Leslie P. Weiner, MD proposed in 1980 that the mechanism of motor neuron death is sometimes related to the loss of androgen receptors.


A recently published article brings some substance to his hypothesis.

Weiner based his hypothesis on characteristic of ALS.

  1. Male-to-female ratio. There have been frequent reports of preponderance of male to female patients with ALS. The ratio of 1.5 to 2.5 has been reported. A 1:1 ratio has been calculated for patients over the age of 65.

  2. Age. The average age of ALS patients is 55 to 60 years.

  3. Sparing of neuronal populations. In almost all cases of ALS, the extraocular muscles are not involved. The urinary and anal sphincters are also spared. The neurons of cranial nerves III, IV, and VI and sacral spinal cord motor neurons (S-2) are left intact even in far advanced cases of ALS.

  4. Axonal changes. There are changes in ALS that suggest axonal involvement.

  5. Certain types of axonal injury and axonal repair.

Leslie P. Weiner hypothesis:

  1. Could androgen receptors, and hence, androgens themselves, be important in motor neuron function?
  2. Could the sparing of cranial nerves in ALS be due to the lack of dependence of these neurons on androgens?
  3. Could the role of androgens be important in repair processes following axonal injury?

One could postulate that normal people have insults to their nerves and muscles hundreds of times in a life time. The neuron, with the "anabolic" help of androgen, can repair its axon. In ALS, whether due to toxins, viruses, trauma, or an accelerating "aging" process, androgen receptors are lost and axonal changes result in the death of the motor neuron.

What about dihydrotestosterone in ALS?

Fast forward in 2020, dr Nishit Sawal and colleagues aimed at testing Cerebrospinal fluid (CSF) levels of free testosterone and dihydrotestosterone in 13 ALS patients [7 males, 6 females] and 22 controls [12 males, 10 females].

While testosterone is well known for its role in sexual development, it does not stop here. Androgen including testosterone enhances muscle growth. Testosterone also regulates platelet aggregation in humans. It has been correlated with health deterioration in several neurodegenerative diseases, including Alzheimer.

Adult testosterone effects are more clearly demonstrable in males than in females, but are likely important to both sexes. Some of these effects may decline as testosterone levels might decrease in the later decades of adult life.

Androgens affect the cerebral vasculature and may contribute to sex differences in cerebrovascular diseases. Men are at a greater risk for stroke and vascular contributions to cognitive impairment and dementia (VCID) compared to women throughout much of the lifespan. In men, low androgen levels have been linked to metabolic and cardiovascular diseases including hypertension, diabetes, hyperlipidemia, and obesity, which greatly increase the risk of stroke and VCID.

Dihydrotestosterone (DHT) is the most potent natural androgen in humans. There has been an increasing interest in this androgen and its role in the development of primary and secondary sexual characteristics as well as its potential roles in diseases ranging from prostate and breast cancer to Alzheimer's disease. Dihydrotestosterone is created when testosterone is converted into a new form, dihydrotestosterone. About 10% of the testosterone in the bodies of both men and women is converted into dihydrotestosterone in adults, with a much higher amount in puberty. This may be why it is so closely related to the triggering of puberty. The dihydrotestosterone hormone is much more powerful than testosterone.

What the scientists found

What they found was that CSF free testosterone levels did not show any significant differences but CSF dihydrotestosterone levels were significantly decreased in all male and female ALS patients.

What did the scientists conclude?

They concluded that dihydrotestosterone is probably integral to survival of motor neurons. In patients predisposed to develop ALS, there is possibly a sort of “testosterone resistance” at level of blood–brain barrier [BBB] existing right from birth and is likely the result of dysfunctional transport protein involved in testosterone transfer across the BBB. In these patients, lesser amount of testosterone is able to breach the BBB and enter the central neural axis.

Lesser amount of testosterone is available to dihydrotestosterone and so fewer dihydrotestosterone is generated. There is inadequate negative feedback suppression of Luteinizing hormone at the level of anterior pituitary by dihydrotestosterone. As a result of higher Luteinizing hormone levels, testosterone levels rise in the peripheral testosterone fraction [the fraction outside the BBB] and this explains the various physical attributes of ALS patients like lower Ratio of the index and ring finger lengths (2D:4D ratio), increased incidence of early onset alopecia etc.

This deficiency of dihydrotestosterone leads to motor neuron death causing ALS.


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.

La maladie d'Alzheimer est une maladie neurodégénérative chronique qui commence généralement lentement et accélère progressivement. Bien qu'elle soit variable, l'espérance de vie typique après le diagnostic est de trois à neuf ans.

enter image description here Source Alzforum

Les deux principales hypothèses sur l’origine de cette maladie, affirment que des quantités anormales de protéines amyloïdes ou encore de protéines tau s’agglomèrent dans le cerveau. Les plaques issues de l’agglomération de protéines, entraîneraient une perte progressive de la fonction cérébrale.

