Un grand pas en avant dans la recherche sur la SLA?

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Si de nombreux défauts génétiques ont été impliqués dans la SLA (maladie de Charcot), les plus courants sont C9orf72, SOD1 et TARDBP. Ces défauts génétiques ne se retrouvent que chez 20% des cas, alors que dans la très grande majorité des cas de SLA on trouve des agrégats de protéines (essentiellement TDP-43) dans le cytosol des cellules.

Très récemment il a été annoncé qu'un grand pas en avant a été fait. Parmi les chercheurs impliqués on trouve Aaron D. Gitler, qui est un chercheur réputé dans le monde de la SLA. Ce grand pas a été fait par deux équipes indépendantes ce qui ajoute à la crédibilité de l'annonce.

Cependant l'annonce elle même interroge. Essentiellement elle consiste à dire que la déplétion nucléaire de TDP-43 réduit l'expression de UNC13A, un gène essentiel à la fonction neuronale normale. Dans ce modèle, une déplétion nucléaire sévère de TDP-43 dans la maladie en phase terminale induit une inclusion d'expression cryptique dans UNC13A dans tous les cas.

Dans ce cas cela ne devrait affecter qu'un cas sur cinq, puisque que c'est la fréquence approximative à laquelle est associé le variant rs12608932 de UNC13A avec la SLA.

La lecture des deux articles ne me permet pas de comprendre si le modèle proposé par les deux équipes explique la cause de l'épuisement nucléaire du TDP-43, ou encore la formation d'agrégats de TDP-43 dans le cytosol, ni pourquoi un tel défaut génétique frapperait de préférence les personnes âgées ?

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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 and physical activity

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There are no recommendations for physical activity in patients with amyotrophic lateral sclerosis (ALS), which is a little odd because the most striking feature of ALS is muscle wasting.

An immobilized person loses muscle in a few weeks and needs months or years to recover. If you add to muscle wasting, the fact that most ALS patients need far more calories than they are fed and can ingest, inactivity and inadequate diet are a recipe for disaster.

It is not necessary to invoke complex molecular events to understand why ALS leads to death within a few years.

Polish scientists therefore studied the relationship between physical activity and the rate of functional decline,

They assessed 96 ALS patients for 6 months at 3-month intervals for site of disease onset, disease duration, delay in diagnosis, functional status, muscle strength, fatigue, and prevalence. physical activity.

They found that 70% of patients engaged in regular physical activity and reported a positive effect of physical activity on functional status and mood. Individuals who exercised regularly showed a higher bulbar ALSFRS-R score and a smaller decline in ALSFRS-R respiratory subscore compared to patients who did not exercise regularly.

Counterintuitively, they found bulbar onset to be a negative prognostic factor for regular exercise.

The authors concluded that regular light physical activity may lead to a slower deterioration in functional status, particularly respiratory function.

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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.

Does the Heart Fall Asleep? - Diurnal Variations of Heart Rate Variability in Patients with Disorders of Consciousness

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The current study investigated heart rate (HR) and heart rate variability (HRV) across day and night in patients with disorders of consciousness (DOC). the authors recorded 24-h ECG in 26 patients with unresponsive wakefulness syndrome (UWS) and (exit) minimally conscious state ((e)MCS).

A persistent vegetative state or post-coma unresponsiveness is a disorder of consciousness in which patients with severe brain damage are in a state of partial arousal rather than true awareness. After four weeks in a vegetative state, the patient is classified as in a persistent vegetative state.

A minimally conscious state is a disorder of consciousness distinct from persistent vegetative state and locked-in syndrome. Unlike persistent vegetative state, patients with minimally conscious state have partial preservation of conscious awareness.

To examine diurnal variations, HR and HRV indices in the time, frequency, and entropy domains were computed for periods of clear day and nighttime.

Results indicate that patients interbeat intervals (IBIs) were larger during the night than during the day indicating heart rate slowing. Additionally, higher heart rate variability entropy was associated with higher EEG entropy during the night. Patients in unresponsive wakefulness syndrome showed larger interbeat intervals compared to patients in minimally conscious state, and patients with non-traumatic brain injury showed lower ECG entropy than patients with traumatic brain injury.

Thus, cardiac activity varies with a diurnal pattern in patients with disorder of consciousness and can differentiate between patients diagnoses and etiologies. Moreover, also the interaction of heart and brain appears to follow a diurnal rhythm.

Thus, heart rate and heart rate variability seem to mirror the integrity of brain functioning and consequently might serve as supplementary measures for improving the validity of assessments in patients with disorder of consciousness.

