and even other neurodegenerative diseases, slower, deeper sleep is associated with better cognitive performance and slower motor progression over time.

Yet, these patients have very serious sleep problems. They often take a nap intermittently, which fails to address the phase of deeper, more restorative slow wave sleep in which waste disposal speeds up in the brain as demonstrated in several previous studies.

More recently, scientists have begun to understand that slow wave sleep abnormalities also affect people with Parkinson's disease (Schreiner et al., 2021). Could their slow wave sleep disruption be similarly related, to the major protein aggregates of PD and their clearance?

The main finding of a new study is indeed that the modulation of slow waves in sleep influences neuropathological outcomes in two different mouse models of synucleinopathy. http://www.ncbi.nlm.nih.gov/pubmed/34878820

The study showed less synuclein buildup after improving slow waves with sodium oxybate compared to placebo, while sleep deprivation had the opposite effect.

The scientists used mice deficient in the vesicular monoamine transporter of dopamine transport protein 2 (VMAT2). Without VMAT2, dopamine builds up and damages neurons, causing α-synuclein aggregation, loss of motor function. and sleep disturbances.

They implanted an electroencephalography / electromyography machine in the skulls of young mice to track their sleep over 24 hours. Animals deficient in VMAT2 actually spent more time awake, with less REM and non-REM sleep, than their wild-type siblings.

What about old mice? As the aged mice deficient in VMAT2 did not tolerate the EEG / EMG implantation procedure, the scientists were therefore unable to analyze their sleep. Instead, they did it on 14 month old wild type mice.

They either sedated them with sodium oxybate, a narcolepsy drug, or kept them awake by placing them on a small platform over water for 16 hours. During 24 hours of EEG / EMG recording in each condition, mice that took sodium oxybate had slower waves during non-REM sleep, while sleep-deprived animals had shallower waves and less depth. more fragmented non-REM sleep.

Well-rested mice had less phosphorylated synuclein and less aggregates than controls, while the reverse was true in sleepless mice.

In addition, the researchers gave sodium oxybate to 5.5-month-old A53T mice (another animal model of Parkinson), which carry mutant human α-synuclein and develop Lewy body-like synuclein aggregates.

The drug increased clearance of α-synuclein aggregates so well that the western spots of their mesencephalic tissue almost looked like wild-type ones. "I thought it was fascinating that sleep so drastically alters the pathology in mice genetically intended to accumulate synuclein," Schreiner said.

Morawska et al. have also added a sleep deprivation arm using the platform over water method. They found that, in general, sleep deprivation increased synuclein aggregation, while improvement in SWS reduced it. However, it is difficult to directly compare the methods of sleep deprivation and improvement, as one is pharmacological (oxybate) and the other behavioral, and potentially stressful.

These results are consistent with previous studies on the link between slow sleep and pathological protein accumulation in Alzheimer's disease and imply that similar mechanisms may be present in synucleinopathies such as Parkinson's disease.

The present study is exciting because it provides more rationale to further explore the role and therapeutic potential of sleep, particularly slow-wave sleep, in clinical populations with neurodegenerative disorders, including synucleinopathies.

This is of interest because there are highly specific pharmacological and emerging non-pharmacological methods to improve sleep on the in humans.

Even so, the change in sleep in mice may not translate directly to humans, as humans and rodents have different stages of sleep (Matsumoto & Tsunematsu, 2021). Scientists are also uncertain whether sodium oxybate affects the neuropathology of people with Parkinson's disease.

It is a paper that complements for synucleinopathies what previous articles by Kang and colleagues (Kang et al., 2009) and Holth and colleagues (Holth et al., 2019) have done for amyloid and protein tau, respectively.

It is likely that for an intervention to be effective in patients, it will need to be given over the long term, and possibly to neurologically asymptomatic patients, and it is not certain whether sodium oxybate will work given the its propensity to cause side effects in the elderly adults.

In addition, we lack excellent biomarker readings for the burden of synuclein pathology in humans, so hampering clinical trials.

In their next study the researchers will use auditory stimulation by playing certain tones during slow sleep to try to specifically improve or decrease these brain waves in mouse models of Alzheimer's and Parkinson's disease.