On ne sait pas pourquoi ces dysfonctionnements protéiques se produisent. De nombreux essais cliniques ayant pour but de réduire ces plaques, n’ont jamais réussi à améliorer la condition des patients, aussi les scientifiques se tournent petit à petit vers des hypothèses concurrentes.

D’après une nouvelle étude publiée le 12 Octobre 2020 dans le Journal of Neuroscience, au cours de la maladie d'Alzheimer une altération du flux sanguin vers les régions du cerveau coïncide avec l'accumulation de protéines tau et β amyloïde. Cette relation se renforce à mesure que la cognition diminue. Les chercheurs ont aussi testé l’hypothèse selon laquelle un mauvais fonctionnement de la barrière hémato-encéphalique peut être impliqué et leurs résultats semblent la confirmer. Albrecht et ses collègues de la Keck School of Medicine of the University of Southern California ont utilisé l'IRM et la TEP pour comparer le flux sanguin et l'accumulation de protéine tau dans le cerveau des personnes âgées.

Cette corrélation concerne de plus en plus de régions du cerveau au fur et à mesure que la maladie progresse en gravité. Ces résultats suggèrent que le ciblage de la fonction vasculaire pourrait être essentiel pour prévenir et traiter la démence d'Alzheimer.

Dr. Silvia Pozzi, Jean-Pierre Julien and colleagues have designed a second antibody therapy against misplaced TDP-43, the most obvious cellular problem in ALS. enter image description here

2020 has seen several announcements in this area, which could create a vaccine against ALS. Penetrating the cell is a challenge. Promis neurosciences had announced that they designed a peptide (a tiny protein) targeting TDP-43, and JP Julien's lab worked on single chain antibodies. Single chain antibodies are miniaturized antibodies, their size is roughly half of a normal antibody.

Now JP Julien's team now announced that they successfully designed and tested a monoclonal antibody on a mice model of the disease. Some signs that they have hope it may progress towards clinical trials is that they tested several administration modes and applied for a patent (US 15/532,909).

This is great news and a further step toward a vaccine, as monoclonal antibodies production is well controlled.


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.

A hypothesis describing a mechanism leading to Alzheimer's disease.

Scientists in an interdisciplinary team, have developed a hypothesis that the disease begins when we ingest excess fructose, this phenomenon would be accentuated if there is concomitant consumption of salt and /or alcohol. This excess fructose induces behavioral and metabolic changes, which ultimately lead to Alhzeimer's disease.

The study was published in Frontiers in Aging Neuroscience, it brought together an interdisciplinary team of neurologists, neuroscientists and experts on sugar metabolism

Behavioral and metabolic changes

In the wild, starving animals activate behavioral and metabolic changes to aid their survival once fat stores are depleted. This includes the development of foraging behavior, reduced energy production, and the development of insulin resistance which reduces the uptake of glucose into muscle, thereby promoting preferential uptake by the brain (Koffler and Kisch, 1996; Cahill, 2006).

Studies in humans have largely confirmed these results. The administration of fructose has unique effects on the attention and reward centers, resulting in more hunger and desire for sugary foods than glucose and which is linked to reduced cortical activity (Purnell et al., 2011).

In addition to stimulating hunger, thirst and the search for food, fructose increases the storage of fats, including in the liver, blood (triglycerides) and adipose tissue, thus providing stored energy as well as metabolic water when needed (Johnson et al., 2016).

Deleterious effects of uric acid. Uric acid, generated by fructose, increases blood pressure responses by reducing endothelial nitric oxide, stimulating oxidative stress, and activating the renin-angiotensin system. There is also a very active stimulation of innate immunity, probably mediated by uric acid. These are all protective systems to help survive extreme conditions like famine.

But it is speculated that if it lasts too long, chronic mitochondrial oxidative stress results in impaired mitophagy with the buildup of damaged mitochondria and fewer functioning mitochondria (Shefa et al., 2019), thus affecting overall energy production. and metabolism and resulting in increased dependence on glycolysis.

Generation of fructose in the body Certain foods that do not contain fructose also activate aldose reductase (AR) and stimulate endogenous fructose production, including high glycemic carbohydrates, salty foods, and alcohol (Lanaspa et al., 2013, 2018 ; Wang et al., 2020).

Aldose reductase is expressed in neurons, including the hippocampus (Picklo et al., 2001; Hwang et al., 2017). The activation of aldose reductase leading to the generation of fructose has been shown in the brain after dehydration in rats (Song et al., 2017) as well as after glucose loading in humans (Hwang et al. , 2017). Importantly, there is evidence of endogenous fructose production in patients with Alzheimer's disease, with intracerebral sorbitol and fructose levels 3-5 times higher than normal (Xu et al., 2016) .

Conclusion In one of the scenarios described by Johnson and colleagues, glucose hypometabolism increases oxidative stress and induces progressive loss of mitochondria, ultimately leading to neuronal dysfunction and death. In this scenario, the amyloid plaques and neurofibrillary tangles are part of the inflammatory response and participate in the injury, but are not the central factors of the disease.


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.

Une hypothèse décrivant un mécanisme aboutissant à la maladie d’Alzheimer.

