La maladie d'Alzheimer est une maladie neurodégénérative chronique qui commence généralement lentement et accélère progressivement. Bien qu'elle soit variable, l'espérance de vie typique après le diagnostic est de trois à neuf ans.

enter image description here Source Alzforum

Les deux principales hypothèses sur l’origine de cette maladie, affirment que des quantités anormales de protéines amyloïdes ou encore de protéines tau s’agglomèrent dans le cerveau. Les plaques issues de l’agglomération de protéines, entraîneraient une perte progressive de la fonction cérébrale.

On ne sait pas pourquoi ces dysfonctionnements protéiques se produisent. De nombreux essais cliniques ayant pour but de réduire ces plaques, n’ont jamais réussi à améliorer la condition des patients, aussi les scientifiques se tournent petit à petit vers des hypothèses concurrentes.

D’après une nouvelle étude publiée le 12 Octobre 2020 dans le Journal of Neuroscience, au cours de la maladie d'Alzheimer une altération du flux sanguin vers les régions du cerveau coïncide avec l'accumulation de protéines tau et β amyloïde. Cette relation se renforce à mesure que la cognition diminue. Les chercheurs ont aussi testé l’hypothèse selon laquelle un mauvais fonctionnement de la barrière hémato-encéphalique peut être impliqué et leurs résultats semblent la confirmer. Albrecht et ses collègues de la Keck School of Medicine of the University of Southern California ont utilisé l'IRM et la TEP pour comparer le flux sanguin et l'accumulation de protéine tau dans le cerveau des personnes âgées.

Cette corrélation concerne de plus en plus de régions du cerveau au fur et à mesure que la maladie progresse en gravité. Ces résultats suggèrent que le ciblage de la fonction vasculaire pourrait être essentiel pour prévenir et traiter la démence d'Alzheimer.

A hypothesis describing a mechanism leading to Alzheimer's disease.

Scientists in an interdisciplinary team, have developed a hypothesis that the disease begins when we ingest excess fructose, this phenomenon would be accentuated if there is concomitant consumption of salt and /or alcohol. This excess fructose induces behavioral and metabolic changes, which ultimately lead to Alhzeimer's disease.

The study was published in Frontiers in Aging Neuroscience, it brought together an interdisciplinary team of neurologists, neuroscientists and experts on sugar metabolism

Behavioral and metabolic changes

In the wild, starving animals activate behavioral and metabolic changes to aid their survival once fat stores are depleted. This includes the development of foraging behavior, reduced energy production, and the development of insulin resistance which reduces the uptake of glucose into muscle, thereby promoting preferential uptake by the brain (Koffler and Kisch, 1996; Cahill, 2006).

Studies in humans have largely confirmed these results. The administration of fructose has unique effects on the attention and reward centers, resulting in more hunger and desire for sugary foods than glucose and which is linked to reduced cortical activity (Purnell et al., 2011).

In addition to stimulating hunger, thirst and the search for food, fructose increases the storage of fats, including in the liver, blood (triglycerides) and adipose tissue, thus providing stored energy as well as metabolic water when needed (Johnson et al., 2016).

Deleterious effects of uric acid. Uric acid, generated by fructose, increases blood pressure responses by reducing endothelial nitric oxide, stimulating oxidative stress, and activating the renin-angiotensin system. There is also a very active stimulation of innate immunity, probably mediated by uric acid. These are all protective systems to help survive extreme conditions like famine.

But it is speculated that if it lasts too long, chronic mitochondrial oxidative stress results in impaired mitophagy with the buildup of damaged mitochondria and fewer functioning mitochondria (Shefa et al., 2019), thus affecting overall energy production. and metabolism and resulting in increased dependence on glycolysis.

Generation of fructose in the body Certain foods that do not contain fructose also activate aldose reductase (AR) and stimulate endogenous fructose production, including high glycemic carbohydrates, salty foods, and alcohol (Lanaspa et al., 2013, 2018 ; Wang et al., 2020).

Aldose reductase is expressed in neurons, including the hippocampus (Picklo et al., 2001; Hwang et al., 2017). The activation of aldose reductase leading to the generation of fructose has been shown in the brain after dehydration in rats (Song et al., 2017) as well as after glucose loading in humans (Hwang et al. , 2017). Importantly, there is evidence of endogenous fructose production in patients with Alzheimer's disease, with intracerebral sorbitol and fructose levels 3-5 times higher than normal (Xu et al., 2016) .

Conclusion In one of the scenarios described by Johnson and colleagues, glucose hypometabolism increases oxidative stress and induces progressive loss of mitochondria, ultimately leading to neuronal dysfunction and death. In this scenario, the amyloid plaques and neurofibrillary tangles are part of the inflammatory response and participate in the injury, but are not the central factors of the disease.

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Une hypothèse décrivant un mécanisme aboutissant à la maladie d’Alzheimer.

Des scientifiques dans une équipe interdisciplinaire, ont développé une hypothèse selon laquelle la maladie commence lorsque nous ingérons un excès de fructose, ce phénomène serait accentué s’il y a une consommation concomitante de sel et/ou d’alcool. Cet excès de fructose induit des changements comportementaux et métaboliques, qui à terme induisent la maladie d’Alhzeimer.

