Studies in health risks from medical radiation diagnostic procedures, radiotherapy and environmental nuclear contamination as well as for Earth-orbit and space missions have shown that low-dose irradiation (10 cGy) causes down-regulation of neural pathways associated with cognitive dysfunctions that are also down-regulated in normal human aging and Alzheimer's disease. Curiously Mice exposed to high-dose radiation (2 Gy)did not show these effects and associations. Intriguily, there are also reports indicating stimulatory or beneficial effects after exposure to cell phone radiofrequency radiation.

Increased brain glucose consumption after exposure to radiofrequency radiation, as confirmed by PET studies, may be a potential mechanism in this phenomenon. Some scientists think that this is related to the possible beneficial effects of infrared exposure that are sometimes asserted.

Moreover, Schuz et al. in 2009 reported that long-term cell phone users had a 30–40% decreased risk of hospitalization due to AD and vascular dementia!

Following similar observations, Beaumont Cancer Center in Michigan USA, began treated patients Alzheimer's disease with ionizing radiation at doses of 30 to 60 Gray (Gy) given in 2 Gy fractions.

In 2015 in Canada, a patient in hospice with Alzheimer's disease was treated with ionizing radiation to her brain using repeated CT scans. Improvement in cognition, speech, movement, and appetite was observed. These improvements were so momentous that she was discharged from the hospice to a long-term care home.

This was described in a report which was criticized for failing to acknowledge alternate hypotheses and confounding variables.

Two clinical trials were conducted in Canada with 5 patients in one case and 4 patients in the other, but no results were posted which presumably was due to an absence of positive results. Yet minor improvements on quantitative measures were noted. It should be noted that for having statistical significance a clinical trial should enroll several hundreds to thousands patients. Otherwise it's easy to make unsubstantiated claims.

A clinical trial with 5 patients was interrupted by COVID-19.

It seems history is repeated, a new publication describes another clinical trial with 5 patients, this time in USA at Barrow Neurological Institute.

Five patients were treated with LD-WBRT (a new acronym for radiotherapy) (2Gy x 5). Three subjects were female and two male. Four of the 5 patients experienced minimal improvement or stability in MMSE-2 scores comparing baseline before treatment and post-treatment scores at 12 months. The mini–mental state examination (MMSE) or Folstein test is a 30-point questionnaire that is used extensively in clinical and research settings to measure cognitive impairment. Three patients saw their scores improve, another remained stable, and the last experienced a considerable drop in the MMSE score. Curiously the publication does not provide any clinical trial registration number.

Parkinson patients sometimes complain that their symptoms are not due to their disease, but to their medication. This review shed some light on this problem.

For patients with Parkinson’s disease, dopamine replacement is the treatment of choice, and the most commonly used drug is levodopa (L-dopa), a dopamine precursor. Because dopamine itself cannot cross the blood-brain barrier (BBB) owing to its large molecular weight, L-dopa is administered.

However, L-dopa can easily convert to other structures, such as 3-O-methyldopa catalyzed by the enzyme catechol-O-methyl transferase (COMT) before it crosses the BBB or reaches the brain. To prevent this undesirable conversion, L-dopa is often prescribed along with COMT inhibitors, such as entacapone. Moreover, it can cause serious side effects, such as dyskinesia. It accelerates PD progression by inducing neuronal cell death through self-oxidation.

These treatments of Parkinson's disease tends to further elevate circulating homocysteine levels and peripheral nerves damage. High levels of homocysteine in the blood have been associated with certain pathologies, cardiac, neurological, rheumatic or psychiatric. Evidence exists linking elevated homocysteine levels with vascular dementia and Alzheimer's disease.

There is also evidence that elevated homocysteine levels and low levels of vitamin B6 and B12 are risk factors for mild cognitive impairment and dementia. Oxidative stress induced by homocysteine may also play a role in schizophrenia.

Accumulating deficiencies of B12, B6 vitamins and folic acid are presumed to be the substrate for the homocysteine elevation.

So B-vitamin therapy may reduce homocysteine levels. This begs the question of whether Parkinson's disease patients on levodopa should be concurrently treated with ongoing B-vitamin therapy. There is a substantial literature on this topic that has accumulated over the last quarter-century, and this topic is still debated.

This review summarizes the relevant literature with the aim of approximating closure on this issue. Also, noteworthy is that Parkinson's disease patients with renal insufficiency may not tolerate cyanocobalamin, the standard oral B12 supplement due to facilitation of renal decline.

