ALS患者的体重减轻是不可避免的吗?

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肌肉萎缩是 ALS 最显着的症状之一。 Kasaskies 和其他人的研究表明,ALS 患者必须摄入比可比较的健康人更多的卡路里。我们的网站有自己的卡路里计算器

乌尔姆大学的 Johannes Dorst 及其同事对 64 名可能的、可能的或确诊的 ALS 患者进行了一项随机对照研究(超高热量食品补充剂在肌萎缩侧索硬化症 (ALS) 中的安全性和耐受性;TOLCAL-ALS 研究)。埃斯科里亚尔标准。患者被随机分为四组:

高热量脂肪补充剂(405 kcal/天,100% 脂肪), 超高热量脂肪补充剂(810 kcal/天,100% 脂肪), 一种超高热量、富含碳水化合物的补充剂(900 kcal/天,49% 碳水化合物) 没有任何补充的开放控制(OC)组。主要终点是耐受性。对患者进行了 4 周以上的随访。 胃肠道副作用在超高热量脂肪补充剂组中最常见(75.0%),而食欲不振在超高热量、富含碳水化合物的补充剂组中最常见(35.3%)。

干预期间,高热量脂肪补充剂组和超高热量脂肪补充剂组患者体重增加+0.9 kg/月。对照组患者体重持续下降(-0.5 kg/月)。

研究结果表明,高热量食品补充剂经常会导致 ALS 患者出现轻度至中度耐受性问题,最明显的是高脂肪补充剂中的胃肠道症状,以及高碳水化合物补充剂中的食欲不振。测试的所有三种高热量食品补充剂都适合增加体重。

La perte de poids n'est pas inéluctable dans la SLA

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La fonte musculaire est l'un des symptômes les plus frappants de la SLA (maladie de Charcot). Il y a des études par Kasaskies et d'autres, qui ont démontré que les patients SLA doivent ingérer beaucoup plus de calories que les personnes comparables qui sont en bonne santé . Notre site Web a son propre calculateur de calories.

Johannes Dorst et ses collègues de l'université d'Ulm, ont mené une étude contrôlée randomisée (Safety and Tolerability of Ultra-high-caloric Food Supplements in Amyotrophic Lateral Sclerosis (ALS) ; étude TOLCAL-ALS) chez 64 patients atteints de ou SLA définitive selon les critères d'El Escorial. Les patients ont été randomisés en quatre groupes :

  • un complément lipidique hypercalorique (405 kcal/jour, 100% lipides),
  • un complément lipidique ultra-hypercalorique (810 kcal/jour, 100% lipides),
  • un complément hypercalorique riche en glucides (900 kcal/jour, 49% de glucides)
  • un groupe de contrôle ouvert (OC) sans supplément. Le critère principal était la tolérance. Les patients ont été suivis pendant 4 semaines.

Au cours de l'intervention, les patients ont pris +0,9 kg/mois de poids corporel dans le groupe des suppléments gras hypercaloriques et le groupe des suppléments gras hypercaloriques. Les patients du groupe témoin ont continué à perdre du poids corporel (−0,5 kg/mois).

Les effets secondaires gastro-intestinaux étaient les plus fréquents dans le groupe des suppléments gras ultra-caloriques (75,0 %), tandis que la perte d'appétit était la plus fréquente dans le groupe des suppléments ultra-caloriques riches en glucides (35,3 %).

Les résultats suggèrent que les compléments alimentaires riches en calories provoquent fréquemment des problèmes de tolérance légers à modérés chez les patients atteints de SLA, notamment des symptômes gastro-intestinaux dans les suppléments riches en graisses et une perte d'appétit dans les suppléments riches en glucides. Les trois compléments alimentaires hautement caloriques testés sont adaptés pour augmenter le poids corporel.

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Cet ouvrage (en Anglais) retrace les principaux acquis de la recherche sur la SLA au cours des 30 dernières années, présente les médicaments en essai clinique, ainsi que les recherches en cours sur les futurs traitements susceptibles de pouvoir stopper la maladie dans quelques années et d'apporter une guérison complète en une ou deux décennies.

Is weight loss inevitable in ALS?

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Muscle wasting is one of the most striking symptoms of ALS. There were studies by Kasaskies and others, that demonstrated ALS patients have to ingest much more calories than comparable healthy persons. Our website has its own calorie calculator.

Johannes Dorst and colleagues from Ulm's university, conducted a randomised controlled study (Safety and Tolerability of Ultra-high-caloric Food Supplements in Amyotrophic Lateral Sclerosis (ALS); TOLCAL-ALS study) in 64 patients with possible, probable or definite ALS according to El Escorial criteria. Patients were randomised into four groups:

  • a high-caloric fatty supplement (405 kcal/day, 100% fat),
  • an ultra-high-caloric fatty supplement (810 kcal/day, 100% fat),
  • an ultra-high-caloric, carbohydrate-rich supplement (900 kcal/day, 49% carbohydrates)
  • an open control (OC) group without any supplement. The primary endpoint was tolerability. Patients were followed up over 4 weeks.

