There is growing interest in the possibility that Alzheimer's disease is triggered by infection because the Alzheimer's disease brain signature protein, Aβ peptide, has antimicrobial activity and therefore Alzheimer's disease could be a consequence rather than a cause of Alzheimer's disease. Alzheimer's disease Several observational cohort and case-control studies have shown reduced rates of dementia after certain types of vaccines. Twenty years ago, Verreault and his colleagues reported that vaccine exposure (diphtheria / tetanus, polio, influenza) was associated with a 25-60% reduction in the subsequent development of Alzheimer's disease.

Klinger and colleagues have demonstrated a significantly reduced risk of developing Alzheimer's disease in patients with bladder cancer exposed to repeated intravesical applications of the Bacillus Calmette-Guérin vaccine, particularly in the 75-year-old population. and more.

Scherrer and his colleagues showed a significantly reduced rate of dementia in people vaccinated against tetanus, diphtheria and pertussis and shingles compared to those unvaccinated.

Liu and his colleagues found a reduced rate of dementia in patients with chronic kidney disease vaccinated with the influenza vaccine.

Population-wide observational cohort studies indicate a moderate to no positive association between a diagnosis of human herpes virus infection and incident dementia, and some studies indicate a potential mediating role of antiherpetic drugs.

The varicella-zoster virus (called VZV, for varicella-zoster virus) is a herpesvirus, also called HHV-3 (human herpesvirus 3), which causes chickenpox or shingles.

Human herpes viruses, also known as varicella-zoster virus, are usually contracted in early childhood when they cause chickenpox, but the virus persists throughout life and may recur in older people as shingles, and has also been associated with postherpetic neuralgia, encephalitis and / or meningitis, and respiratory disease.

To reduce the effects of the re-emergence of human herpes viruses in the elderly, national vaccination strategies have been implemented in the UK and elsewhere.

In Wales, a national shingles vaccination has been carried out since 2013, with the aim of vaccinating people aged 70 years, and a catch-up vaccination at 79 years for unvaccinated people at 70 years.

Until 2018, the only shingles vaccine available in Wales was a live attenuated vaccine against the human herpes virus (Zostavax). Since June 2018, a small proportion of the Welsh population has received the recombinant shingles vaccine (Shingrix).

In this new pre-print publication, Christian Schnier, Janet Janbek, Richard Lathe and Jürgen Haas analyzed the association of shingles vaccination with incident dementia in people vaccinated in Wales between 2013 and 2020 in an observational cohort study using national health data collected retrospectively. In addition, they analyzed whether this association was mediated by a reduction in diagnosed shingles and whether the association had a different degree in Alzheimer's disease and vascular dementia.

People exposed to the vaccine had a 39% reduced risk of being diagnosed with dementia after vaccination. This association is close to that published by Scherrer and colleagues who found a 43% reduction in dementia in people vaccinated against shingles.

The reduction in dementia in people exposed to the vaccine was slightly more pronounced for vascular dementia than for Alzheimer's disease. If true, their results suggest an association between shingles vaccination and cerebrovascular disease, rather than an association of vaccination with the pathological accumulation of toxic proteins in the brain such as the beta-amyloid peptide and the protein tau.

However, their results should be interpreted with caution because the total duration of follow-up of those vaccinated and subsequently diagnosed with herpes zoster was low, resulting in wide confidence intervals in the estimate. People exposed to the shingles vaccine had a lower risk of death from all causes except cancer, this finding could indicate a nonspecific effect of the shingles vaccination.

One potential interpretation of their results, therefore, is that the live attenuated varicella-zoster vaccine acts as an adjuvant that plays a role in immune responses against microbes.

This interpretation is supported by: (i) documented cross-immune protection when infection with one pathogen can alleviate disease caused by a second unrelated pathogen, (ii) the fact that an immune adjuvant (alum) has been reported to delay the development of Alzheimer's disease, (iii) the fact that a potent adjuvant vaccine (Bacillus Calmette-Guérin) reduces the rates of Alzheimer's disease in patients with bladder cancer.

These theories of the negative association between varicella zoster virus vaccination and dementia, however, should be considered, alongside other potential theories. Indeed, their results could come from a selection bias. Indeed, non-specific effects of the vaccine, such as lower mortality, have already been described in observational cohort studies of vaccine efficacy by Simonsen and colleagues, who attributed the association to selection bias for fragility .

To control for the selection bias of frailty, scientists at the Universities of Edinburgh and Copenhagen adjusted frailty between 65 and 70 years of age, retirement home residency, and the multiple illnesses that make up the Charlson Co-morbidity Index.

The authors cannot exclude with certainty that unvaccinated people may have a lower healthy life expectancy. This observation would be supported by the results of vaccine efficacy studies for Zostavax, which showed no significant difference in mortality between people exposed to the vaccine and those exposed to a placebo.

In addition, although their study population was large and representative of the Welsh population, the average follow-up period was rather short, as the introduction of the vaccine into a national campaign was made in 2013, which gave maximum follow-up time. about 6 years old (up to the age of 76).

