Mitochondria are organelles that have their own genomes, which are small and only encode 13 proteins, compared to around 20,000 for the genome of human cells. By National Human Genome Research Institute - via Wikipedia

More than 1000 proteins are used by the mitochondria to perform their functions, the mitochondria therefore rely on the importation of proteins encoded in the nucleus of the host cell. The majority of mitochondrial proteins are synthesized in the cytosol and must be actively transported to the mitochondria, a process that occurs via a sophisticated system.

In many neurodegenerative diseases, there are dysfunctions in the management of proteins. This is called proteopathies. Proteopathies are found in diseases such as Creutzfeldt-Jakob disease and other prion diseases, Alzheimer's disease, Parkinson's disease, ALS and a wide range of other disorders.

Since proteins share a common structure known as the polypeptide backbone, all proteins have the potential to fold badly under certain circumstances. Mitochondrial defects might be responsible in part for those misfolded proteins that accumulate in the cytosol.

However, it is still unclear whether mitochondrial defects appear as a consequence of neurodegeneration, or if they contribute to it, or both. Since the accumulated mitochondrial protein precursors can form toxic aggregates, host cells have a mechanism to respond to and cope with them properly.

In an excellent eLife publication, Urszula Nowicka and colleagues at the University of Warsaw hypothesized that mitoprotein-induced stress induces a general response to precursor proteins which then accumulate in the cytosol and this contributes to the onset and progression neurodegenerative disorders. In this study, the authors propose a new mechanism of proteostasis.

Studies have shown that specific mitochondrial proteins that are functionally related to oxidative phosphorylation are downregulated by transcription in Alzheimer's disease. In the present study, scientists at the University of Warsaw investigated why these proteins are downregulated.

They used yeast homologues of these proteins to show the consequences of this cytosolic accumulation as well as of C. elegans worms. They applied mutations to the import machines, overexpression of mitochondrial proteins and CCCP (a decoupler of oxidative phosphorylation). They studied two disease-relevant aggregation models - α synuclein and Amyloid beta aggregation.

They found that importation of compromised mitochondrial proteins caused overall changes in the levels of transcriptome and proteins, especially chaperones, including Hsp104 and Hsp42, ABC transporters and mitochondrial proteins, which can lead to growth defects. (yeast) and decreased motility (C. elegans).

This new hypothesis complements the recent findings very well that unprocessed (but imported!) Precursor proteins aggregate in the mitochondrial matrix and initiate an mtUPR-like response.

These proteins trigger a molecular chaperone response specific to the host cell that aims to minimize the consequences of protein aggregation. However, when this rescue mechanism is insufficient, these aggregates stimulate cytosolic aggregation of other mitochondrial proteins and lead to downstream aggregation of non-mitochondrial proteins.

The present study showed that a group of mitochondrial proteins that are downregulated in Alzheimer's disease (i.e. Rip1, Atp2, Cox8 and Atp20) can aggregate in the cytosol and that the overexpression of these proteins upregulates Hsp42 and Hsp104, two molecular chaperones. Cellular stress responses induced by mitochondrial proteins mitigate the danger.

Urszula Nowicka's findings indicate why and how metastable mitochondrial proteins can be downregulated during neurodegeneration to minimize the imbalance in cellular protein homeostasis caused by their poor targeting.

Several stress response pathways have recently been identified to counteract import defects in mitochondrial proteins. It is not known, however, whether they act independently or whether simultaneous actions of all of these stress responses are necessary to ensure balanced homeostasis of cellular proteins.

It is likely that the study of the mechanisms of protection against stress, whether at the cellular level or at the mitochondrial level, will make it possible to better understand neurodegenerative diseases and to develop drugs to treat them.

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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.

The previous revision of this book was done in February 2021. The new version has fewer pages because it focuses on research and less on clinical trials.

At that time, we were still awaiting the results of clinical trials with Arimoclomol. What a disappointment after that of Nurown! There may be a few lessons in this debacle, that a small molecule cannot help stop the progression of ALS (the corollary being that ALS is not due to single molecular dysfunction like a failed cell receptor) and that a single drug cannot be effective in the face of the diversity of cases encountered in a clinical trial.

There has been little news on the research front in 2021, especially compared to 2020.

On a regulatory front, what is a bit surprising is the turnaround of the FDA decision on AMX0035 under. the pressure of public opinion. AMX0035 is not a cure, during a clinical trial it can extend life expectancy by 6 months, which is both a lot and too little.

