The direct link between neuropathology and the symptoms that emerge from damage to the brain is often difficult to discern. In this perspective, the authors of this new publication argue that a satisfying account of neurodegenerative symptoms most naturally emerges from the consideration of the brain from the systems-level. enter image description here Source.

Specifically, the authors will highlight the role of the neuromodulatory arousal system, which is uniquely positioned to coordinate the brain's ability to flexibly integrate the otherwise segregated structures required to support higher cognitive functions.

Neuromodulatory systems, including the noradrenergic, serotonergic, dopaminergic, and cholinergic systems, track environmental signals, such as risks, rewards, novelty, effort, and social cooperation. These systems provide a foundation for cognitive function in higher organisms; attention, emotion, goal-directed behavior, and decision-making derive from the interaction between the neuromodulatory systems and brain areas, such as the amygdala, frontal cortex, hippocampus, and sensory cortices.

The existence of extensive lines of communication between the nervous system and immune system represents a fundamental principle underlying neuroinflammation.

Important sources in the above neuropathologies appear to be microglia and mast cells, together with astrocytes and possibly also oligodendrocytes. Understanding neuroinflammation also requires an appreciation that non-neuronal cell—cell interactions, between both glia and mast cells and glia themselves, are an integral part of the inflammation process.

Given their strong influence on behavior and cognition, these systems also play a key role in disease states and are the primary target of many current treatment strategies. The fact that these systems interact with each other either directly or indirectly, however, makes it difficult to understand how a failure in one or more systems can lead to a particular symptom or pathology.

Importantly, the neuromodulatory arousal system is highly heterogeneous, encompassing structures that are common sites of neurodegeneration across Alzheimer's and Parkinson's disease.
The scientists here will review studies that implicate the dysfunctional interactions amongst distributed brain regions as a side-effect of pathological involvement of the neuromodulatory arousal system in these neurodegenerative disorders.

From this perspective, the authors will argue that future work in clinical neuroscience should attempt to consider the inherent complexity in the brain and employ analytic techniques that do not solely focus on regional functional impairments, but rather captures the brain as an inherently dynamic, distributed, multi-scale system.

Through this lens, the authors hope that the authors will devise new and improved diagnostic markers and interventional approaches to aid in the treatment of neurodegenerative disorders.

Read the original article on Pubmed

Recently, the amyloid hypothesis of Alzheimer's disease has been questioned

Apolipoprotein E (APOE) is a protein involved in the metabolism of fats in the body of mammals. APOE transports lipids, fat-soluble vitamins, and cholesterol into the lymph system and then into the blood. It is synthesized principally in the liver, but has also been found in other tissues such as the brain, kidneys, and spleen. In the nervous system, non-neuronal cell types, most notably astroglia and microglia, are the primary producers of APOE, while neurons preferentially express the receptors for APOE.

The ε4 variant of apolipoprotein E is the strongest and most common genetic risk factor for Alzheimer's disease. However, the E4 variant does not correlate with risk in every population. Women are more likely to develop AD than men across most ages and APOE genotypes.

While the mechanism of conveyed risk is incompletely understood, promotion of inflammation, dysregulated metabolism, and protein misfolding and aggregation are contributors to accelerating disease.

In this new publication the authors determined the concurrent effects of systemic metabolic changes and brain inflammation in young and aged male and female mice carrying the APOE4 gene.

Using functional metabolic assays alongside multivariate modeling of hippocampal cytokine levels, the authors found that brain cytokine signatures are predictive of systemic metabolic outcomes, independent of Alzheimer's disease proteinopathies.

Male and female mice each produce different cytokine signatures as they age and as their systemic metabolic phenotype declines. The authors found that these signatures are APOE genotype dependent.

They propose that, because APOE4 is present from birth and has been shown to have deleterious effects on immune function and metabolism well before the age of AD onset, long-term APOE4-driven systemic and brain immunometabolic effects can provoke an AD-inducible environment independent of interactions with Aβ or tau.

The authors determine that aging-related cytokine patterns in the hippocampus can predict systemic metabolic outcomes of young and aged humanized APOE3 and APOE4 male and female mice. Specifically, they uncover unique patterns of cytokines in APOE3 versus APOE4 mice that correlate with body adiposity, glucose tolerance, and insulin sensitivity. Male and female mice exhibit differing cytokine signatures that correlate with peripheral metabolic function, emphasizing important sex differences in biomarker outcomes.

In its proposed role as a controller of glucose metabolism, altered hippocampal immune signaling could be the stimulus for APOE variant-specific differences in adiposity and glucose tolerance.

Alternatively, peripheral changes in adiposity, glucose tolerance, and insulin sensitivity may impact hippocampal cytokine levels through upregulation of factors that can pass the blood-brain barrier, or through affecting vascular integrity and allowing infiltration of peripheral immune cells and signaling molecules.

Most likely, both of these scenarios could be occurring simultaneously.

The authors' results highlight the effects of APOE4 beyond the brain and suggest the potential for bi-directional influence of risk factors in the brain and periphery.

Some researchers have suggested that lowering serum cholesterol levels may reduce a person's risk for Alzheimer's disease, even if they have two ApoE4 alleles, thus reducing the risk from nine or ten times the odds of getting AD down to just two times the odds.

Read the original article on Pubmed

The bile acid TUDCA reduces age-related hyperinsulinemia in mice.

- Posted by admin in English

This article is about TUDCA and type 2 diabetes, but is likely of interest to our readers who are primarily interested in neurodegenerative publications.

