The current paper is about an untested hypothesis. Scientists have proposed thousands of assumptions about the etiology of ALS, and the same is true for many other diseases. Single-authored papers are often dismissed, as are papers that make wild hypotheses without trying to test them. I mention this paper because the single author is a remarkable scientist in the field, not one of the countless hacks who write a paper on ALS today with very little knowledge of the disease and will never write about it again.

Another reason might be because it may have some relation with a drug developed by Richard B. Silverman, and P. Hande Ozdinler at Northwestern University. AKAVA Therapeutics, started last year by Silverman, is carrying out studies of the drug AKV9 (ex NU-9).

This article discusses the possible relationship between sleep, the glymphatic system, and neurodegenerative diseases. It suggests that sleep issues might exacerbate ALS disease progression by impairing the brain's waste-clearance mechanisms and compromising neuronal health, but it does not describe any experiment. It also tells that neuron health is diminished when the organism is sleep-deprived, in particular neurons experience dendritic spine loss.

Sleep is crucial for brain health because the clearance of metabolic waste and the remodeling of synapses happens during sleep. Many ALS and Parkinson's patients experience sleep disturbances. Disrupted sleep patterns, especially those associated with conditions like sleep apnea, a condition where upper airways collapse during sleep, can lead to impaired glymphatic function. The author equals poor glymphatic function with accumulation of agglomerates of misfolded proteins in cellular cytosol. I am not sure there is any evidence of this relation.

The glymphatic system is responsible for clearing waste products from the brain, primarily during sleep. It is facilitated by cerebrospinal fluid (CSF) circulation. During sleep, the glymphatic system operates optimally, removing waste products from the brain. Impaired glymphatic clearance, especially when sleep is disrupted, might be a significant contributor to protein buildup and possibly subsequent neurodegeneration.

Evidence from studies shows a faster CSF clearance during sleep, suggesting that adequate sleep is crucial for maintaining brain health. Dysfunction of this system can contribute to the accumulation of toxic proteins, such as amyloid-beta and tau, associated with neurodegenerative diseases. Yet this clearance happens in the periphery of the brain, so it's hard to see how a good clearance would improve the health of those neurons that are deep inside the brain.

Early signs of neurodegeneration in ALS include the loss of dendritic spines. A dendritic spine is a small membrane protrusion from a neuron's dendrite that typically receives input from a single axon at the synapse. Motor neurons in the spinal cord, for example, can have a dense arrangement of dendritic spines in certain regions, as these neurons need to process a large number of excitatory and inhibitory signals to regulate muscle activity effectively. Sleep plays a vital role in spine pruning and remodeling, ensuring healthy neuronal connectivity.

Synaptic connections, especially dendritic spines, are dynamic and undergo constant remodeling, particularly during sleep. This process is crucial for maintaining neuronal network stability and function. Sleep deprivation or sleep apnea disrupts spine pruning, leading to excessive or unhealthy connections, which stresses neurons and hampers brain connectivity. Experiments show that even brief sleep deprivation reduces spine elimination, resulting in abnormal spine density and neuronal hyperactivity in brain areas like the hippocampus. This disruption may have a profound impact on memory and cognitive function.

Therefore investigating the relationship between sleep, glymphatic function, and biomarkers in CSF could lead to earlier diagnosis and more effective disease monitoring.

Yet, sleep is not routinely assessed in clinical diagnostics for neurodegeneration. Integrating sleep studies into patient assessments could enhance diagnostic precision and enable targeted interventions. Moreover, understanding the molecular changes in CSF associated with sleep problems could provide valuable biomarkers for monitoring disease progression. There’s potential for developing therapies focused on improving sleep quality, as addressing hypoxia and improving glymphatic function might reduce protein buildup and protect against neuronal damage.

A couple of days ago, I complained about the lack of publications on ALS metabolism in skeletal muscles, which represent only a tiny fraction of the huge number of ALS (mostly useless) publications.

