Keto diet and neurodegenerative diseases, caution is required

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Introduction The ketogenic diet has been used since the beginning of the 20th century to reduce the incidence of epileptic seizures, and over time its application to other diseases has been studied.

This diet is characterized by a high content of unsaturated fatty acids, few carbohydrates and a normal protein content. While in a traditional diet there is about 55% of the energy value in the form of carbohydrates, about 30% fat and 15% protein, these proportions in the classic ketogenic diet are 8% for carbohydrates, 90% for lipids and about 7% for proteins. The most common form of the ketogenic diet includes mostly long-chain fatty acids.

The drastic changes induced by the ketogenic diet in eating habits are difficult to maintain in a long-term perspective. This is because high volumes of high fat components in the diet (cheeses, eggs, butter, oils, meat, etc.) can lead to nausea, vomiting, constipation and loss of appetite.

Adverse effects of the ketogenic diet The ketogenic diet, as a high-fat, low-carb diet, is associated with some insufficiency in the energy value of food portions and leads to metabolic effects that ultimately reduce body weight. People suffering from neurodegenerative diseases are at high risk of malnutrition and therefore this type of diet seems a priori to be contraindicated for them. People with neurodegenerative diseases suffer from sarcopenia which is often fatal.

According to current recommendations, people at risk should consume 1.0 to 1.2 g of protein/kg per day, or even more if they are physically active. The ketogenic diet, particularly when the energy value of the diet decreases, may therefore lead to a protein intake that is too low, although its contribution to the energy value of the diet may be normal or even higher than recommended. Such a situation can lead to the catabolism of structural proteins (especially in the muscles).

In individuals with insulin resistance, diabetic acidosis can be identified, which is a disease state with ketone body concentrations above 25 mmol/L, resulting from insulin deficiency with a simultaneous increase in glucose concentration ( > 300 mg/dL) and a decrease in blood concentration. pH (pH < 7.3), which can cause death.

Ketogenic diet and Alzheimer's disease It is not easy to formulate a ketogenic diet, in fact saturated fatty acids are present everywhere in large quantities, particularly in foods associated with pleasure, desserts, dairy products, chocolates. Eating a single meal high in saturated fat is enough to reduce our ability to concentrate, much more than if it is a meal high in unsaturated fat. Epidemiological studies show that a diet rich in saturated fatty acids increases the risk of Alzheimer's disease.

Studies conducted on an animal model of Alzheimer's disease, however, indicate a possible beneficial effect of the ketogenic diet for this medical condition.

Reger et al. concluded that oral administration of medium-chain triglycerides elevates plasma levels of ketone bodies and may improve cognitive functioning in older adults with memory impairment.

Henderson et al. administered medium-chain triglycerides to subjects with mild and moderate Alzheimer's disease. Administration of this type of fat resulted in improved cognitive functioning. It should be noted, however, that no effect of this type was observed in subjects carrying the APOEε4 genotype.

Ota et al. administered medium-chain triglycerides to 20 patients with mild to moderate Alzheimer's disease. After 8 weeks, patients showed significant improvement in their immediate and delayed logical memory tests compared to their baseline score. At 12 weeks, they showed significant improvement in the Numerical Symbol Coding Test and Logical Immediate Memory tests compared to baseline.

In the Ketogenic Diet Retention and Feasibility Trial, 15 patients with Alzheimer's disease maintained a ketogenic diet supplemented with medium-chain triglycerides (approximately 70% of energy as fat, including triglycerides at medium chain; 20% of energy as protein; and less than 10% of energy as carbohydrate). They have observed that when fully achieved ketosis, the mean score of the cognitive subscale of the Alzheimer's Disease Rating Scale improved significantly during the diet but returned to baseline at its termination.

Krikorian et al. applied a high carbohydrate diet to 23 subjects with mild cognitive impairment. After 6 weeks of intervention, the authors observed an improvement in verbal memory performance in subjects on a low carbohydrate diet. The authors concluded that even short-term use of a low-carb diet could improve memory function in older adults at increased risk for Alzheimer's disease. Although the observed effect may be partly attributable to the correction of hyperinsulinemia, other mechanisms associated with ketosis, such as reduced inflammation and improved energy metabolism, may also have contributed to the improved neurocognitive functioning.

Adapted from "Role of Ketogenic Diets in Neurodegenerative Diseases (Alzheimer’s Disease and Parkinson’s Disease)" Dariusz Włodarek doi: 10.3390/nu11010169

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.

Protocatechuic acid alleviate neurons damage in in vivo and in vitro models of Alzheimer's disease.