Here are some key points: • Levodopa treatment of Parkinson's disease (PD) elevates circulating homocysteine levels. • Elevated homocysteine and/or B-vitamin depletion correlates with an increased risk of cognitive decline. • Lifetime monitoring of B-vitamin levels could address this problem. • It may be necessary to prescribe oral B12, B6, folic acid to levodopa-treated PD patients. • Levodopa-treated PD patients with renal insufficiency should take methylcobalamin rather than cyanocobalamin.

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A new article discusses recent technological advances in respiratory support and monitoring that have dramatically enhanced the utility of long-term noninvasive ventilation. With these technological advances, improvements in quality of life and prolonged survival at home have been demonstrated for several common chronic neuromuscular diseases. Many adults with progressive neuromuscular respiratory disease can now comfortably maintain normal ventilation at home to near total respiratory muscle paralysis without needing a tracheostomy. However, current practice in many communities falls short of that potential.

Mastery of the new technology calls for detailed awareness of the respiratory cycle, expert knowledge of mechanical devices, facial interfaces, quantitative monitoring tools for home ventilation, and a willingness to stay current in a rapidly expanding body of clinical research. The depth and breadth of the expertise required to manage home assisted ventilation is giving rise to a new focused medical subspecialty in chronic respiratory failure at the interface between pulmonology, critical care, and sleep medicine.

For clinicians seeking pragmatic "how to" guidance, this primer presents a comprehensive, physician-directed management approach to long-term noninvasive ventilation of adults with chronic neuromuscular respiratory disease.

Bilevel devices, portable ventilators, ventilation modalities, terminology, and monitoring strategies are reviewed in detail. Building on that knowledge base, the authors present a step-by-step guide to initiation, refinement, and maintenance of home noninvasive ventilation that is tailored to patient-centered goals of therapy.

The "quantitative" approach recommended here fully incorporates routine monitoring of home assisted ventilation using technologies that have only recently become widely available including cloud-based device telemonitoring and noninvasive measurements of blood gases. Strategies for troubleshooting and problem solving are included.

Here is the table of content of the document:

• PART I. DEVICES

Devices for home assisted ventilation

The assisted breathing cycle

Modes of assisted ventilation

Monitoring assisted ventilation

• PART II. MANAGEMENT

Indications for initiation of home noninvasive ventilation Initiation Phase

Adaptation and refinement phase

Maintenance phase

Diurnal ventilation

Tracheostomy

End of life respiratory care

• PART III. TROUBLESHOOTING AND PROBLEM SOLVING

Face mask discomfort

Excessive air leak

Excessive airway secretions

Upper airway resistance

Patient-ventilator asynchrony

Aerophagia

• Conclusion

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It is often observed that the central nervous system of higher primates is quite different from that of other mammals. For example, other mammals have inter-neurons between upper and lower motor neurons, while in higher primates there is a direct connection that could explain their better ability. This difference could explain why some mouse models are ineffective in modeling neurodegenerative diseases. Source: Peterwchen via Wikipedia

Neurodegenerative diseases are complex multifactorial conditions for which no effective treatments are currently available. Animal models are necessary to understand the causes and progression of neurodegeneration. Nonhuman primates offer significant advantages for the study of neurodegenerative disease.

Among them, the common marmoset, Callithrix jacchus, stands out due to its easy handling, complex brain architecture, and occurrence of spontaneous beta-amyloid and phosphorylated tau aggregates with aging.

Furthermore, marmosets present physiological adaptations and metabolic alterations associated with the increased risk of dementia in humans. In this review, the authors from Center of Research and Advance Studies, Mexico City, discuss the current literature on the use of marmosets as a model of aging and neurodegeneration.

The common marmoset is an important model partly because of their ability to live for an extended period after adulthood. Age-dependent cognitive changes in executive function and spatial working memory have been observed in marmosets. Marmosets display the spontaneous appearance of beta-amyloid aggregates with aging. Amyloid pathology starts as diffuse plaques in young animals. Tau hyperphosphorylation occurs in both young and aging marmosets. However, aged marmosets do not develop neurofibrillary tangles, perhaps due to different isoform expression or amino acid sequence compared with humans and Old World monkeys. Microglia dystrophy and atrophy of astrocytes are associated with neurodegenerative processes in aging marmosets. Common marmosets living in captivity develop various metabolic and gastrointestinal disorders, providing an opportunity to study potential links between metabolic or gut–microbiota alterations and vulnerability to neurodegeneration.

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Metabolism is the conversion of energy from food into energy for life-sustaining tasks such as breathing, circulating blood, building and repairing cells, digesting food, and eliminating waste. For sedentary adults, basal metabolic rate (the metabolic rate at rest) accounts for about 50% to 70% of total energy output, dietary thermogenesis for 10% to 15%, and physical activity for the remaining 20% to 30%.