L'étude a été publiée dans les Frontiers in Aging Neuroscience, elle a réuni une équipe interdisciplinaire de neurologues, de neuroscientifiques et d'experts sur le métabolisme du sucre

Changements comportementaux et métaboliques

Dans la nature, les animaux qui meurent de faim activent des changements comportementaux et métaboliques pour favoriser leur survie une fois que les réserves de graisse sont épuisées. Cela comprend le développement d’un comportement de recherche de nourriture, une réduction de la production d'énergie et le développement d'une résistance à l'insuline qui réduit l'absorption du glucose dans le muscle, favorisant ainsi l'absorption préférentielle par le cerveau (Koffler et Kisch, 1996; Cahill, 2006).

Pour éviter la famine, les animaux stockent de la graisse en prévision des périodes de pénurie alimentaire, comme avant l'hibernation, la migration sur de longues distances ou la nidification. Une approche utilisée par de nombreux animaux consiste à ingérer des aliments riches en fructose, tels que des fruits et du miel.

Au fil du temps, les animaux développent une résistance à la leptine qui entraîne une consommation excessive de nourriture tout en réduisant l'oxydation des graisses (Shapiro et al., 2008).

Des études chez l'homme ont largement confirmé ces résultats. L'administration de fructose a des effets uniques sur les centres d'attention et de récompense, ce qui entraîne plus de faim et de désir d'aliments sucrés que le glucose et qui est lié à une activité corticale réduite (Purnell et al., 2011).

En plus de stimuler la faim, la soif et la recherche de nourriture, le fructose augmente préférentiellement le stockage des graisses, y compris dans le foie, le sang (triglycérides) et les tissus adipeux, fournissant ainsi de l'énergie stockée ainsi que de l'eau métabolique en cas de besoin (Johnson et al. ., 2016).

Effets délétères de l'acide urique. L'acide urique, généré par le fructose, augmente les réponses de la pression artérielle en réduisant l'oxyde nitrique endothélial, en stimulant le stress oxydatif et en activant le système rénine-angiotensine. Il existe également une stimulation très active de l'immunité innée probablement médiée par l'acide urique. Ce sont tous des systèmes de protection pour aider à survivre dans des conditions extrêmes comme une famine.

Mais il est spéculé que s'il dure trop longtemps, le stress oxydatif mitochondrial chronique entraîne une mitophagie altérée avec l'accumulation de mitochondries endommagées et moins de mitochondries fonctionnelles (Shefa et al., 2019), affectant ainsi la production d'énergie globale et le métabolisme et entraînant une dépendance accrue à la glycolyse.

Génération de fructose dans l'organisme Certains aliments qui ne contiennent pas de fructose activent également l'aldose réductase (AR) et stimulent la production endogène de fructose, y compris les glucides à indice glycémique élevé, les aliments salés et l'alcool (Lanaspa et al., 2013, 2018; Wang et al., 2020).

L'aldose réductase est exprimée dans les neurones, y compris dans l'hippocampe (Picklo et al., 2001; Hwang et al., 2017). L'activation de l’aldose réductase entrainant la génération de fructose a été montrée dans le cerveau après une déshydratation chez le rat (Song et al., 2017) ainsi qu'après une charge en glucose chez l'homme (Hwang et al., 2017). Surtout, il existe des preuves d'une production endogène de fructose chez les patients atteints de la maladie d'Alzheimer, avec des niveaux intracérébraux de sorbitol et de fructose 3 à 5 fois plus élevés que la normale (Xu et al., 2016).

Conclusion Dans l'un des scénarios décrits par Johnson et ses collaborateurs, l'hypométabolisme du glucose augmente le stress oxydatif et induit une perte progressive des mitochondries , conduisant finalement à un dysfonctionnement neuronal et à la mort. Dans ce scénario, les plaques amyloïdes et les enchevêtrements neurofibrillaires font partie de la réponse inflammatoire et participent à la blessure, mais ne sont pas les facteurs centraux de la maladie.

Alzheimer's disease is a severe neurodegenerative disease characterized by progressive damage to synaptic bonds and neuronal cells mainly in the cerebral region of the hippocampus.

Optical spectroscopy methods can provide a unique means of analyzing body fluids, enabling rapid, sensitive, non-invasive and reliable diagnosis.

enter image description here * Source: Toommm via Wikipedia. *

The development of Alzheimer's disease has been associated with a dysfunctional blood-brain barrier with a reduced ability to clear Aβ and tau proteins from the brain. These two substances are biomarkers of the progression of Alzheimer's disease and are a reliable sign of a neurodegenerative process even at an early stage. These biomarkers can be transported in the vascular system across the blood-brain barrier. The blood-brain barrier plays an important role in the selective passage of several substances between the brain and the blood system and in the maintenance and integrity of the brain.

Traces of these biomarkers are present in the systemic bloodstream and can be found in the vasculature of other areas of the body. The relevance of changes occurring in the eye as a consequence of Alzheimer's disease has been reported by Lim et al. Therefore, tears are an interesting way to study the changes induced by neurodegenerative pathologies. They are easily accessible and can be collected using minimally invasive methods.