TUDCA most likely has a positive effect on ALS patients. About half of ALS (and Alzheimer's) patients have insulin resistance. Insulin resistance is a disease state in which cells do not respond normally to the hormone insulin. In other words, cells starve, and motor neurons and fast muscle cells suffer first, and then the stress response begins, and so does protein aggregation. Eventually, type 2 diabetes occurs.

Aging is associated with glucose metabolism disturbances, such as insulin resistance and hyperinsulinemia, which contribute to the increased prevalence of type 2 diabetes and its complications in the elderly population. In this sense, some bile acids have emerged as new therapeutic targets to treat type 2 diabetes, as well as associated metabolic disorders.

The taurine conjugated bile acid, tauroursodeoxycholic acid improves glucose homeostasis in T2D, obesity, and Alzheimer's disease mice model. However, its effects in aged mice have not been explored yet.
Here, the authors evaluated the actions of TUDCA upon glucose-insulin homeostasis in aged C57BL/6 male mice treated with 300 mg/kg of TUDCA or its vehicle.

TUDCA attenuated hyperinsulinemia and improved glucose homeostasis in aged mice, by enhancing liver insulin-degrading enzyme expression and insulin clearance.

Furthermore, the improvement in glucose-insulin homeostasis in these mice was accompanied by a reduction in adiposity, associated with adipocyte hypertrophy, and lipids accumulation in the liver.

TUDCA-treated aged mice also displayed increased energy expenditure and metabolic flexibility, as well as a better cognitive ability.
Taken together, authors' data highlight TUDCA as an interesting target for the attenuation of age-related hyperinsulinemia and its deleterious effects on metabolism.

Read the original article on Pubmed

When patients carry out clinical trials

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Here is a somewhat strange and moving story about smart and desperate people.

A few days ago a company, Neuvivo, published an article about their drug for ALS. Neuvivo researchers studied combined data from failed phase 2a (NCT01281631) and phase 2b (NCT02794857) trials of NP001. They found that NP001 slowed disease progression in a group of patients between the ages of 40 and 65, with high levels of inflammation at the start of their study.

NP0001 has been a known name for a long time in the field of drugs to fight ALS. A quite similar drug is WF-10.

Neuvivo actually looks a lot like the defunct Neuraltus company. Neuraltus was created in 2009 by Ari Azhir, now CEO of Neuvivo, and Michael McGrath, now Chief Scientific Officer of Neuvivo. Neuraltus ceased operations in 2019, after disappointing data from the phase 2 trials cited above, of NP0001.

NP0001 is similar to sodium chlorite, a common disinfectant which is promoted as a cure-all by a number of quacks, but this story is about an attempt by ALS patients to replicate this drug, design and conduct their own clinical trial.

Beginning in September 2011, some of those diagnosed with this fatal disease began researching published literature on NP0001, they communicated on the ALS Therapy Development Institute forum.

First patient effort in 2008

On this forum, this was not the first patient effort to study a potential therapy for ALS. One remarkable effort took place in 2008 following a promising phase 1 trial in Italy for treating the disease with lithium carbonate. The study of 44 patients suggested that lithium significantly slowed disease progression and none of the 16 lithium-treated participants died during the 15 months of the study. ALS patient discussion forums then began to discuss this result, as they do with every clinical trial and also the possibility of taking lithium.

It could be years before lithium was approved as a treatment for ALS, but the drug was already marketed for bipolar disorder, so it was not difficult for these patients to obtain it.

Some 350 ALS patients have therefore started trying lithium to treat their symptoms. An ALS patient posted a Google Docs spreadsheet to track self-reported ALSFRS-R scores. And Karen Felzer, a research scientist with the US Geological Survey's earthquake hazard team whose father had ALS, set up a website to host the project.

Felzer, who had a background in statistics, looked at patient outcomes at 3 and 6 months. Unfortunately both times she found no evidence that lithium slowed progression. So in November 2008, when Felzer published its second report on the project's website, most of the patients participating in the forum stopped taking the lithium.

In 2001, patients want to replicate a clinical trial

In September 2011, based on published papers and patents, ALS patients, such as Olly or HappyPhysicist on forum conclude that the active ingredient in NP001 is sodium chlorite, a chemical used primarily to bleach paper pulp or to disinfect the water.

Some then buy the precursor to NP001, WF10, which was known to contain just over 50% sodium chlorite and could be ordered in Thailand, where the drug had been approved for the treatment of autoimmune consequences of cancer radiation.

But for many, the $12,000 cost for a one-year supply was prohibitive. Sodium chlorite, on the other hand, could be purchased from online suppliers for only $50 per liter, or 15 years at the dosage indicated in the patients' documented protocol.

Patients contacted the inventors of the drugs and talked to their doctors and to each other about the risks and the proper dosage.

Tom P..., Silverfox on the forum, who does not have ALS, posted on the forum information on the purity of chlorite solutions available for purchase, dilution and mixing, and the behavior of the chemical. More than a year and 1,000 forum posts later, twenty ALS patients decide that ingesting sodium chlorite was worth it.

This was not welcomed by some scientists of the domain. Organizing ALS clinical trials is not easy, there are few patients with ALS and due to the rapid deterioration (sometimes within a few months) and the risk of being assigned to the placebo group, patients could be more likely to get this drug on their own, to make sure they get the active compound.

Official ALS clinical trials already suffer from this patient shortage. With a small group of patients, and especially in the case of a heterogeneous disease like ALS, there is an imprecise measure of the rate of decline, therefore of the effectiveness of the drug being tested.

Additionally, self-reported data can include countless biases. Desperate patients are indeed likely to perceive an improvement where there is none.