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Here we will discuss about two recent studies about the relation between protocatechuic acid and Alzheimer's disease.

Diet appears to be have some relation with the progression of Alzheimer's disease, maybe related to the gut microbiome. There is a clear relation between gut's microbiome and Alzheimer's disease which was formalized in Braak's stages.

The aims of the first study were to detect the main anthocyanins of blueberry extract; then to verify the protective effects of anthocyanin-rich blueberry extract on hippocampal neurons and the promotion of autophagy; and finally to investigate the main protective effects and mechanisms of protocatechuic acid, a major metabolite of blueberry extract, for promoting autophagy and thus playing a neuroprotective role.

Protocatechuic acid is a type of phenolic acid increasing bringing plants resistance against fungus. It is a major metabolite of antioxidant polyphenols found in green tea. It has mixed effects on normal and cancer cells in in vitro and in vivo studies. Açaí oil, obtained from the fruit of the açaí palm (Euterpe oleracea), is rich in protocatechuic acid (630±36 mg/kg). enter image description here

Protocatechuic acid is regarded as an active component in traditional Chinese herbal medicine. For example the dried and mature fruits of the Zingiberaceae plant Alpinia oxyphylla Miq, is a choice in traditional Chinese medicine to treat Alzheimer's disease.

Recent studies have demonstrated its potent activities in modulating multiple signaling pathways associated with β-amyloid deposition, tau protein phosphorylation, chronic inflammation, oxidative stress.

In this study mice models of Alzheimer's disease (APP/PS1) were given 150 mg/kg blueberry extract daily for 16 working days. The mice were then sacrificed and morphology of neurons was observed under transmission electron microscope and autophagy-related proteins were detected.

Protocatechuic acid also promoted autophagy of neurons and the mechanism was mainly involved in increasing autophagosome degradation.

Neuron damage in morphology was reduced and the expression of autophagy-related proteins in APP/PS1 mice were promoted after blueberry extract treatment. In vitro, Aβ25-35-induced cytotoxicity, including decreased neuron viability and increased levels of lactate dehydrogenase and reactive oxygen species, was effectively reversed by protocatechuic acid.

Furthermore, by adding autophagy inducers rapamycin and autophagy inhibitors Bafilomycin A1, it was verified that degradation of autophagosomes was upregulated and autophagy was promoted by protocatechuic acid.

Yet it seems unlikely that any chemical coumpound would dramatically improve Alzheimer's disease in a few weeks and we all know that few results like that are credible. However other recent studies have hinted at similar results.

Protocatechuic acid is a dihydroxybenzoic acid with is a precursor of some insecticides and neurotransmitters like catecholamines, so it is indeed a potent and possibly dangerous drug.

In the treatment of Alzheimer's disease, it is important to develop alternative cholinesterase inhibitors with antioxidant properties that will reduce acetylcholine deficiency and free radical formation.

The aim of this other study was to investigate the effect of hydroquinone, 4-hydroxybenzoic acid, 3,5-dihydroxybenzoic acid, caffeic acid, vanillic acid and chlorogenic acid against acetylcholinesterase (AChE), partially purified from serum.

Binding of compounds with effective inhibitory potential to the AChE active site as competitive was illuminated by molecular docking.

Hydroquinone, chlorogenic acid and 4-hydroxybenzoic acid have been found to have higher inhibitory potential than others against the AChE. IC50 and KI values of the phenolic compounds against AChE were found in the range of 0.26 ± 0.01-36.34 ± 2.72 mM and 0.72 ± 0.00-29.23 ± 2.62 mM, respectively.

The effectiveness of the compounds has been associated with its structure. Consequently, the phenolic compounds, which have AChE inhibitory potential and antioxidant properties, can be considered as alternative drugs in the treatment of Alzheimer's disease.

Does ALS have anything in common with diabetes?

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Metabolic disorders are associated with the progression of amyotrophic lateral sclerosis. This new study by Tanya S McDonald and colleagues from the University of Queensland is very interesting because it focuses on physiology and not on molecular phenomenas.

Throughout the progression of ALS disease in laboratory mice, researchers have identified increased glucose uptake, possibly due to insulin-independent mechanisms. This glucose was then stored as glycogen in tissues such as the liver, rather than being used as an energy source. This might explain ALS' hypermetabolism.

Normally, in a healthy human, the postprandial state (after-meal) elevates glucose levels and triggers the release of insulin from the pancreas. As insulin levels rise, there is an increase in glucose uptake and then storage of excess glucose in peripheral tissues.