The only therapy that would be effective in stopping the progression of most cases of ALS is a TDP-43 therapy. A number of these therapies have been designed in laboratories for a few years, but no company has taken the risk of doing a clinical trial. Instead, companies prefer to bet on new compounds made from existing drugs, which helps speed up the passage of regulatory hurdles. A godsend for any investor including, curiously, some NGOs.

This once again illustrates how disorganized our pharmaceutical industry is. The biotechs care little about academic research, which is of poor quality anyway. Biotechs just want a quick payoff as they are essentially a gamble for investors, but they have a high death rate anyway. Large companies wait for successful biotechs, but generally do not research rare diseases because they are deemed unprofitable.

The new version of the book has also been updated in the last part which deals with the generation of new motor neurons in-vivo. This is the only way to restore health. Yet we have learned that new motor neurons derived from the patient's astrocytes are also carriers of the disease, so there is a phenomenon here that is not well understood.

Perhaps ALS and other neurodegenerative diseases belong to a spectrum of diseases where cells are not functional, for example because they are in a perpetual UPR / ISR state. An Italian clinical trial hints at something like this, let's hope Sephin1 / IFB-088 will be tried soon and give good news.

The French book is still not updated.

Otherwise the best advice ALS patients could be given in 2021 is still to keep their BMI at 27.

Jean-Pierre Le Rouzic Please do not hesitate to send me any feed-back

The ability to generate in-vivo spinal cord motor neurons from human pluripotent stem cells would be a major milestone in motor neuron-based diseases such as ALS.

A key step in the design of human pluripotent stem cells differentiation strategies aiming to produce in-vitro motor neurons involves induction of the appropriate anteroposterior (A-P) axial identity, an important factor influencing motor neuron subtype specification, functionality, and disease vulnerability.

The anterior grey column contains motor neurons that affect the skeletal muscles while the posterior grey column receives information regarding touch and sensation. The anterior grey column is the column where the cell bodies of alpha motor neurons are located.

In-vitro generation of neural progenitors from human pluripotent stem cells holds a great promise for the development of cell-therapy-based approaches and the study of the specification of lineages and hence has attracted a considerable amount of research interest.

The protocols reported in literature generally are based on a multistep process that includes multiple neural induction, differentiation and maturation phases. This multistep process last weeks.

Scientists have previously described the generation of neural crest populations corresponding to various levels along the anteroposterior (A-P) axis from human pluripotent stem cells, including vagal neural crest (Frith et al., 2018). Yet stem cell derived motor neurons are often functionally immature.

Neural crest is a temporary group of cells unique to vertebrates that arise from the embryonic ectoderm germ layer, and in turn give rise to a diverse cell lineage—including melanocytes, craniofacial cartilage and bone, smooth muscle, peripheral and enteric neurons and glia. The ectoderm is the outermost layer of the three primary germ layers formed in early embryonic development.

To date, differentiation strategies have either implemented human pluripotent stem cells in the presence of EGF, FGF signals (Li et al., 2018; Workman et al., 2017) or employed a monolayer differentiation approach that relies on transforming growth factor β (TGF-β) signaling suppression, bone morphogenetic protein (BMP) signaling regulation and WNT pathway stimulation to generate an neural crest like population (Barber et al., 2019; Lau et al., 2019).

Patterning of the in vitro derived neural crest to a vagal axial identity is routinely achieved by retinoic acid (RA) addition while further commitment has been mediated by co-culture with intestinal/colonic organoids (Lau et al., 2019), gut tissue explants (Li et al., 2018), or further differentiation following culture in neurotrophic medium (Barber et al., 2019; Lau et al., 2019).

An efficient method of directed differentiation, generates progenitors from human pluripotent stem cells via the combined WNT signaling stimulation and TFG-β pathway inhibition together with precise levels of bone morphogenetic protein signaling.

Most current protocols for induction of motor neurons from human pluripotent stem cells produce predominantly cells of a mixed hindbrain/cervical axial identity marked by expression of Hox paralogous group (PG) members 1-5, but are inefficient in generating high numbers of more posterior thoracic/lumbosacral Hox PG(8-13)+ spinal cord motor neurons.