Des scientifiques dans une équipe interdisciplinaire, ont développé une hypothèse selon laquelle la maladie commence lorsque nous ingérons un excès de fructose, ce phénomène serait accentué s’il y a une consommation concomitante de sel et/ou d’alcool. Cet excès de fructose induit des changements comportementaux et métaboliques, qui à terme induisent la maladie d’Alhzeimer.

L'étude a été publiée dans les Frontiers in Aging Neuroscience, elle a réuni une équipe interdisciplinaire de neurologues, de neuroscientifiques et d'experts sur le métabolisme du sucre

Changements comportementaux et métaboliques

Dans la nature, les animaux qui meurent de faim activent des changements comportementaux et métaboliques pour favoriser leur survie une fois que les réserves de graisse sont épuisées. Cela comprend le développement d’un comportement de recherche de nourriture, une réduction de la production d'énergie et le développement d'une résistance à l'insuline qui réduit l'absorption du glucose dans le muscle, favorisant ainsi l'absorption préférentielle par le cerveau (Koffler et Kisch, 1996; Cahill, 2006).

Pour éviter la famine, les animaux stockent de la graisse en prévision des périodes de pénurie alimentaire, comme avant l'hibernation, la migration sur de longues distances ou la nidification. Une approche utilisée par de nombreux animaux consiste à ingérer des aliments riches en fructose, tels que des fruits et du miel.

Au fil du temps, les animaux développent une résistance à la leptine qui entraîne une consommation excessive de nourriture tout en réduisant l'oxydation des graisses (Shapiro et al., 2008).

Des études chez l'homme ont largement confirmé ces résultats. L'administration de fructose a des effets uniques sur les centres d'attention et de récompense, ce qui entraîne plus de faim et de désir d'aliments sucrés que le glucose et qui est lié à une activité corticale réduite (Purnell et al., 2011).

En plus de stimuler la faim, la soif et la recherche de nourriture, le fructose augmente préférentiellement le stockage des graisses, y compris dans le foie, le sang (triglycérides) et les tissus adipeux, fournissant ainsi de l'énergie stockée ainsi que de l'eau métabolique en cas de besoin (Johnson et al. ., 2016).

Effets délétères de l'acide urique. L'acide urique, généré par le fructose, augmente les réponses de la pression artérielle en réduisant l'oxyde nitrique endothélial, en stimulant le stress oxydatif et en activant le système rénine-angiotensine. Il existe également une stimulation très active de l'immunité innée probablement médiée par l'acide urique. Ce sont tous des systèmes de protection pour aider à survivre dans des conditions extrêmes comme une famine.

Mais il est spéculé que s'il dure trop longtemps, le stress oxydatif mitochondrial chronique entraîne une mitophagie altérée avec l'accumulation de mitochondries endommagées et moins de mitochondries fonctionnelles (Shefa et al., 2019), affectant ainsi la production d'énergie globale et le métabolisme et entraînant une dépendance accrue à la glycolyse.

Génération de fructose dans l'organisme Certains aliments qui ne contiennent pas de fructose activent également l'aldose réductase (AR) et stimulent la production endogène de fructose, y compris les glucides à indice glycémique élevé, les aliments salés et l'alcool (Lanaspa et al., 2013, 2018; Wang et al., 2020).

L'aldose réductase est exprimée dans les neurones, y compris dans l'hippocampe (Picklo et al., 2001; Hwang et al., 2017). L'activation de l’aldose réductase entrainant la génération de fructose a été montrée dans le cerveau après une déshydratation chez le rat (Song et al., 2017) ainsi qu'après une charge en glucose chez l'homme (Hwang et al., 2017). Surtout, il existe des preuves d'une production endogène de fructose chez les patients atteints de la maladie d'Alzheimer, avec des niveaux intracérébraux de sorbitol et de fructose 3 à 5 fois plus élevés que la normale (Xu et al., 2016).

Conclusion Dans l'un des scénarios décrits par Johnson et ses collaborateurs, l'hypométabolisme du glucose augmente le stress oxydatif et induit une perte progressive des mitochondries , conduisant finalement à un dysfonctionnement neuronal et à la mort. Dans ce scénario, les plaques amyloïdes et les enchevêtrements neurofibrillaires font partie de la réponse inflammatoire et participent à la blessure, mais ne sont pas les facteurs centraux de la maladie.

A study which has just been published in the leading neurology journal Brain, indicates that Parkinson's disease is not one but two diseases, starting either in the brain or in the intestines.

These two groups of patients displayed strikingly different profiles on multimodal imaging battery.

These profiles support the existence of a brain-first and body-first subtype of Parkinson’s disease, and furthermore, that premotor rapid eye movement sleep (REM) sleep behaviour disorder is a highly predictive marker of the body-first subtype. enter image description here

Neuropathological autopsy studies of patients with Parkinson’s disease, dementia with Lewy bodies, or incidental Lewy body disease have shown discrepant results.

Heiko Braak’s staging system was derived from a cohort of patients, who were selected based on the presence of Lewy pathology in the dorsal motor nucleus of the vagus, and all these patients conformed to a brainstem predominant type.