Furthermore, the patients who choose to participate in such DIY experiments do not necessarily represent the entire ALS population. For example, patients who resort to self-experimentation must be able to read scientific articles, understand the intricacies of dosage and benefit from medical supervision, which is not the case for all patients.

On August 15, 2011, after his sixth dose of sodium chlorite, Eric Valor recorded his first positive effect.

"Apparently clearer speech," he wrote in his blog. Others have noted similar improvements. Excitement was sparked on the group's forum when one of the most pessimistic patients, Ron Schaffer, reported slight improvements in his energy levels.

In September, Valor, using only his right eye, completed construction of the project's website where those taking sodium chlorite could post their results.

First doubts

However in January 2012 the first doubts appear. HappyPhysicist writes on PatientLikeme; “It has now been 8 weeks since my last infusion. Over the past 4 weeks I have noticed a significant decline in my condition. My speech is considerably worse and my left leg is showing signs of weakness to the point that my gait has changed and I feel a little off balance. My swallowing is also worse. I now have to sip water to avoid choking and find that I have difficulty swallowing food, even choking on food on occasion. I feel like my progress has now picked up where it left off just before starting the NP001. infusions.”

In mid-July 2012, active patients on the forum received an email from Jennifer Askt, editor of The Scientist magazine, about an article she had written about the CSO DIY trial and saying that she intended to write a book. She mentions that she is in contact with Eric Valor (ENV), Happy Physicist and Persevering in relation to the book. The Economist also publishes an article.

The common goal and the extremely disabling and deadly disease did not prevent doubts, ego disputes and other quibbles. Only a third and then four patients initially seem to have obtained beneficial effects from ingesting sodium chlorite, but years later only one patient will make this claim.

There is also what has been called by Ron Schaffer the "chlorite rage" People with ALS often have little patience, are harsh with others, including their caregivers. Chlorite makes it ten times worse. Some patients thought it might have something to do with frontotemporal dementia (FTD).

A regular forum participant, Ollie, remarks: "This disease is not static - once you initially alter the immune response, say with OSC (Oral Sodium Chlorite), any treatment has less and less effect as the system immune changes. There will come a time when taking a substance that worked in the beginning no longer has any value or may even block other repair pathways. Then, as the disease does not stop but progresses more slowly, other biological pathways become more important - the type of cascade action has changed. Any pharmacological intervention, if it does anything, will alter the disease state, and in doing so, the dosage rate becomes less effective over time, which means that as your system changes, you should have need fewer OSC. If this does not cure the disease, then the intervention strategy should change depending on the state of the disease and this change in dosage levels of the substance should be based on the rate of disease over time. "

Commentators like Nemesis doubted the benefits of NP001. He believed that NP001 only worked for ALS patients whose neuro-inflammatory component was stronger than the neurodegenerative component. For him, the problem is that it is difficult in advance whether you are a category A or B patient.

Disturbingly, the inventors of NP001 say sodium chlorite taken orally shouldn't work at all because the chemical will quickly be converted to chlorine dioxide, which is not only ineffective at suppressing macrophages, but could even be toxic. Indeed, a report published by PatientsLikeMe investigators last October on found that "sodium chlorite has a potentially negative effect; we are over 80% confident that it worsens the rate of patient progression ."

SilverFox had warned forum attendees: “You must first realize that chlorite is a free radical. It can cause oxidative stress to the body. The body runs on oxidation, so it is able to handle oxidative stress to some degree. However, when you pass this point, you can do damage."

Frank Provost, who had participated in one of the clinical trials, said: "I felt a significant burn from NP001 at the injection site. I can only imagine how much damage would be caused if taken by orally at the dose required to be effective against ALS."

Since the work on WF-10 in 2001, it has been known that the reaction of chlorite with hemoproteins is a central step in the process of drug activation. The mode of administration therefore seems to be imperatively intravenously, while the patients of the forum ingest sodium chlorite orally.

Similarly, Silverfox believed that since the pH of sodium chlorite is between 8 and 12, when injected into the blood there is an adverse reaction. WF10 had this flaw. For him, Neuraltus lowered the pH to be much closer to normal blood pH and far fewer side effects.

The mechanism evoked for WF-10 and NP000 involves a conversion of chlorite mainly to chloramine taurine which is a long-lived molecule with immunomodulatory properties. For example, chloramine taurine inhibits the generation of macrophage inflammatory mediators such as nitric oxide, prostaglandin E2 (PGE2), tumor necrosis factor alpha (TNF-alpha), and interleukin-6 (IL-6) .


In the end, it turns out that only Ron Schaffer seems to have benefited from this DIY trial of sodium chlorite because his disease did not seem to have progressed afterwards. The next years he remained the sympathetic but pessimistic patient described above and passed away on September 22, 2022. He said the drug benefited him because unlike the other testers, he wanted to take an undiluted dose. He also said that only the dose initially administered had been beneficial, subsequent doses had brought him nothing.

These years were not easy, Ron remained an ALS patient almost paralyzed. Impossible to turn over in bed, to swallow without choking, no modesty possible. Yet he had a fierce sense of humor.

Quand les malades font des essais cliniques

- Posted by admin in Français

Voiçi une histoire un peu étrange. Il y a quelques jours une société, Neuvivo, a publié un article sur leur médicament, NP0001, contre la SLA. Les chercheurs de Neuvivo ont étudié les données combinées d’anciens essais de phase 2a (NCT01281631) et de phase 2b (NCT02794857) qui d’après eux, ont montré que le NP001 ralentissait la progression de la maladie dans un groupe de patients âgés de 40 à 65 ans, présentant des niveaux élevés d'inflammation au début de leur étude.