Gastrointestinal side effects were most frequent in the ultra-high-caloric fatty supplement group (75.0%), while loss of appetite was most frequent in the ultra-high-caloric, carbohydrate-rich supplement group (35.3%).

During intervention, patients gained +0.9 kg/month of body weight in the high-caloric fatty supplement group and the ultra-high-caloric fatty supplement group. Patients in the controlled group continued to lose body weight (−0.5 kg/month).

The findings suggest that high-caloric food supplements frequently cause mild to moderate tolerability issues in patients with ALS, most notably gastrointestinal symptoms in high-fat supplements, and loss of appetite in high-carbohydrate supplements. All three high-caloric food supplements tested are suited to increase body weight.

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

ALS is not just a disease of the primary motor area of the brain.

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Amyotrophic lateral sclerosis (ALS) is a rapidly progressive neurodegenerative disease with a median survival of 26 months after diagnosis. It usually affects older adults and is characterized by progressive weakness in the muscles of the limbs and difficulty speaking and swallowing.

Also and to differentiate this disease from other diseases with similar symptoms, for over a century ALS has been defined as a disease of the higher motor neurons. However, this definition is artificial in that for most of these 100 years it has been impossible to directly verify the state of upper motor neurons in patients.

The very great diversity of symptoms has led "theoretical" doctors to introduce new pathologies (PLS, PMA, MMA, PLS, PBP) which seem very far from clinical reality.

Finger and foot tapping scores have long been used as a surrogate for upper motor neuronal dysfunction in ALS studies. Myography studies are also very subjective.

Moreover, a minority of scientists do not share this point of view and prefer a hypothesis called "dying backward" where the disease begins either in a muscle or at the muscle / lower motor neuron junction, which is found in the peripheral nervous system. .

For the past fifteen years, scientists have recognized that frontotemporal dementia (FTD) is present in about 10% of patients at the time of diagnosis, with up to 50% of patients showing cognitive and behavioral deficits on detailed neuropsychometric tests. Frontotemporal dementia also has molecular characteristics similar to the majority of cases of ALS.

Fortunately, more and more doctors and scientists are using medical imaging to examine patients with neurodegenerative diseases. Functional MRI studies have demonstrated reduced cortical activity in the prefrontal cortices during voluntary movement tasks in patients with ALS. This indicates that the classic definition of ALS, as only a disease of the higher motor neurons, is wrong. Obviously the new imaging techniques are not well received by classical neurologists. enter image description here

Motor weakness associated with volitional tasks in ALS is associated with failures and compensations in larger networks and not with isolated dysfunctions in the primary motor area where the body of higher motor neurons is located.

However previous functional MRI studies were limited by small sample sizes (n <20) and the majority of studies either examined gray matter only with T1-weighted images, or white matter with diffusion tensor imaging ( DTI). So far, only four studies have included more than 20 ALS patients with a multimodal MRI protocol to study progressive whole brain changes, although none have included more than 35 ALS patients. Two of these studies demonstrated progressive changes in the corticospinal tract and found no change in gray matter after 6 to 8 months (Cardenas-Blanco et al., 2016; de Albuquerque et al., 2017). In contrast, generalized gray matter degeneration was reported with limited white matter involvement in the other two studies (Bede and Hardiman, 2018; Menke et al., 2014). More comprehensive analyzes were therefore necessary.

Texture analysis is a computer image processing technique that quantifies the variations and relationships between the intensities of voxels in an image, variations that are difficult to detect by qualitative visual inspection and may not be detectable by the methods. common image analysis

Two-dimensional (2D) texture analysis methods have been widely used in other neurological conditions such as brain tumors, stroke, epilepsy, and multiple sclerosis to detect and classify lesions. Scientists have developed an analysis of the texture characteristics of the whole brain (Maani, Yang & Kalra, 2015).

With this technique, the authors of a new article have shown that the autocorrelation calculated from T1-weighted images is altered in ALS compared to controls in the regions of the motor cortex, the frontal lobe. , temporal lobe and posterior limb internal capsule (PLIC).

A comprehensive assessment of progressive brain degeneration in ALS is essential to further understanding the pathophysiology of the disease. As such, the main objectives of this new study were (1) to examine brain changes in patients with ALS over an 8-month period with texture analysis of T1-weighted images, and (2) to assess whether the gradual changes are different between patients at slow and rapid evolution.

The study design included whole brain and region of interest (ROI) based approaches to study changes in texture. The authors hypothesized that

  • (1) texture alterations in T1-weighted images are present in gray and white matter and associated with the known pathology and clinical alteration of ALS;
  • (2) progressive brain degeneration is evident as texture alterations over time;
  • (3) gradual brain changes in rapidly progressing patients are more important than changes in slowly progressing patients.