Il y a un intérêt croissant dans la possibilité que la maladie d'Alzheimer soit déclenchée par une infection car la protéine de signature du cerveau de la maladie d'Alzheimer, le peptide Aβ, a une activité antimicrobienne et donc la maladie d'Alzheimer pourrait être une conséquence plutôt qu'une cause de la maladie d'Alzheimer. enter image description here Plusieurs études observationnelles de cohorte et cas-témoins ont montré une réduction des taux de démence après certains types de vaccins. Il y a vingt ans, Verreault et ses collègues ont rapporté que l'exposition au vaccin (diphtérie/tétanos, polio, grippe) était associée à une réduction de 25 à 60 % du développement ultérieur de la maladie d'Alzheimer.

Klinger et ses collègues ont démontré un risque significativement réduit de développer la maladie d'Alzheimer chez les patients atteints d'un cancer de la vessie exposés à des applications intravésicales répétées du vaccin Bacillus Calmette-Guérin, en particulier dans la population âgée de 75 ans et plus.

Scherrer et ses collègues ont montré un taux de démence significativement réduit chez les personnes vaccinées contre le tétanos, la diphtérie et la coqueluche et le zona par rapport à celles non vaccinées.

Liu et ses collègues ont trouvé un taux de démence réduit chez les patients atteints d'insuffisance rénale chronique vaccinés avec le vaccin antigrippal.

Des études de cohorte observationnelles à l'échelle de la population indiquent une association positive modérée à inexistante entre un diagnostic d'infection par le virus de l'herpès humain et une démence incidente, et certaines études indiquent un rôle médiateur potentiel des médicaments antiherpétiques.

Le virus varicelle-zona (appelé VZV, pour varicella-zoster virus) est un herpèsvirus, également appelé HHV-3 (human herpesvirus 3), responsable de la varicelle ou du zona.

Les virus de l'herpès humain, également connus sous le nom de virus varicelle-zona, sont généralement contractés dans la petite enfance lorsqu'ils provoquent la varicelle, mais le virus persiste toute la vie et peut réapparaître chez les personnes âgées sous forme de zona, et a également été associé à la névralgie post-zostérienne, à l'encéphalite et/ ou méningite et maladie respiratoire.

Pour réduire les effets de la réémergence des virus de l'herpès humain chez les personnes âgées, des stratégies nationales de vaccination ont été mises en œuvre au Royaume-Uni et ailleurs.

Au Pays de Galles, une vaccination nationale contre le zona est menée depuis 2013, dans le but de vacciner les personnes âgées de 70 ans, et une vaccination de rattrapage à 79 ans pour les personnes non vaccinées à 70 ans.

Jusqu'en 2018, le seul vaccin contre le zona disponible au Pays de Galles était un vaccin vivant atténué contre le virus de l'herpès humain (Zostavax). Depuis juin 2018, une faible proportion de la population galloise a reçu le vaccin recombinant contre le zona (Shingrix).

Dans cette nouvelle pré-publication, Christian Schnier, Janet Janbek, Richard Lathe et Jürgen Haas ont analysé l'association de la vaccination contre le zona avec la démence incidente chez les personnes vaccinées au Pays de Galles entre 2013 et 2020 dans une étude de cohorte observationnelle utilisant des données de santé nationales collectées rétrospectivement. De plus, ils ont analysé si cette association était médiée par une réduction du zona diagnostiqué et si l'association avait un degré différent dans la cas de la maladie d'Alzheimer et de la démence vasculaire.

Les personnes exposées au vaccin présentaient un risque réduit de 39 % de diagnostic de démence après la vaccination. Cette association est proche de celui publié par Scherrer et ses collègues qui ont trouvé une réduction de 43 % de la démence chez les personnes vaccinées contre le zona.

La réduction de la démence chez les personnes exposées au vaccin était légèrement plus prononcée pour la démence vasculaire que pour la maladie d'Alzheimer. Si cela est vrai, leurs résultats suggèrent une association entre la vaccination contre le zona et les pathologies cérébrovasculaires, plutôt qu'une association de la vaccination avec l'accumulation pathologique de protéines toxiques dans le cerveau telles que le peptide bêta-amyloïde et la protéine tau.

Pourtant, leurs résultats doivent être interprétés avec prudence car la durée totale de suivi des personnes vaccinées et ayant reçu un diagnostic ultérieur de zona était faible, ce qui a entraîné de larges intervalles de confiance dans l'estimation. Les personnes exposées au vaccin contre le zona présentaient un risque plus faible de mortalité toutes causes confondues sauf du cancer, ce résultat pourrait indiquer un effet non spécifique de la vaccination contre le zona.

Une interprétation potentielle de leurs résultats est donc que le vaccin vivant atténué contre le virus varicelle-zona agit comme un adjuvant qui joue un rôle dans les réponses immunitaires contre les microbes.