Le sommeil profond peut ralentir la progression de la maladie de Parkinson

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Chez les personnes atteintes de la maladie de Parkinson, de démence avec corps de Lewy, et même d'autres maladies neurodégénératives, un sommeil lent plus profond est associé à de meilleures performances cognitives transversalement et à une progression motrice plus lente au fil du temps. Cependant ces malades ont justement de gros problèmes de sommeil. Ils font souvent une sieste par intermittence, ce qui ne permet pas d'aborder la phase de sommeil à ondes lentes plus profond et plus réparateur au cours duquel l'élimination des déchets s'accélère dans le cerveau comme démontré dans plusieurs études précédentes. Plus récemment, les scientifiques ont commencé à comprendre que les anomalies du sommeil à ondes lentes affectent également les personnes atteintes de la maladie de Parkinson (Schreiner et al., 2021). Leur perturbation SWS pourrait-elle être liée de la même manière, au niveau moléculaire, aux principaux agrégats protéiques de la MP et à leur clairance ?

La principale découverte d'une nouvelle étude est que la modulation des ondes lentes du sommeil influence les résultats neuropathologiques dans deux modèles murins différents de synucléinopathie. http://www.ncbi.nlm.nih.gov/pubmed/34878820

l'étude a montré moins d'accumulation de synucléine après avoir amélioré les ondes lentes avec de l'oxybate de sodium par rapport au placebo, alors que la privation de sommeil a eu un effet opposé. Curieusement, les auteurs ont identifié des changements dans la voie AQP4/glymphatique et plusieurs processus liés à l'homéostasie des protéines comme mécanismes potentiels par lesquels les ondes lentes du sommeil pourraient influencer l'accumulation d'α-synucléine.

Les scientifiques ont utilisés des souris déficientes en transporteur de monoamine vésiculaire de la protéine de transport de la dopamine 2. Sans VMAT2, la dopamine s'accumule et endommage les neurones, provoquant l'agrégation de la -synucléine, une perte de la fonction motrice et des troubles du sommeil. Les chercheurs ont implanté un appareil d'électroencéphalographie/électromyographie dans le crâne de souris âgées de 5 mois pour suivre leur sommeil sur 24 heures. Les animaux déficients en VMAT2 passaient effectivement plus de temps éveillés, avec moins de sommeil paradoxal et non paradoxal, que leurs frères et sœurs de type sauvage.

Et les vieilles souris ? Comme les souris âgées déficientes en VMAT2 n'ont pas toléré la procédure d'implantation EEG/EMG, les scientifiques n'ont donc pas pu analyser leur sommeil. Au lieu de cela, ils l'ont fait sur des souris de type sauvage âgées de 14 mois. Les scientifiques les ont soit sous sédatifs avec l'oxybate de sodium, un médicament contre la narcolepsie, soit maintenus éveillés en les plaçant sur une petite plate-forme au-dessus de l'eau pendant 16 heures. Pendant 24 heures d'enregistrement EEG/EMG dans chaque condition, les souris qui ont pris de l'oxybate de sodium avaient des ondes plus lentes pendant le sommeil non-REM, tandis que les animaux privés de sommeil avaient des ondes moins profondes et un sommeil non-REM plus fragmenté.

Les souris bien reposées avaient moins de synucléine phosphorylée et moins d'agrégats que les témoins, alors que l'inverse était vrai chez les souris sans sommeil.

De même, les chercheurs ont donné de l'oxybate de sodium à des souris A53T âgées de 5,5 mois, qui portent une α-synucléine humaine mutante et développent des agrégats de synucléine de type corps de Lewy. Le médicament a si bien augmenté leur clairance que les taches occidentales de leur tissu mésencéphalique ressemblaient presque à celles de type sauvage. "Je pensais qu'il était fascinant que le sommeil modifie si radicalement la pathologie chez des souris génétiquement destinées à accumuler de la synucléine", a déclaré Schreiner.

Morawska et al. ont également ajouté un bras de privation de sommeil en utilisant la méthode de la plate-forme sur l'eau. Ils ont constaté qu'en général, la privation de sommeil augmente l'agrégation de la synucléine, tandis que l'amélioration du SWS l'atténue. Il est cependant difficile de comparer directement les méthodes de privation et d'amélioration du sommeil, car l'une est pharmacologique (oxybate) et l'autre comportementale, et potentiellement stressante.

Ces résultats correspondent à des études antérieures sur le lien entre le sommeil lent et l'accumulation pathologique de protéines dans la maladie d'Alzheimer et impliquent que des mécanismes similaires pourraient être présents dans les synucléinopathies telles que la maladie de Parkinson.