Other studies reported that some post-mortem cases do not harbour Lewy pathology in the dorsal motor nucleus of the vagus, and a minority of patients do not follow the Braak staging scheme.

A pathological hallmark of Parkinson’s disease is the presence of intraneuronal a-synuclein inclusions termed Lewy pathology. However, it remains unknown from where the initial a-synuclein aggregates originate.

It has been hypothesized that a-synuclein inclusions initially form in nerve terminals of the enteric nervous system, and then subsequently spread via autonomic connections to the dorsal motor nucleus of the vagus and intermediolateral cell columns of the sympathetic system (Braak et al., 2003).

In addition, Lewy pathology has been detected in gastrointestinal nerve fibres years prior to Parkinson’s disease diagnosis. There is also epidemiological evidence that complete but not partial vagotomy may protect against later Parkinson’s disease.

Autopsy studies have shown that a minority of cases with Lewy pathology do not have pathological inclusions in the dorsal motor nucleus of the vagus, and that a fraction of cases display a limbic-predominant distribution of a-synuclein inclusions with less pathology in the brainstem.

The scientists hypothesized that the appearance of isolated REM sleep behaviour disorder well before parkinsonism is a strong marker of the body-first subtype. The presence of REM sleep behaviour disorder in the premotor phase is a marker of the body-first type, probably a reflection of ascending a-synuclein pathology reaching the pons before the substantia nigra. enter image description here The substantia nigra in the brain. Source Wikipedia

To test this hypothesis, they recruited de novo patients with Parkinson’s disease and performed video-polysomnography to divide patients into de novo Parkinson’s disease without REM sleep behaviour disorder and de novo Parkinson’s disease with pre-motor REM sleep behaviour disorder. The study was conducted between August 2018 and January 2020.

The scientists have shown that prodromal and de novo patients with Parkinson’s disease can be categorized by means of multimodal imaging into distinct clusters, which are compatible with a brain-first and body-first Parkinson’s disease subtype.

Their conclusion is that the Parkinson’s disease comprises two subtypes: (i) a body-first (bottom-up) subtype, where the pathology originates in the enteric or peripheral autonomic nervous system, and then ascends via the vagus nerve and sympathetic connectome to the CNS;

(ii) a brain-first (top-down) subtype, in which the a-synuclein pathology initially arises in the brain itself or sometimes enters via the ol- factory bulb, and subsequently descends to the peripheral autonomic nervous system.

Body-first (bottom-up) subtype: The initial a-synuclein pathology appears in the enteric or peripheral autonomic nervous system. It then propagates via the sympathetic connectome to the heart, and via the vagus nerve to the dorsal motor nucleus of the vagus. enter image description here The pons area in the brain. Source Wikipedia

Ascending pathology affects pontine structures giving rise to REM sleep behaviour disorder before the substantia nigra shows substantial involvement. When parkinsonism appears, signifying a loss of 450% of nigrostriatal dopamine terminals, all lower Braak stage structures show marked damage on relevant imaging markers.

Brain-first (top-down) subtype: In the brain-first type, the initial a-synuclein pathology appears in the CNS. The most likely site of origin seems to be the amygdala or connected structures, or the pathology may in some cases enter via the olfactory bulb. Rarely, the pathology arises in the upper brainstem (substantia nigra or locus coeruleus). The pathology spreads from the site of origin to the brainstem and cortex. When parkinsonism appears, the brainstem shows a rostro-caudal gradient of pathology with marked involvement of the substantia nigra, moderate involvement of the neighbouring pons, but little involvement of the medulla and autonomic nervous system.

Citation: Jacob Horsager et al, Brain-first versus body-first Parkinson's disease: a multimodal imaging case-control study, Brain (2020). DOI: 10.1093/brain/awaa238

Des scientifiques du Medical College of Georgia rapportent dans la revue Aging Cell que peu de temps après le choc hémorragique, une population de cellules hépatiques devient rapidement sénescente. La sénescence cellulaire est un processus dans lequel les cellules entrent dans un état d'arrêt stable du cycle cellulaire. Les cellules, si elles attirent l'attention du système immunitaire, sont éliminées par les macrophages. On sait maintenant que la sénescence peut être déclenchée ou accélérée par un stress excessif.

enter image description here

Mais, parce que les cellules sénescentes sont moins consommatrices d’énergie, la sénescence cellulaire peut aussi rendre ces cellules beaucoup moins vulnérables aux dommages irréparables, comme ceux qui peuvent résulter d'une perte dramatique de sang et d'oxygène. Les auteurs de l’article ont émis l'hypothèse qu’une lésion aiguë causée par un choc hémorragique au niveau du foie pourrait conduire à un développement rapide de la sénescence in vivo et que cette sénescence serait un mécanisme d’adaptation au traumatisme.

Pour savoir si le mouvement rapide de certaines cellules hépatiques vers la sénescence pour était bon ou mauvais, les auteurs ont administré une association de produits sénolytiques (dasatinib et quercétine) à ces rats qui venaient de subir un traumatisme hépatique.