To test their hypotheses, they conducted the study in a large multicenter cohort of 256 participants (119 controls and 137 patients with ALS). The mean age of the ALS patients was higher than that of the controls (p = 0.02) and there were proportionally more men than women in the ALS group than in the control group.

In the whole-brain group comparison, patients with ALS had reduced autocorrelation compared to controls in bilateral pre-central gyri, subcortical white matter, left supplemental motor area, left upper and middle frontal gyri, bilateral frontal white matter, bilateral insular cortex and bilateral temporal white matter.

Compared to controls, the slowly progressing ALS group had alterations in autocorrelation in bilateral precentral gyri, left middle frontal gyrus, bilateral frontal white matter, left insular cortex, and bilateral pyramidal tracts. In contrast, the rapidly progressing ALS group had fewer regions of altered autocorrelation in the frontal cortex, but greater involvement of bilateral pyramidal tracts, temporal white matter, and parahippocampal regions.

Conclusion: In this study, the authors set out to investigate progressive brain degeneration in ALS with texture analysis of T1-weighted images in a large multicenter cohort. they first showed that the texture abnormalities in the gray and white matter at the start were spatially congruent with the brain pathology of ALS.

It is important to note that textural alterations in the pyramidal tract have also been shown to be highly specific for clinical dysfunction of the upper motor neurons. This contrasted with the ALSFRS-R and finger and foot tapping scores which showed diffuse associations with gray and white matter structures. In addition, longitudinal analyzes revealed that the progression of gray matter was characterized by the spread of the pathology to the frontotemporal regions.

They observed progressive changes in the pyramidal tracts after only 4.5 months. This is a new and important observation because clinical dysfunction of the upper motor neurons did not progress during this period. Finally, they showed that progressive brain degeneration in ALS was based on the rate of disease progression at baseline. Taken together, these results also strongly suggest that texture analysis of T1-weighted images is a sensitive marker for longitudinal mapping of disease-related brain degeneration in ALS.

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

La SLA n'est pas seulement une maladie de la zone motrice primaire du cerveau.

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La sclérose latérale amyotrophique (SLA) est une maladie neurodégénérative à progression rapide avec une survie médiane de 26 mois après le diagnostic. Elle affecte généralement les adultes âgés et se caractérise par une faiblesse progressive des muscles des membres et des difficultés d'élocution et de déglutition.

Aussi et pour différencier cette maladie d'autres maladies ayant des symptômes proches, depuis plus d'un siècle la SLA est définie comme une maladie des neurones moteurs supérieurs. Cependant cette définition a un caractère artificiel dans la mesure où pendant la plus grande partie de ces 100 ans il a été impossible de vérifier directement l'état des neurones moteurs supérieurs chez les patients.

La très grande diversité de symptômes a conduit les médecins "théoriciens" à introduire de nouvelles pathologies (PLS, PMA, MMA, PLS, PBP) qui semblent très éloignées de la réalité clinique.

Les scores de tapotement des doigts et des pieds ont longtemps été utilisés comme substituts du dysfonctionnement de l'neurones moteurs supérieurs dans les études sur la SLA. Les études de myographies sont elles aussi très subjectives.

D'ailleurs une minorité de scientifiques ne partagent pas ce point de vue et préfèrent une hypothèse appelée "dying backward" où la maladie commence soit dans un muscle, soit à la jonction muscle/neurone moteur inférieur, qui se trouve dans le système nerveux périphérique.

Depuis une quinzaine d'années, les scientifiques reconnaissent que la démence frontotemporale (DFT) est présente chez environ 10 % des patients au moment du diagnostic, avec jusqu'à 50 % des patients présentant des déficits cognitifs et comportementaux lors de tests neuropsychométriques détaillés. La démence frontotemporale présente d'ailleurs des caractéristiques moléculaires similaire à la majorité des cas de SLA.

Heureusement de plus en plus de médecins et scientifiques utilisent l'imagerie médicale pour examiner les patients atteints de maladies neurodégénératives. Des études d'IRM fonctionnelles ont démontré une activité corticale réduite dans les cortex préfrontaux lors de tâches de mouvement volontaire chez des patients atteints de SLA. Cela indique que la définition classique de la SLA, comme seulement une maladie des neurones moteurs supérieurs, est erronée. Evidemment les nouvelles techniques d'imageries sont mal accueillies par les neurologues classiques. enter image description here La faiblesse motrice liée aux tâches volitives dans la SLA est associée à des échecs et des compensations dans des réseaux plus vastes et non à des dysfonctionnements isolés dans la zone motrice primaire où se trouve le corps des neurones moteurs supérieurs.