Read the original article on medRxiv

Liver diseases may be unrecognized risk factors for dementia.

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Medical textbooks tell that there are many subtypes of dementia:

  • Alzheimer's disease
  • Vascular
  • Lewy bodies
  • Parkinson's disease
  • Frontotemporal
  • Huntington's disease
  • HIV
  • Creutzfeldt-Jakob disease
  • Alcoholism

These well delineated classifications are based on molecular characteristics of certain proteins aggregates and often scientists do not agree with their peers which protein causes which disease.

In general there is no recognized biomarkers for such diseases which tells a lot about the confidence biologists have in their own art.

In addition it is clear from clinical trials that the idea that dementia are caused by protein clumps, are useless to design effective drugs.

There is growing recognition of the role of chronic liver disease in brain health, but the impact of liver fibrosis on dementia risk was unclear.

The liver is a major organ which supports almost every other organ in the body. It performs near 500 essential biological functions such as detoxification of the organism, and the synthesis of proteins and biochemicals necessary for digestion and growth.

The liver produces the enzyme catalase to break down hydrogen peroxide, a toxic oxidising agent, into water and oxygen. Indeed oxidation plays an important role in aging and neurodegenerative diseases. The oxidative capacity of the liver decreases with aging.

Scientists in this pre-print describe how they evaluated the association between liver fibrosis and incident dementia using data from a large prospective cohort study.

They performed a cohort analysis using data from the UK Biobank study, which prospectively enrolled approximately 500,000 adults starting 2007 and continues to follow them. Liver fibrosis was defined using validated cutoffs of the Fibrosis-4 (FIB-4) liver fibrosis score.

The FIB-4 Index is a blood-based diagnostic test that looks at underlying fibrosis that can be used as a measure to help determine NAFLD/NASH status. While originally developed to detect liver fibrosis among patients with Hepatitis C and HIV, FIB-4 scoring has been increasingly used by the diabetes and NAFLD/NASH. The FIB-4 scoring system is determined from the values of patient age, platelet count, aspartate aminotransferase (AST), and alanine aminotransferase (ALT).

The primary outcome was incident dementia, ascertained using a validated approach based on participants hospital record and mortality data. Secondary outcomes were Alzheimers disease and vascular dementia. The scientists here excluded participants with prevalent dementia.

The scientists evaluated the association between liver fibrosis and incident dementia while adjusting for potential confounders. Prespecified interaction analyses tested for effect modification by sex, metabolic syndrome, and apolipoprotein E4 carrier status. Among 455,226 participants included in this analysis, the mean age was 56.5 years and 54% were women. Standard liver chemistries were largely in the normal range. enter image description here

However, 2.17% had liver fibrosis based on their FIB-4 score. In this subset, the rate of dementia per 1,000 person-years was 1.76 in participants with liver fibrosis while the rate of dementia was 0.52 in those without liver fibrosis. So this provides a clear indication that liver diseases are somehow associated with dementia.

Many confounding factors could exist so after adjusting for demographics, socioeconomic deprivation, educational attainment, metabolic syndrome, hypertension, diabetes, dyslipidemia, tobacco and alcohol use, the scientists found that liver fibrosis was still associated with an increased risk of dementia.

The classic symptoms of liver damage include the following:

Pale stools occur when stercobilin, a brown pigment, is absent from the stool. Stercobilin is derived from bilirubin metabolites produced in the liver. Dark urine occurs when bilirubin mixes with urine Jaundice (yellow skin and/or whites of the eyes) This is where bilirubin deposits in skin, causing an intense itch. Itching is the most common complaint by people who have liver failure. Often this itch cannot be relieved by drugs.

John Trojanowski est décédé à l'âge de 75 ans

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John Q. Trojanowski est décédé le 8 février, à l'âge de 75 ans. Avec sa femme et partenaire de recherche de longue date, Virginia Lee, Trojanowski était une rockstar dans le domaine de la neurodégénérescence. enter image description here

Ses travaux couvraient un vaste domaine de recherche, qui comprenait la neuropathologie et la physiopathologie non seulement de la maladie d'Alzheimer, mais aussi des tauopathies et de la maladie de Parkinson.

Il était particulièrement passionné par les causes multifactorielles de la démence, des maladies cérébrovasculaires et d'autres pathologies comme causes et contributeurs au déclin cognitif et à la démence.

John a établi le rôle de l'α-synucléine dans la maladie d'Alzheimer et la démence à corps de Lewy, et a identifié la protéinopathie TDP-43 dans la dégénérescence lobaire frontotemporale, la sclérose amyotrophique et la maladie d'Alzheimer. C'était aussi un des partisans de l'importance de la protéine Tau dans la maladie d'Alzheimer.