Cette interprétation est appuyée par : (i) une protection immunitaire croisée documentée lorsque l'infection par un agent pathogène peut soulager la maladie causée par un deuxième agent pathogène non apparenté, (ii) le fait qu'un adjuvant immunitaire (alun) a été signalé comme retardant le développement de la maladie d'Alzheimer, (iii) le fait qu'un vaccin adjuvant puissant (Bacillus Calmette-Guérin) réduit les taux de maladie d'Alzheimer chez les patients atteints de cancer de la vessie.

Ces théories de l'association négative entre la vaccination contre le virus varicelle-zona et la démence, doivent cependant être considérées, aux côtés d'autres théories potentielles. En effet, leurs résultats pourraient provenir d'un biais de sélection. En effet, des effets non spécifiques du vaccin, tels qu'une mortalité plus faible, ont déjà été décrits dans des études de cohorte observationnelles sur l'efficacité du vaccin par Simonsen et ses collègues, qui ont attribué l'association à un « biais de sélection de fragilité ».

Pour contrôler le biais de sélection de la fragilité, les scientifiques des universités d'Édimbourg et de Copenhague ont ajusté la fragilité entre 65 et 70 ans, la résidence en maison de retraite et les multiples maladies qui composent l'indice de comorbidité de Charlson.

Les auteurs ne peuvent exclure avec certitude que les personnes non vaccinées pourraient avoir une espérance de vie en bonne santé plus faible. Cette observation serait étayée par les résultats des études d'efficacité du vaccin pour Zostavax, qui n'ont montré aucune différence significative de mortalité entre les personnes exposées au vaccin et celles exposées à un placebo.

De plus, même si leur population étudiée était importante et représentative de la population galloise, la période de suivi moyenne était plutôt courte, car l'introduction du vaccin dans une campagne nationale a été faite en 2013, qui a donné un temps de suivi maximum d'environ 6 ans (jusqu'à l'âge de 76 ans).

It is well known that approximately 10% cognitively well patients undergoing surgery will develop symptoms of cognitive dysfunction after their procedure but will recover quickly. A few percent of them will develop a Parkinson disease. It is known that persistent degree of cognitive impairment will appear in up to 10% of elderly patients up to three months after a surgical procedure. No large studies had studied the impact of surgery and anesthesia on Alzheimer disease.

There is some relation between Parkinson disease and the digestive system. Aggregated alpha synuclein is a pathologic feature of Parkinson’s disease. It has been found in the gastrointestinal tract early in the onset of the Parkinson’s disease. There has been conflicting reports on whether appendectomies increase the risk of Parkinson’s disease. The overall Relative Risk (RR) of developing Parkinson’s disease in patients after appendectomies is usually estimated at a few percent.

The aim of the current study by Chih-Sung Liang, Mu-Hong Chen of National Yang-Ming University, Taipei, was to examine the risk of Alzheimer's disease (AD) and other types of dementia following appendicitis or appendectomy for appendicitis.

The scientists used claims data from the Taiwan National Health Insurance Research Database. Participants aged ≥45 years with acute appendicitis or who received appendectomy for appendicitis were enrolled and followed up for more than 15 years.

Patients developing appendicitis and those receiving appendectomy for appendicitis had higher incidences of Alzheimer disease than the controls during the follow-up period. A Cox regression analysis showed that those patients were more likely to develop Alzheimer disease than the controls.

These patients also had higher risks all types of dementia but not for vascular dementia (which is often associated with aging) than the controls. The age at dementia diagnosis was 88.51 years in the controls; however, among people who developed dementia following appendicitis, the mean age at diagnosis was 70.18 years, and dementia occurred 5.84 years after appendicitis.

Alzheimer's disease has a multifactorial etiology. Diet, cardiovascular disease, low grade systemic inflammation have been associated with it. All of these factors have some relationship with the gastrointestinal tract.

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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.

Here is an example of systematic review about an anti-depressant which has also putative benefits in human neurodegenerative diseases.

A systematic review are designed to provide an exhaustive summary of current evidence relevant to a research question. This should not be confused with meta-analysis. A meta-analysis is a statistical analysis that combines the results of multiple scientific studies. A key benefit of this approach is the aggregation of information leading to a higher statistical power. 

However most meta-analysis are cheap attempts at publishing without doing real research. Systematic reviews must follow strict protocols. There is no cheap or easy way to do a systematic review. enter image description here.

Although it is FDA-approved only for use in the treatment of major depression, trazodone is widely used off-label to control agitation and insomnia in Alzheimer’s disease (AD) and other diseases. Yet the list of trazodone side-effects is long and some of them are frightening.

Trazodone hydrochloride and dibenzoylmethane were identified by the National Institute of Neurological Disorders and Stroke (NINDS) small-molecule library screening performed on 1040 drugs. Both drugs reversed p-eIF2α mediated translational attenuation and were neuroprotective in two mouse models of neurodegeneration. In prion-diseased mice, both drugs restored memory deficits, abrogated development of neurological signs, prevented neurodegeneration and significantly prolonged survival.