NP0001 est un nom connu depuis une quinzaine d’années dans le domaine des médicament pour lutter contre la SLA. Un médicament similaire est WF-10.

Neuvivo est en fait la résurrection de la société Neuraltus. Neuraltus a été créé en 2009 par Ari Azhir, aujourd'hui PDG de Neuvivo, et Michael McGrath, directeur scientifique de Neuvivo. Neuraltus a cessé ses activitées en 2019, après des données décevantes les essais de phase 2 cités plus haut, de NP0001.

NP0001 est également associé à au moins deux controverses, l’une parce qu’essentiellement c’est du chlorite de sodium, un désinfectant courant et qu’un certain nombre de charlatans promotent comme remède universel.

L’autre controverse concerne une tentative par des malades de la SLA de reproduire ce médicament.

A partir de septembre 2011, certaines des personnes diagnostiquées avec cette maladie mortelle ont commencé rechercher la littérature publiée sur NP0001, elles communiquaient sur le forum de l’ALS Therapy Development Institute.

Premier effort de patients en 2008

Sur ce forum, le premier effort de patients pour étudier une thérapie potentielle de la SLA, avait eu lieu en 2008 à la suite d'un essai prometteur de phase 1 en Italie pour le traitement de la maladie avec du carbonate de lithium. L'étude de 44 patients a suggéré que le lithium ralentissait considérablement la progression de la maladie et aucun des 16 participants traités au lithium n'était décédé au cours des 15 mois de l’étude. Les forums de discussion des patients SLA ont alors commencé à discuter de ce résultat, comme ils le font de chaque essai clinique et aussi de la possibilité de prendre du lithium.

Comme il pouvait s'écouler des années avant que le lithium ne soit approuvé comme traitement de la SLA, mais que le médicament était déjà commercialisé pour le trouble bipolaire, il n'était pas difficile pour ces patients de s’en procurer.

Quelque 350 patients atteints de SLA ont donc commencé à essayer le lithium pour traiter leurs symptômes. Un patient SLA a publié une feuille de calcul Google Docs pour suivre les scores ALSFRS-R autodéclarés. Et Karen Felzer, une chercheuse scientifique de l'équipe des risques sismiques de l'US Geological Survey dont le père était atteint de la SLA, a créé un site Web pour héberger le projet.

Felzer, qui avait une formation en statistiques a examiné les résultats des patients à 3 et 6 mois. Les deux fois, elle n'a trouvé aucune preuve que le lithium ralentissait la progression. Aussi en novembre 2008, alors que Felzer publiait son deuxième rapport sur le site Web du projet, la plupart des patients participant au forum,avaient cessé de prendre le médicament.

En 2001, des patients veulent répliquer un essai clinique

En septembre 2011, sur la base d'articles et de brevets publiés, des patients de la SLA, comme Olly ou HappyPhysicist concluent que l'ingrédient actif du NP001 est le chlorite de sodium, un produit chimique utilisé principalement pour blanchir la pâte à papier ou pour désinfecter l'eau.

Certains achetent alors le précurseur de NP001, WF10, qui était connu pour contenir un peu plus de 50% de chlorite de sodium et pouvait être commandé en Thaïlande, où ce médicament avait été approuvé pour le traitement des conséquences auto-immunes des radiations cancéreuses.

Mais pour beaucoup, le coût de 12 000 $ pour un approvisionnement d'un an était prohibitif. Le chlorite de sodium, en revanche, pourrait être acheté auprès de fournisseurs en ligne pour seulement 50 $ par litre, soit 15 ans à la posologie indiquée dans le protocole documenté des patients.

Les patients ont contacté les inventeurs des médicaments et ont parlé à leurs médecins et entre eux des risques et du dosage approprié. Tom Poast, Silverfox sur le forum, qui n'est pas atteint de la SLA, était intervenu sur le forum avec des informations sur la pureté des solutions de chlorite disponibles à l'achat, la dilution et le mélange, et le comportement du produit chimique. Plus d'un an et 1 000 messages sur le forum plus tard, une vingtaine de patients SLA décident que l'ingestion de chlorite de sodium valait le coup.

Organiser des essais cliniques de la SLA n’est pas facile, il y a peu de patients atteints de la SLA et en raison de la dégradation rapide (parfois en quelques mois) et du risque d'être assignés au groupe placebo, les patients pourraient être plus enclins à obtenir ce médicament par eux-mêmes, afin de s'assurer qu'ils obtiennent le composé actif.

Les essais cliniques de la SLA souffrent déjà de ce manque de patient, avec un petit groupe de patients, et surtout dans le cas d’une maladie hétérogène comme la SLA dont la présentation varie grandement d’un patient à l’autre, et aussi au cours du temps, il y a une mesure imprécise du taux de déclin, donc de l’efficacité du médicament testé.

De plus les données autodéclarées peuvent inclure d'innombrables biais. Les patients désespérés sont en effet susceptibles de percevoir une amélioration là où il n'y en a pas.

Par ailleurs, les patients qui choisissent de participer à de telles expériences ne représentent pas nécessairement l'ensemble de la population SLA. Par exemple, les patients qui ont recours à l'auto-expérimentation doivent être capable de lire les articles scientifiques, comprendre les subtilitées du dosage et bénéficier d’une supervision médicale, ce qui n’est pas le cas de tous les malades.

Le 15 août 2011, après sa sixième dose de chlorite de sodium, Eric Valor enregistre son premier effet positif.