Cependant les études d'IRM fonctionnelles précédentes étaient limitées par la petite taille des échantillons (n < 20) et la majorité des études ont soit examiné uniquement la matière grise avec des images pondérées en T1, ou substance blanche avec imagerie du tenseur de diffusion (DTI). Jusqu'à présent, seules quatre études ont inclus plus de 20 patients atteints de SLA avec un protocole d'IRM multimodal pour étudier les changements progressifs du cerveau entier, bien qu'aucune n'ait inclus plus de 35 patients atteints de SLA. Deux de ces études ont démontré des changements progressifs dans le tractus corticospinal et n'ont trouvé aucun changement dans la matière grise après 6 à 8 mois (Cardenas-Blanco et al., 2016 ; de Albuquerque et al., 2017). En revanche, une dégénérescence généralisée de la matière grise a été signalée avec une implication limitée de la matière blanche dans les deux autres études (Bede et Hardiman, 2018 ; Menke et al., 2014). Des analyses plus complètes étaient donc nécessaires

L'analyse de texture est une technique de traitement d'image informatique qui quantifie les variations et les relations entre les intensités de voxels dans une image, variations qui sont difficiles à détecter par une inspection visuelle qualitative et peuvent ne pas être détectables par les méthodes d'analyse d'images courantes

Les méthodes d'analyse de texture bidimensionnelle (2D) ont été largement utilisées dans d'autres affections neurologiques telles que les tumeurs cérébrales, les accidents vasculaires cérébraux, l'épilepsie et la sclérose en plaques pour détecter et classer les lésions. Des scientifiques développé une une analyse des caractéristiques de texture au niveau du cerveau entier (Maani, Yang et Kalra, 2015).

Avec cette technique, les auteurs d'un nouvel article ont montré que l'autocorrélation calculée à partir d'images pondérées en T1 est altérée dans la SLA par rapport aux contrôles dans les régions du cortex moteur, du lobe frontal, du lobe temporal et du membre postérieur de la capsule interne (PLIC).

Une évaluation complète de la dégénérescence cérébrale progressive dans la SLA est essentielle pour approfondir la compréhension de la physiopathologie de la maladie. En tant que tel, les objectifs principaux de cette nouvelle étude étaient (1) d'examiner les changements cérébraux chez les patients atteints de SLA sur une période de 8 mois avec une analyse de texture d'images pondérées en T1, et (2) d'évaluer si les changements progressifs sont différents entre patients à évolution lente et rapide.

La conception de l'étude comprenait des approches basées sur le cerveau entier et la région d'intérêt (ROI) pour étudier les changements dans la texture. Les auteurs ont émis l'hypothèse que (1) des altérations de texture dans les images pondérées en T1 sont présentes dans la matière grise et blanche et associées à la pathologie connue et à l'altération clinique de la SLA ; (2) la dégénérescence cérébrale progressive est évidente sous forme d'altérations de la texture au fil du temps ; (3) les changements cérébraux progressifs chez les patients à progression rapide sont plus importants que les changements chez les patients à progression lente.

Pour tester leurs hypothèses, ils ont mené l'étude dans une large cohorte multicentrique de 256 participants (119 témoins et 137 patients atteints de SLA). L'âge moyen des patients SLA était plus élevé que celui des témoins (p = 0,02) et il y avait proportionnellement plus d'hommes que de femmes dans le groupe SLA que dans le groupe témoin.

Dans la comparaison du groupe cerveau entier, les patients atteints de SLA présentaient une autocorrélation réduite par rapport aux témoins dans les gyri précentraux bilatéraux, la substance blanche sous-corticale, l'aire motrice supplémentaire gauche, les gyri frontaux moyens et supérieurs gauches, la substance blanche frontale bilatérale, le cortex insulaire bilatéral et la substance blanche temporale bilatérale.

Par rapport aux témoins, le groupe SLA à progression lente présentait des altérations de l'autocorrélation dans le gyri précentral bilatéral, le gyrus frontal moyen gauche, la substance blanche frontale bilatérale, le cortex insulaire gauche et les faisceaux pyramidaux bilatéraux. En revanche, le groupe SLA à progression rapide avait moins de régions d'autocorrélation altérée dans le cortex frontal, mais une plus grande implication des faisceaux pyramidaux bilatéraux, de la substance blanche temporale et des régions parahippocampiques

Conclusion: Dans cette étude, les auteurs ont entrepris d'étudier la dégénérescence cérébrale progressive dans la SLA avec une analyse de texture d'images pondérées en T1 dans une grande cohorte multicentrique. ils ont d'abord montré que les anomalies de texture dans la matière grise et blanche au départ étaient spatialement congruentes avec la pathologie cérébrale de la SLA.