Glycogen is one of two forms of energy storage, with glycogen being short-term storage and the other being triglyceride stores in adipose tissue (i.e. body fat) for long term storage.

Patients with ALS cannot maintain their weight, and experience rapid muscle loss. Curiously, this muscle loss is not the subject of much attention from scientists who are interested only in motor neurons. They often deplore a lack of biomarkers, while the loss of muscle mass is an obvious biomarker. This article suggests that ALS is a form of diabetes, although this is not formally expressed in the article.

Rapid weight loss in patients with ALS is associated with rapid disease progression, while conversely, a higher body mass index (~ 27) tends to increase the survival rate. Studies also suggest that insulin resistance plays a role in disease progression in patients and animal models of ALS.

Glucose homeostasis is fundamental for the human body and is mainly regulated by the levels of 4 major hormones: 1. Insulin 2. Glucagon 3. Cortisol 4. Epinephrine The ratios of these circulating hormones will dictate the activity of specific metabolic pathways that control glucose homeostasis. There are many other hormones (thyroid hormone, growth hormone, etc.) and adipokines (adiponectin, leptin, etc.) that can influence glucose homeostasis, as well as neural mechanisms that control higher level functions such as hunger and satiety.

Insulin secretion depends on oxidative metabolism. In humans, glycogen is made and stored primarily in liver cells and skeletal muscle cells.

SOD1G93A mice exhibit loss of body weight and lean body mass with reduced activity and increased oxygen uptake in the mid-symptomatic stage of disease.

McDonald and his colleagues first investigated whether the weight loss frequently observed in SOD1G93A mice was due to reduced food intake or increased energy expenditure.

At the onset of the disease, the mice showed no difference in body weight, but still had a 10% loss of their lean body mass (body mass other than fat, including bones, muscles, blood, skin, etc.). That is, fat was substituted for muscle mass.

At the mid-symptomatic stage, the SOD1G93A mice weighed significantly less than their normal counterparts, with a loss of 8 and 10% of total body weight and lean body mass, respectively.

However, the total food intake was similar between normal mice and SOD1G93A mice at these two stages of the disease.

While at the initial stage there was no difference in oxygen uptake between mutated and normal mice, at the mid symptomatic stage the mean oxygen uptake in SOD1G93A mice was significantly higher than in normal mice.

This increase in oxygen uptake in the mid-symptomatic stage was not, however, due to an increase in average locomotor activity, as the reduction in locomotor activity was only measured during the dark cycle in the dying stages. onset and semi-symptomatic. Indeed, during the light phase, the mid-symptom SOD1G93A mice were 126% more active than their normal counterparts.

No correlation was found between the decrease in lean body mass and the average oxygen uptake over a 24-hour period.This increase in oxygen uptake at the mid-symptomatic stage is therefore unexplained.

Exogenous glucose uptake is increased in SOD1G93A mice at the mid-symptomatic stage of the disease

The scientists then set out to determine whether glucose management was impaired in SOD1G93A mice. At the onset of symptoms, SOD1G93A mice and their normal counterparts responded similarly to glucose. However, in the mid-symptomatic stage of the disease, SOD1G93A mice showed a faster rate of blood glucose clearance.

The authors then confirmed that the loss of body weight in SOD1G93A mice was not responsible for the decrease in blood glucose concentration. Although the baseline insulin concentration remained unchanged, the response of plasma insulin to exogenous glucose was significantly lower in SOD1G93A mice, with a 44% reduction in insulin concentrations.

At the onset of the disease and at its mid-symptomatic stage there was no difference in the immunoreactive zone of the glucagon-positive cells. But at the mid-symptomatic stage McDonald and his colleagues found in the pancreas of SOD1G93A mice, a 22% reduction in insulin-positive β cells compared to the pancreas of normal mice.

Despite this difference in baseline blood glucose concentrations, normal and SOD1G93A mice responded similarly to insulin. This is a major difference between diabetes and ALS.

Although the SOD1G93A mice weighed less at onset and during the middle of symptoms, the amount of insulin did not correlate with the inverse of blood sugar levels. This indicates that the detection of oxidative metabolism was inoperative, which is one of the characteristics of diabetes.

In addition to insulin and glucagon levels, the authors also demonstrated that glycogen concentrations were 210 and 480% higher in the liver of SOD1G93A mice at onset and mid-symptom stages, respectively.