At approximately 60 years old, BMR begin to decline, along with fat mass. However, declines in energy expenditure exceed that expected from reduced body mass alone. This is similar that what is found in several neurodegenerative diseases, albeit at a much slower rate.

Numerous studies suggest that metabolic dysfunction increases the risk of Alzheimer's disease. For instance, impaired glucose metabolism in the brain has been linked to Alzheimer's disease and may start several years before the onset of clinical symptoms.

Due to the long incubation period between exposure and results, randomized controlled trials, the gold standard for causal reasoning, are not feasible. In addition causation and confounding often substantially impede or mislead the interpretation of results from epidemiological studies. So scientists use Mendelian randomization, which is a method for obtaining unbiased estimates of the effects of a putative causal variable without conducting a traditional randomized controlled trial.

In a new publication, scientists determined the causal relationship between BMR and Alzheimer's disease by two-way Mendelian randomization and investigated the impact of factors associated with BMR on Alzheimer's disease.

The authors searched for a possible causal relationship between Alzheimer's disease and factors related with BMR, hyperthyroidism and type 2 diabetes, height and weight.

BMR was found to have a causal relationship with Alzheimer's disease, but there was no causal relationship between hyperthyroidism or type 2 diabetes in one hand and Alzheimer's disease in the other hand.

The authors' study showed that higher BMR reduced the risk of Alzheimer's disease, and patients with Alzheimer's disease had a lower BMR.

A person may be able to change their BMR through regular cardiovascular exercise.

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Le sujet de l’alimentation des malades de la SLA ne fait guère l’objet d’études. Pourtant les malades de la SLA, tout au moins tant qu’ils ne sont pas alités de façon permanente, doivent recevoir plus d’énergie (de calories) qu’une personne en bonne santé. Il y a un calculateur en ligne sur ce site.

Tout d’abord il y a des problèmes méchaniques évidents, difficulté à avaler, mucus, risque de fausse route, problème de digestion, appétence. Trop souvent la diète se limite à ajouter un produit industriel enrichie en protéines.

Ensuite il y a le problème du choix des aliments et la confusion que le personnel médical (en dehors bien entendu des spécialistes de la SLA) peut faire entre les besoin des personnes en bonne santé et ceux des malades de la SLA. En effet dans la population générale, des taux accrus de triglycérides sont associés à une mortalité accrue en raison d'événements cardiovasculaires et il est souvent recommandé de réduire cet apport. Pourtant on sait que les personnes ayant un IMC d’environ 27 (surpoids) ont les meilleurs chances de survie.

Contrairement à ce qui est souvent affirmé, la perte de poids dans la SLA n’est pas seulement due à l’inactivité des moto-neurones (ce qui est le cas des accidentés ayant une section de la moelle épinière), mais aussi à la présence d’un important catabolisme. C’est à dire à un rythme de destruction des protéines qui est supérieur à celui de leur création.

Des effets bénéfiques ont été rapportés pour les interventions avec des suppléments nutritionnels riches en graisses, y compris une survie prolongée chez les patients à évolution rapide, une diminution de la fonction motrice, une stabilisation du poids corporel et une réduction des biomarqueurs. Voir cette étude, ou celle ci, ou encore celle là

Les triglycérides sont produits principalement par les hépatocytes et les adipocytes et sont largement issus des aliments. La fonction principale des triglycérides est de stocker et de transporter l'énergie sous forme d'acides gras dans les cellules et de fournir des sources d'énergie dans un état de pénurie de glucose via la conversion en glucose ou en corps cétoniques. Or les malades de la SLA sont souvent insulino-résistants donc leurs cellules sont en manque de glucose, c’est à dire d’énergie. Ainsi, des niveaux élevés de triglycérides pourraient potentiellement contrecarrer le catabolisme lié à la SLA.

À ce jour, le rôle des taux de lipides sanguins et leur association avec l'apparition et le pronostic de la SLA sont assez controversés. Voici une nouvelle recherche qui a exploré ces associations dans une vaste étude cas-témoin sur la population sdu ud-ouest de l'Allemagne. Cette nouvelle recherche confirme les résultats des études précédentes.

Entre 2010 et 2014, 336 patients SLA et 487 témoins appariés selon le sexe et l'âge de la même région géographique ont été recrutés dans le registre SLA du sud-ouest de l'Allemagne.