Furthermore, in an animal model of tauopathy-FTD (frontotemporal dementia), these compounds rescued memory deficits and hippocampal atrophy. Finally, both compounds were not toxic to the pancreas.

A common factor in neurodegenerative diseases, and beyond many chronic diseases is a cellular stress response that is abnormally prolonged. The response to this cellular stress (UPR, ISR and others) involves the shutdown of functions that are essential for the proper functioning of the body.

A cell main purpose is to produce proteins. This production is done in several steps: a blueprint is assembled from RNA fragments copied from DNA (a very long molecule). This blueprint is used by ribosomes to produce linear chains of amino acids. Ribosomes are often located in the rough endoplasmic reticulum, probably the most complex organelle in the cell. The endoplasmic reticulum folds this linear chain of amino-acids, thereby giving it new properties and sends it where it is needed.

When there is a cellular stress response, the endoplasmic reticulum stops working, so the newly produced proteins stay in the cytosol where they form protein aggregates named stress granules. Normally this state is of short duration, so quickly the endoplasmic reticulum works again and the stress granules are disposed by the proteolysis mechanism. In a state of stress response, there is hardly any protein production but the protein consumption resulting from metabolism continues, so if the stress response persists a long time the cells become gradually beyond repair and are destroyed by apoptosis.

A drug able to end the anomalous cellular stress response would therefore be very interesting. Indeed it would be valuable only in early phases of the disease, before too much cells died. And canceling completely the UPR mechanism is a bad idea.

UPR acts as a cellular mechanism for the regulation of protein homeostasis when there are misfolded proteins and coordinates this process through three ER transmembrane proteins: PERK, inositol-requiring enzyme 1 (IRE1), and activating transcription factor 6 (ATF6).

Trazodone acts in the PERK branch of the UPR pathway downstream of eIF2α-P, preventing it from reducing levels of the ternary complex, allowing protein translation to occur, restoring neuronal protein synthesis rates, enabling a boost of memory and preventing neurodegeneration in mice models.

In summary of the systematic review, 12 of 16 clinical studies demonstrated a neutral or even a beneficial effect of trazodone on cognitive functions. The majority of these studies demonstrated a positive effect that is possibly not due to the direct effects of trazodone on cognition, but is instead mediated through an improvement in sleep disorders and depressive symptoms.

The results also highlight the possibility of a dose-independent dual effect of trazodone on human cognition, with acute utilization associated with impaired cognitive function and longitudinally long-term use with prevention of cognitive deterioration.

None of the studies evaluated its effects on the UPR pathway, and there was no evidence that trazodone could be used as an active treatment of neurodegenerative diseases itself, although this review suggests that trazodone can be integrated into the therapeutic arsenal in these cases as a safe and well-tolerated adjuvant treatment for dementia comorbidities, with minimal adverse events.

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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.

Several articles have recently appeared that should make the pharmaceutical industry reflect on the value of therapies that suppress human proteins or decrease the expression of human genes.

This is the case, for ASOs, this is also the case for the many proposals for immunotherapies against human proteins. We obviously remember the hundreds of unsuccessful clinical trials against ALS or Parkinson's, and the 2,500 unsuccessful trials against Alzheimer's disease.

How did we get there?

In the past 30 years many neurodegenerative diseases, including Huntington's disease, Alzheimer's disease, Parkinson's disease and amyotrophic lateral sclerosis (ALS), have been correlated with DNA damage, resulting in incorrect RNA sequences and therefore poorly translated proteins.

Although initially scientists postulated a mechanism of loss of function (the mutated protein having lost its function). At the turn of the century they realized that this was not a plausible explanation, so they expressed the hypothesis of a gain of function. Which is much more difficult to refute. But this hypothesis is attractive because a gain of function mechanism can be easily suppressed with ASO or immunotherapy.

Case of a vaccine against the Tau protein

For example, the results of a phase II trial of AADvac - a vaccine against pathologic forms of the tau protein - were published on June 14 in Nature Aging by Petr Novak and colleagues.

This vaccine met its primary endpoint in this Phase II study, so it appears reasonably appears safe. It also elicited antibody responses in almost all of the participants, who were diagnosed with mild Alzheimer's disease, and attenuated a gradual increase in plasma NfL over the two-year trial.

By analyzing cerebrospinal fluid samples taken from a small subset of volunteers, the scientists were able to confirm that the vaccine reduced the concentration of Tau protein in the cerebrospinal fluid.

Unfortunately, as usual, the vaccine did not slow the cognitive decline of the patients.

Case of an ASO against C9orf72

Antisense oligonucleotide therapy are strands of RNA that prevent protein translation of certain strands of messenger RNA by binding to them, in a process called hybridization.