Il est important de noter que les altérations de la texture dans le tractus pyramidal se sont également révélées hautement spécifiques du dysfonctionnement clinique de l'neurones moteurs supérieurs. Cela contrastait avec les scores ALSFRS-R et de tapotement des doigts et des pieds qui montraient des associations diffuses avec les structures de la matière grise et blanche. De plus, des analyses longitudinales ont révélé que la progression de la matière grise était caractérisée par la propagation de la pathologie vers les régions frontotemporales.

ils ont observé des modifications progressives des faisceaux pyramidaux après seulement 4 mois et demi. Il s'agit d'une observation nouvelle et importante car le dysfonctionnement clinique de l'neurones moteurs supérieurs n'a pas progressé au cours de cette période. Enfin, ils ont montré que la dégénérescence cérébrale progressive dans la SLA était fondée sur le taux de progression de la maladie au départ. Pris ensemble, ces résultats suggèrent également fortement que l'analyse de la texture des images pondérées en T1 est un marqueur sensible pour la cartographie longitudinale de la dégénérescence cérébrale liée à la maladie dans la SLA.

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

A new peptide may be at the heart of a future ALS therapy.

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Yet another in-vitro and mice study was recently published. So even if there is eventually a positive outcome, it is many years in the future. Basically it tells about experimentation done on the axon of in-vitro and in a mice model. The conclusion is that TDP-43 (which is found in misfolded aggregates in >95% of ALS patients) impairs local mitochondria in neuromotor junctions (NMJ). enter image description here

However some questions could be asked: * The authors say TDP-43 in ALS plays an important role at NMJ. This is certainly NOT a mainstream statement: For most (but not all) scientists, ALS starts in the brain (upper motor neurons), not in the NMJs (lower motor neurons).

  • They use transgenic mice expressing the human TDP-43 lacking the nuclear-localization-signal (∆NLS). No wonder TDP-43 goes in weird places into the cell. To remind, once a protein is produced by the ribosomes and folded by the endoplasmic reticulum (ER), it is packaged and sent to its final destination (the nucleus for TDP-43) by the Golgi apparatus. If there is no NLS, then the newly protein is not sent somewhere, it just accumulates and moves at random pushed by the Brownian movement, but it is correctly folded because it went through the ER. This is not what scientists tell, for them in ALS the TDP-43 proteins do not enter in the ER, or the ER is dysfunctional, so they stay misfolded.

  • They confirm that misfolded TDP-43 is found in mitochondria, but this was first found by Gao and al at Case Western Uni in 2016.

  • When they reintroduce doxycycline in mice diet (a classic trick to switch ON/OFF a gene in a genetically modified mice), the TDP-43 got again its NLS and the mice health improved. Again this was shown in the past, specially by Gao and al in 2016 who designed a credible TDP-43 genetic therapy by adding a NLS signal to neuron cells. It remain to see in real life in humans if this would improve their health. After all "normal" TDP-43 got its NLS signal in the Golgi apparatus, so why this is not the case in ALS patients?

  • Something really interesting is that when they used TAT-fused peptide corresponding to residues 190-208 of G3BP1, a decrease in translation was reversed by axonal-exclusive application of (G3BP1 peptide) and mice health improved. This result mirrors other several experiments, yet this is done with peptides, not with costly genetic therapeis. This is something very low cost that could be easily tried in other labs in pre-clinical studies and may lead to a future therapy.

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

Natural products targeting the UPR signaling to tilt it towards pro-survival

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During 2019 January I thought a TDP-43 therapy was really missing and the next month I wrote a plea to develop a TDP-43 therapy. I am not sure it had any effect, but I sent emails to nearly 250 scientists the next months. A flurry of patents have been written which indicates it is now an active research topic. Now we are at a phase where there are even clinical trials targeting TDP-43.

Reducing the TDP-43 misfolded mislocated aggregates may stop ALS progression and it could help as well in other neurodegenerative diseases.

Now I think that a part of the set of drugs needed to really recover (in addition to TDP-43 therapies) is something targeting faulty UPR (Unfolded Protein Response). Here is a list of natural products targeting the UPR signaling to tilt it towards pro-survival. Some, it will not surprise you, have been discussed since a long time on Internet forums. (source doi: 10.1007/s11010-021-04223-0)


Name of compound / Mode of action / References


  • Ginkgolide / K(GK) Reduce ER by accentuating the IRE1/XBP1 activity. / [136]

  • Elatoside C / Inhibit ER stress induced genes like GRP78, CHOP, caspase-12 and JNK, reduce apoptosis. / [137]

  • Sulforaphane (SFN) /Inhibit GRP78,CHOP and caspase-12 by activating the SIRT1 pathway.SIRT1 decrease ER induced apoptosis by deacetylating eIF2α / [138]