Here, the authors describe a protocol for efficient generation of thoracic spinal cord cells and motor neurons from human pluripotent stem cells. This step-wise protocol relies on the initial generation of a neuromesodermal-potent axial progenitor population, which is differentiated first to produce posterior ventral spinal cord progenitors and subsequently to produce posterior motor neurons exhibiting a predominantly thoracic axial identity.

Replacing defective neurons is an attractive goal in diseases such as Parkinson's disease or ALS, but one that still seemed unrealistic. Recently impressive progress has been made.

Parkinson's disease is a neurodegenerative disorder caused by the selective degeneration of dopaminergic cells in the substantia nigra leading to major problems in the motor system. The substancia nigra is a tiny part of the mid brain. Source Wikipedia: FrozenMan - Own work

One futuristic therapeutic approach for Parkinson's disease is dopaminergic cell-replacement therapy, in which dopaminergic precursors are grafted into the striatum to restore the lost dopaminergic neurotransmission.

Previous clinical trials based on foetal dopamine neuron transplantation have shown promising results, but also significant limitations including the survival of grafted dopaminergic neurons, which is very poor.

A major limiting factor for cell therapy in Parkinson's disease is the poor survival and reinnervation capacity of grafted dopaminergic neurons.

Major factors responsible for the high levels of dopaminergic cell loss during the transplantation process and early post-transplantation period have not been totally clarified. However, grafting-related cell trauma, lack of growth factors, poor vascularization, neuroinflammation and other factors have been involved.

MSCs have been effective against several of the above-mentioned factors, and a neuroprotective effect on grafted dopaminergic neurons could be expected. Mesenchymal stromal cells are multipotent cells originally isolated from the stroma of the bone marrow. Different studies have shown their capability to regulate the local environment through the release of immunomodulatory, antiapoptotic and trophic factors. These properties make them an attractive cell source for repairing damaged tissue.

In this work, Jannette Rodriguez-Pallares and colleagues from Spain, investigated whether co-grafting of MSCs could improve the survival and reinnervation ability of dopaminergic precursors transplanted in animal models of Parkinson's disease.

Rats with total unilateral dopaminergic denervation were grafted with a cell suspension of rat dopaminergic precursors (500,000 cells) with or without a high (200,000 cells) or low (25,000 cells) number of MSCs. Eight weeks after grafting, rats were tested for motor behaviour and sacrificed for histological analysis.

Results showed that the survival of dopaminergic neurons and graft-derived striatal dopaminergic innervation was higher in rats that received co-grafts containing a low number of MSCs than in non-co-grafted controls.

Surprisingly, the increase in the number of co-grafted MSCs led to detrimental effects. The mechanisms responsible for this effect are still unclear. A high concentration of MSCs may induce MSC senescence, damaged mitochondrial transfer or dysregulation of pro-inflammatory cytokine production.

In conclusion, co-grafting with MSCs or MSCs-derived products may constitute a useful strategy to improve dopaminergic graft survival and function. However, a tight control of MSCs density or levels of MSCs-derived products is necessary.

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Premorbid body mass index, physical activity, diabetes and cardiovascular disease have been associated with an altered risk of developing amyotrophic lateral sclerosis (ALS).

A very large prospective on UK Biobank was published in BMJ. It permits the study of a range of metabolic parameters and the risk of subsequent diagnosis of ALS.

The UK Biobank is a prospective cohort study of over 500 000 people aged between 39 and 72 years (www.ukbiobank.ac.uk).

The risk of subsequent Amyotrophic Lateral Sclerosis diagnosis in those enrolled prospectively to the UK Biobank was examined in relation to baseline levels of blood high and low density lipoprotein, total cholesterol, total cholesterol:HDL ratio, apolipoproteins A1 and B, triglycerides, glycated haemoglobin A1c and creatinine, plus self-reported exercise and body mass index.

Controlling for age and sex, higher HDL and apoA1 were associated with a reduced risk of Amyotrophic Lateral Sclerosis.

High-density lipoprotein (HDL) is one of the five major groups of lipoproteins. Increasing concentrations of HDL particles are associated with decreasing accumulation of atherosclerosis within the walls of arteries, reducing the risk of vascular diseases. HDL particles are commonly referred to as "good cholesterol",

On contrary higher total cholesterol versus HDL was associated with an increased risk of Amyotrophic Lateral Sclerosis.

Coronary artery disease, cerebrovascular disease and increasing age were also associated with an increased risk of Amyotrophic Lateral Sclerosis.