La présente étude est passionnante, car elle fournit plus de justification pour explorer davantage le rôle et le potentiel thérapeutique du sommeil, en particulier du sommeil à ondes lentes, dans les populations cliniques atteintes de troubles neurodégénératifs, y compris les synucléinopathies. Ceci est intéressant car il existe des méthodes pharmacologiques et émergentes non pharmacologiques hautement spécifiques pour améliorer le sommeil lent chez l'homme. Malgré tout, la modification du sommeil chez la souris peut ne pas se traduire directement chez les humains, car les humains et les rongeurs ont des stades de sommeil différents (Matsumoto et Tsunematsu, 2021). Les scientifiques ne savent pas non plus si l'oxybate de sodium affecte la neuropathologie des personnes atteintes de la malaide de Parkinson.

C'est un papier qui complète pour les synucléinopathies ce que les articles précédents de Kang et ses collègues (Kang et al., 2009) et Holth et ses collègues (Holth et al., 2019) ont fait pour l'amyloïde et la protéine tau, respectivement.

D'un point de vue translationnel, nous aurons besoin d'interventions thérapeutiques appropriées pour le sommeil chez les personnes âgées qui auront un effet similaire sur le sommeil lent comme l'oxybate de sodium, sans les problèmes de sécurité qui entourent l'utilisation de ce médicament chez les patients plus âgés. Il est probable que pour qu'une intervention soit efficace chez les patients, elle devra être administrée à long terme, et éventuellement à des patients neurologiquement asymptomatiques, et il n'est pas certain que l'oxybate de sodium fasse l'affaire étant donné sa propension à provoquer des effets indésirables chez les personnes âgées. adultes.

Cependant, nous manquons d'excellentes lectures de biomarqueurs pour le fardeau de la pathologie de la synucléine chez l'homme.

L'oxybate de sodium est un médicament difficile à prendre, surtout à long terme. Il y a un titrage compliqué pour trouver la bonne dose initiale pour chaque personne, et ils doivent la prendre deux fois par jour - avant de se coucher et au milieu de la nuit - pour une efficacité optimale. Dans leur prochaine étude les chercheurs utiliseront la stimulation auditive en jouant certains tons pendant le sommeil lent pour essayer d'améliorer ou de diminuer spécifiquement ces ondes cérébrales dans les modèles murins de maladie d'Alzheimer et Parkinson.

α-突触核蛋白敲低肽的开发及其在帕金森病模型中的疗效评估

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帕金森病(Parkinson's disease)是一种主要的神经退行性疾病。 它目前缺乏可以直接针对致病过程的临床相关治疗方法。 目前的临床方法,如深部脑刺激和左旋多巴和多巴胺激动剂的药物治疗,只能缓解症状。 这些治疗的功效在很大程度上受到其不良并发症和副作用的限制。  α-synuclein 资料来源:Ajpolino 通过维基百科

由于 α-突触核蛋白在帕金森病的某些病理条件下过度表达,而这些上调的蛋白质会干扰许多生理过程,如内质网到高尔基体的转运、突触传递和线粒体功能和形态,有力地击倒过度表达的 α-突触核蛋白可能 与简单地抑制有毒 α-突触核蛋白寡聚体的形成相比,在恢复帕金森病大脑中的正常细胞功能方面具有更好的神经保护功效。

使用反义寡核苷酸和小干扰 RNA (siRNA) 等遗传操作敲除 α-突触核蛋白,已在各种帕金森病模型中显示出对多巴胺能神经元的保护作用。

然而,将这些操作转化为有效的帕金森病疗法的临床转化成本高昂且不舒服,因为它主要是通过侵入性注射或病毒感染来完成的。 这些技术在临床上可能不适用于人类患者的治疗用途。

在这里,科学家们报告了一种短的、血脑屏障和质膜渗透性合成肽的开发,该肽可以通过蛋白酶体降解快速减少内源性 α-突触核蛋白。

科学家们使用帕金森病的体外和体内模型,为使用这种小的 α-突触核蛋白敲低肽作为潜在的帕金森病治疗提供了原理证明。

作者首先证明了 Tat-βsyn-degron 肽可以在体外和体内特异性地降低 α-突触核蛋白的水平。 作者随后表明,肽诱导的 α-突触核蛋白敲低与保护多巴胺能神经元免受帕金森病培养模型中毒素诱导的损伤有关。