L’association dasatinib + quercétine a été testé avec succès chez la souris et l'homme et permet d’éliminer les cellules sénescentes. De façon contre-intuitive, les cinq animaux ayant reçu Dasatinib + Quercetin, sont décédés au cours de la période d'observation de deux heures. Ce résultat suggère donc que l'induction d'une sénescence aiguë peut être un processus d’adaptation en cas de choc hémorragique.

Les scientifiques se sont demandé s’il n’y avait pas d’autres explications, par exemple les dasatinib et la quercétine auraient pu induire le décès des animaux. Cependant, lorsque les scientifiques ont donné des sénolytiques à des rats en bonne santé, ceux-ci n’en ont pas souffert.

Les scientifiques voulaient savoir si l'administration d'un cocktail médicamenteux améliorant la fonction des organes diminuerait l'émergence des cellules sénescentes dans le foie. Les auteurs ont traité des rats avec NiDaR (niacine, dichloroacétate et resvératrol), une combinaison de médicaments qui améliore la fonction des organes et la survie après une blessure de choc hémorragique. Le traitement NiDaR après un choc hémorragique n'a cependant pas inhibé l'émergence d'un processus moléculaire semblable à la sénescence dans le foie. Les scientifiques ont découvert que la population cellulaire qui émerge avec ce traitement était essentiellement la même que celle sans traitement NiDaR.

Raju et ses collègues soupçonnent que la transition rapide vers la sénescence qui s'est produite dans une population de cellules hépatiques était une tentative de stabilisation après le traumatisme, et probablement transitoire. Ils pensent que si les cellules passent immédiatement à un état sénescent, elles peuvent aider à prévenir la défaillance des organes.

Ces travaux tendent à montrer que la sénescence cellulaire peut se développer en quelques heures après une lésion tissulaire, et que les cellules sénescentes qui émergent, loin d’être préjudiciables, font au contraire partit du processus de guérison.

I increasingly believe that the consistently negative results of clinical trials in most degenerative diseases are not because these diseases are difficult to understand, but because most of the scientists who contribute to them are molecular biologists and not doctors or system biology engineers.

enter image description here

*Detail from "Triumph of St. Thomas Aquinas over Averroes" by Benozzo Gozzoli (1420–97)*

Molecular biologists do not care for anatomy of physiology, even worse, they treat the 200 different types of cells in the body as mostly similar. Even if most of neurodegenerative diseases involve anatomical structures that are found only in primates, their animal models are non-primate, and indeed they are astonished that good clinical results in mice do not translate in human beings.

They do not even agree if ALS starts in the brain or in muscles ("dying forward" hypothesis versus "dying backward" hypothesis). Astonishingly several times they "proved" that each of their favorite hypothesis was true and that indeed the competing hypothesis was false.

For ALS alone they implicated more than 120 genes, even if the notion of gene (as a single DNA region which is uniquely implicated in coding a specific strand of RNA) is extremely vague. And they did this before finding that, what was thought as a non coding region (C9orf72) was implicated in ~50% of familial ALS cases. Now C9orf72 is called a gene, so everything is safe again.

Like medieval scholars who discussed how many angels could stand on the tip of a pin, they proposed thousands of small molecules as the causal mechanism for Alzheimer's, Parkinson's, or ALS. The profusion of proposals and the lack of discussion of competing proposals should surely question anyone with a rational mind?

And some authors have stated non-mainstream research proposals were blocked since decades.

This kind of scientist has lost credibility.

There are alternating views, notably by Heiko Braak who says that Parkinson and Alzheimer start with a pathogen invasion in guts and its subsequent progression into the brain. And he and his colleagues provided good evidence for that.

Braak is a medical doctor, but molecular biology scientists did not think much of his findings. Braak is cited only by 0.3% of articles on Parkinson disease.

For a better explanation of why trying to understand something by dissecting it in components and making experiments on isolated components does not help to comprehend how a system works, look at the famous article "Can a biologist fix a radio?"

So in my current view we call different neurodegenerative diseases with different names, but they are mostly the same disease. Whatever neurons are dying in the substantia nigra (Parkinson), primary motor cortex (ALS), or lobes (Alzheimer) it is mainly about neurons dying in the brain. And it is a problem that cannot be solved with molecular biology.

James A. Bashford and colleagues aimed to identify a novel quantitative biomarker related to fasciculations that could monitor patients with amyotrophic lateral sclerosis over time.

Fasciculations are a hallmark of amyotrophic lateral sclerosis. Their presence precedes the onset of muscle weakness. However benign fasciculation syndrome is not considered a prodrome of amyotrophic lateral sclerosis.

The authors have recently developed Surface Potential Quantification Engine (SPiQE), which is an automated analytical tool designed to detect and characterize fasciculation potentials from resting high-density surface electromyography. SPiQE is capable of analysing 30-min recordings, producing simple outputs related to fasciculation frequency, amplitude, inter-fasciculation intervals and data quality. SPiQE’s analytical pipeline achieved a classification accuracy of 88% when applied to 5318 fasciculation potentials that had been identified manually.