  • Resveratrol / Reduce ER stress mediated apoptosis by downregulating the expression of GRP78, GRP94 and CHOP and upregulating the expression of Bcl-2 and Bax. Lowers the expression of GRP78 and CHOP in doxorubicin treated H9c2 cell. / [139–141]

  • Baicalin / Target the CHOP/eNOS/NO pathway by inhibiting CHOP and thus reducing apoptosis / [142]

  • Berberine / Decrease apoptosis by decreasing the phosphorylation rate of PERK and eIF2α and downregulating the expression of ATF4 and CHOP / [143]

  • Anisodamine / Downregulate the expression GRP78, CHOP, and cleaved caspase 3 and thus reduce cell death / [144, 145]

  • Rare ginsenoside-standardized extract (RGSE) / Inhibit the overexpression of GRP78, GRP94 and CHOP as well as decrease the phosphorylation level of PERK and IRE1α / [146]

  • Panax quinquefolium saponin (PQS) Improve ventricular remodeling by downregulating the expression of GRP78, CHOP, and Bax protein as well as increasing the expression of Bcl-2 protein, thus reducing apoptosis. Also inhibits apoptosis by targeting the PERK-eIF2α- ATF4- CHOP pathway / [147–149]

  • Notoginsenoside R1 (NGR1) Protect cells from acute ER stress by delaying the onset of ER stress by decreasing the expression of GRP78, p-PERK, ATF6, IREα. Inhibit the expression of CHOP, caspase-12, and p-JNK. Scavenges free radicals, thereby increasing the activity of antioxdidases / [150]

  • Paeonol / Relieve ER stress by activating AMPK/PPARδ pathway which in turn results in down regulation GRP78, eIF2α as well as lower ROS overproduction / [151]

  • Tournefolic acid B / Accentuate the phosphorylation of P13K and AKT as well as it downregulates the expression CHOP, caspase-12 thus inhibiting apoptosis during ER stress via PI3K/AKT pathways / [152]

  • Crocetin / Impair the function of nuclear factor erythroid-2 related factor 2 (Nrf2)/heme oxygenase-1 signaling. Loss of Nrf2 activity was in turn shown to attenuate the expression of ER stress associated proteins / [153, 154]

  • Salvianolic acid B / Exert its cardioprotective role by improving cellular survival and reducing ER stress mediated apoptosis / [155, 156]

  • Flavonoids of astragalus (TFA) / Restores the mRNA and protein level of ER chaperone calumenin, rescues the interaction between SERCA2 and calumenin thus restoring ER homeostasis / [157]

  • Curcumin and masoprocol / Rescue Protein disulfde isomerase (PDI). Reduces the ROS generated ER stress by increasing the expression of GRP98 and inhibiting the activation of caspase-12 / [158]

  • SP600125 / Ameliorate the expression of CHOP in cardiomyocytes, reduce apoptosis [159] Panax Notoginseng Saponins (PNS) Protects cardiomyocytes against ER stress mediated mitochondrial injury by augmenting the autophagic response / [160]

  • Inonotus obliquus (IO) / Protects heart against Myocardial I/R injury by activating SIRT1 which in turn inhibits ER stress induced apoptosis - [161]

  • Fuziline Imparts its cardioprotective role by attenuating isoproterenol induced ER stress by targeting the PERK/eIF2α/ATF4/CHOP signaling axis / [162]

  • Protocatechualdehyde Imparts its anti-apoptotic role during oxygen–glucose deprivation/reoxygenation (OGD/R) mediated myocardial ischemic injury via targeting the PERK/ATF6α/IRE1α signaling molecules / [163]

  • Beta carotene / Exhibits its cardioprotective role in advanced glycation end products (AGEs)-induced cardiomyocyte apoptosis during diabetic cardiomyopathy by decreasing hyperactive ER stress molecules CHOP, ATF4 and GRP78 / [164]

  • Qishen granule (QSG) / Imparts its cardioprotective role during myocardial ischemia by augmenting the inositol requiring enzyme 1 (IRE-1)-αBcrystallin (CRYAB) signaling pathway thereby decreasing cardiac apoptosis / [165]

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


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Disappointing results from the VALOR study on Tofersen (BIIB067)

- Posted in Disappointing results from the VALOR study on Tofersen (BIIB067) by English by

Biogen announced the first results of its pivotal phase 3 VALOR study in tofersen (BIIB067), an experimental antisense oligonucleotide (ASO) under evaluation for people with amyotrophic lateral sclerosis (ALS) who carry a mutation on the SOD1 gene.

The results are depressing.

enter image description here

The VALOR study showed that there was no slowing of disease progression, as measured by the overall score of the ALSFRS-R scale.

However, improvements have appeared on specific points or technical aspects.

In particular, the therapy has achieved its technical goal, although this does not translate into clinical terms. The production of SOD1 protein was indeed reduced, as differences were observed between the Tofersen and placebo groups of 38% and 26% in the faster and slower progressing populations respectively.