Here is one article describing the evolution of the masseter muscle, one of the muscles of mastication, during the disease course in a SOD1 mice model. Why study the masseter muscle in ALS? Because it is one of the few skeletal muscles that is not affected by the disease. The authors observed that, despite a decrease in limb motor functions, the feeding function of these mice was preserved until the late stages of the disease. Remarkably, the masseter muscle showed no reduction in muscle volume, wet weight, or muscle fiber cross-sectional area. Furthermore, no changes were observed in muscle fiber types, indicating a possible resistance of the masseter muscle to ALS-induced impairment. A potential reason for the lack of atrophy in the masseter muscle could be its higher number of muscle satellite cells compared to that of the gastrocnemius muscle. This abundance may promote the maintenance of muscle fiber nuclei, thereby contributing to muscle tissue regeneration.

What they are saying in the background is: * Something is stressing the skeletal muscles in ALS, which looks quite a reasonable assumption to me. * Maybe it would be possible to design an ALS therapy targeting muscle satellite cells. This looks less likely to me.

While the authors promote the idea that the disease may, at least partly, start in muscles, I can't help myself thinking that maybe the reason it is preserved is simply that this muscle (as for eye movements) is activated by the trigeminal nerve which is usually preserved in ALS.

It seems to me that in spinal ALS, the longer motoneurones fail early (hands, feet) and the shorter ones survive longer. Indeed in bulbar ALS, the situation is reversed, but ALS mice models attempt only to model spinal ALS. So in my opinion, the authors should have considered that the lack of wasting of mice's masseter muscle may stem from a still functioning trigeminal nerve.

We previously reported that Memantine was found ineffective in an ALS clinical trial for the fifth time. Several articles about persistent failure in ALS clinical trials appeared in the last issue of The Lancet Journal.

Trial designs for motor neuron disease in the 21st century

A new era of drug discovery for amyotrophic lateral sclerosis

Scientists attribute Memantine's (and the many other drugs that were tried) lack of efficacy to the "complexity of the pathophysiological mechanisms."

In simpler words, they have no idea why it failed, yet it was tested for the fifth time in ALS, so in a rational world, they should, on the contrary, have expected it to fail. In addition, no pre-clinical studies have shown any special value of Memantine in ALS.

And it's not only about Memantine, hundreds of drugs with dozens of different mechanisms of action have been trialed in ALS, as well as in other neurodegenerative diseases. For example, in the same journal issue, there are the results of the ROCK-ALS phase II clinical trial which has a purported mechanism of action entirely different from the usual suspects (glutamate excitotoxicity, impaired proteostasis, autophagy, and neuroinflammation).

Clearly, scientists know nearly nothing about these diseases, otherwise, they would concentrate their efforts on specific drugs.

It is time to reconsider century-old and unquestioned assumptions about these diseases. What makes ALS patients die? Skeletal muscle wasting which leads to respiratory failure. Efforts should concentrate in this direction. We also know that ALS is not always a death sentence, for example Stephen Hawking lived 76 years and 55 years with the disease. We know that a BMI in the 27 range helps for survivability, yet publications on ALS metabolism in skeletal muscles represent only a tiny fraction of the huge amount of ALS publications. In 2023 there were only 23 publications on this topic, versus 2507 publications on ALS.

Why this situation? Laboratories and CRO are not organized to study whole-body mechanisms in large mammals. It would cost a lot, universities and biotech prefer to work on small rodents or even worse on immortalized cell lines.

There is also the question of the time span, most studies are conducted within 6 months, or even two months, because students are used as a cheap workforce. You can't detect any statistically meaningful clinical change in neurodegenerative diseases in two months.

Studies must last at least one year and use large mammals, if possible mammals which have a corticospinal tract similar to ours, with direct connection between upper and lower motor neurons for fine control of skeletal muscles such as in hands..

A recent publication poses a question that has become increasingly pressing in the face of numerous unsuccessful trials for the treatment of amyotrophic lateral sclerosis (ALS), also known as Lou Gehrig's disease. "Why is the treatment and management of amyotrophic lateral sclerosis so difficult?"