Source: https://backyardbrains.com/

A motor unit comprises the motor neuron cell body, axon, terminal branches and connecting muscle fibres. Amyotrophic lateral sclerosis leads to a process called chronic partial denervation. This means that as motor units succumb to the disease and die, surviving motor units are instructed to sprout and branch to reinnervate orphaned muscles fibres.

This is an evolutionary, compensatory mechanism designed to maintain muscle power in the face of a reduced motor unit pool. In amyotrophic lateral sclerosis, a reinnervating motor unit steadily acquires new muscle fibres and consequently produces motor unit action potentials of larger amplitude, longer duration and greater complexity.

However, due to the relentless loss of motor units in amyotrophic lateral sclerosis, this process of reinnervation cannot maintain muscle strength indefinitely. A saturation point is reached and muscle fibres consequently atrophy, leading swiftly to clinical weakness. By assessing fasciculation amplitude serially as a surrogate of this reinnervation process, the scientists hoped to gain insight into this process.

It had been suggested that motor unit firing pattern is evidence for motoneuronal or axonal fasciculations; namely interspike intervals of approximately 5 ms (doublet intervals) provide evidence for the axonal firing. Fasciculation doublets have been shown to occur in biceps brachii, vastus lateralis and tibialis anterior from patients with amyotrophic lateral sclerosis, as well as the gastrocnemius (along with the soleus muscle, the gastrocnemius forms half of the calf muscle) from both patients with amyotrophic lateral sclerosis and benign fasciculation syndrome.

Fasciculation doublets are defined as the occurrence of two almost identical motor unit potentials, presumed to both arise from the same motor unit, with a very short IFI of <100 ms. Shorter inter-fasciculation intervals (5–10 ms) are likely to arise distally in the terminal branches, whereas longer inter-fasciculation intervals (40–80 ms) are thought to originate proximally at the soma.

Faced with the low occurrence rate of doublets during electrical stimulation, the scientists hypothesized that collection of vast numbers of fasciculations would be required to observe IFI peaks in these ranges. In turn, this might help to elucidate the origin of fasciculations in amyotrophic lateral sclerosis.

So in this study, Bashford and colleagues compared amyotrophic lateral sclerosis patients with control subjects who have benign fasciculation syndrome, a condition that is defined by the isolated presence of fasciculations, particularly in muscles of the lower limbs, without evidence of underlying motor neuron degeneration

Twenty patients with amyotrophic lateral sclerosis and five patients with benign fasciculation syndrome each underwent up to seven assessments at intervals of 2 months A total of 420 (210 biceps, 210 gastrocnemius) amyotrophic lateral sclerosis and 116 (58 biceps, 58 gastrocnemius) benign fasciculation syndrome recordings were analyzed. Ten biceps recordings from two patients with amyotrophic lateral sclerosis were excluded due to contamination from a Parkinsonian resting tremor

The scientists tested whether the presence of muscle weakness in patients with amyotrophic lateral sclerosis influenced the change in fasciculation frequency over time. The scientists divided the data into strong and weak muscles. The scientists divided each muscle into pre-weakness, peri-weakness and post-weakness groups. This allowed them to assess the chronology of disease by equating these groups to early, middle and late stages of disease, respectively. This was only possible due to the anatomical specificity of the high-density surface electromyography technique, which is a major strength in this setting.

For biceps, fasciculation frequency in strong amyotrophic lateral sclerosis muscles was 10× greater than the benign fasciculation syndrome baseline, while fasciculation frequency in weak muscles started at levels 40× greater than the benign fasciculation syndrome baseline. Over the 14 months of the study, fasciculation frequency decreased in weak muscles at a rate three times faster than average. This supported the suspicion of the authors that biceps fasciculation frequency was non-linear, first rising steadily from a pre-morbid baseline in strong muscles and subsequently falling as weakness ensued.

Given that there was no significant change in biceps fasciculation frequency over the 14 months of the study in strong amyotrophic lateral sclerosis muscles, Bashford and colleagues hypothesize that the rising phase is slow, perhaps starting many years before clinical weakness. In contrast to biceps, gastrocnemius demonstrated a significant decline in fasciculation frequency in strong muscles, but plateaued in weak muscles.

The most striking implication from these results was the rise and subsequent fall of fasciculation frequency in amyotrophic lateral sclerosis biceps muscles. This non-linear pattern had been previously suggested after statistically modelling fasciculation counts using muscle ultrasound and might explain why a previous surface EMG study of fasciculation frequency did not show a significant linear change over time.

The scientists hypothesize that the two main contributing factors to fasciculation frequency are the size of the affected motor unit pool and the relative degree of hyperexcitability. The size of the viable motor unit pool declines over time in biceps muscles, even while muscles remained strong (albeit at a slower rate than weak muscles). However, it remains unknown what proportion of motor units are affected (and therefore hyperexcitable) at a given stage of the disease.