Regarding the baseline value of the plasma neurofilament light chain (NfL), a potential marker of neuronal degeneration, differences were observed between the tofersen and placebo groups of 67% and 48% in the more rapidly progressing populations. and slower respectively.

In the fastest growing population, respiratory function evolved somewhat slower than expected (SVC); difference of 7.9%). This is also the case for muscle strength.

However, serious neurological events have been reported in one in twenty patients receiving Tofersen, including 2 cases of myelitis (2.0%). One death was reported in the Tofersen group in the VALOR study, which was determined to be unrelated to Tofersen.

Tofersen binds to SOD1 mRNA, allowing its degradation by RNase-H1 to reduce the synthesis of mutant SOD1 protein production.

The idea that the production of a mutated gene should be reduced is very common among biologists, but it is medically counter-intuitive. Indeed our genes would not have been constantly selected through a billion year if they were useless, and if we could put them "KO" without serious consequences. SOD1 is a gene that is essential for survival. It is present in most organisms. So it's not surprising cases of myelitis appear when SOD1 production was inhibited. It happened as well in other clinical trials.

Moreover, an ASO is only effective for a certain type of mutation, but there are more than a hundred known mutations for SOD1, some with very rapid progression, others on the contrary almost harmless.

If the problem was due to a "gain of function" of the mutated protein, then it was not enough to reduce its production, it had to be corrected, or to increase the production of SOD2. Even the key 1993 article on SOD1 involvement in ALS suggested something similar.

Hopefully this failure will trigger a global strategic reflection at Biogen, which has stopped all research on ALS in general a few years, to concentrate on ALS subsets deemed (at the time) less risky through licenses with Ionis Pharmaceuticals.

This failure is not only that of an ALS therapy, it is the overall failure of research on neurodegenerative diseases which is unable to produce results despite colossal investments (more than 500 unsuccessful clinical trials for ALS, nearly 2,500 unsuccessful clinical trials for Alzheimer's). These numbers are dizzying and insane.

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

Résultats décevants de l'étude VALOR sur le Tofersen (BIIB067)

- Posted in Résultats décevants de l'étude VALOR sur le Tofersen (BIIB067) by Français by

Biogen a annoncé les premiers résultats de son étude pivot de phase 3 VALOR sur le tofersen (BIIB067), un oligonucléotide antisens expérimental (ASO) en cours d'évaluation pour les personnes atteintes de sclérose latérale amyotrophique (SLA) et porteuse d'une mutation sur le gène SOD1.

Les résultats sont déprimants.

L'étude VALOR a montré qu'il n'y avait aucun ralentissement de la progression de la maladie, tel que la mesure le score global de l'échelle ALSFRS-R.

Cependant des améliorations sont apparues sur des points particuliers ou des aspects techniques.

En particulier la thérapie a bien atteint son but technique, même si cela ne se traduit pas en terme cliniques. La production de protéine SOD1 a bien été réduite, des différences ont été observées entre les groupes Tofersen et placebo de 38 % et 26 % dans les populations à progression plus rapide et plus lente respectivement.

En ce qui concerne la valeur initiale de la chaîne légère des neurofilaments plasmatiques (NfL), un marqueur potentiel de dégénérescence neuronale, des différences ont été observées entre les groupes tofersen et placebo de 67 % et de 48 % dans les populations à progression plus rapide et plus lente respectivement.

Dans la population qui progresse le plus rapidement, la fonction respiratoire a évoluée un peu moins vite que prévu (SVC) ; différence de 7,9 %). C'est aussi le cas pour la force musculaire.

Des événements neurologiques graves ont cependant été rapportés chez un patient sur vingt recevant du Tofersen, dont 2 cas de myélite (2,0 %). Un décès a été signalé dans le groupe traité au Tofersen dans l'étude VALOR, qui a été déterminé comme n'étant pas lié au Tofersen.

Tofersen se lie à l'ARNm de SOD1, permettant sa dégradation par la RNase-H1 pour réduire la synthèse de la production de protéines SOD1 mutantes.

L'idée qu'il faille réduire la production d'un gène muté est très courante chez les biologistes, elle est cependant contre-intuitive sur le plan médical. En effet nos gènes n'auraient pas été sélectionnés s'ils étaient inutiles, et qu'on pouvait les mettre "KO" sans conséquences graves. SOD1 est un gène qui est indispensable à la survie. Il est présent dans la plupart des organismes.

Par ailleurs, un ASO n'est efficace que pour un certain type de mutation, or il y a plus d'une centaine de mutations connues pour SOD1, certaines à progression très rapide, d'autres au contraire quasi inoffensives.

Si le problème était dû à un "gain de fonction" de la protéine mutée, alors il ne suffisait pas de réduire sa production, il fallait la corriger, ou augmenter la production de SOD2.