Les triglycérides et le cholestérol (lipoprotéines de haute densité (HDL), lipoprotéines de basse densité (LDL), total) ont été mesurés. Chez les patients SLA uniquement, des modèles de survie ont été utilisés pour évaluer la valeur pronostique.

Une concentration élevée de cholestérol total, a été trouvé associée au risque de SLA. Au contraire le risque de SLA n’a pas été associé aux taux de HDL, de LDL ou de triglycérides, ni au rapport LDL-HDL. En revanche, des taux de triglycérides plus élevés étaient associés à une mortalité plus faible.

Ces résultats soulignent l'importance de distinguer l’impact du cholestérol de celui des triglycérides lorsque l'on considère le rôle pronostique du métabolisme des lipides dans la SLA.

Cela renforce encore la justification d'un régime riche en triglycérides dans le cadre de la SLA, tandis que l'impact négatif du cholestérol doit être exploré plus avant.

La dérégulation du fer a été impliquée dans de multiples maladies neurodégénératives, y compris la maladie de Parkinson et la sclérose latérale amyotrophique (SLA). Les cellules constituant la microglie se trouvent fréquemment chargées de fer dans les régions cérébrales touchées, mais la façon dont l'accumulation de fer influence la physiologie de la microglie et contribue à la neurodégénérescence est mal comprise.

Dans une nouvelle publication, les auteurs montrent qu'une tri-culture de cellules de microglie dérivée de cellules souches pluripotentes humaines est très sensible au fer et sensible à la ferroptose, une forme de mort cellulaire dépendante du fer. La microglie est une population de cellules gliales — des macrophages que l'on retrouve dans le système nerveux central et qui en forme la principale défense immunitaire active grâce à ses capacités phagocytaires. Les cellules gliales sont les cellules qui forment l'environnement des neurones. Elles jouent un rôle de soutien et de protection du tissu nerveux en apportant les nutriments et l'oxygène, en éliminant les cellules mortes et en combattant les pathogènes.

Les cultures in vitro d'astrocytes et de microglies sont des outils puissants pour étudier les voies moléculaires spécifiques impliquées dans la neuroinflammation. Cependant, afin de mieux comprendre l'influence de la diaphonie cellulaire sur la neuroinflammation, de nouveaux modèles de culture multicellulaires sont nécessaires. En effet, les interactions entre les neurones, les astrocytes et la microglie influencent de manière critique les réponses neuro-inflammatoires à l'insulte dans le système nerveux central. La « tri-culture » composée à la fois de neurones, d'astrocytes et de microglie imite plus fidèlement les réponses neuro-inflammatoires in vivo que les mono-cultures standard.

Parmi les trois types de cellules, la microglie a eu la réponse transcriptionnelle la plus forte à la dérégulation du fer, et les scientifiques ont identifié un sous-ensemble de microglie avec une signature transcriptomique distincte associée à la ferroptose qui est enrichie dans la moelle épinière SLA post-mortem et la microglie du mésencéphale du patient PD post-mortem.

L'élimination de la microglie du système de tri-culture a considérablement retardé la neurotoxicité induite par le fer.

Dans la maladie, l'absorption microgliale de fer peut initialement être protectrice, mais, lorsque les cellules succombent à la ferroptose, elles entrent dans un état cellulaire neurotoxique qui entraîne des lésions et elles meurent en masse.

Pour élucider les mécanismes régulant la réponse du fer dans la microglie, les scientifiques ont effectué un criblage CRISPR à l'échelle du génome et identifié de nouveaux régulateurs de la ferroptose, y compris le gène de trafic de vésicule SEC24B. Enfin, les auteurs ont effectué un criblage de petites molécules pour identifier les inhibiteurs de la ferroptose de la microglie. Sur les 546 composés, ils ont trouvé 39 composés qui inhibaient la ferroptose dans la microglie. Parmi ceux-ci Rhapontigenin, Xanthotoxol, Tenovin-1, Curcumin, ATP ou encore sésamol. La rhapontigénine est un stilbénoïde. Il peut être isolé de la vigne du Japon (Vitis coignetiae) ou du Gnetum cleistostachyum. Il montre une action sur les cellules cancéreuses de la prostate. Il a été démontré qu'il inhibe le cytochrome humain P450 1A1, une enzyme impliquée dans la biotransformation d'un certain nombre de composés cancérigènes et immunotoxiques. Le xanthotoxol est une furanocoumarine. C'est l'un des principes actifs majeurs de Cnidium monnieri. Cnidium monnieri (L.) Cuss. est l'une des plantes médicinales traditionnelles les plus largement utilisées et ses fruits ont été utilisés pour traiter diverses maladies en Chine, au Vietnam et au Japon. Le sésamol est un composé organique naturel qui entre dans la composition des graines de sésame et de l'huile de sésame, aux propriétés anti-inflammatoires, antioxydantes, antidépressives et neuroprotectrices.