The decline in fasciculation frequency can be attributed to the relentlessly shrinking motor unit pool. The picture above highlight the proposed model of the interactions between muscle power, size of viable motor unit pool (as assessed by MUNIX) and fasciculation frequency in benign fasciculation syndrome and three stages of disease in amyotrophic lateral sclerosis.

The diagrams depict the dynamic changes in motor unit architecture and relative hyperexcitability (depicted by electric bolts) as a consequence of motor neuron degeneration and motor unit loss.

In benign fasciculation syndrome, there is global hyperexcitability affecting all motor units to a similar degree in the absence of motor neuron degeneration.

In early amyotrophic lateral sclerosis, a subset of motor units are hyperexcitable, motor unit loss has begun and mild–moderate compensatory reinnervation has occurred. Due to the stability of biceps fasciculation frequency in strong muscles over 14 months (at a firing rate ~10 greater than the benign fasciculation syndrome baseline), the rising phase is hypothesized to begin many years before muscle weakness first appears.

It is postulated that towards the latter end of the rising phase, the rate of increase in fasciculation frequency speeds up, so that by the onset of weakness, fasciculation frequency is ~40 the benign fasciculation syndrome baseline.

In the middle stage, the ongoing loss of motor units has promoted extensive re-innervation of surviving motor units, which then become hyperexcitable themselves. This compensatory mechanism leads to fasciculations of greater amplitude and allows muscles to remain strong by staving off muscular atrophy.

However, as a tipping point is reached, these compensatory mechanisms saturate, leading to the onset of muscle atrophy and weakness.

In late amyotrophic lateral sclerosis, the death of the most re-innervated motor units leads to worsening muscle atrophy and weakness. The relentless loss of motor units drives the falling fasciculation frequency. Evidence of doublets with inter-fasciculation intervals in the 20–80 ms range is consistent with the period of motor unit subtypes (fast-slow), supporting a proximal origin of fasciculations at the soma. Throughout all stages of amyotrophic lateral sclerosis and in benign fasciculation syndrome, the degree of hyperexcitability of the lower motor neuron is likely to be driven and/or influenced by descending corticospinal inputs.


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.

Something is wrong with clinical trials for ALS. It seems difficult, if not impossible, to do worse than current experts in the field. The situation is similar for other neurodegenerative diseases such as Alzheimer's or Parkinson's.

Over 700 clinical trials, nearly 500 of which are interventional studies [15], have been conducted over the past 15 years on amyotrophic lateral sclerosis. In the case of Alzheimer's, there have been over 1900 interventional clinical trials and over 2000 of them for Parkinson's disease.

The cumulative cost of these unsuccessful attempts is colossal.

While the average success rate for a phase III clinical trial is over 40%, it is close to zero for neurodegenerative diseases. In fact, there have been more than 80 negative phase III clinical trials in the case of ALS [14].

The public might expect it to be truly unlikely that experts would fail 500 times in a row, or fail 82 times in Phase III, without any success, when the success rate of phase III clinical trials is close to 50%.

Is it an exaggeration to say that this huge number of failures means that not only do we have no idea of ​​the cause and mechanism of this disease, but that experts in charge have no clues about this type of disease?

One of the first paradigms was that since ALS is caused by the death of upper motor neurons (it's the medical definition of ALS), drugs and treatments for stroke should be effective. It shows the thinking of a doctor, not a biologist.

It has been the main paradigm for decades. There is indeed good reason to think that ALS is similar to an extremely slow stroke. In particular, it mainly occurs in the elderly and the symptoms start locally, for example in the muscle of the hand called the thenar. The symptoms then reach increasingly larger areas of the anatomy as the disease develops.

One of the two drugs approved for ALS, Edaravone, is an intravenous drug used to aid healing after stroke. In line with this paradigm that says ALS is a kind of stroke, oxidative stress has long been suspected to be a major factor in the spread of the disease. This is why Rilutek has been approved for ALS.

Then, over the last century, there has been the extraordinary expansion of molecular biology. Biologists then, considerably surpassed physicians in numbers and publications. Biologists became the de-facto experts in ALS.

The promise of molecular biology is indeed revolutionary, and that is to find a simple solution to any non-contagious disease.

It is also a promise of considerable simplicity in tooling, which seems to come out of a kitchen rather than from a sophisticated laboratory. In particular, it becomes possible for biologist students to publish on these subjects a few years earlier than if they were studying medicine.

Molecular biology involves a complete paradigm shift in the way we think about ALS disease.

The brains, the nerves and the muscles are forgotten. The cells, whose internal mechanisms are however still largely unknown at the end of the XX century, are rejected as irrelevant in a process of thought which is centered on the translation of the genome in proteins.

The blindness towards medicine, is however difficult to understand for neurodegenerative diseases, because for example reactive astrocytes have been repeatedly identified as a component of senile amyloid plaques in the cortex of patients with Alzheimer's disease. from 1988 [9-12]. But not long ago, 30 years later, the theory implicating amyloid plaques in Alzheimer's disease was still the dominant theory.