Tofersen est également à l'étude dans l'étude de phase 3 ATLAS, qui est conçue pour évaluer la capacité de Tofersen à retarder l'apparition clinique lorsqu'elle est initiée chez des individus présymptomatiques présentant une mutation génétique SOD1 et des preuves biomarqueurs de l'activité de la maladie.

Espérons que cet échec va déclencher une réflexion stratégique globale chez Biogen qui a déjà arrêté toute recherche sur la SLA en général, pour ce concentrer sur des segments jugés (à l'époque) moins risqués à travers des licenses avec Ionis Pharmaceuticals.

Cet échec n'est pas seulement celui d'une thérapie de la SLA, c'est globalement l'échec d'une recherche sur les maladies neurodégénérative qui est incapable de produire des résultats malgré des investissements colossaux (plus de 500 essais cliniques infructueux pour la SLA, près de 2500 essais cliniques infructueux pour Alzheimer). Les chiffres sont vertigineux et insensés, un sorcier Vaudou aurait statistiquement de meilleurs résultats.

Il est temps d'arrêter de recruter des "meilleurs élèves" ou des leaders d'opinion comme scientifiques, la société a besoin de personnes innovantes pas de scientifiques courants après leur carrière ou les plateaux de télévision.

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

Alzheimer may be a comorbidity of ALS

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As observed in other neurodegenerative conditions, mixed pathologies also exist in ALS. In similar fashion to TDP-43 pathology playing a role in Alzheimer disease, Shuangwu Liu, Chuanzhu Yan and colleagues suggest here that Alzheimer disease pathology also plays a role in ALS. Indeed they found alterations at early stage in the subiculum, which is located in the temporal lobe of the brain, a region different from the frontal lobe which hosts the motor cortex which is classically implicated in ALS.


enter image description here Source: Wikipedia. The temporal lobe is shown in green, while the motor area is in the frontal lobe in blue


ALS is now considered a multisystemic disorder in which almost half of patients present with varying degrees of cognitive deficits, yet unfolded TDP-43 aggregates in cytosol are found in most ALS cases.

TDP-43 pathology in ALS can be divided into four stages (Braak stages): it begins focally, and then spreads persistently in sequential and regional patterns that typically originate from the motor cortex and extend to the prefrontal cortex, thalamus and eventually, the hippocampus.

However neuroimaging studies of hippocampal volumes in patients with amyotrophic lateral sclerosis (ALS) have reported inconsistent results. The group of Chinese scientists from 10 institutions, aimed to demonstrate that such discrepancies are largely due to atrophy of different regions of the hippocampus that emerge in different disease stages of ALS and to explore the existence of co-pathology in ALS patients.

They used King’s clinical staging system for ALS to classify patients into different disease stages. The scientists then investigated in vivo hippocampal atrophy patterns across subfields and anterior-posterior segments in different King’s stages using structural MRI in 76 ALS patients and 94 health controls.

The thalamus, corticostriatal tract and perforant path were used as structural controls to compare the sequence of alterations between these structures and the hippocampal subfields.

In summary:

  • ALS patients at King’s stage 1, had lower volumes in the bilateral posterior subiculum and presubiculum;
  • ALS patients at King’s stage 2 exhibited lower volumes in the bilateral posterior subiculum, left anterior presubiculum and left global hippocampus;
  • ALS patients at King’s stage 3 showed significantly lower volumes in the bilateral posterior subiculum, dentate gyrus and global hippocampus. Thalamic atrophy emerged at King’s stage 3.

White matter tracts remained normal in a subset of ALS patients.

In the present study, the authors demonstrated that the earliest hippocampal alterations in ALS patients occurred in the posterior subiculum and presubiculum, and these alterations emerged at King’s stage 1. This indicates that subiculum atrophy occurs earlier and independent of TDP-43 pathology in ALS.


enter image description here Hagmann P, Cammoun L, Gigandet X, Meuli R, Honey CJ, et al. 


Taken together, their data suggest that patients with ALS have additional pathologies that are independent of TDP-43 pathology.

Increasingly, studies have shown that at least 20% of ALS patients present significant Alzheimer disease pathology of both Aβ and tau proteins. Recently, Gómez-Pinedo and colleagues showed that in ALS patients, the amyloid cascade of the amyloid precursor protein is activated in the hippocampus of ALS patients, and cytoplasmic Aβ peptide and pTDP-43 expression levels are moderately correlated.

Thus the motor cortex and subiculum seem to represent two independent centres of ALS during the early stages of the disease, which represent TDP-43 pathology and Alzheimer disease pathology, respectively, and these pathologies may converge as the disease progresses toward advanced stages.

If these findings are confirmed in further studies, they will have a profound effect on the understanding of the aetiology and pathogenic mechanisms underlying ALS and other neurodegenerative diseases.

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


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