Biomedical research has revealed many similarities between neurodegenerative diseases at the cellular level, including atypical protein assemblies. These similarities suggest that therapeutic advances against one neurodegenerative disease might ameliorate other diseases as well. In each disease, neurons gradually lose function as the disease progresses with age. It is though that repeated viral exposures, even seemingly innocuous, can significantly elevate risks of neurodegenerative disease, including up to 15 years after infection.

Yet the search for a specific viral or auto-immune origin in these diseases have mostly failed. This article published on medRxiv by scientists from Netherlands, aims at identifying overlap at genetic level between four investigated neurodegenerative disorders (Alzheimer’s disease, amyotrophic lateral sclerosis, Lewy body dementia, and Parkinson’s disease).

As these diseases are mostly associated with age, they have a poor heritability, so it would be difficult to associate with some gene.

As in previous studies, the authors failed to identify any region, gene, gene-set, cell or tissue type that was shared between all four neurodegenerative diseases. However, they found that HLA locus was significantly associated with these traits. It is not clear how it is associated because the scientists used a tool named FUMA. FUMA is an automatic tool which annotates GWAS findings and prioritizes the most likely causal SNPs and genes. Yet it is a bit obscure like all these "ontological" tools, like too often in molecular biology it is a qualitative, not quantitative tool.

HLA is a part of the genome which plays an important role in immune systems. The major histocompatibility complex (MHC) is a large locus on vertebrate DNA containing a set of closely linked polymorphic genes that code for cell surface proteins essential for the adaptive immune system. This genetic complex is called HLA in humans.

These cell surface proteins are called MHC molecules. The proteins encoded by HLAs are those on the outer part of body cells that are (in effect) unique to that person. The immune system uses the HLAs to differentiate self cells and non-self cells. Any cell displaying that person's HLA type belongs to that person and is therefore not an invader.

While this study does not try to explain what is the relation between those diseases and the HLA region, it is possible to make some guesses.

If aging (and DNA) degradation is a function of the number of viral attacks during life, then it makes sense to find a correlation between immune system and these non-communicable diseases.

But again many studies have not found any relations between viral or auto-immune insults and neurodegenarative diseases.

Des scientifiques de l'université de Virginie ont découvert que l'exposition aux inhibiteurs nucléosidiques de la transcriptase inverse était associée à une incidence significativement plus faible de la maladie d'Alzheimer dans deux des plus grandes bases de données d'assurance maladie aux États-Unis.

La signalisation immunitaire innée via l'inflammasome NLRP3 semble être impliquée dans la pathogenèse de la maladie d'Alzheimer, du diabète ou de la dégénérescence maculaire. NLRP3 is expressed predominantly in macrophages and as a component of the inflammasome, it  detects products of damaged cells such as extracellular ATP and crystalline uric acid. Activated NLRP3 in turn triggers an immune response. Mutations in the NLRP3 gene are associated with a number of organ specific autoimmune diseases.

Dans la présente étude, les scientifiques démontrent que l'exposition aux NRTI inhibiteurs de l'inflammasome est associée à une incidence significativement plus faible de la maladie d'Alzheimer dans deux des plus grandes bases de données d'assurance maladie aux États-Unis. Une thérapie qui inhibe l'activation de l'inflammasome pourrait donc peut-être être neuroprotectrice dans la maladie d'Alzheimer.

Cependant, les toxicités associées à l'utilisation systémique des NRTI, réduisent l'enthousiasme pour de telles entreprises thérapeutiques. Fait intéressant, la fonction anti-inflammatoire des NRTI est indépendante de leur capacité à inhiber la transcriptase inverse. Les dérivés alkylés de NRTI modifiés connus sous le nom de Kamuvudines, conservent la capacité d'inhiber l'activation de l'inflammasome mais n'ont pas la capacité d'inhiber la transcriptase inverse et, par conséquent, n'ont pas non plus les toxicités associées aux NRTI classiques.