Researchers led by Rita Sattler of the Barrow Neurological Institute in Phoenix and Robert Baloh of Cedars-Sinai Medical Center in Los Angeles carried out experiments to suppress the C9orf72 gene on a laboratory mouse model that reproduces the disease Alzheimer's disease, or at least the appearance of amyloid plaques.

enter image description here

Baloh and his colleagues previously reported in 2016 that in myeloid cells from C9orf72 knockout mice and C9 carriers with ALS / FTD, reporting of lysosomal function leads to escalation of interferon and increased inflammation.

To determine how C9orf72 deficiency affects the way microglia processes plaques and synapses, the researchers made an Alzheimer mice model deficient in C9orf72 expression.

In 3-month-old mice, which begin to develop amyloid plaques, scientists did not detected any obvious effect of C9orf72 deficiency on plaque deposition.

However, at 6 months, the mice lacking C9orf72 had fewer plaques, and those that remained were smaller and more compact than the aggregates of the control mice. Approximately twice as many microglia gathered around each plaque as in the control mice.

At the end of the experiment, the C9orf72 knockout mice had fewer plaques, these were smaller, but neurons had fewer synapses due to overzealous pruning performed by the microglia.

Conclusion

One can only wonder at the interest in therapies that suppress human proteins or decrease the expression of human genes. By what conceptual leap, or by what blindness are we led to think that a potentially deleterious mechanism can become a successful therapy?

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

Plusieurs articles sont parus récemment qui devraient faire réfléchir l’industrie pharmaceutique quant à l’intérêt de thérapies supprimant ou diminuant l’expression de gènes.

C’est le cas par exemple de Biogen qui a quatre thérapies de ce type contre la SLA. C'est aussi le cas des nombreuses proposition d'immunothérapies, contre des protéines humaines. On a évidemment en mémoire les centaines d'essais cliniques infructueux contre la SLA ou Parkinson, et les 2500 essais infructueux contre la maladie d'Alzheimer.

Comment ont est-on arrivé là?

Dans les 30 dernières années de nombreuses maladies génétiques, notamment la maladie de Huntington, la maladie d'Alzheimer, la maladie de Parkinson et la sclérose latérale amyotrophique (SLA), ont été corrélées à des altérations de l'ADN, ce qui entraîne des séquences d'ARN incorrectes et donc des protéines mal traduites.

Bien qu'initialement les scientifiques aient postulés un mécanisme de perte de fonction (la protéine mutée ayant perdue sa fonction). Au tournant du siècle ils se sont rendu compte que ce n'était pas une explication plausible, aussi ils ont exprimés l'hypothèse d'un gain de fonction. Ce qui est nettement plus difficile à réfuter. Mais cette hypothèse est séduisante car un mécanisme de gain de fonction peut être aisément supprimé avec un ASO ou une immunothérapie.

Cas d'un vaccin contre la protéine Tau

Par exemple, les résultats d'un essai de phase II d'AADvac - un vaccin contre les formes pathologiques de la protéine tau - ont été publiés le 14 juin dans Nature Aging par Petr Novak et ses collègues.

Ce vaccin a atteint son critère d'évaluation principal dans cette étude de phase II, il semble donc raisonnablement semble sûr. Il a également suscité des réponses en anticorps chez presque tous les participants, qui avaient reçu un diagnostic de maladie d'Alzheimer légère, et a atténué une augmentation progressive du NfL plasmatique au cours de l'essai de deux ans.

En analysant les prélèvements de liquide céphalo-rachidien effectués parmi un petit sous-ensemble de volontaires, les scientifiques ont pu confirmer que le vaccin avait réduit la concentration de protéine Tau dans le liquide céphalo-rachidien.

Hélas, comme d'habitude, le vaccin n'a pas ralenti le déclin cognitif des patients.

Cas d'un ASO contre C9orf72

Les thérapie oligonucléotides antisens sont des brins d'ARN qui empêchent la traduction protéique de certains brins d'ARN messager en se liant à eux, dans un processus appelé hybridation.

Des chercheurs dirigés par Rita Sattler du Barrow Neurological Institute à Phoenix et Robert Baloh du Cedars-Sinai Medical Center à Los Angeles ont ainsi réalisé des expériences de suppression du gène C9orf72 sur un modèle de souris de laboratoire qui reproduit la maladie d’Alzheimer, ou tout au moins l’apparition de plaques d’amyloides.

enter image description here

Baloh et ses collègues avaient déjà rapporté en 2016 que dans les cellules myéloïdes de souris knock-out C9orf72 et chez des porteurs de mutations de C9orf72 atteints de SLA/FTD, le signalement de la fonction lysosomale entraîne une escalade de l'interféron et une inflammation accrue.

Pour déterminer comment la carence en C9orf72 affecte la façon dont la microglie traite les plaques et les synapses, les chercheurs ont créé un modèle de souris Alzheimer déficient en expression C9orf72.

Chez des souris de 3 mois, qui commencent à développer des plaques amyloïdes, les scientifiques n'ont détecté aucun effet évident de la carence en C9orf72 sur le dépôt de plaque.