Insulin tolerance is not affected in SOD1G93A mice, despite decreased fasting blood sugar

After an overnight fast, the accumulation of glycogen in the liver was still 400-500% higher in SOD1G93A mice amid symptoms compared to their normal counterparts. These changes are insulin independent because there was no difference in the elimination of glucose in response to exogenous insulin. In addition, SOD1G93A mice exhibit reduced insulin-expressing cell surface area and impaired insulin release in response to exogenous glucose. SOD1G93A mice also showed an accumulation of glycogen in the liver, despite increased circulating glucagon concentrations and gene expression data, suggesting a decrease in both glycogen synthesis and degradation.

This indicates that glucagon signaling may be altered in the liver of SOD1G93A mice. Finally, the gene expression profile of several metabolic enzymes suggested that the liver switches from using glucose to fatty acids as an energy source, which has already been found in skeletal muscle and CNS tissues in the body. SLA.

This confirms the results in other affected tissues which show a shift from the use of glucose to lipids as the primary fuel source for the TCA cycle. Although the exact trigger that leads to this change is unknown, it has been proposed that an increase in fatty acid metabolism occurs to compensate for the inability of tissues to use glucose and glycogen as energy substrates. Although this is a beneficial short-term compensatory mechanism, chronic dependence on fatty acid metabolism via β-oxidation can lead to the accumulation of toxic byproducts, especially reactive oxygen species. (ROS).

Conclusion What is described in this article is a reminder of the evolution of diabetes. When diabetes begins, the pancreas normally produces insulin. Muscle cells preferably use fatty acids as an energy source. Gradually the cells of the body responsible for collecting and using glucose become insensitive to insulin. Since glucose cannot enter the cells, the beta cells of the islets of Langerhans in the pancreas will produce more insulin to force the cells to take up glucose. In this article the mechanism is a little different, instead of making more insulin, the body stores glucose in the form of glycogen. The more diabetes progresses, the more beta cells are depleted, until they disappear. This disappearance was also noted in the article.

However, this does not explain the local appearance of the onset of ALS and the geographical progression of the disease, and it is a work on model mice for ALS. It is known that work on mice is rarely transferable to humans, particularly for neurodegenerative diseases.

Yet, this article is unique. This is an article that talks about physiology, it does not appeal to obscure molecules that are arbitrarily assigned biological roles, it suggests a mechanism for ALS that is down to earth.

Of course there are still many unknowns as to why ALS often starts with a specific muscle and then progresses. We don't know how to treat diabetes any more than we do with ALS, but I believe that an important step has been accomplished.

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This book retraces the main achievements of ALS research over the last 30 years, presents the drugs under clinical trial, as well as ongoing research on future treatments likely to be able stop the disease in a few years and to provide a complete cure in a decade or two.

Precision Medicine Approach to Alzheimer’s Disease: Successful Proof-of-Concept Trial

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Alzheimer’s disease has become the third leading cause of death.

Studies have provided candidate mechanisms for the neurodegeneration associated with Alzheimer’s disease, such as neuroinflammation, insulin resistance, and reduction in trophic support.

One complicating feature is that their etiology remains controversial, with many competing theories, such as “type 3 diabetes”, viral infection, misfolded or prions proteins, none of which has led to effective treatment.

The approach utilized in a new innovative trial departs sharply from traditional treatment strategies for MCI and Alzheimer’s disease, which have largely been monotherapeutic, monophasic, non-personalized, and blind, i.e., cause-independent, thus not targeted to the underlying drivers of the disease in each person, but rather to common downstream consequences and/or secondary drivers, such as amyloidosis.

In the field of oncology, a personalized, precision medicine approach, in which the presumptive molecular drivers of the disease process are targeted therapeutically, has improved outcomes in at least some studies.

However, this strategy has not been applied successfully to neurodegenerative diseases.

A recent BioRxiv article presents a proof-of-concept trial of precision medicine approach to Alzheimer’s disease.

Twenty-five patients with Alzheimer’s disease or mild cognitive impairment, ages 50-76, were recruited to three clinical sites and were evaluated for markers of inflammation, chronic infection, dysbiosis, insulin resistance, protein glycation, vascular disease, nocturnal hypoxemia, hormone insufficiency or dysregulation, nutrient deficiency, toxin or toxicant exposure (metals, organic toxicants, and biotoxins), genetic predisposition to cognitive decline, and other biochemical parameters associated with cognitive decline. Brain magnetic resonance imaging with volumetrics was performed at baseline and study conclusion.

Patients were treated for nine months with a personalized, precision medicine protocol that addressed each patient’s identified potentially contributory factors.