Il était un partisan de l'examen de l'ensemble du spectre physiopathologique des troubles démentiels neurodégénératifs, plutôt que de se concentrer sur les aspects moléculaires.

Très tôt, il a reconnu et promu publiquement l'importance de l'exercice pour éviter la démence. Il se rendait au travail à vélo, tous les jours.

Association of cytoplasmic mislocalized FUS with mitochondrial dysfunction in skeletal muscles

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ALS (Lou's Gehrig's disease) is characterized by skeletal muscle weakness, spasticity and intense muscle wasting. By analogy with what happens following a spinal cord injury, scientists hypothesized a century ago that ALS is an upper motor neuron disease.

Scientists being very conservative, this hypothesis is still in force. ALS is even called MND in the UK because the wide and diverse spectrum of symptoms of ALS makes it difficult to categorize it as a single disease while it shares aspects with other neurodegenerative diseases such as FTD or Alzheimer's disease. Parkinsons.

However, the scientific literature displays a wide range of opinions on this subject since approximately a quarter of the articles argue for a disease that begins in the neuromuscular junctions or even in the muscles.

It is hardly surprising that few alternative hypotheses have developed about ALS because motor neurons are located entirely within the CNS, with a tight barrier separating it from the rest of the body. The CNS has its own mechanisms which are entirely different from the rest of the body, sometimes scientists joke that we are a chimera of two different organisms: the CNS and the rest of the body. However, it seems curious that a disease would only affect the upper motor neurons and not the other neurons, especially since ALS is sometimes associated with disorders that have nothing to do with motor, such as dementia.

Thus, research on skeletal muscle in ALS is always welcome on this blog. Mutations in the fused sarcoma (FUS) gene have been reported to be the most common genetic cause of early-onset amyotrophic lateral sclerosis (ALS).

Yet, the role of FUS in muscle degeneration remains unclear. In this study, Chinese scientists investigated the distribution of FUS proteins in skeletal muscle fibers in ALS-FUS. Their data show that mislocalized cytoplasmic FUS in the unaggregated form represented a remarkable pathologic feature in affected muscle fibers in ALS-FUS.

Additional studies found that cytoplasmic FUS colocalized with some mitochondria and was associated with mitochondrial swelling.

RNA sequencing and quantitative real-time polymerase chain reaction analyses indicated downregulation of the key subunits of mitochondrial oxidative phosphorylation complexes in the affected skeletal muscle in ALS-FUS patients.

Further immunoblot analysis showed increased levels of FUS, but decreased levels of Cox I (subunit of complex IV) in ALS-FUS patients compared with age-matched controls. Cytochrome c oxidase is a key enzyme in aerobic metabolism.

Mutations in Cox I lead to a wide variety of clinical manifestations ranging from isolated myopathy to a severe multisystem disease affecting multiple organs and tissues. Symptoms may include liver dysfunction, hypotonia, muscle weakness, exercise intolerance, delayed motor development, mental retardation, or a CNS disease: Leigh disease.

As this demonstrate association of cytoplasmic mislocalized FUS with mitochondrial dysfunction in skeletal muscle, this is further evidence that ALS is not just an upper motor neuron disease.

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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.

Keto diet and neurodegenerative diseases, caution is required

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Introduction The ketogenic diet has been used since the beginning of the 20th century to reduce the incidence of epileptic seizures, and over time its application to other diseases has been studied.

This diet is characterized by a high content of unsaturated fatty acids, few carbohydrates and a normal protein content. While in a traditional diet there is about 55% of the energy value in the form of carbohydrates, about 30% fat and 15% protein, these proportions in the classic ketogenic diet are 8% for carbohydrates, 90% for lipids and about 7% for proteins. The most common form of the ketogenic diet includes mostly long-chain fatty acids.

The drastic changes induced by the ketogenic diet in eating habits are difficult to maintain in a long-term perspective. This is because high volumes of high fat components in the diet (cheeses, eggs, butter, oils, meat, etc.) can lead to nausea, vomiting, constipation and loss of appetite.

Adverse effects of the ketogenic diet The ketogenic diet, as a high-fat, low-carb diet, is associated with some insufficiency in the energy value of food portions and leads to metabolic effects that ultimately reduce body weight. People suffering from neurodegenerative diseases are at high risk of malnutrition and therefore this type of diet seems a priori to be contraindicated for them. People with neurodegenerative diseases suffer from sarcopenia which is often fatal.