This may correspond to what was known at the time, as astrocytes and microglia were then considered almost useless. This is, however, something astonishing to say, even at the end of the 20th century, since these cells clearly constitute a large part of the matter of the brain and the spine.

It started off well for the application of cell biology in neurodegenerative diseases, with an apparent success in 1998, when mutations in the SOD1 gene were implicated in familial ALS. Unfortunately, it quickly became clear that SOD1 mutations only affect a small number of familial cases of ALS and they presented a great diversity with a life expectancy varying from one year in severe forms to 10 years or more in other less dangerous mutations.

Although the vast majority of articles on ALS concern SOD1, mutations in SOD1 therefore appear to be an epiphenomenon in the case of ALS, both because of their very low frequency but also for the diversity of phenotypes.

The main cause of familial ALS was not found until 2011, 20 years after promises from like those of the human genome project. Mutations in C9orf72 create repeats motifs in some proteins. Geneticists had been investigating familial ALS for about 30 years, and the lack of progress raised concerns. C9orf72 is not a gene, it is an area that was considered non-coding until then, hence the difficulty in using molecular biology tools.

Strangely enough, these pattern repeats are also present in everyone, but more pronounced in the elderly. They are also present in other diseases. So it seems that the number of repetitions could involve different diseases.

Molecular biology has proposed more than a hundred genes as participating in the etiology of ALS and has proposed thousands of drugs and at one point scientists started to be reluctant to incriminate even more genes in ALS (or Alzheimer's, etc.).

Thus, for scientists who had decided to pursue a career in molecular biology and who thought they were in an impasse, there was a strong temptation to turn towards translation and post-translational modifications of proteins.

We were then inundated with studies claiming that this or that protein was poorly translated, poorly conformed or poorly localized in the cell. The subject of misfolded proteins even created small wars between biologists (Tauiste against Baptiste). The problem is that most of these proposed proteins are found in most neurodegenerative diseases, Tau, TDP-43, etc [1]. So they do not seem specific to ALS, Alzheimer's or Parkinson's. If they are not specific, how can they be causative of one, but not other neurodegenerative diseases?

There are however alternative views among scientists working in the field of ALS, one is that ALS starts in muscles, not in the brain. This hypothesis has been both * proven and disproved * on several occasions, which seems very confusing from a non-specialist's point of view. But anyway this hypothesis does not explain what would cause the muscle disease, it only pushes the explanation of this muscle wasting, away to future works.

If we think globally, like a doctor, there are two common reasons for cells to die (be it muscle cells or upper motor neurons). There is no need for extremely sophisticated explanations for this.

Either their blood supply is faulty (see the similarity to stroke above) or the cellular metabolism is faulty (hence the appearance of reactive stress).

It seems that articles on a defective metabolism are quite rare, but they could be found, here are examples [7-8, 13]. Some articles have even blamed the use of methionine sulfoximine (MSO) in a now abandoned flour bleaching process [8] or other environmental contaminants as contributing factors to ALS. It is surprising that although there have been many publications on these two topics, no clinical trial has tried drugs linked to metabolic dysfunction.

For example, clinical trials could study: * MAO-B inhibitors [2], * Methionine sulfoximine (MSO) which dramatically extended the lifespan of a SOD1 G93A mouse model for ALS. [3] * Pathological inhibition of glutamine synthetase (GS). In the brain, GS is exclusively localized in astrocytes where it is used to maintain the glutamate-glutamine cycle, as well as nitrogen metabolism. Changes in GS activity have been identified in a number of neurological conditions [4]. * Methionine sulfoximine (MSO), a well-characterized glutamine synthetase inhibitor, is a convulsant, particularly in dogs, but shows significant therapeutic benefits in animal models for several human diseases [5, 6] * But also many other drugs related to the brain and spine metabolism.

[1] https://www.statnews.com/2019/06/25/alzheimers-cabal-thwarted-progress-toward-cure/

[2] https://pubmed.ncbi.nlm.nih.gov/32852645/

[3] https://pubmed.ncbi.nlm.nih.gov/28323087/

[4] https://pubmed.ncbi.nlm.nih.gov/27885636/

[5] https://pubmed.ncbi.nlm.nih.gov/28292200/

[6] https://pubmed.ncbi.nlm.nih.gov/24136581/

[7] https://pubmed.ncbi.nlm.nih.gov/7148401/

[8] https://pubmed.ncbi.nlm.nih.gov/10052866/

[9] https://www.ncbi.nlm.nih.gov/pubmed/3196922/

[10] https://www.ncbi.nlm.nih.gov/pubmed/2531723/

[11] https://www.ncbi.nlm.nih.gov/pubmed/2808689/

[12] https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5996928/

[13] https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5063041/

[14] https://clinicaltrials.gov/ct2/results?cond=Amyotrophic+Lateral+Sclerosis&term=&cntry=&state=&city=&dist=&Search=Search&phase=2&phase=3

[15] https://clinicaltrials.gov/ct2/results?cond=Amyotrophic+Lateral+Sclerosis&age_v=&gndr=&type=Intr&rslt=&Search=Apply

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