"Discours apparemment plus clair", a-t-il écrit dans son blog. D'autres ont noté des améliorations similaires. L'excitation a été suscitée sur le forum du groupe lorsque l'un des patients les plus pessimistes, Ron Schaffer, signale de légères améliorations de son niveau d'énergie.

"Aucun placebo n'est nécessaire", plaisante alors un commentateur - "si à la fin Ron dit que le truc fonctionne, c'est un niveau de confiance de 99,9% avec N = 1." En septembre, Valor, n'utilisant que son œil droit, a terminé la construction du site Web du projet où ceux qui prenaient du chlorite de sodium pouvaient publier leurs résultats.

Premiers doutes

Cependant en Janvier 2012 les premiers doutes apparaissent. HappyPhysicist écrit sur PatientLikeme ; « Cela fait maintenant 8 semaines depuis ma dernière perfusion. Au cours des 4 dernières semaines, j'ai remarqué une baisse significative de mon état. Mon élocution est considérablement moins bonne et ma jambe gauche montre des signes de faiblesse au point que ma démarche a changé et que je me sens un peu déséquilibré. Ma déglutition est également pire. Je dois maintenant boire de l'eau à petites gorgées pour éviter de m'étouffer et je constate que j'ai de la difficulté à avaler de la nourriture, voire à m'étouffer avec de la nourriture à l'occasion. J'ai l'impression que ma progression a maintenant repris là où elle s'était arrêtée juste avant de commencer les perfusions de NP001. ».

À la mi-juillet 2012, des patients actifs du forum reçoivent un e-mail de Jennifer Askt, rédactrice en chef du magazine The Scientist, au sujet d'un article qu'elle avait écrit sur l'essai OSC DIY et disant qu'elle avait l'intention d'écrire un livre. Elle mentionne qu'elle est en contact avec Eric Valor (ENV), Happy Physicist and Persevering en rapport avec le livre. The economist publie aussi un article.

Le but commun et la maladie extrêmement handicapante et mortelle n’a pas empêché les doutes, les querelles d’égos et autres chicaneries. Seuls un tiers, puis quatre patients semblent initialement avoir obtenu des effets bénéfiques de l’ingestion de chlorite de sodium, mais des années plus tard seul un patient fera cette revendication.

Il y a aussi ce qui a été appelé par Ron la "rage de la chlorite" Les personnes atteintes de SLA ont souvent peu de patience, sont dure avec les autres, y compris leurs soignants. La chlorite rend cela dix fois pire. Certains patients pensaient que cela pouvait avoir un lien avec la démence fronto-temporale (FTD).

Un participant assidu au forum, Ollie, remarque : « Cette maladie n'est pas statique - une fois que vous avez initialement modifié la réponse immunitaire, disons avec OSC, tout traitement a de moins en moins d'effet à mesure que le système immunitaire change. Il viendra un moment où la prise d'une substance qui a fonctionné au début, n'a plus aucune valeur ou peut même bloquer d'autres voies de réparation. Ensuite, à mesure que la maladie ne s'arrête pas mais progresse plus lentement, d'autres voies biologiques deviennent plus importantes - le type d'action en cascade a changé. Toute intervention pharmacologique, si elle fait quoi que ce soit, modifiera l'état de la maladie et, ce faisant, le taux de dosage devient moins efficace avec le temps, ce qui signifie que, à mesure que votre système change, vous devriez avoir besoin de moins d'OSC. Si cela ne guérit pas la maladie, comme dans la SLA, alors la stratégie d'intervention doit changer en fonction de l'état de la maladie et ce changement des niveaux de dosage de la substance doit être basé sur le taux de maladie au fil du temps. »

Des commentateurs comme Némésis doutent des bienfaits de NP001. Il pensait que NP001 fonctionnait seulement pour les patients SLA dont la composante neuro-inflammatoire était plus forte que la composante neurodégénérative. Pour lui, le problème est qu'il est difficile de dire à l'avance si vous êtes un patient de catégorie A ou B.

De manière troublante, les inventeurs de NP001 disent que le chlorite de sodium pris par voie orale ne devrait pas fonctionner du tout car le produit chimique sera rapidement converti en dioxyde de chlore, qui est non seulement inefficace pour réprimer les macrophages, mais pourrait même être toxique. En effet, un rapport publié par les enquêteurs de PatientsLikeMe en octobre dernier sur a révélé que "le chlorite de sodium a un effet potentiellement négatif ; nous sommes convaincus à plus de 80 % que cela aggrave le taux de progression des patients."

SilverFox (Tom Poast) avait pourtant prévenu les participants du forum : « Vous devez d'abord réaliser que le chlorite est un radical libre. Il peut provoquer un stress oxydatif pour le corps. Le corps fonctionne à l'oxydation, il est donc capable de gérer le stress oxydatif jusqu'à un certain point. Cependant, lorsque vous dépassez ce point, vous pouvez faire des dégâts. »

Frank Provost, qui avait participé à l’un des essais cliniques, racontait : "J'ai ressenti une brûlure importante de NP001 au site d'injection. Je ne peux qu'imaginer combien de dégâts seraient causés s'ils étaient pris par voie orale à la dose nécessaire pour être efficaces contre la SLA."

Depuis les travaux sur WF-10 en 2001, on sait que la réaction du chlorite avec les hémoprotéines est une étape centrale du processus d'activation du médicament. Le mode d’administration semble donc être impérativement par voie intraveineuse, alors que les patients du forum ingère le chlorite de sodium par voie orale.