Diet was a plant-rich, high-fiber, mildly ketogenic diet, high in leafy greens and other nonstarchy vegetables(raw and cooked), high in unsaturated fats, with a fasting period of 12- 16 hours each night.

Exercise, both aerobic and strength training, was encouraged for at least 45 minutes per day, at least six days per week, and facilitated by the personal trainers. High-intensity interval training (HIIT) was recommended a minimum of twice per week.

Sleep hygiene was supported to ensure 7-8 hours of quality sleep per night, and all patients without known sleep apnea were tested over several nights using home sleep study devices.

For those patients with suboptimal hormonal status, bioidentical hormone replacement and appropriate supplements were provided to optimize sex hormone levels, neurosteroids, and thyroid medications as indicated for sub-optimal thyroid function.

Infectious agents associated with cognitive decline or systemic inflammation were identified and treated.

All outcome measures revealed improvement: statistically highly significant improvement in MoCA scores, CNS Vital Signs Neurocognitive Index, and AQ-C were documented. No serious adverse events were recorded.

On overall results support the notion that a precision medicine approach to the cognitive decline of Alzheimer’s disease and mild cognitive impairment may be an effective strategy, especially with continued optimization over time.

Study of changes during aging in mice shows increased oxidative stress

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The progression of aging-related traits varies considerably among individuals, influenced by their environment, lifestyle and genetics. The notion of biological rather than chronological aging states that aging varies not only with the passage of time but also with that of the organism. In this new study, Michael Petr, Rafael de Cabo and their colleagues performed physiological and functional tests throughout the lifespan of male C57BL/6N mice. The C57BL/6 mouse, which can live up to 4 years, exhibits many characteristics unusual for a laboratory mouse: it is exceptionally sensitive to pain and cold, and analgesic drugs are less effective in it. Unlike most strains of mice, this type of mouse is more susceptible to addiction, atherosclerosis and hearing loss with age.

In parallel with the functional tests, the scientists performed metabolomic analyzes of serum, brain, liver, heart and skeletal muscles in order to identify the signatures associated with age. enter image description here The authors performed an in-depth characterization of these differences among three groups of animals: Young, Adult and Old.

This analysis showed that: (i) decreased walking speed is a major functional biomarker of aging in mice; (ii) the deterioration of locomotor activity is associated with a dramatic increase in the energy cost of physical activity from the age of about 19 months, and is accompanied by a sustained decrease in working capacity;

To further explore the molecular changes that may contribute to or result from these changes, scientists performed metabolomic analysis in a number of key metabolic tissues and showed that: (i) different organs reshape their metabolism in response to specific functional demands, eg energy supply and detoxification. (ii) depletion of glucose, 3-HB and glycerol in the serum of elderly mice shows reduced contribution from liver and adipose tissue to other organs; (ii) aging in mice promotes upward modulation of glucose metabolism in cardiac and skeletal muscles as well as in the liver, where gluconeogenesis and urea cycling are also enhanced. There is a similar but less pronounced pattern in the brain.

The authors then assessed the associations between metabolites and phenotypic parameters by selecting the 24 most representative metabolites regardless of age and organ. The main results showed that the variance of the energy cost and the respiratory exchange ratio can be explained by a distinct model of metabolic remodeling in the liver (eg, mixed metabolism of glucose, lipids and amino acids), muscles cardiac and skeletal (eg, glucose and lipids), and brain (mixture of amino acids in addition to glucose and ketone body catabolism).

The increase in energy demand has prompted an increasingly mixed use of substrates (glucose, lipids, amino acids) leading to an increase in oxidative stress in organs which have a lower antioxidant capacity compared to the heart and the liver. .

The accumulation of visceral fat is associated with insulin resistance, while subcutaneous fat plays a role in lowering insulin levels and improving insulin sensitivity. Indeed, the increase in the percentage of body fat from young mice to adult mice coincided with a higher subcutaneous / visceral fat ratio, which, in turn, was associated with a significant decrease in circulating insulin levels and insulin resistance.

The authors assume that older animals can rely less on fat oxidation (using stored fat) and more on less efficient use of carbohydrates for energy needs.

This increasingly mixed use of glucose and lipids has led to a trend towards greater abundance of methionine sulfoxide and depletion of glutathione in response to an increased rate of respiratory exchange in the heart and liver, while the brain had significantly less methionine sulfoxide, but a greater accumulation of methionine and nicotinamide compared to glutathione. This pattern is consistent with systemic oxidative stress and lower antioxidant capacity.