最重要的是,科学家们能够在两个充分表征的帕金森病动物模型中证明全身应用 Tat-βsyn-degron 肽作为有效的帕金森病治疗方法的治疗潜力。

他们的 α-突触核蛋白敲低肽 (Tat-βsyn-degron) 具有创新性,因为该肽直接针对致病过程之一,有望阻止或减缓疾病的进展。

此外,肽介导的敲低比反义或 siRNA 介导的敲低具有明显的时间优势。 α-突触核蛋白是一种非常稳定的蛋白质,具有很长的半衰期,而通过劫持细胞中的内源性蛋白酶体降解系统,Tat-βsyn-degron 肽在几个小时内产生了 α-突触核蛋白的快速而稳健的降解。

有趣的是,α-突触核蛋白也在中枢神经系统以外的组织中表达,科学家发现单次腹膜内注射 Tat-βsyn-degron 肽同样降低了肾脏和脾脏中的 α-突触核蛋白表达 野生型 C57BL/6 小鼠。

最近在 3 期临床试验中取得的成功已经证明,Tat 融合短肽不仅安全,而且在保护神经元免受人体缺血性损伤方面具有治疗效果。作者希望这种 α-突触核蛋白敲低肽也有可能被迅速转化为临床,作为一种直接针对帕金森病致病过程的有效改善疾病的治疗方法。

由于他们的肽介导的蛋白质敲低方法的多功能性,科学家们理论上可以通过简单地改变靶向肽的蛋白质结合序列来靶向引起疾病的细胞蛋白质。由于许多人类疾病,包括一些与年龄相关的神经退行性疾病,如 ALS、阿尔茨海默氏病和亨廷顿氏病,在病理上是由蛋白质由于其突变和/或表达水平增加而获得功能引起的,拟议的研究有望促进帕金森病以外的人类疾病新疗法的开发

Photobiomodulation: a proof of concept study in Parkinson disease

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Parkinson's disease is a progressive neurodegenerative disease with no cure and few treatment options.

Photobiomodulation has been used successfully in animal models. enter image description here A new medRxiv preprint describes a proof-of-concept clinical study to assess the efficacy of photobiomodulation in Parkinson's disease, in order to inform on treatment regimens and outcome measures for a future randomized, placebo-controlled study.

Photobiomodulation therapy is the use of narrow wavelength bands of non-thermal light to modulate cellular responses. The main target of photobiomodulation is probably the cytochrome-C-oxidase, which absorbs red and near infrared light. Photobiomodulation therapy has a good safety profile.

The photobiomodulation was administered transcranially with a VieLight Gamma device (4 LEDs, 240 joules), intranasally with a VieLight Gamma nasal device (1 LED, 15 joules), transdermally to the C1/C2 region of the neck and to the abdomen with an Irradia MID 2.5 laser device (4 laser diodes, 39.6 joules) or a MIDCARE laser device (2 diodes 39.6 joules).

All participants received the same dose of total energy from the photobiomodulation treatment throughout the study. The treatment protocol made it possible to not to use safety glasses. Participants' adherence to the treatment protocol was monitored by caregivers and reported during the final assessment.

The primary outcome measure was improvement timed up and go (TUG) as a measure of mobility. Secondary outcome measures were mobility, cognition, fine motor skill, micrographia and static balance. Quality of life outcome measures and patient-reported symptomatic changes, including depression, are reported separately.

Twelve participants with idiopathic Parkinson's disease were recruited. Six were randomly selected to start 12 weeks of transcranial, intranasal, cervical and abdominal photobiomodulation. The other 6 were put on a waiting list for 14 weeks before starting treatment. After the 12 week treatment period, all participants received photobiomodulation devices to continue treatment at home.

Participants were assessed for mobility, fine motor skills, balance, and cognition before the start of treatment, after 4 weeks of treatment, after 12 weeks of treatment and the end of the home treatment period.

Measures of mobility, cognition, dynamic balance and fine motor skills were significantly improved (p <0.05) with photobiomodulation treatment for 12 weeks and up to one year. Individual improvements varied, but many continued for up to a year with sustained home treatment. Improvements were maintained as long as treatment continued, up to a year in neurodegenerative disease where a decline is generally expected. No side effects of the treatment were observed.

The current study did not have a placebo arm to quantify the placebo effect, but the related Hawthorne effect was assessed. The Hawthorne effect occurs in response to participation in research. It happens when a patient is observed during a study and has been recognized as a confounding factor in the results of clinical trials in Parkinson's disease, for example depending on whether an evaluation is done openly or secretly.