The article suggests that when a phase II clinical trial succeeds while its phase III trial fails, it's because they have a different profile of patient population.

The authors argue that because they recruit fewer patients, the characteristics of patients enrolled in phase II trials are more homogeneous than those in phase III trials, which aim to recruit hundreds of participants. This is contrary to what statistics teaches.

I also find this hypothesis unlikely, given the constraints on patient recruitment and the sensitivity of principal investigators to the fragility of ALS diagnoses and the variability of patient phenotypes.

The authors also propose specifically that edaravone and Relyvrio (AMX0035) phase II studies yielded better results than their phase III studies. However, the phase II trials for these two drugs did not provide clear evidence of a therapeutic benefit, only showing marginal improvements in the ALSFR-R criterion, which is known to be influenced by non-medical factors such as access to better equipment. Relyvrio/AMX0035 in particuliar benefited from the intense pressure by ALS organisations. It should be noted that one of these organisations would have financially greatly benefited in a market authorization.

Furthermore, post-hoc analyses, which are often favored by drug manufacturers, are statistically unreliable. It is too easy to select favorable results from a small sample and attribute them to a common characteristic, which is why large-scale clinical trials are necessary.

In my opinion, it is time to recognize that we are on the wrong track in relying on molecular biology experts to develop treatments for neurodegenerative diseases. The current pharmacological approach is heavily influenced by our understanding of communicable diseases, where identifying the pathogen and suppressing it can lead to recovery. Molecular biology is conceptually far removed from medicine, as it ignores cellular mechanisms, tissue-level interactions, physiological systems, and the complex interplay between organs.

I believe that we would be better served by acknowledging that neurodegenerative diseases are the result of a complex interplay of factors, including a patient's medical history, lifestyle, and environmental exposures. Each patient over the age of 50 likely has a unique combination of age-related neurological diseases, with some having a history of strokes, high-intensity sports, environmental toxins, or head trauma. Some may have also had a history of substance abuse or smoking.

In summary, I believe that neurodegenerative diseases are the result of a complex interplay of factors in a patient's history, rather than a single molecular event. Therefore, funding for most molecular biology efforts should be gradually shifted to regenerative medicine, which addresses the restoration of damaged tissues and organs.

Vitamin B12 injections are sometimes proposed by neurologists to ALS patients. Patients often decide to start the treatment because of the perceived low risk of side effects and the potential benefit to their quality of life. It is typically shipped as a sealed frozen package with several vials containing a 25-mg injectable dose. Patients are typically advised to inject 50 mg of B12 daily, which is 100 times the daily recommended dose. Usually, ALS patients recognize some benefits from the injections, such as increased energy, reduced fatigue, and improved balance. However, the high cost of injection, lack of insurance coverage, and inconsistent syringes are significant challenges faced by patients.

High-dose methylcobalamin treatment involves intramuscular injection of 25mg to 50mg of methylcobalamin twice a week, which is 50 to 100 times the dose of existing drug injections.

A phase II/III clinical trial for ALS patients was started in Japan, and the results were published in 2019. 373 ALS patients who had been onset for less than 3 years were recruited for a methylcobalamin clinical trial with three branches where patients have daily administrated 50mg, 25mg, or a placebo. It was conducted over 3.5 years. As a result, the methylcobalamin group showed a tendency to show better results in terms of the decline in ALSFRS-R, but the difference was not significant, and overall efficacy could not be demonstrated to Japanese authorities.

However, when a subanalysis was conducted only for patients who were enrolled within 12 months of onset (close to diagnostic), the 50 mg group, the 25 mg group, and the placebo group showed less decline in ALSFRS-R and a longer time to the primary endpoint. Post-analysis is frowned on because in small groups there are always statistical flukes and it's easy to cherry-pick some of these to prove whatever. But here the size of the trial was a bit larger than usual so there was more confidence in the findings.

The difference in decline in ALSFRS-R between the 50 mg group and the placebo group was statistically significant. Based on these results, a clinical trial (JETALS trial) was conducted in 2017 to confirm the reproducibility of the subanalysis, and the results were announced in May 2022. Results were reported on this blog.