Cependant, à 6 mois, les souris dépourvues de C9orf72 avaient moins de plaques, et celles qui restaient étaient plus petites et plus compactes que les agrégats des souris témoins. Environ deux fois plus de microglies se sont rassemblées autour de chaque plaque que chez les souris témoins.

À la fin de l'expérience, les souris knock-out C9orf72 avaient moins de plaques, celles-ci étaient plus petites, mais les neurones avaient moins de synapses en raison de l'élagage trop zélé effectué par la microglie.

Conclusion

On ne peut que s’étonner de l’intérêt pour les thérapies supprimant les protéines d'origine ou diminuant l’expression protéique de gènes humains. Par quel saut conceptuel, ou par quel aveuglement est-on amené à penser qu’un mécanisme potentiellement délétère puisse devenir une thérapie à succès?

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Ce livre retrace les principales réalisations de la recherche sur la SLA au cours des 30 dernières années. Il présente les médicaments en cours d’essai clinique ainsi que les recherches en cours sur les futurs traitements susceptibles d’ici quelques années, d’arrêter la maladie et de fournir un traitement complet en une décennie ou deux.

Researchers of University of California at San Francisco, led by Karen Krukowski and Susanna Rosi have provided evidence for a direct involvement of the integrated stress response (ISR) in age-related cognitive decline. enter image description here Cellular stress response is an umbrella concept for molecular changes that cells undergo in response to exposure to extreme temperature, viral infection, toxins, stroke or injury.  

In response to cellular stress, mammalian cells induce coordinated cytoprotective programs that are critical for survival: the unfolded protein response and integrated stress response. On contrary the mammalian target of rapamycin (mTOR), is the other important pathway associated with growth, that cells employ to respond to insulin, growth factors, cellular nutrient and oxygen.

Those cytoprotective programs most of the time are slowing the cell activity to minimize damages while the stress condition happens. If the stress condition persists, the cell undergoes one or another form of apoptosis. Those manifest themselves in the form of denatured proteins and it is the detection of those denatured proteins that triggers the cellular stress response.

While aging, a decline in adaptive homeostasis affects the central nervous system (CNS), which results also in the appearance of non-native protein aggregates.

Nearly stopping cellular activity has indeed frightened consequences, for example many chronic illnesses such as Alzheimer, Parkinson or ALS are characterized by the apparition of unfolded protein aggregates. For example it is known since a long time that blocking protein synthesis prevents long-term memory storage (Flexner et al., 1962).

One signaling pathway that allows cell adaptation is the integrated stress response (ISR). The integrated stress response can be triggered by hypoxia, amino acid deprivation, glucose deprivation, viral infection and presence of oxidants. The main intrinsic factor is endoplasmic reticulum stress due to the accumulation of unfolded proteins.

As protein synthesis is critical for memory consolidation and the ISR pathway is one of the major nodes for protein synthesis control, so the scientists investigated how interference with the ISR impacted healthy age-related cognitive decline. To interfere with ISR, they used an ISR inhibitor on old mices. Stress signals can cause protein kinases, known as EIF-2 kinases, to phosphorylate the α subunit of a protein complex called translation initiation factor 2 (eIF2).

There are few ISR inhibitors, for example, Salubrinal is a drug which acts as a specific inhibitor of eIF2α  and is primarily used experimentally, to study stress responses in eukaryotic cells. Proper functioning of eIF2α appears essential for preventing diet-induced type II diabetes.

The researchers used ISRIB (integrated stress response inhibitor) is an experimental drug which reverses the effects of eIF2α phosphorylation. It was discovered by the Walter lab at University of California, San Francisco (UCSF).

They trained aged those mice to escape from a watery maze by finding a hidden platform, a task that is typically hard for older animals to learn. But animals who received small daily doses of ISRIB during the three-day training process were able to accomplish the task as well as youthful mice.

Several weeks after the initial ISRIB treatment, they trained the same mice to find their way out of a maze whose exit changed daily. The mice who had received brief ISRIB treatment three weeks before, still performed at youthful levels, while untreated mice continued to struggle.

ISRIB treatment impacted T cell levels both in the brain and periphery. The changes in T cells and IFN responses directly correlated with cognitive performance and, again, were restored by ISRIB to the levels observed in young animals.  One might think that interfering with the ISR, a critical cellular safety mechanism, would be sure to have serious side effects.

Some involved researchers say there is no side effects and that this is likely due to two factors. First, the scientists used too small doses for them to be toxic. Second, they say ISRIB is ineffective when there is a real threat to the cell.

One can ask how it would be possible that a powerful biological pathway used to mitigate cellular stress could be ineffective when there is a real threat to the cell?

Some information could be found in termination of the integrated stress response. The protein phosphatase 1 complex (PP1) aids in the dephosphorylation of eIF2α. However, dephosphorylation of eIF2α can also facilitate the production of death-inducing proteins in cases where the cell is so severely damaged that normal functioning cannot be restored.