De façon similaire, Silverfox pensait que comme le pH du chlorite de sodium se situe entre 8 et 12, lorsqu'il est injecté dans le sang, il y a une réaction indésirable. WF10 avait ce défaut. Pour lui, Neuraltus réduisait le pH pour être beaucoup plus proche du pH sanguin normal et beaucoup moins d'effets secondaires.

Le mécanisme évoqué pour WF-10 et NP000 implique une conversion du chlorite principalement en taurine chloramine qui est une molécule à longue durée de vie dotée de propriétés immunomodulatrices. Par exemple, la taurine chloramine inhibe la génération de médiateurs inflammatoires des macrophages tels que l'oxyde nitrique, la prostaglandine E2 (PGE2), le facteur de nécrose tumorale alpha (TNF-alpha) et l'interleukine-6 (IL-6).

Au final, il s’avère que seul Ron Schaffer semble avoir bénéficié de cet essai du chlorite de sodium car sa maladie ne semblait pas avoir progressé par la suite. Il est resté le patient sympathique mais pessimiste décrit plus haut et s’est éteint le 22 septembre 2022. Il disait que le médicament lui avait bénéficié car contrairement aux autres testeurs, il avait voulu prendre une dose unique, non diluée. Il disait aussi que seule la dose administrée initialement avait été bénéfique, les essais ultérieurs ne lui avaient rien apportés. Ces années n’ont pourtant pas été facile, Ron est resté un malade de la SLA quasiment paralysé. Impossible de se retourner dans son lit, d'avaler sans s'étouffer, aucune pudeur n’est possible. Il avait un humour féroce.

Since a long time there are competing hypotheses about ALS, does it start in the brain as a majority of scientists think, or does it start in a distal way as some talented scientists suggest?

Magnetic resonance imaging of the brain and cervical spinal cord is often performed in diagnostic evaluation of suspected motor neuron disease/amyotrophic lateral sclerosis. enter image description here Anatomist90 via Wikipedia

Analysis of MRI-derived tissue damage metrics in a common domain facilitates group-level inferences on pathophysiology.

This approach was applied to address competing hypotheses of directionality of neurodegeneration, whether anterograde, cranio-caudal dying-forward from precentral gyrus (posterior frontal lobe of the brain) toward the cervical spinal cord, or dying-back with the disease progressing in the other direction.

In this cross-sectional study, MRI was performed on 75 Motor neuron disease patients and 13 healthy controls. MRI scans were reviewed by a consultant neuroradiologist to exclude significant confounding pathology.

Precentral gyral thickness was estimated from volumetric T1-weighted images using FreeSurfer, corticospinal tract fractional anisotropy from diffusion tensor imaging using FSL, and cross-sectional cervical cord area between C1-C8 levels using Spinal Cord Toolbox.

To analyse these multimodal data within a common domain, individual parameter estimates representing tissue damage at each corticospinal tract level were first converted to z-scores, referenced to healthy control norms.

Mixed-effects linear regression models were then fitted to these z-scores, with gradients hypothesized to represent directionality of neurodegeneration.

The results are a bit confusing, it seems that from C5, there is a forward propagation toward lower cervical vertebras, while above C1 there is a backward propagation toward precentral gyrus! enter image description here

A major limitation of this study is that they only studied the brain and the upper part of the spinal cord. Upper motor neurons have their body in the motor area and extend to the junction with lower motor neurons (with eventually inter-neurons in between). The lowest corticospinal nerve they studied C8, contributes to the motor innervation of many of the muscles in the trunk and upper limb. Its primary function is the flexion of the fingers. So this study would be conclusive only if all patients had a bulbar pathology, yet only 17 patients on 75 had a bulbar onset.

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Il y a trois décennies, les scientifiques pensaient avoir percé le mystère médical de ce qui cause la maladie d'Alzheimer avec une idée connue sous le nom d'hypothèse de la cascade amyloïde. Dans cette hypothèse une protéine appelée bêta-amyloïde forme des plaques collantes et toxiques entre les neurones et font dépérir le cerveau. Les amyloïdes sont des agrégats de protéines, les amyloïdes sont connus pour provenir de nombreuses protéines différentes. Les raisons pour lesquelles l'amyloïde provoque des maladies ne sont toujours pas claires. Les plaques amyloïdes sont des dépôts extracellulaires de bêta-amyloïde. La bêta-amyloïde (Aβ) est une petite protéine qui est libérée à partir d'une protéine mère plus longue appelée protéine précurseur Aβ (APP). L'APP est produite par de nombreux types de cellules dans le corps, mais elle est particulièrement abondante dans les neurones.

L'hypothèse de la cascade amyloïde était simple et convaincante, et des décennies de travail et des milliards de dollars ont été investis dans le financement d'essais cliniques de dizaines de composés médicamenteux ciblant les plaques amyloïdes. Pourtant, presque aucun de ces essais n'a montré d'avantages significatifs pour les patients atteints de la maladie. Cela jusqu'en septembre 2022, lorsque les géants pharmaceutiques Biogen et Eisai ont annoncé que dans un essai clinique de phase 3, les patients prenant le médicament anti-amyloïde lecanemab présentaient une baisse de leur cognition de 27 % inférieure à celle des patients prenant un placebo.

Une lacune majeure dans les théories centrées sur l'amyloïde de la maladie d'Alzheimer est cependant que les fibrilles amyloïdes en soi ne sont pas toxiques, bien que le diagnostic de maladie d'Alzheimer est clairement corrélé à la densité des dépôts de bêta-amyloïde (Aβ).