In the JETALS study, 130 ALS patients within 12 months of onset were recruited and assigned to a twice-weekly 50 mg group or a placebo group. As a result, the reduction in ALSFRS-R score at 16 weeks was −2.66 in the methylcobalamin 50 mg group and −4.63 in the placebo group, which was significantly better in the active drug group.

There was no difference in side effects of the drug between placebo or methylcobalamin-treated participants. There was a marked reduction in serum homocysteine levels. Homocysteine is neurotoxic and has been associated with ALS cases but also with Alzheimer's and Parkinson's diseases. It may be a byproduct of methionine metabolism and there are a few studies that discuss the influence of diet on homocysteine via methionine in diet. High levels of methionine can be found in eggs, meat, and fish; sesame seeds, Brazil nuts.

These results are better than most previous drug results in ALS, but indeed it does not stop the disease progression. Based on these results, it was announced in January 2024 that a new drug application for methylcobalamin had been submitted in Japan.

Eisai Co. announced last week that it has obtained manufacturing and marketing authorization approval for amyotrophic lateral sclerosis (ALS) treatment “Rozebalamin® for Injection 25 mg” (mecobalamin) in Japan as a treatment for slowing progression of functional impairment in amyotrophic lateral sclerosis.

It should be noted that although there were statistically significant reductions in ALSFRS-R, other measures such as muscle strength, forced vital capacity, and the ALSAQ-40 total score, were not changed. This is a bit confusing as ALSFRS-R and ALSAQ-40 while not identical are similar enough, ALSAQ-40 adds a well-being dimension to the usual questionnaire. How could ALSFRS-R show an improvement if it's not reflected in ALSAQ-40?

As UK's Alsa-Mnd remarks, as the drug was only tested on participants early in the disease process, it is unclear if the treatment would be appropriate for participants with more advanced diseases.

In addition, Alsa-Mnd says it may not have been a truly blinded trial as methylcobalamin treatment results in a marked change in urine color which could mean that participants may have known whether they were receiving a placebo or methylcobalamin, and that could have influenced results (including a potential “nocebo” effect). This is supported by the fact that the placebo group appeared to worsen their rate of disease progression once the trial commenced.

It's possible that regulation agencies are afraid of the considerable political pressure from patient organizations who accuse them of being inactive, and that as for Alzheimer's disease and (temporarily) for AMX0035/Relyvrio they prefer to authorize new drugs even if they are ineffective, instead of waiting decades for an effective drug.

If our readers do not belong to academic or pharmaceutical circles, they certainly think that rationality guides the choice of drugs tested in clinical trials. They also certainly think a drug is tested in a clinical trial only if pre-clinical works show a strong signal of efficacy in the targeted disease.

We live in a human, imperfect world, but sometimes it borders on stupidity. Let's discuss the case of memantine. It's a drug that has been known for 60 years. It was bizarrely applied to a large variety of mostly unrelated diseases, like diabetes, OCD, autism, depression, Parkinson's, and Alzheimer's diseases as well as COVID-19.

In all these cases it had consistently shown it was ineffective. If one is especially interested in ALS, it's interesting to note that there is no published preclinical work on memantine in ALS.

Yet there were 5 clinical trials of memantine in ALS!

The latest had just published its results/ Two of them were phase III clinical trials, the others were phase II, so it cost probably $50M overall.

What is behind this strange behavior? Are we so irrational as a species to make repetitively so impressively huge mistakes?

One layperson may be troubled to learn that in ALS only, there were more than 500 unsuccessful clinical trials.

Every week academics are claiming to have made breakthroughs in neurodegenerative diseases. Obviously, most if not all of these claims were wrong.

It seems that academic and pharmaceutical scientists are just throwing spaghetti at the wall to see if it sticks. Most of them are paid well at the end of the month for doing crappy work, so why bother working harder?