As usual, while the scientific title is quite sober, the university PR publication is as usual enthusiastic "Drug Reverses Age-Related Mental Decline Within Days" even if this research has little chance to be translated in humans.

There are powerful commercial interests around ISRIB, as it has been licensed by Calico, a company exploring the biology of aging, and the idea of targeting the ISR to treat disease has been picked up by many other pharmaceutical companies.

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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.

Two recent articles, one about China and the other from Europe, are pointing at a link between childhood trauma and Alzheimer disease.
The first article was published by Zhuoer Lina and Xi Chen of Yale university and Alzheimer's Disease Research Center, New Haven in USA.

The scientists explored the long-term relationship between childhood circumstances and cognitive aging.

Applying a linear mixed-effect model to three waves of China Health and Retirement Longitudinal Surveys they found that key domains of childhood circumstances are significantly associated with both the level of cognitive deficit and the rate of decline.

These key areas are family socioeconomic status (SES), neighborhood cohesion, friendship, and health conditions.

In contrast, childhood neighborhood safety only affects the level of cognitive deficit.

The scientists found that relationship with mother can buffer against cognitive decline in later life; whereas the relationship with father cannot. This pattern can be explained by the different roles that father and mother play at home, which contribute differently to children's cognitive development.

For Zhuoer Lina and Xi Chen, the effects of adverse childhood circumstances are generally larger on level of cognitive deficit than on rate of cognitive decline. Moreover for them, education plays a more important role in mediating the relationships compared to other later-life factors. They suggest that exposure to disadvantaged childhood circumstances can exacerbate cognitive deficit as well as cognitive decline over time, which may be partially ameliorated by educational attainment.

Yet adulthood social engagement is likely an underlying pathway through which neighborhood cohesion and friendship in childhood influence cognitive aging. Overall, education seems the most important mediator.

In the other article Sandra Van der Auwera, Hans J Grabe and their colleagues from the German Centre for Neurodegenerative Diseases in Greifswald, Germany, looked at miRNAs as a feature in common between childhood abuse and Alzheimer's Disease.

Many studies point towards an involvement of miRNAs in neuropsychiatric disorders such as Alzheimer's Disease, schizophrenia or depression. In a recent study the German scientists identified a possible relationship between childhood traumatization and miRNAs associated with Alzheimer's Disease in the general population as well as in a small psychiatric clinical sample.

In their previous study the authors identified a possible relationship between childhood traumatization and miRNAs associated with Alzheimer's Disease in the general population as well as in a small psychiatric clinical sample. In this new study they aimed to confirm this biological link in an independent psychiatric clinical sample (N = 104) and to also explore the impact of different childhood trauma dimensions (sum score, abuse dimension and neglect dimension).

They found different impact on disease in the combined sample (N = 154; N = 50 from the recent study) and could confirm associations for all of their four recently identified miRNAs in the replication sample (N = 104) on a suggested significance level of p < 0.08 (two with p < 0.05).

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In the combined sample (N = 154) fifteen miRNAs were significantly associated with the childhood trauma sum score after correction for multiple testing. Most of them showed recently significant associations for Alzheimer's Disease. For the subscores of abuse and neglect only one miRNA was identified in addition, associated with childhood neglect. 

A sizable body of research has focused on the long-term health impacts of childhood circumstances. But any mechanism of action remained elusive.

miRNAs are small single-stranded non-coding RNA molecules, that functions in RNA silencing and post-transcriptional regulation of gene expression. They appear to regulate the development and function of the nervous system and are involved at various stages of synaptic development synapse formation and maturation.

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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.

In a new publication Gadd et al. apply blood-derived epigenetic signatures of lifestyle traits to matched blood and brain samples, uncovering variability in how well blood translates across brain regions and a relationship between smoking and the prefrontal cortex. These preliminary results contribute to understanding how lifestyle-related DNA methylation affects the brain. enter image description here These factors have been extensively linked with blood-based genome-wide DNA methylation, but it is unclear if the signatures from blood translate to the target tissue of interest-the brain. To investigate this, the authors apply blood-derived epigenetic predictors of four lifestyle traits to genome-wide DNA methylation from five post-mortem brain regions and the last blood sample prior to death in 14 individuals in the Lothian Birth Cohort 1936 (LBC1936).

This cohorte is a longitudinal study of healthy ageing in individuals who reside in Scotland. Participants completed a childhood intelligence test at age 11 years in 1947 and were then recruited for this cohort at the mean age of 70 years. They have been followed up approximately every 3–4 years (currently at the sixth wave), collecting a series of cognitive, physical, clinical and social data, along with blood donations that have been used for genetic, epigenetic, and proteomic measurement. Approximately 15% of individuals in the LBC1936 have consented to post-mortem tissue collection.