Taken together, these data suggest that as mice age, organs such as the liver and heart, which are exposed to higher oxidative stress due to their function (detoxifying the liver and generating energy in the heart). ), remodel their metabolism towards higher expression / activity of redox-related metabolic pathways, eg, pentose phosphate, NAD + recovery and transsulfurization. Conversely, skeletal muscle and the brain do not appear to be able to reshape these pathways, thus becoming more vulnerable to increased oxidative stress with aging. This metabolic model is consistent with the idea of different rates of aging among organs.

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This book retraces the main achievements of ALS research over the last 30 years, presents the drugs under clinical trial, as well as ongoing research on future treatments likely to be able stop the disease in a few years and to provide a complete cure in a decade or two.

Everything points to mTOR dysfunction in ALS

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Here we review recent publications about ALS and try to connect the dots between autophagy, insulin resistance, C9orf72, FUS, proteopathies, mitophagy and defective neuromuscular junction. It seems autophagy dysregulation is central to all those aspects of ALS.

TDP-43

Over the past decade, it has become increasingly clear that the most notable neurodegenerative diseases, such as ALS, FTLD, and AD, share a common prominent pathological feature known as TAR DNA-binding protein 43 (TDP-43) proteinopathy, which is usually characterized by the presence of aberrant phosphorylation, ubiquitination, cleavage and/or nuclear depletion of TDP-43 in neurons and glial cells. The role of TDP-43 as a neurotoxicity trigger has been well documented in different in vitro and in vivo experimental models.

There is increasing evidence that autophagy is defective in neurodegenerative disorders, including motor neurons affected in amyotrophic lateral sclerosis (ALS). Restoring impaired autophagy in motor neurons may therefore represent a rational approach for ALS. In this publication the clinically approved anti-hypertensive drug rilmenidine was used to stimulate mTOR-independent autophagy in double transgenic TDP-43WTxQ331K mice to alleviate impaired autophagy.

Although rilmenidine treatment induced robust autophagy in spinal cords, this exacerbated the phenotype of TDP-43WTxQ331K mice, truncated lifespan, accelerated motor neuron loss, and pronounced nuclear TDP-43 clearance.

Importantly, rilmenidine significantly promoted mitophagy in spinal cords TDP-43WTxQ331K mice, evidenced by reduced mitochondrial markers and load in spinal motor neurons. These results suggest that autophagy induction accelerates the phenotype of this TDP-43 mouse model of ALS, most likely through excessive mitochondrial clearance in motor neurons.

C9orf72

The coordinated activities of autophagy and the ubiquitin proteasome system (UPS) are key to preventing the aggregation and toxicity of misfold-prone proteins which manifest in a number of neurodegenerative disorders.

Both C9ORF72 and androgen receptors regulate autophagy, while their aberrantly-expanded isoforms may lead to a failure in both autophagy and the UPS, further promoting protein aggregation and toxicity within motor neurons and skeletal muscles.

In fact, autophagy and the UPS intermingle with endocytic/secretory pathways to regulate axonal homeostasis and neurotransmission by interacting with key proteins which operate at the NMJ.

FUS

The mechanism by which FUS affects the translation of polyribosomes has not been established. In a recent publication, the authors show that FUS can associate with stalled polyribosomes and that this association is sensitive to mTOR (mammalian target of rapamycin) kinase activity. Specifically, they show that FUS association with polyribosomes is increased by Torin1 treatment or when cells are cultured in nutrient-deficient media, but not when cells are treated with rapamycin, the allosteric inhibitor of mTORC1.

Moreover, they report that FUS is necessary for efficient stalling of translation because deficient cells are refractory to the inhibition of mTOR-dependent signaling by Torin. The scientists also show that FUS is an important RNA-binding protein that mediates translational repression through mTOR-dependent signaling and that ALS-linked FUS mutants can cause a toxic gain of function in the cytoplasm by repressing the translation of mRNA at polyribosomes.

Stress granules

It was recently reported that the stress granule (SG) protein Staufen1 (STAU1) was overabundant in neurodegenerative disorder spinocerebellar ataxia type 2 (SCA2) patient cells, animal models, and ALS-TDP-43 fibroblasts, and provided a link between SG formation and autophagy.

The authors demonstrate STAU1 overabundance and increased total and phosphorylated mammalian target of rapamycin (mTOR) in fibroblast cells from patients with ALS with mutations in TDP-43, patients with dementia with PSEN1 mutations, a patient with parkinsonism with MAPT mutation, Huntington's disease (HD) mutations, and SCA2 mutations.