Jean-Pierre Le Rouzic (my email is at the bottom of the page)

Ceci est un post très court à propos d'un développement d'une thérapie dans un lointain futur concernant les blessures voire le sectionnement de la moelle spinale, mais sur ce blog c’est ce que cela pourrait impliquer pour les patients ayant une SLA qui nous importe. Si dans la SLA/Maladie de Charcot les neurones moteurs meurent (ce dont je ne suis pas sûr 1), alors la seule solution est de les remplacer. Pour l’instant c’est impossible pour au moins deux raisons : 1. Cela implique de recréer le faisceau cortico-spinal à l’intérieur de la colonne vertébrale. 2. Il n’est pas envisageable actuellement d’accéder simultanément à l’intérieur des multiples vertèbres qui composent la colonne vertébrale.

Un progrès concernant le premier point vient d’être accompli. Il s’agit de recréer in-vitro un neurone moteur et de diriger la croissance de son axone dans une direction préférentielle. C’est un progrès conséquent de l’état de l’art. Par contre ce neurone moteur ne s’est pas connecté via des synapses à d’autres cellules comme d’autres neurones moteurs, des interneurones ou des cellules de fibres musculaires. Il ne s’agit que d’un seul neurone, très court, pas des milliers de neurones moteurs long jusqu'à un mètre, qui composent la moelle spinale. De plus des neurones qui ne seraient pas accompagnés par une multitude de cellules non-neuronales (astrocytes, oligodendrocytes, etc..), mourraient rapidement. Enfin dans la moelle spinale il n’y a pas que des neurones moteurs.

On est donc loin d’un remplacement des neurones moteurs de la moelle spinale, mais c’est un progrès intéressant dans cette direction.

(1) Je crois qu'ils sont plutôt dans une sorte de stase cellulaire qu'on appelle "réponse au stress cellulaire". En tout cas plusieurs médicaments sont actuellement en cours de développement qui adressent ce stress cellulaire. Il y a aussi des cas de rémissions, au moins temporaires, qui sont inexplicables si les neurones moteurs meurent.

S'il y a quelque chose de controversé à propos de la SLA (maladie de Charcot/Lou Gehrig), c'est la pratique d'une activité physique comme moyen de ralentir la progression de la maladie. Il y a quantité de témoignages contradictoires sur Internet. Cette confusion est engendrée par de multiples facteurs.

Le premier c'est peut-être que les médecins comme Charcot ont eu tort d'appeler d'un nom commun "SLA", un ensemble de maladies aux symptômes similaires. Au fur et à mesure de la progression de nos connaissances, et notamment face à l'absence de moyen de diagnostic indiscutable et après la découverte de multiples problèmes biologiques menant à ce type de maladie (mutations dans SOD1, FUS, C9orf72, TDP-43), agrégations de protéines malformés, diversité de phénotypes (spinal, bulbaire), durée de vie après diagnostic allant de 6 mois à 20 ans, les scientifiques auraient pu réviser cette catégorisation faite il y a 150 ans. Il y a aussi quelque chose de fondamentalement contre-intuitif, voire obscène, dans l'idée que pour ralentir la progression d'une maladie caractérisée principalement par la perte intense de masse musculaire, il faudrait faire davantage d’exercice physique. Pourtant on sait que chez des sujets sains l'absence de mouvement pendant quelques jours à la suite d'un alitement, fait fondre spectaculairement la masse musculaire et qu'il faut des semaines pour retrouver le niveau antérieur de masse musculaire.

Plusieurs études ont documenté une incidence plus élevée et un diagnostic de la SLA à un âge plus précoce chez les athlètes de haut niveau. Plusieurs études ont suggéré que les personnes ayant un mode de vie actif et une masse grasse corporelle réduite ont un risque accru de développer la SLA. Il semble avéré qu'une activité physique fréquente et intense favorise l'apparition de la SLA, en particulier chez les patients ayant un contexte génotypique prédisposant comme l’expansion de C9ORF72.