The association of HDL, apoA1 and LDL levels with risk of Amyotrophic Lateral Sclerosis contributes to an increasing body of evidence that the premorbid metabolic landscape may play a role in ALS pathogenesis, at least for a subset of patients.

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Electrical impedance myography (EIM) technology is finding application in neuromuscular disease research as a tool to assess muscle health.

Correlations between electrical impedance myography outcomes, functional, imaging and histological data have been established in a variety of neuromuscular disorders.

Electrical impedance myography (EIM) is a non-invasive technique for the evaluation of neuromuscular disease that relies upon the application and measurement of high-frequency, low-intensity electrical current.

The EIM technique has proven useful in the diagnosis of radiculopathy, with specificity and sensitivity similar to that of needle electromyography (EMG).

Unlike needle EMG, however, there is no dichotomous outcome (e.g., presence vs absence of fibrillation potentials). For this reason and also because there is a fairly wide range of normal values, in order to employ EIM for this purpose, it is necessary to compare measures on the affected side to those on the unaffected side.

Differing results notwithstanding, the concept of using impedance to measure contractile properties in health and disease is attractive as it could offer new insights into the mechanics of muscle contraction, one area in which standard electrophysiologic techniques are relatively weak. In fact, current standard approaches such as needle EMG or nerve conduction studies only measure up to the point of muscle fiber depolarization, ignoring entirely the contractile process itself.

The tongue is an extraordinarily complex muscle, with fibres running through multiple planes. Thus, assessment of muscle impedance in a number of different directions using multiple frequencies should encapsulate maximal information.

Yet, a potential problem lies in interpreting this large amount of data to give an objective measure of disease. Thus, decomposition of the data is required in order to draw out the most important features and facilitate interpretation/graphical representation.

The authors of this article used a new dimension reduction technique (Non-negative tensor factorisation), to provide a framework for identifying clinically relevant features within a high dimensional EIM dataset.

Non-negative tensor factorisation was applied to the dataset for dimensionality reduction. It provides highly significant differentiation between healthy and Amyotrophic Lateral Sclerosis patients.

Similarly this new technique to analyze datasets differentiates between mild and severe disease states and significantly correlates with symptoms.

Tensor EIM thus can provide clinically relevant metrics for identifying Amyotrophic Lateral Sclerosis- related muscle disease.

This procedure has the advantage of using the whole spectral dataset, with reduced risk of overfitting. The process identifies spectral shapes specific to disease allowing for a deeper clinical interpretation.

Des scientifiques Japonais, dont le célèbre spécialiste de la SLA Makoto Urushitani , ainsi que le premier auteur Ryutaro Nakamura, ont voulu étudier si l'hypermétabolisme, mais aussi le métabolisme des lipides, pouvait prédire le pronostic de patients atteints de sclérose latérale amyotrophique (SLA) précoce, ayant des profils nutritionnels différents lors de leur hospitalisation.

En effet de nombreux éléments montrent l'importance du traitement non pharmacologique qui peut améliorer la qualité de vie, diminuer la progression ou augmenter la durée de survie lors de la SLA.

L'introduction précoce de la ventilation à pression positive non invasive, en particulier avec les dispositifs d'assistance à la toux, prolongerait la durée de vie de la SLA.

De plus un régime riche en calories ralentit efficacement la progression de la SLA, en particulier chez les patients à progression rapide.

Étonnamment, dans la SLA à progression rapide, un régime hypercalorique à dominance grasse inhibe l'élévation du neurofilament-L (NFL) sérique, un biomarqueur convaincant des dommages neuronaux.

Un indice de masse corporelle (IMC) inférieur à 18,5 lors de la première visite chez les neurologues est reconnu comme un facteur de mauvais pronostic.

Malgré ces éléments cliniques, et bien que de nombreuses études aient montrées que l’âge et l’IMC sont les meilleurs marqueurs biologiques pour prédire l’évolution de la SLA, ces études se heurtent à une sorte de barrière narrative consensuelle qui dit que la SLA est une maladie des neurones moteurs supérieurs et que la perte de masse musculaire est exclusivement due à l’absence d’activation par les neurones moteurs inférieurs.

De façon similaire alors que les scientifiques disent qu’une protéopathie de type TDP-43 est présente dans l’ensemble des cellules du corps des malades, particulièrement dans les muscles squelettiques (ceux impliqués dans la SLA) dans 97 % des cas, il semble bien improbable que la SLA ne ciblerait que certaines cellules et uniquement dans le cerveau et la moelle épinière.