Tout au long des analyses de bases de données d'assurance maladie, des mesures ont été prises pour atténuer les biais potentiels et promouvoir la validité interne. Au départ, les scientifiques ont ajusté un grand nombre de variables démographiques et cliniques en les incluant comme covariables de facteurs de risque fixes. Dans l'ensemble, ces mesures appuient la validité et les conclusions des analyses de bases de données.

Bien que les échantillons de la base de données aient été limités aux patients atteints du VIH ou de l'hépatite B, il est tentant de supposer que les résultats de l'étude peuvent être généralisés à d'autres populations de patients.

Ainsi, les effets neuroprotecteurs des NRTI et de la Kamuvudine-9 dans la maladie d'Alzheimer s'étendent probablement au-delà du cadre d'une infection virale coexistante.

Ceci est cohérent avec des études antérieures par nous et d'autres qui démontrent les avantages anti-inflammatoires des NRTI et de la Kamuvudine-9 dans d'autres modèles de maladies non infectieuses.

Les auteurs présentent également des éléments indiquant que le traitement par Kamuvudine-9 de souris âgées 5xFAD (un modèle génétique de la maladie d'Alzheimer) inverse considérablement les déficits de mémoire spatiale et d'apprentissage et améliore leurs performances par rapport à celles des jeunes souris non modifiées génétiquement.

Néanmoins, des essais contrôlés randomisés prospectifs chez l'homme sont justifiés pour mieux comprendre les effets des NRTI ou de la Kamuvudine-9 sur les résultats cliniques dans la maladie d'Alzheimer. En effet, des essais sont en cours sur deux NRTI, la lamivudine (NCT04552795) et l'emtricitabine (NCT04500847), dans la maladie d'Alzheimer. Il convient de noter que l'utilisation isolée d'inhibiteurs nucléosidiques de la transcriptase inverse peut faciliter le développement d'une résistance virale. De plus, les NRTI ont été associés à une toxicité mitochondriale hors cible en raison de leur inhibition de la gamma polymérase mitochondriale23. Il convient donc de tester si Kamuvudine-9, qui ne présente pas ces inconvénients, pourrait être une alternative plus sûre aux NRTI en milieu clinique.

Il convient de noter qu'Inflammasome Therapeutics, une société privée de Newton, Massachusetts est fondée par Ambati et Paul Ashton.

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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La sclérose latérale amyotrophique est une maladie hétérogène en termes de vitesse d'apparition et de progression, y compris chez les porteurs des mêmes mutations génétiques. Cette étude s'inscrit dans la continuité d'une décennie de travail. Cette étude par des chercheurs Italiens, confirme qu'une analyse comparative entre les souris à progression rapide et progression lente ALS portant la même quantité de SOD1 mutant permet d'identifier les processus moléculaires régissant la variabilité de l'évolution de la maladie.

Même si les souris de laboratoire ont un génome commun, il existe de nombreuses souches différentes qui réagissent très différemment à divers événements. Par exemple, certaines souris avec la même mutation peuvent avoir une progression très différente de la SLA. Les scientifiques préfèrent donc travailler avec des lignées de souris génétiquement bien connues car fortement consanguines.

Les souris transgéniques SOD1G93A sur fond C57 ou 129Sv ont respectivement un taux de progression de la maladie lent et rapide, ce qui évoque la variabilité observée chez les patients. Sur la base de preuves inférant l'influence active du muscle squelettique sur la pathogenèse de la sclérose latérale amyotrophique, les auteurs ont exploré si la dérégulation du muscle squelettique des membres postérieurs reflétait la différence phénotypique entre les deux modèles de souris.

Les souris à progression rapide présentaient une fonte musculaire brutale au début de la maladie, tandis que les souris à progression lente présentaient une atrophie musculaire présymptomatique qui restait stable tout au long de la progression de la maladie, suggérant l'activation de mécanismes compensatoires pouvant retarder l'apparition des symptômes.