According to current recommendations, people at risk should consume 1.0 to 1.2 g of protein/kg per day, or even more if they are physically active. The ketogenic diet, particularly when the energy value of the diet decreases, may therefore lead to a protein intake that is too low, although its contribution to the energy value of the diet may be normal or even higher than recommended. Such a situation can lead to the catabolism of structural proteins (especially in the muscles).

In individuals with insulin resistance, diabetic acidosis can be identified, which is a disease state with ketone body concentrations above 25 mmol/L, resulting from insulin deficiency with a simultaneous increase in glucose concentration ( > 300 mg/dL) and a decrease in blood concentration. pH (pH < 7.3), which can cause death.

Ketogenic diet and Alzheimer's disease It is not easy to formulate a ketogenic diet, in fact saturated fatty acids are present everywhere in large quantities, particularly in foods associated with pleasure, desserts, dairy products, chocolates. Eating a single meal high in saturated fat is enough to reduce our ability to concentrate, much more than if it is a meal high in unsaturated fat. Epidemiological studies show that a diet rich in saturated fatty acids increases the risk of Alzheimer's disease.

Studies conducted on an animal model of Alzheimer's disease, however, indicate a possible beneficial effect of the ketogenic diet for this medical condition.

Reger et al. concluded that oral administration of medium-chain triglycerides elevates plasma levels of ketone bodies and may improve cognitive functioning in older adults with memory impairment.

Henderson et al. administered medium-chain triglycerides to subjects with mild and moderate Alzheimer's disease. Administration of this type of fat resulted in improved cognitive functioning. It should be noted, however, that no effect of this type was observed in subjects carrying the APOEε4 genotype.

Ota et al. administered medium-chain triglycerides to 20 patients with mild to moderate Alzheimer's disease. After 8 weeks, patients showed significant improvement in their immediate and delayed logical memory tests compared to their baseline score. At 12 weeks, they showed significant improvement in the Numerical Symbol Coding Test and Logical Immediate Memory tests compared to baseline.

In the Ketogenic Diet Retention and Feasibility Trial, 15 patients with Alzheimer's disease maintained a ketogenic diet supplemented with medium-chain triglycerides (approximately 70% of energy as fat, including triglycerides at medium chain; 20% of energy as protein; and less than 10% of energy as carbohydrate). They have observed that when fully achieved ketosis, the mean score of the cognitive subscale of the Alzheimer's Disease Rating Scale improved significantly during the diet but returned to baseline at its termination.

Krikorian et al. applied a high carbohydrate diet to 23 subjects with mild cognitive impairment. After 6 weeks of intervention, the authors observed an improvement in verbal memory performance in subjects on a low carbohydrate diet. The authors concluded that even short-term use of a low-carb diet could improve memory function in older adults at increased risk for Alzheimer's disease. Although the observed effect may be partly attributable to the correction of hyperinsulinemia, other mechanisms associated with ketosis, such as reduced inflammation and improved energy metabolism, may also have contributed to the improved neurocognitive functioning.

Adapted from "Role of Ketogenic Diets in Neurodegenerative Diseases (Alzheimer’s Disease and Parkinson’s Disease)" Dariusz Włodarek doi: 10.3390/nu11010169

Régime cétonique et maladies neurodégénératives, la prudence est de rigueur

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Introduction Le régime cétogène a été utilisé dès le début du XX siècle pour réduire l'incidence des crises d'épilepsie et, au fil du temps, son application à d'autres maladies a été étudiée,.

Ce régime se caractérise par une teneur élevée en acides gras non saturées, peu de glucides et une teneur normale en protéines. Alors que dans un régime traditionnel il y a environ 55% de la valeur énergétique sous forme de glucides, environ 30% de lipides et 15% de protéines, ces proportions dans le régime cétogène classique sont de 8% pour les glucides, 90% pour les lipides et environ 7% pour les protéines. La forme de régime cétogène la plus fréquente comprend principalement des acides gras à longue chaîne.

Les changements drastiques induits par le régime cétogène dans les habitudes alimentaires, sont difficiles à maintenir dans une perspective à long terme. En effet des volumes élevés de composants riches en matières grasses dans l'alimentation (fromages, œufs, beurre, huiles, viande, etc.) peuvent entraîner des nausées, des vomissements, de la constipation et une perte d'appétit.