Enfin, plus de la moitié des patients de la SLA sont atteints d’hypermétabolisme, c’est-à-dire que pour effectuer une certaine tâche, leur corps a besoin de davantage d’énergie que le corps d’une personne en bonne santé.

Les patients atteints de SLA ont une tolérance au glucose qui est altérée dès un stade précoce, et les acides gras libres sont plus élevés chez ces patients que chez ceux ayant une tolérance normale au glucose. Il a été rapporté que la voie de production d'énergie passe du métabolisme glycolytique au métabolisme lipidique au cours de la maladie.

Cela indique que les lipides pourraient être le principal carburant chez les patients souffrant de malnutrition ainsi que chez les souris SLA, bien qu'aucune étude n'ait examiné les changements du métabolisme en réponse à l'état nutritionnel des humains.

Des taux élevés de cholestérol total et de cholestérol à lipoprotéines de basse densité (LDL) et un rapport LDL/cholestérol à lipoprotéines de haute densité (HDL) plus élevé ont été associés à une survie plus longue, ce qui pourrait indiquer un métabolisme utilisant principalement les lipides plutôt que le glucose.

Par conséquent, Ryutaro Nakamura et ses collègues ont examiné rétrospectivement les informations disponibles sur quarante-huit patients (25 hommes ; 23 femmes) de plus de 49 ans, atteints de SLA et admis à l'hôpital de l'Université des sciences médicales de Shiga de mars 2018 à février 2021.

Le but des scientifiques était de tester l'hypothèse selon laquelle l'impact de l'hypermétabolisme sur la survie pourrait différer selon l'état nutritionnel.

Fig. 1: Comparaison du taux de survie entre le groupe hypermétabolique et le groupe métabolique normal chez tous les patients (a), le groupe de poids normal (b), le groupe de malnutrition (c). Les analyses de Kaplan-Meier et le test du log-rank ont montré qu'il n'y avait pas de différence chez tous les patients ; cependant, le groupe hypermétabolique avait un temps de survie significativement plus court dans le groupe de poids normal et un temps de survie plus long dans le groupe malnutrition, bien que la différence ne soit pas significative.

Fig. 2: Comparaison du taux de survie entre les patients atteints de sclérose latérale amyotrophique stratifiée par perte de poids excessive (a), pourcentage de graisse corporelle (b) et cholestérol à lipoprotéines de basse densité (LDL) (c). les analyses ont montré que les patients avec une perte de poids excessive et un faible pourcentage de graisse corporelle avaient un temps de survie significativement plus court.

Dans cette étude, les scientifiques Japonais ont exploré l'effet de l'hypermétabolisme sur la survie par rapport à l'état nutritionnel des patients atteints de SLA, et ont constaté que les patients hypermétaboliques avec un poids normal avaient une survie plus courte, alors que la survie était plus longue chez les patients hypermétaboliques souffrant de malnutrition. Ils constatent que la survie est corrélée avec le taux de LDL.

Le niveau faible de muscle squelettique et de masse des tissus mous, qui est un facteur de mauvais pronostic, pourraient être la raison pour laquelle le pronostic du groupe hypermétabolique de poids normal est plus mauvais que celui des autres groupes.

Étonnamment, l'hypermétabolisme était un meilleur facteur pronostique dans le groupe malnutrition (Fig. 1). Les biomarqueurs lipidiques étaient caractéristiques dans ce groupe, ce qui pourrait contribuer à une survie plus longue.

Le groupe de malnutrition hypermétabolique avait la valeur médiane de LDL la plus élevée parmi tous les groupes, et un pourcentage de graisse corporelle plus élevé, qui étaient de bons facteurs pronostiques dans les études précédentes.

En effet, les patients avec un pourcentage de graisse corporelle élevé avaient une survie plus longue dans leur étude (Fig. 2), et les patients avec un LDL élevé ont montré une tendance similaire.

Il convient de noter que le quotient respiratoire était inférieur à 0,85 chez huit des neuf patients de ce groupe et que la glycémie à jeun était significativement plus élevée dans ce groupe, ce qui pourrait indiquer un changement du métabolisme lipidique par rapport à l'hypothèse de glucose.

Le quotient respiratoire était associé à l'ALSFRS-R et au temps écoulé depuis le début, et il est intéressant d'émettre l'hypothèse qu'un « commutateur de carburant » puisse sous-tendre les profils métaboliques dans la progression de la SLA.