Increased STAU1 levels and mTOR activity were seen in human ALS spinal cord tissues as well as in animal models. Changes in STAU1 and mTOR protein levels were post-transcriptional. Exogenous expression of STAU1 in wildtype cells was sufficient to activate mTOR and downstream targets and form SGs.

mTOR

The mTOR pathway is a central regulator of mammalian metabolism and physiology, with important roles in the function of tissues including liver, muscle, white and brown adipose tissue, and the brain, and is dysregulated in human diseases, such as diabetes, obesity, depression, and certain cancers.

As usual it must be underlined that mTOR is important for living beings, and simply inhibiting it is out of question. It would simply further starve motor neurons and exacerbate the disease as shown above.

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This book retraces the main achievements of ALS research over the last 30 years, presents the drugs under clinical trial, as well as ongoing research on future treatments likely to be able stop the disease in a few years and to provide a complete cure in a decade or two.

1 doi: 10.3390/ijms21114021. Cell-Clearing Systems Bridging Repeat Expansion Proteotoxicity and Neuromuscular Junction Alterations in ALS and SBMA Fiona Limanaqi 1, Carla Letizia Busceti 2, Francesca Biagioni 2, Federica Cantini 1, Paola Lenzi 1, Francesco Fornai 1 2 2 doi: 10.1016/j.nbd.2021.105359. Online ahead of print. Stimulation of mTOR-independent autophagy and mitophagy by rilmenidine exacerbates the phenotype of transgenic TDP-43 mice Nirma D Perera 1, Doris Tomas 1, Nayomi Wanniarachchillage 1, Brittany Cuic 1, Sophia J Luikinga 1, Valeria Rytova 1, Bradley J Turner 2 3 doi: 10.1074/jbc.RA120.013801. Epub 2020 Oct 20. FUS contributes to mTOR-dependent inhibition of translation Myriam Sévigny 1, Isabelle Bourdeau Julien 1, Janani Priya Venkatasubramani 1, Jeremy B Hui 1, Paul A Dutchak 1, Chantelle F Sephton 2 4 doi: 10.1002/ana.26069. Online ahead of print. Staufen1 in Human Neurodegeneration Sharan Paul 1, Warunee Dansithong 1, Karla P Figueroa 1, Mandi Gandelman 1, Daniel R Scoles 1, Stefan M Pulst 1

Muscle cells of sporadic ALS patients secrete neurotoxic vesicles

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Amyotrophic lateral sclerosis is a non-cell autonomous disease, and motor neuron degeneration is modulated by intracellular and intercellular damages. Or at least this is what tells some scientists, indeed there is an abundance of proposal for ALS etiology and no consensus.

Another dissension point between ALS scientists is if the disease starts in the brain, or in a muscle. The former is the mainstream hypothesis. Both camps have proven again and again that their proposal was the right one.

A third mystery is that scientists almost never bothered to explore the most obvious manifestation of ALS: The muscle wasting.

With the amelioration of tools' performance, scientist's attention is turning to extra cellular vesicles.

Extra cellular vesicles

In the Central Nervous System (CNS), intercellular crosstalk happens among neurons, between neurons and glia or cells of the innate immune system, through different modalities, involving the release into the extracellular space of molecules such as neurotransmitters, neurotrophic factors, metabolites, and mutant proteins encapsulated or not in vesicles.

C9orf72, which presents aberrant hexanucleotide (GGGGCC) expansion in the non-coding region in ALS patients, regulates vesicle trafficking. Other proteins such as SOD1, TDP-43 or FUS are found in vesicles in ALS.

Where we discuss of muscles

Although much less studied than for motor neurons, abnormalities have been also described in skeletal muscle from ALS patients.

Accumulation of misfolded mutant proteins is observed in skeletal muscle.

In line with the pivotal role of defective mitochondrial respiratory chain and oxidative stress in ALS skeletal muscle, increasing levels of PGC‐1α, a transcription coactivator that promotes mitochondrial biogenesis, can improve muscle function even at late stages of the disease.

Skeletal muscle is a major site of glucose storage in the form of glycogen, which is transformed into ATP through glycolysis. The dysfunction of fast‐twitch type IIb myofibres in ALS is consistent with glucose intolerance and insulin resistance reported in ALS patients.

Myofibres from transgenic mice over expressing wild‐type TDP‐43 show impaired insulin‐mediated glucose uptake.

Does muscles kill motor neurons? In ALS, muscles are supposed to die from inactivity as motor neurons do not anymore activate them. A publication on MedRxiv proposes that it is actually the other way round: Muscles kill motor neurons. After all it is well known that many ALS patients were having intense sport activities. And an ALS-like phenotype was observed in mice when exogenous human mutant SOD1 expression was restricted to the skeletal muscle.