In the present study, participants on the waiting list (group B) showed an improvement in outcome measures before the start of treatment, with some of these improvements being sufficient to qualify as IMID, thus demonstrating a measurable Hawthorne effect. The other possibility is that the participants improved due to a practice effect with repeated assessments.

In conclusion, photobiomodulation has been shown to be a safe and potentially effective treatment for a range of clinical signs and symptoms of Parkinson's disease. Home treatment for Parkinson's disease on its own or with the help of a caregiver can be an effective treatment option. The results of this study indicate that a large double-blind clinical trial of the application of this technology to Parkinson's disease is warranted.

TRIAL REGISTRATION: Australian New Zealand Clinical Trials Registry, registration. number: ACTRN12618000038291p, registered on 12/01/2018

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Increased Accumulation of α-Synuclein in Inflamed Appendices of Parkinson's Disease Patients

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Alpha-synuclein is a neuronal protein that regulates synaptic vesicle trafficking and subsequent neurotransmitter release. alpha-synuclein aggregates to form insoluble fibrils in pathological conditions characterized by Lewy bodies, such as Parkinson's disease, dementia with Lewy bodies and multiple system atrophy.

It is abundant in the brain, while smaller amounts are found in the heart, muscle and other tissues. In the brain, alpha-synuclein is found mainly at the tips of neurons in specialized structures called presynaptic terminals.

The accumulation of α-synuclein (α-Syn) aggregates that leads to the onset of Parkinson's disease (Parkinson's disease) has been postulated to begin in the gastrointestinal tract. The normal human appendix contains pathogenic forms of α-Syn, and appendectomy has been reported to affect the incidence of Parkinson's disease.

In 2007, Braak and co-authors advanced a ‘dual-hit hypothesis’ about the pathogenesis of idiopathic Parkinson's disease, according to which an unknown pathogen akin to a slow-virus may enter the nervous system through both the nasal and intestinal mucosae, eventually resulting in a cascade of neurodegenerative events in the brain. enter image description here

In 2018 Killinger, Labrie and colleagues reported that in two independent epidemiological datasets, involving more than 1.6 million individuals and over 91 million person-years, they observed that removal of the appendix decades before PD onset was associated with a lower risk for PD, particularly for individuals living in rural areas, and delayed the age of PD onset.

After studying 48 subjects without Parkinson disease, they also found that the healthy human appendix contained intraneuronal α-synuclein aggregates and an abundance of PD pathology–associated α-synuclein truncation products that are known to accumulate in Lewy bodies, the pathological hallmark of PD.

In this new study by Yuhua Chen, Feng Yu and colleagues in University of Science and Technology of China in Hefei, investigated appendix abnormality in patients with Parkinson's disease.

The scientists assessed appendix morphology in 100 patients with Parkinson's disease and 50 control subjects by multislice spiral computed tomography. They analyzed the clinical characteristics of patients with Parkinson's disease with diseased appendices, which was confirmed in seven patients by histopathological analysis.

Chronic appendicitis-like lesions were detected in 53% of patients with Parkinson's disease, but these were not associated with the duration of motor symptoms.

Appendicitis-like lesions, impaired olfaction, and rapid eye movement sleep behavior disorder are known risk factors for Parkinson's disease.

The seven patients with Parkinson's disease who were diagnosed with chronic appendicitis underwent appendectomy, and histopathological analysis revealed structural changes associated with chronic appendicitis and α-Syn aggregation.

These results indicate an association between chronic appendicitis-like lesions and Parkinson's disease, and suggest that α-Syn accumulation in the diseased appendix occurs in Parkinson's disease. The appendix may play a role in the pathogenesis of Parkinson's disease, but the exact mechanism remains unclear. The appendix could be a source of pathological α-syn that propagates to the central nervous system, but a “second-hit” may be required for this phenomenon to occur. Factors like chronic inflammation, microbiome perturbations, formation of α-syn truncation products, and impaired cellular clearance of α-syn aggregates may serve to promote the generation and spread of pathology from the appendix to the brain. The vagus nerve, compromised BBB integrity, and/or age-dependent degeneration of the CNS lymphatic system may be routes by which α-syn seeds accumulate in the brain.

Alternatively (or in addition), immunosurveillance functions of the appendix may contribute to acquiring autoimmunity towards α-syn, including the generation of self-reactive T cells and autoantibodies. Hence, studying the accumulation and possible spreading of α-syn from appendix to brain could help our understanding of the origins of Parkinson's disease.

Can infrared light improve symptoms of Parkinson's disease?