De plus, Steyn et al. ont rapporté qu'une oxydation élevée des acides gras augmente la dépense énergétique du corps entier et ralentit la progression de la maladie, ce qui pourrait étayer les résultats décrits ici et indiquer la contribution du métabolisme hyperlipidique à une survie plus longue. ces résultats mettent en garde contre la mesure de l'hypermétabolisme comme seul indicateur de pronostic.

Sur la base de l'implication possible de l'hypermétabolisme des muscles squelettiques dans le pronostic de la SLA, les scientifiques Japonais proposent l'équation suivante «BMM = (IMC − 19,8) × (mREE/LSTM − 38) », qui a prédit avec succès le facteur pronostique, quels que soient les états nutritionnels. BMM = BMI-métabolisme musculaire mREE = dépense énergétique au repos mesurée LSTM = masse maigre des tissus mous

En conclusion, ces travaux démontrent qu'une perte de poids de plus de 10 % était un facteur de mauvais pronostic. Le taux de perte de poids était plus rapide dans le groupe à indice BMM élevé ; ainsi, l'indice BMM pourrait être un indicateur précieux pour envisager une intervention nutritionnelle agressive, y compris le PEG (gastrostomie endoscopique percutanée), à un stade précoce de la pratique clinique.

La supplémentation calorique riche en graisses ou en glucides est encore un sujet de débat. Certains rapports suggèrent que la supplémentation en calories riches en graisses est un meilleur traitement nutritionnel chez les patients atteints de SLA, tandis que d'autres recommandent une supplémentation en calories riches en glucides.

Pour les patients atteints de maladie pulmonaire obstructive chronique qui ont des émissions de CO2 réduites, un régime riche en graisses est recommandé car le métabolisme des lipides produit moins de dioxyde de carbone. Sur la base de leur résultat selon lequel la tendance à la modification des lipides pourrait contribuer à un meilleur pronostic, un apport riche en graisses pourrait être une option attrayante dans un régime riche en calories pour la SLA. Bien entendu, le choix de la nutrition doit être fait avec prudence, en fonction des profils métaboliques des patients.

La définition que les auteurs ont adoptée pour l'hypermétabolisme est un mREE/LSTM élevé, plutôt que l'indice mondial populaire, mREE/pREE, car le PRE estimé par l'équation de Harris-Benedict ne serait pas approprié pour l'évaluation métabolique des Japonais.

Japanese scientists, including the famous ALS specialist Makoto Urushitani, as well as the first author Ryutaro Nakamura, wanted to study whether hypermetabolism, but also lipid metabolism, could predict the prognosis of patients with Early amyotrophic lateral sclerosis (ALS), with different nutritional profiles when they are hospitalized.

Indeed, many elements show the importance of non-pharmacological treatment which can improve quality of life, decrease progression or increase survival time in ALS.

The early introduction of non-invasive positive pressure ventilation, especially with cough assistants, would prolong the life of ALS.

In addition, a high calorie diet effectively slows the progression of ALS, especially in patients with rapid progression.

Surprisingly, in rapidly progressing ALS, a fat-dominant high calorie diet inhibits the elevation of serum neurofilament-L (NFL), a convincing biomarker of neuronal damage.

A body mass index (BMI) of less than 18.5 on the first visit to neurologists is recognized as a factor of poor prognosis.

Despite these clinical evidence, and although many studies have shown that age and BMI are the best biomarkers for predicting the course of ALS, these studies encounter a sort of consensus narrative barrier that says ALS is a disease of the upper motor neurons and the loss of muscle mass is exclusively due to the lack of activation by the lower motor neurons.

Similarly while scientists say that TDP-43-like proteopathy is present in all cells of the body of patients, particularly in skeletal muscles (those involved in ALS) in 97% of cases, it seems it is unlikely that ALS would target only certain cells and only in the brain and spinal cord.

Finally, more than half of ALS patients have hypermetabolism, that is, to perform a certain task, their body needs more energy than the body of a healthy person.

Patients with ALS have impaired glucose tolerance from an early stage, and free fatty acids are higher in these patients than in those with normal glucose tolerance. The energy production pathway has been reported to switch from glycolytic metabolism to lipid metabolism during disease.