The LBC1936 group were born in 1936 and there are socioeconomic and cultural trends in their lifestyles that must be taken into consideration; many may have worked in factories or in shipbuilding yards, exposing them to high levels of respiratory pollutants and poorer socioeconomic status in this era was related to behaviours such as smoking. Though Scotland has a historic and sustained high prevalence of unhealthy lifestyle behaviours such as smoking and alcohol consumption, with a large proportion of the current population either overweight or obese, cohort profiling has found both the Generation Scotland and Lothian Birth Cohorts to be healthier and of higher socioeconomic status than the general population.

The majority of the 14 individuals within the brain bank subset either had been or were still smokers (86%) at the time of death, which was a higher proportion than in the reference group (46%). Most of the 14 individuals (86%) had high HDL cholesterol (> 1 mmol/l), drank alcohol weekly (92%) and had mean BMI of 25.5 kg/m2. Five of the individuals did not smoke.

Using these matched samples, the authors found that correlations between blood and brain DNA methylation scores for smoking, high-density lipoprotein cholesterol, alcohol and body mass index were highly variable across brain regions.

Smoking scores in the dorsolateral prefrontal cortex had the strongest correlations with smoking scores in blood and smoking behaviour. This was also the brain region which exhibited the largest correlations for DNA methylation at AhRR/site cg05575921 - which is the single strongest correlate of smoking in blood-in relation to blood and smoking behaviour. The aryl hydrocarbon receptor (AhRR) gene may act as a tumor suppressor but it is known that Dioxins and dioxin-like compounds are teratogens that exert their effects through the AhRR. This suggested a particular vulnerability to smoking-related differential methylation in this region.

The authors' work contributes to understanding how lifestyle factors affect the brain and suggest that lifestyle-related DNA methylation is likely to be both brain region dependent and in many cases poorly proxied for by blood. Though these pilot data provide a rarely-available opportunity for the comparison of methylation patterns across multiple brain regions and the blood, due to the limited sample size available authors' results must be considered as preliminary and should therefore be used as a basis for further investigation.

All R code used in this study is available with open access at the following Gitlab repository: https://gitlab.com/dannigadd/blood-brain-lifestyle-traits.

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

Alzheimer’s disease has become the third leading cause of death.

Studies have provided candidate mechanisms for the neurodegeneration associated with Alzheimer’s disease, such as neuroinflammation, insulin resistance, and reduction in trophic support.

One complicating feature is that their etiology remains controversial, with many competing theories, such as “type 3 diabetes”, viral infection, misfolded or prions proteins, none of which has led to effective treatment.

The approach utilized in a new innovative trial departs sharply from traditional treatment strategies for MCI and Alzheimer’s disease, which have largely been monotherapeutic, monophasic, non-personalized, and blind, i.e., cause-independent, thus not targeted to the underlying drivers of the disease in each person, but rather to common downstream consequences and/or secondary drivers, such as amyloidosis.

In the field of oncology, a personalized, precision medicine approach, in which the presumptive molecular drivers of the disease process are targeted therapeutically, has improved outcomes in at least some studies.

However, this strategy has not been applied successfully to neurodegenerative diseases.

A recent BioRxiv article presents a proof-of-concept trial of precision medicine approach to Alzheimer’s disease.

Twenty-five patients with Alzheimer’s disease or mild cognitive impairment, ages 50-76, were recruited to three clinical sites and were evaluated for markers of inflammation, chronic infection, dysbiosis, insulin resistance, protein glycation, vascular disease, nocturnal hypoxemia, hormone insufficiency or dysregulation, nutrient deficiency, toxin or toxicant exposure (metals, organic toxicants, and biotoxins), genetic predisposition to cognitive decline, and other biochemical parameters associated with cognitive decline. Brain magnetic resonance imaging with volumetrics was performed at baseline and study conclusion.

Patients were treated for nine months with a personalized, precision medicine protocol that addressed each patient’s identified potentially contributory factors.

Diet was a plant-rich, high-fiber, mildly ketogenic diet, high in leafy greens and other nonstarchy vegetables(raw and cooked), high in unsaturated fats, with a fasting period of 12- 16 hours each night.

Exercise, both aerobic and strength training, was encouraged for at least 45 minutes per day, at least six days per week, and facilitated by the personal trainers. High-intensity interval training (HIIT) was recommended a minimum of twice per week.

Sleep hygiene was supported to ensure 7-8 hours of quality sleep per night, and all patients without known sleep apnea were tested over several nights using home sleep study devices.

For those patients with suboptimal hormonal status, bioidentical hormone replacement and appropriate supplements were provided to optimize sex hormone levels, neurosteroids, and thyroid medications as indicated for sub-optimal thyroid function.

Infectious agents associated with cognitive decline or systemic inflammation were identified and treated.

All outcome measures revealed improvement: statistically highly significant improvement in MoCA scores, CNS Vital Signs Neurocognitive Index, and AQ-C were documented. No serious adverse events were recorded.

On overall results support the notion that a precision medicine approach to the cognitive decline of Alzheimer’s disease and mild cognitive impairment may be an effective strategy, especially with continued optimization over time.

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