Il y a des alternatives à l'hypothèse de la cascade amyloïde. De nombreux chercheurs ont pensé que la réponse pourrait résider dans les enchevêtrements Tau – des faisceaux anormaux de protéines à l'intérieur des neurones qui sont également caractéristiques de la maladie d'Alzheimer et encore plus étroitement liés aux symptômes cognitifs que les plaques amyloïdes. D'autres pensent qu'une activité immunitaire excessive ou mal placée pouvait enflammer et endommager les tissus nerveux délicats. D'autres encore ont suspecté des dysfonctionnements dans le métabolisme du cholestérol ou dans les mitochondries qui alimentent les neurones.

Des chercheurs ont développé un modèle mathématique expliquant en quoi les plaques amyloides seraient toxiques. Leur modèle a fait l'objet d'une pré-publication sur MedRxiv.

Le problème ne serait pas leur formation, mais plutôt leur destruction qui serait toxique. les scientifiques ont supposé que l'absorption cellulaire d'amyloïde est un facteur important définissant la toxicité de l'Aβ in vivo. Leur hypothèse est qu'en raison de l'intensité du renouvellement des protéines, les graines d'agrégation ne se forment pas dans le liquide interstitiel, mais apparaissent d'abord de manière intracellulaire à partir de l'Aβ endocytosé. Après avoir été exocytosées, ces graines se développent en agrégeant l'Aβ soluble et deviennent des plaques séniles.. Des idées similaires sont proposées depuis une vingtaine d'années. enter image description here Source Merrill Sherman/Quanta Magazine

Dans ce modèle, les dommages cytotoxiques sont proportionnels à l'absorption cellulaire d'Aβ, tandis que la probabilité d'un diagnostic de maladie d'Alzheimer est définie par la cytotoxicité Aβ accumulée pendant la durée de la maladie.

Après absorption, Aβ est concentré par voie intralysosomale, favorisant la formation de germes de fibrillation à l'intérieur des cellules. Ces graines ne peuvent pas être digérées et sont soit accumulées de manière intracellulaire, soit exocytosées.

Aβ commence à s'agréger sur les graines extracellulaires et, par conséquent, sa concentration diminue dans le liquide interstitiel.

La dépendance de la toxicité et de l'agrégation de l'Aβ sur le même processus - l'absorption cellulaire de l'Aβ - explique la corrélation entre le diagnostic de maladie d'Alzheimer et la densité des agrégats amyloïdes dans le cerveau.

Les chercheurs ont testé leur modèle à l'aide de données cliniques obtenues auprès de l'Alzheimer's Disease Neuroimaging Initiative (ADNI), qui comprenait des enregistrements de la concentration de bêta-amyloïde dans le liquide céphalo-rachidien (CSF-Aβ42) et de la densité des dépôts de bêta-amyloïde mesurés à l'aide de la tomographie par émission de positrons. (ANIMAUX). Le modèle prédit la probabilité de diagnostic de maladie d'Alzheimer en fonction du CSF-Aβ42 et de la TEP et ajuste les données expérimentales au niveau de confiance de 95 %.

Cette étude montre que les données cliniques existantes permettent d'inférer des paramètres cinétiques décrivant le renouvellement de la bêta-amyloïde et la progression de la maladie. Chaque combinaison de valeurs CSF-Aβ42 et PET peut être utilisée pour calculer le taux d'absorption cellulaire de l'individu, la durée effective de la maladie et la toxicité accumulée. Ce modèle serait le premier à expliquer mécaniquement la corrélation négative entre la concentration d'Aβ42 dans le LCR et la probabilité d'un diagnostic de maladie d'Alzheimer.

We know that in ALS it is important to maintain the BMI at 27, which is incredibly difficult practically for patients but also psychologically for caregivers who do not understand that becoming mildly obese can be beneficial. This is especially true if the patient previously had a very healthy weight profile.

Several publications hint at similar benefits of weight gain in Parkinson's disease. Early weight loss is a typical symptom in Parkinson's disease patients and this may be accompanied by cognitive decline.

This observational study used data from the Parkinson’s Progression Markers Initiative cohort. The patients underwent annual non-motor assessments covering neuropsychiatric, sleep-related, and autonomic symptoms for up to 8 years of follow-up. Cognitive function was measured using the Montreal Cognitive Assessment (MoCA) and detailed neuropsychological testing. Linear mixed-effects models were applied to investigate the association of early weight change with longitudinal evolution of cognitive and other non-motor symptoms.

358 individuals with Parkinson's disease who had just received a diagnosis but had not yet begun taking medication for the condition were the subject of the study. They were 61 years old on average. 174 individuals free of Parkinson's disease were compared to them. While observational studies generally produce results similar to those conducted as randomized controlled trials, an observational study draws inferences from a sample to a population where the independent variable is not under the control of the researcher so it is possible there are some hidden bias in such studies.

A change in body weight of more than 3% during the study's first year was deemed to be either weight gain or loss. 98 individuals lost weight, 59 individuals gained weight, and 201 individuals maintained their weight.

Prior to the study's start and then once a year for up to eight years, participants took a test of their thinking abilities. They also looked for other non-motor symptoms, like anxiety, depression, and difficulty falling asleep, that Parkinson's patients might experience.

When compared to Parkinson's patients who maintained their weight, those who lost weight saw a decline in their scores annually. Fluency skills, showed the greatest decline in thinking abilities.

Conversely, Parkinson's patients who gained weight saw a slower decline in their processing speed test scores than those who kept their weight.

Weight change did not correlate with any other nonmotor symptoms.