This indicates that lipids could be the primary fuel in malnourished patients as well as in ALS mice, although no studies have examined changes in metabolism in response to nutritional status in humans.

Elevated levels of total and low density lipoprotein (LDL) cholesterol and a higher LDL / high density lipoprotein (HDL) cholesterol ratio have been associated with longer survival, which could indicate a metabolism primarily using lipids rather than glucose.

Therefore, Ryutaro Nakamura and colleagues retrospectively reviewed the available information on forty-eight patients (25 men; 23 women) over 49 years of age with ALS admitted to Shiga University of Medical Sciences Hospital. from March 2018 to February 2021.

The aim of the scientists was to test the hypothesis that the impact of hypermetabolism on survival might differ depending on nutritional status.

Fig. 1: Comparison of the survival rate between the hypermetabolic group and the normal metabolic group in all patients (a), the normal weight group (b), the malnutrition group (c). Kaplan-Meier analyzes and the log-rank test showed that there was no difference in all patients; however, the hypermetabolic group had a significantly shorter survival time in the normal weight group and a longer survival time in the malnutrition group, although the difference was not significant.

Fig. 2: Comparison of survival rate between patients with amyotrophic lateral sclerosis stratified by excessive weight loss (a), body fat percentage (b) and low density lipoprotein (LDL) cholesterol (c). analyzes showed that patients with excessive weight loss and a low percentage of body fat had a significantly shorter survival time.

In this study, Japanese scientists explored the effect of hypermetabolism on survival versus nutritional status of patients with ALS, and found that hypermetabolic patients with normal weight had a shorter life, while survival was longer in hypermetabolic patients with malnutrition. They find that survival is correlated with LDL levels.

The low level of skeletal muscle and soft tissue mass, which is a factor of poor prognosis, could be the reason why the prognosis of the normal weight hypermetabolic group is worse than that of the other groups.

Surprisingly, hypermetabolism was a better prognostic factor in the malnutrition group (Fig. 1). Lipid biomarkers were characteristic in this group, which may contribute to longer survival.

The hypermetabolic malnutrition group had the highest median LDL value among all groups, and a higher body fat percentage, which were good prognostic factors in previous studies.

Indeed, patients with a high body fat percentage had a longer survival in their study (Fig. 2), and patients with high LDL showed a similar trend.

It should be noted that the respiratory quotient was less than 0.85 in eight of the nine patients in this group and that the fasting blood sugar was significantly higher in this group, which could indicate a change in lipid metabolism compared to the glucose hypothesis.

Respiratory quotient was associated with ALSFRS-R and time from onset, and it is interesting to hypothesize that a "fuel switch" may underlie metabolic profiles in progression. of ALS.

In addition, Steyn et al. reported that high fatty acid oxidation increases whole body energy expenditure and slows disease progression, which may support the findings described here and indicate the contribution of hyperlipid metabolism to longer survival. these results caution against measuring hypermetabolism as the only prognostic indicator.

Based on the possible involvement of skeletal muscle hypermetabolism in the prognosis of ALS, Japanese scientists propose the following equation "BMM = (BMI - 19.8) × (mREE / LSTM - 38)", which successfully predicted the prognostic factor regardless of nutritional status. BMM = BMI-muscle metabolism mREE = measured rest energy expenditure LSTM = lean soft tissue mass

In conclusion, these studies show that a weight loss of more than 10% was a factor of poor prognosis. The rate of weight loss was faster in the high BMM group; thus, the BMM index could be a valuable indicator for considering aggressive nutritional intervention, including PEG (percutaneous endoscopic gastrostomy), at an early stage of clinical practice.

Calorie supplementation high in fat or carbohydrate is still a matter of debate. Some reports suggest that high-fat calorie supplementation is a better nutritional treatment in patients with ALS, while others recommend high-carbohydrate calorie supplementation.

For patients with chronic obstructive pulmonary disease who have reduced CO2 emissions, a high fat diet is recommended because lipid metabolism produces less carbon dioxide. Based on their finding that the tendency to alter lipids might contribute to a better prognosis, a high fat intake might be an attractive option in a high calorie diet for ALS. Of course, the choice of nutrition should be made with caution, depending on the metabolic profiles of the patients.

The definition the authors adopted for hypermetabolism is a high mREE / LSTM, rather than the popular world index, mREE / pREE, as the PRE estimated by the Harris-Benedict equation would not be appropriate for the assessment. metabolic rate of the Japanese.