Malgré le fait que la ferroptose a été impliquée dans de nombreux troubles, on ne connait aucun traitement efficace pour atténuer la ferroptose. Les chélateurs du fer sont une approche potentielle, mais beaucoup od'entre eux peuvent perturber les fonctions redox homéostatiques. Cependant, les études précliniques existantes utilisant des inhibiteurs de la peroxydation lipidique, tels que lip-1, et les données présentées dans cette étude fournissent une justification solide pour le développement de thérapies ciblant la ferroptose. Plusieurs composés ciblant la peroxydation lipidique et le stress oxydatif sont d'ailleurs en cours d'essais cliniques, notamment le dérivé de la vitamine E vatiquinone, l'acide linoléique deutéré et les activateurs de la voie antioxydante NRF2.

Iron dysregulation has been implicated in multiple neurodegenerative diseases, including Parkinson's disease and amyotrophic lateral sclerosis (ALS).

Cells making up microglia are frequently found loaded with iron in affected brain regions, but how iron accumulation influences microglia physiology and contributes to neurodegeneration is poorly understood.

In a new publication, authors show that a tri-culture of microglia cells derived from human pluripotent stem cells is highly iron-sensitive and susceptible to ferroptosis, a form of iron-dependent cell death.

Microglia is a population of glial cells, macrophages that are found in the central nervous system and which form the main active immune defense thanks to their phagocytic abilities. Glial cells are the cells that form the environment of neurons. They play a role in supporting and protecting nervous tissue by providing nutrients and oxygen, eliminating dead cells and fighting pathogens.

In vitro cultures of astrocytes and microglia are powerful tools to study the specific molecular pathways involved in neuroinflammation. However, in order to better understand the influence of cell crosstalk on neuroinflammation, new multicellular culture models are needed. Indeed, interactions between neurons, astrocytes and microglia critically influence neuroinflammatory responses to insult in the central nervous system. The "tri-culture" composed of both neurons, astrocytes and microglia more closely mimics neuro-inflammatory responses in vivo than standard mono-cultures.

Of the three cell types, microglia had the strongest transcriptional response to iron dysregulation, and scientists identified a subset of microglia with a distinct transcriptomic signature associated with ferroptosis that is enriched in the spinal cord Postmortem ALS and midbrain microglia from postmortem PD patient.

Removal of microglia from the tri-culture system significantly delayed iron-induced neurotoxicity.

In the disease, microglial iron uptake may initially be protective, but when cells succumb to ferroptosis, they enter a neurotoxic cellular state that leads to damage and they die en masse.

To elucidate the mechanisms regulating the iron response in microglia, scientists performed a genome-wide CRISPR screen and identified novel regulators of ferroptosis, including the vesicle trafficking gene SEC24B. Finally, the authors performed a small molecule screen to identify inhibitors of microglia ferroptosis. Of the 546 compounds, they found 39 compounds that inhibited ferroptosis in microglia. Among these Rhapontigenin, Xanthotoxol, Tenovin-1, Curcumin, ATP or sesamol.

Rhapontigenin is a stilbenoid. It can be isolated from Japanese grapevine (Vitis coignetiae) or Gnetum cleistostachyum. It shows an action on prostate cancer cells. It has been shown to inhibit human cytochrome P450 1A1, an enzyme involved in the biotransformation of a number of carcinogenic and immunotoxic compounds. Xanthotoxol is a furanocoumarin. It is one of the major active principles of Cnidium monnieri. Cnidium monnieri (L.) Cuss. is one of the most widely used traditional herbal medicines and its fruits have been used to treat various diseases in China, Vietnam and Japan. Sesamol is a natural organic compound that is part of the composition of sesame seeds and sesame oil, with anti-inflammatory, antioxidant, antidepressant and neuroprotective properties.

Despite the fact that ferroptosis has been implicated in many disorders, no effective treatment is known to alleviate ferroptosis. Iron chelators are a potential approach, but many of them can disrupt homeostatic redox functions. However, the existing preclinical studies using lipid peroxidation inhibitors, such as lip-1, and the data presented in this study provide strong rationale for the development of therapies targeting ferroptosis. Several compounds targeting lipid peroxidation and oxidative stress are also in clinical trials, including the vitamin E derivative vatiquinone, deuterated linoleic acid and activators of the antioxidant pathway NRF2.

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