Des études récentes ont tenté de répondre à cette question, pour comprendre si l’activité physique pouvait être considérée comme un facteur dans l’étiologie de la SLA. enter link description here

Un entraînement régulier d'intensité modérée réduit le stress oxydatif, diminue les niveaux de marqueurs inflammatoires chez les personnes âgées, aide à préserver la forme cardiovasculaire et la fonction cérébrale et protège les individus des effets négatifs du stress sur le vieillissement cellulaire.

Cependant, un entraînement physique intense génère des niveaux élevés de molécules réactives de l'oxygène (ROS) qui sont connues pour provoquer un stress oxydatif.

Les mitochondries sont le principal site de production de ROS, tout simplement parce que les mitochondries sont les organelles qui oxydent le glucose (il y a d'autres possibilités comme les lipides) qui a pu rentrer dans la cellule quand les récepteurs de celle-ci ont détecté la présence d'insuline dans le milieu intercellulaire. Le résultat de cette oxydation du glucose est une molécule nommée ATP, qui est une sorte de réservoir d'énergie qui est utilisé pour les différents processus interne à la cellule. Cette oxydation du glucose est un phénomène complexe qui produit des déchets dangereux, les fameuses espèces réactives de l'oxygène ROS, quand ils ne sont pas éliminés rapidement.

L'altération du métabolisme représente un événement précoce dans la SLA, il entraine une perte de poids et une masse grasse réduite, une altération de la gestion du glucose et des lipides et une augmentation des dépenses énergétiques au repos.

En conséquence, une teneur accrue en lipides alimentaires offre une neuroprotection et prolonge la survie, tandis que la restriction de l'apport calorique exacerbe les symptômes moteurs de la SLA.

Il a été largement démontré que la survie est meilleure chez les personnes ayant un IMC de l'ordre de 27 (surpoids). Il y a d'ailleurs sur ce site un calculateur de calorie pour personnes ayant la SLA:enter link description here

Bien entendu c'est un challenge extrême pour les malades de la SLA de manger davantage: Manque d'appétit, problèmes de déglutition, choix et attrait de nourritures de qualité alors que celles-ci doivent souvent être mixées.

Le passage du métabolisme vers l'utilisation des lipides précède la dénervation de la jonction neuromusculaire dans les modèles murins. Il est remarquable que l'administration de dichloroacétate (DCA), un acide organique halogéné, force le métabolisme vers l'oxydation du glucose, permet ainsi de contrebalancer le déséquilibre métabolique. https://pubmed.ncbi.nlm.nih.gov/22509356/

Au vu de ces résultats, on s'attend à ce que des exercices physiques spécifiques déplacent le métabolisme énergétique musculaire soit vers un modèle lipidique, en cas d'exercice de faible intensité, soit vers un métabolisme glycolytique, en cas d'exercice de haute intensité. Bien entendu un exercice de haute intensité est le plus souvent impossible pour un malade de la SLA, ce qui fait qu’une solution médicamenteuse serait un préalable à la tenue d’exercise.

Chez les patients atteints de SLA, divers protocoles d’entraînement ont été proposés pour évaluer leurs effets bénéfiques potentiels.

Plusieurs protocoles d'exercices ont été testés chez des patients atteints de SLA et des modèles murins de la maladie. Outre les effets neuroprotecteurs exercés par toute activité physique, les protocoles basés sur la natation ont montré les résultats les plus positifs chez les souris.

En particulier, le protocole basé sur la natation a entraîné une augmentation remarquable de la durée de vie (chez les souris), et était associé à des changements dans le métabolisme énergétique des muscles squelettiques. Bien que la natation soit suggérée comme un type d'exercice avantageux dans de nombreux troubles neurologiques, son rôle bénéfique n'a pas encore été validé expérimentalement chez les patients atteints de SLA.

Dans l'ensemble, l'entraînement en endurance avec un soutien supplémentaire tel que la ventilation ou le soutien calorique à un IMC de surpoids semble avoir des effets positifs sur la capacité respiratoire, la fonctionnalité et la performance physique chez les patients atteints de SLA.

Ces études indiquent malheureusement que si l’entraînement en résistance augmente la force, la puissance et la vigueur musculaires, cela ne ralentit pas la progression de la maladie.