The authors of the pre-print, Laura Le Gall, Stephanie Duguez, Pierre Francois Pradat and colleagues, recall that pathological proteins have been identified in circulating extracellular vesicles of sporadic ALS patients. So they hypothesized that muscle vesicles may be involved in ALS pathology.

An accumulation of multivesicular bodies was observed in muscle biopsies of 27 sporadic ALS patients.

Study of muscle biopsies and biopsy-derived denervation-naïve differentiated muscle stem cells (myotubes) revealed a consistent disease signature in ALS myotubes, including intracellular accumulation of exosome-like vesicles and disruption of RNA-processing.

Compared to vesicles from healthy control myotubes, when administered to healthy motor neurons the vesicles of ALS myotubes induced shortened, less branched neurites, cell death, and disrupted localization of RNA and RNA-processing proteins. enter image description here

This article may revolutionize the understanding of ALS' etiology.

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This book retraces the main achievements of ALS research over the last 30 years, presents the drugs under clinical trial, as well as ongoing research on future treatments likely to be able stop the disease in a few years and to provide a complete cure in a decade or two.

Astrocytes regulate brain extracellular pH

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Lead author of this study, Dr Shefeeq Theparambil (UCL Neuroscience, Physiology & Pharmacology) said: “The human brain consumes an immense amount of energy, the rate of which is estimated to be equal to human leg muscles running a marathon. Such a high metabolic rate produces a significant amount of acid, but until now, it had not been entirely clear how the brain protects itself from harmful acidification.

Bicarbonate, in conjunction with water, hydrogen ions, and carbon dioxide, forms a buffering system, to provide resistance to pH changes in both the acidic and basic directions. This is especially important for protecting tissues of the central nervous system, where pH changes too far outside of the normal range in either direction could prove disastrous. enter image description here Nervous system involvement may be seen with acidosis. Signs and symptoms that may be seen in acidosis include headaches, confusion, feeling tired, tremors, sleepiness, flapping tremor, and dysfunction of the cerebrum of the brain which may progress to coma if there is no intervention.

By studying live mice and brain cell samples, the researchers were able to identify the mechanism by which astrocytes maintain pH balance in active areas of the brain. They found that at least one third of astrocytes in the mouse brain release bicarbonate that counteracts the acidity of the protons released by neuronal cells. The bicarbonate release corresponds to local activity levels in the brain, as the mechanism continually responds to changes in brain activity in order to maintain balance and support the activity of nerve cells processing information.

Little is known about the mechanisms that maintain local carbon dioxide/bicarbonate buffer strength in the extracellular space of the brain. Indeed, the brain extracellular space occupies only ~20% of the tissue volume, and the efficacy of the carbon dioxide/bicarbonate buffering system would rapidly decline if bicarbonate is depleted in conditions of significant extracellular acid loads, such as during periods of increased neuronal activity.

Therefore maintaining stability of brain tissue pH necessitates an effective mechanism capable of supplying bicarbonate to the extracellular space in a responsive mode, i.e., in a neuronal activity-dependent manner.

Among different candidate mechanisms, astrocytes appear to be well suited to provide active control of local brain extracellular pH microenvironment. A single astrocyte occupies a large volume of brain parenchyma with an extensive arborisation covering thousands of individual synapses. enter image description here

Astrocytes monitor local brain activity by sensing neuronal signalling molecules (such as glutamate and ATP) that escape from the synaptic cleft.

Sodium bicarbonate cotransporters (NBCs) mediate the coupled movement of sodium and bicarbonate ions across the plasma membrane of many cells. In brain, NBCe1 is predominantly expressed by astrocytes.

The scientists hypothesised that, in astrocytes, the recruitment of one (or several) of these intracellular mechanisms in response to neuronal signalling molecules can stimulate outward activity of NBCe1 and thus supply bicarbonate to the extracellular space ‘on demand’, and in accord with the level of local neuronal activity.

To test this hypothesis, the researchers examined the effects of purinoceptor activation on bicarbonate transport and intracellular pH (pHi) regulation in astrocytes, investigated the cellular mechanisms of bicarbonate release, and determined the effect of NBCe1 deletion in astrocytes on brain pH regulation.

The results obtained in this study suggest that bicarbonate transport in astrocytes of the forebrain is controlled by purinergic signalling. ATP and downstream purines facilitate bicarbonate release by astrocytes via activation of NBCe1. This astroglial mechanism appears to play an important role in the control of local brain extracellular pH.

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