Les scientifiques Italiens y soulignent que la myogenèse à médiation immunitaire couplée à une expression accrue des sous-unités AChR fœtales et à leur regroupement sont des processus essentiels dans l'homéostasie du muscle squelettique. Le curare, l'hexaméthonium et les toxines présentes dans les venins de serpents et de crustacés bloquent les récepteurs nicotiniques de l'acétylcholine.

Au contraire, la dénervation musculaire précoce chez les souris à progression lente est essentielle pour déclencher un processus pro-régénératif musculaire à médiation immunitaire associé à la génération de nouvelles fibres musculaires et à l'augmentation de l'expression et du regroupement des récepteurs nicotiniques de l'acétylcholine fœtaux (AChR), qui améliorent considérablement les connexions de plaque motrice (NMJ) et retarder l'apparition du déficit de la force musculaire.

Ces processus sont de faible intensité chez les souris à progression rapide, où l'apparition rapide des symptômes lors de la dénervation musculaire est suivie d'une progression accélérée de la maladie et de la dégénérescence des motoneurone. Des découvertes récentes indiquent que la prolifération et la différenciation des cellules souches musculaires engagées dans la régénération musculaire sont sous le contrôle d'une réponse inflammatoire/immunitaire. Notamment, dans le muscle endommagé, les cellules immunitaires recrutées doivent passer d'un phénotype pro-inflammatoire à un phénotype anti-inflammatoire pour soutenir la formation et la croissance de nouvelles myofibres.

Les preuves indiquent que la neurodégénérescence rétrograde (du muscle vers les motoneurones) des motoneurones pourrait faire partie intégrante de la pathogenèse de la SLA dans un scénario de type privation ciblée où la pathologie primaire du muscle squelettique pourrait exacerber la perte de motoneurone. On sait que l'atrophie musculaire associée au démantèlement des Plaque motrice (NMJ) est l'un des premiers événements de la SLA.

Les scientifiques ont récemment démontré le rôle central du système immunitaire dans la promotion et la régulation de l'innervation et de la régénération des muscles squelettiques et, par conséquent, la vitesse de progression de la maladie. Leurs etudes mettent en évidence la contribution distincte de la réponse inflammatoire dans le SNC par rapport à la périphérie dans la SLA.

En effet, alors que l'activation aberrante des cellules gliales, l'infiltration des lymphocytes T et la libération de molécules pro-inflammatoires qui en résulte entraînent la neurodégénérescence de la moelle épinière, le succès de la régénération périphérique des axones et des muscles dépend des efforts coordonnés des cellules immunitaires qui, en plus d'éliminer les débris cellulaires, favorisent la cicatrisation.

La stimulation électrique à basse fréquence des muscles des membres postérieurs du rat, endommagés par des efforts musculaires, induit une augmentation des facteurs myogéniques et de l'activation du cellules souches musculaires conduisant à la régénération musculaire.

Les scientifiques ont précédemment signalé une différence remarquable dans l'apparition de la maladie et la vitesse de progression des symptômes chez des souris transgéniques portant la même quantité de SOD1G93A humaine sur différentes souches (C57BL/6JOlaHsd ou 129/SvHsd). Ils ont constaté que les deux modèles de souris présentaient une tendance similaire dans la perte de motoneurone de la colonne vertébrale mais montraient une différence dans le taux de fonte musculaire au cours de la progression de la maladie.

Les découvertes des auteurs mettent en évidence le rôle central du muscle squelettique dans la sclérose latérale amyotrophique, en fournissant de nouvelles informations sur les mécanismes sous-estimés de la maladie se produisant à le système nerveux périphérie. Dans une perspective de traitement multimédicamenteux visant à contrer la nature multisystémique de la SLA, une approche bien conçue pour cibler le muscle squelettique pourrait être une stratégie supplémentaire pour préserver l'ensemble de l'unité motrice.

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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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