There was no connection between weight change and results on the thinking skills test among individuals without Parkinson's disease.

According to Jun, "These results highlight the potential significance of weight management in the early stages of Parkinson's disease." If taking measures to prevent weight loss can slow cognitive deterioration in people with Parkinson's disease, more research is required to confirm this. ".

This observational study only demonstrates an association; it does not establish a causal relationship between weight changes and changes in thinking abilities. Yet diet change in order to gain weigth in a healthy manner is something that patients and carers can easily do at home.

Association of Early Weight Change With Cognitive Decline in Patients With Parkinson Disease

Body Mass Index, Abdominal Adiposity, and Incidence of Parkinson Disease in French Women From the E3N Cohort Study

Initial BMI and Weight Loss over Time Predict Mortality in Parkinson Disease

I dislike publishing about CRISPR technology or about ALS mice models yet the results in this article, if replicated, are amazing. It means that for 5% of ALS patients, there is an hope that a future drug might extend their survival by more than 12 years!

Although CRISPR-based gene-editing technology has received unreasonable hype, it represents a promising approach to providing genetic therapies for inherited disorders, including amyotrophic lateral sclerosis.

Toxic gain-of-function superoxide dismutase 1 (SOD1) mutations are responsible for approximatively 20% of familial Amyotrophic Lateral Sclerosis cases. This means 5% of all ALS cases.

Current clinical strategies to treat SOD1-Amyotrophic Lateral Sclerosis are designed to lower SOD1 levels, notably throught the use of ASOs. On October 17, 2021, a presentation of the phase 3 VALOR study indicating that Biogen's Tofersen did not demonstrate statistical significance in the primary measure of disease progression.

On June 3, 2022, additional 12-month open label extension data was presented, demonstrating a some positive effect for participants who received Tofersen early in their disease.

In this new publication, authors from Biogen used an AAV-gene therapy to deliver CRISPR guide RNAs designed to disrupt the human SOD1 transgene in SOD1 mice (huSOD1). Those transgenic mice express the human SOD1 gene, not the murine gene, so their disease is closer to the human disease than in other SOD1 mice models.

This intrathecal injection into neonatal huSOD1 mice caused robust and sustained mutant huSOD1 protein reduction in the cortex and spinal cord, and restored motor function.

Neonatal treatment also reduced spinal motor neuron loss, denervation at neuromuscular junction and muscle atrophy, diminished axonal damage and preserved compound muscle action potential throughout the lifespan of treated mice. SOD1 treated mice achieved significant disease-free survival, extending lifespan by more than 110 days. 110 days for a mice that can live 2 years is equivalent to 12 years for humans!

Yet this is not realistic for human patients, as even if we can detect patients at risk at neonatal stage, most of them will not develop ALS, and furthermore reducing their SOD1 level means they will be susceptible to the very diseases that this therapy tries to attenuate.

Importantly, a one-time intrathecal or intravenous injection of this therapy, immediately before symptom onset, also extended lifespan by at least 170 days.

The authors' approach also uncovered key parameters that resulted in improved efficacy compared to similar approaches and can also serve to accelerate drug target validation.

One question I have is why these technologies are not used to convert the mutated SOD1 gene into the normal wild-type SOD1 gene. This is important because living with reduced levels of SOD1 puts the patient at risk for neurodegeneration!

Let's hope this will lead to a full drug development program at Biogen. Yet there will be internal competition with the team in charge of Torfersen.

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Mouse models of neurodegenerative diseases have proven inadequate in translation into clinical research. There are several reasons, one of them is that in these animals the diseases progress at an extreme speed and the other is that mice and primates have quite different nervous systems. For example, in some cases, higher primates have direct connections between upper and lower motor neurons, whereas mice always have interneurons between upper and lower motor neurons. enter image description here Source: Xocolatl via Wikipedia

The common marmoset, Callithrix jacchus, is increasingly being used as the preferred nonhuman primate model in biomedical research. Marmosets share several physiological and biological similarities with humans, and their use in research programs advances knowledge of several fields.

Mice diseases models are highly unrealistic, when transposed to humans it would mean that degeneration would appear at 20 years old! Due to the relatively shorter life span of 15 to 16 years and the smaller body size, studies conducted in marmosets may be more realistic. Since neurodegeneration is prevalent in aging humans, there has been much interest in the neurodegeneration of aging marmosets.

Their unique characteristics, such as small size, high fecundity, and rapid growth, offer additional advances in laboratory settings. This article reviews the developments in experimental disease models using marmosets based on authors' experience at the Central Institute for Experimental Animals in Japan.

The development of genetically modified marmoset models using advanced genome editing technology attracts researchers, particularly in neuroscience-related fields. In parallel, various marmoset models of human diseases induced by surgery or drug administration have contributed to preclinical and translational studies.

Among these are models:

  • for Parkinson's disease, induced by 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine;
  • spinal cord injury models;
  • a model for type 1 diabetes, induced by the combination of partial pancreatectomy and streptozotocin administration;
  • a hepatic fibrosis model induced by thioacetamides.

The development of these models has been supported by refinements in veterinary care, such as the careful design of anesthetic protocols and better understanding of pathogenic microorganisms. In the second part of this review, the authors present a compilation of practices currently in use at at the Central Institute for Experimental Animals that provide optimal animal care and enable safe experimentation.

Indeed, most researchers will be reluctant to use marmosets. Diseases of mice models appear within a month, so the cost is low. No university lab would spend years before the results are available. If only for one thing, it would considerably slow down the pace of publications that condition the careers of scientists.

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