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An international clinical trial, is investigating whether infrared light can improve symptoms of Parkinson's disease. The experimental results, based on preclinical studies, indeed suggest that brain illumination in the near infrared is likely to slow down this neurodegenerative disease.

Hamilton, Mitrofanis and others had previously reported that wearing headphones equipped with infrared LEDs improved quality of life, although it did not have much effect on motor symptoms.

A medical device system (called Ev-NIRT) has been developed by the French scientists and Boston Scientific Corporation, for intracerebral illumination at 670 nm of the black substance pars compacta (SNpc), and will be tested in this pilot study.

Researchers will assess the feasibility and tolerance of surgery and brain illumination using the Ev-NIRT medical device, in a group of 7 patients with Parkinson's disease in whom the innovative medical device will be implanted. The patients will be followed for 4 years. The device will emit pulses at a wavelength of 670 nm for one minute, with a periodicity of 150 Hz. This burst of pulses will be followed by five minutes of rest. enter image description here

The team, led by neurosurgeon Alim-Louis Benabid of the Clinatec Institute, hopes that exposing this area of ​​the brain to infrared light will protect cells from death. Benabid, along with Pierre Pollak, are the pioneers who developed deep brain stimulation (DBS) in 1987. DBS works by sending electrical impulses into the brain. This invention has changed the lives of thousands of patients, but it has long term side effects.

About ten years ago, John Mitrofanis, a neuroanatomist at the University of Sydney, spent a year studying DBS with Benabid with the aim of creating a similar concept, but using infrared light. Mitrofanis was inspired by infrared headsets, used in the Parkinson's community. enter image description here

Benabid and Mitrofanis, however, felt that light from outside the skull would not penetrate deep enough and that an implantable device had to be created. In 2017, in collaboration with researcher Cécile Moro, they injected 20 macaques with a neurotoxin present in certain recreational drugs (MPTP) and known to cause the symptoms of Parkinson's disease. Scientists exposed nine macaques to near infrared in the midbrain region using an implanted device.

The French study will follow 14 patients with early-stage Parkinson's disease for 4 years, seven of whom will be treated periodically with 670 nanometer pulses of light delivered to the brain via a thin laser diode cable. The other seven patients will not be operated on; an ethics review committee has in fact decided not to subject them to surgery without the possibility of benefit.

Some Parkinson's researchers are skeptical. No one has shown why exposure to infrared should have an effect on cells that never see daylight. Neurons do not have a chlorophyll-based metabolism. Much of the encouraging results seen so far may be the result of the placebo effect, skeptics say.

There are three main hypotheses to explain how photomodulation works.

  • The first recalls that molecules sensitive to light in the body called chromophores are excited by photon stimulation. We now know that hemoglobin, myoglobin and COX are the only 3 chromophores in mammalian tissues capable of absorbing near infrared light (wavelength 600 to 900 nm). However, there is no clear mechanism of action linking these chromophores to the increased ATP synthesis which is observed under light stimulation.

  • The second hypothesis explains that the production of mitochondrial energy is the effect of a reduction in the intra-mitochondrial viscosity of water induced by the near infrared. the reduction in near infrared mediated viscosity decreases the friction that opposes the rotation of ATP synthase and results in a "smoother" rotation of the ATP synthase machinery. This theory is supported by the fact that increases in cellular ATP level are immediate after near infrared stimulation.

  • A third hypothesis suggests that the photoabsorbent pyropherophorbide-a (P-a) metabolite of dietary chlorophyll may facilitate light energy production processes in animals. In the experiments, ATP levels increased only in groups where P-a and near infrared light were co-administered, and not in those where P-a or near infrared were administered in isolation. Given the multiplicity of these competing theories, it is possible that the near infrared exerts its modulatory effects through several mechanisms instead of just one.

The main aim of this new clinical study is to prove that the implant is safe, says Benabid, but the researchers will also assess the progression of the disease. “This must lead to a great improvement,” he says. "There would be no reason to have extensive surgery for only slight improvement."

The major problem with all neuroprotection trials in Parkinson's disease is that diagnosis appears to occur after more than 50% of the dopamine-producing cells have disappeared. Unless the improvement is huge, the signal will be too weak to be detected.

The team will also be looking for clinical benefits. But because researchers assess symptoms of Parkinson's disease by observing patients performing specific tasks, the assessments are largely subjective and symptoms vary over time; everyone has good days and bad. Since the control group will not undergo surgery, it will be particularly difficult to rule out placebo effects.


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