Effets indésirables du régime cétogène Le régime cétogène, en tant que régime riche en graisses et pauvre en glucides, est associé à une certaine insuffisance de la valeur énergétique des portions alimentaires et conduit à des effets métaboliques qui finissent par réduire le poids corporel. Les personnes souffrant de maladies neurodégénératives sont à haut risque de malnutrition et donc ce type de régime semble à priori être contre indiqué pour elles. Les personnes atteintes de maladies neurodégénératives souffrent d’une sarcopénie qui est souvent fatale.

Selon les recommandations actuelles, les personnes à risque devraient consommer 1,0 à 1,2 g de protéines/kg par jour, voire plus si elles sont physiquement actives. Le régime cétogène, en particulier lorsque la valeur énergétique du régime diminue, peut donc conduire à un apport général en protéines trop faible, bien que sa contribution à la valeur énergétique du régime puisse être normale ou même supérieure à celle recommandée. Une telle situation peut conduire au catabolisme des protéines structurelles (en particulier dans les muscles).

Chez les personnes souffrant d'insulinorésistance, une acidose diabétique peut être identifiée, qui est un état pathologique avec des concentrations de corps cétoniques supérieures à 25 mmol/L, résultant d'un déficit en insuline avec une augmentation simultanée de la concentration en glucose (> 300 mg/dL) et une diminution de la concentration sanguine. pH (pH < 7,3), pouvant entraîner la mort.

Régime cétogène et maladie d'Alzheimer Il n’est pas aisé de formuler un régime cétogène, en effet les acides gras saturés sont partout présents en grande quantité, particulièrement dans les nourritures associées au plaisir, desserts, produits lactés, chocolats. Prendre un seul repas riche en graisses saturées suffit à diminuer notre capacité de concentration, nettement plus que s'il s'agit d'un repas en graisses non-saturées. Les études épidémiologiques démontrent qu'une alimentation riche en acides gras saturés augmente le risque de maladie d'Alzheimer.

Des études menées sur un modèle animal de la maladie d'Alzheimer indiquent cependant un effet bénéfique possible du régime cétogène pour cette condition médicale.

Réger et al. ont conclu que l'administration orale de triglycérides à chaîne moyenne entraînait une élévation des taux plasmatiques de corps cétoniques et qu'elle pouvait améliorer le fonctionnement cognitif chez les personnes âgées souffrant de troubles de la mémoire.

Henderson et al. ont administrés des triglycérides à chaîne moyenne à des sujets atteints de la maladie d'Alzheimer légère et modérée. L'administration de ce type de graisse la entraîné une amélioration du fonctionnement cognitif. Il convient cependant de noter qu'aucun effet de ce type n'a été observé chez les sujets porteurs du génotype APOEε4.

Ota et al. administré des triglycérides à chaîne moyenne à 20 patients atteints de la maladie d'Alzheimer légère à modérée. Après 8 semaines, les patients ont montré une amélioration significative de leurs tests de mémoire logique immédiate et différée par rapport à leur score de base. À 12 semaines, ils ont montré une amélioration significative du test de codage des symboles numériques et des tests de mémoire logique immédiate par rapport à la ligne de base.

Dans l'étude Ketogenic Diet Retention and Feasibility Trial, 15 patients atteints de la maladie d'Alzheimer ont maintenu un régime cétogène complété par des triglycérides à chaîne moyenne (environ 70 % de l'énergie sous forme de lipides, y compris les triglycérides à chaîne moyenne ; 20 % de l'énergie sous forme de protéines ; et moins de 10 % de l'énergie sous forme de glucides). Ils ont observé qu'en cas de cétose complètement atteinte, la moyenne du score de la sous-échelle cognitive de l'échelle d'évaluation de la maladie d'Alzheimer s'améliorait de manière significative pendant le régime mais revenait à son point de départ à sa cessation.

Krikorian et al. appliqué un régime riche en glucides chez 23 sujets présentant une déficience cognitive légère. Après 6 semaines d'intervention, les auteurs ont observé une amélioration des performances de la mémoire verbale chez les sujets sous régime pauvre en glucides. Les auteurs ont conclu que même l'utilisation à court terme d'un régime pauvre en glucides pourrait améliorer la fonction de mémoire chez les personnes âgées présentant un risque accru de maladie d'Alzheimer. Bien que l'effet observé puisse être attribuable en partie à la correction de l'hyperinsulinémie, d'autres mécanismes associés aux cétoses, tels que la réduction de l'inflammation et l'amélioration du métabolisme énergétique, peuvent également avoir contribué à l'amélioration du fonctionnement neurocognitif.

Adapté de "Role of Ketogenic Diets in Neurodegenerative Diseases (Alzheimer’s Disease and Parkinson’s Disease)" Dariusz Włodarek doi: 10.3390/nu11010169

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