Over the past decades, a large number of studies have been conducted to analyze the composition of tears using conventional biochemical methods.These conventional techniques have been largely replaced by optical spectroscopy methods, such as those based on Raman scattering, which take less time and require only little preparation of the samples.

Raman spectroscopy has already been used to identify biomarkers of Alzheimer's disease in blood serum and saliva and to study the basic aggregation mechanisms of amyloids. However, it has some limitations regarding sensitivity, noise / signal level and repeatability.

The objective of the study which concerns us today was to demonstrate the spectral differences in the SERS spectroscopic response of human tears in subjects suffering from Alzheimer's disease, subjects suffering from mild cognitive and healthy control subjects. Human tears were characterized by SERS coupled with multivariate data analysis.

Thirty-one informed subjects (Ctr, MCI and AD) were considered. Eighteen subjects with Alzheimer's disease (7 women, 11 men and mean age 71 ± 10 years) and seven subjects with mild cognitive impairment (3 women, 4 men and mean age 73 ± 9 years) were included In this study.

While the Raman spectrum does not provide any valuable information apart from very weak characteristics, conversely, the SERS spectrum clearly demonstrated the various contributions of human tears components. SERS measurements were performed with standard microscope glasses coated with a homemade colloid of gold nanoparticles (GNP).

The data processing was implemented using software routines (wavelet toolbox). The fully processed dataset of all mean spectra was analyzed by PCA and i-PCA to describe it using a set of orthogonal eigenvectors separately accounting for different sources of variance in the original data. enter image description here

The differences between the SERS spectra of tears from subjects at different clinical states are sometimes very subtle and are mainly localized in certain specific spectral ranges. Notably, the authors found that PCA performed over the entire spectral range did not differentiate between the subtle changes that occurred in the spectra examined. To better highlight these differences and take advantage of them to classify the spectra, the authors therefore performed the PCA in intervals (interval partial component analysis (i-PCA)).

The average SERS spectra of the Ctr, MCI and AD subjects showed differences related to the protein components of lactoferrin and lysozyme. Quantitative changes were also observed by determining the intensity ratio between the selected bands. Scientists also built a classification model that discriminates between AD, MCI and Ctr subjects. This model was built using the scores obtained by performing a interval principal component analysis on specific spectral regions (i-PCA). enter image description here

Although it has not been possible to discriminate specific biomarkers of Alzheimer's disease, the overall response of SERS reflects small but interesting changes in tear composition that can be attributed to altered levels of specific pathological substances. and stimulated by disease.

The analysis of the partial interval components (i-PCA) of the spectra by the authors made it possible to distinguish subjects with Alzheimer's disease from healthy subjects with MCI. The precision of classification of the constructed method was very encouraging with interesting prospects for medical applications as a support for clinical diagnosis and discrimination of Alzheimer's disease from other forms of dementia.

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La maladie d'Alzheimer est une pathologie neurodégénérative sévère caractérisée par une lésion progressive des liaisons synaptiques et des cellules neuronales principalement dans la région cérébrale de l'hippocampe.

Les méthodes de spectroscopie optique peuvent fournir un moyen unique d'analyser les fluides corporels, permettant un diagnostic rapide, sensible, non invasif et fiable.

enter image description here Source: Toommm via Wikipedia.

Les bêta-amyloïdes (Aβ) et la protéine tau sont impliquées dans le développement de la maladie d'Alzheimer. Ces deux substances sont des biomarqueurs de la progression de la maladie d'Alzheimer et sont un signe fiable d'un processus cérébral neurodégénératif également au stade précoce. Ces biomarqueurs peut être transportés dans le système vasculaire à travers la barrière hémato-encéphalique. La barrière hémato-encéphalique joue un rôle important dans le passage sélectif de plusieurs substances entre le cerveau et le système sanguin et dans le maintien et l'intégrité du cerveau. Le développement de la maladie d'Alzheimer a été associé à une barrière hémato-encéphalique dysfonctionnelle avec une capacité réduite à éliminer les protéines Aβ et tau du cerveau.

Des traces de ces biomarqueurs sont présentes dans la circulation sanguine systémique et peuvent rejoindre la vascularisation d'autres zones du corps, comme la rétine, le cristallin et les régions lacrymales, affectant la composition des larmes. La pertinence des changements survenant dans l'œil en tant que La conséquence de la maladie d'Alzheimer a été rapportée par Lim et al. Par conséquent, les larmes sont un moyen intéressant pour étudier les changements induits par les pathologies neurodégénératives. Elles sont facilement accessibles et peuvent être collectés à l'aide de méthodes peu invasives.

Au cours des dernières décennies, un grand nombre d'études ont été menées pour analyser la composition des larmes en utilisant des méthodes biochimiques conventionnelles.

Ces techniques conventionnelles ont été largement remplacées par les méthodes de spectroscopie optique, telles que celles basées sur la diffusion Raman, qui prennent moins de temps et ne nécessitent qu'une faible préparation préalable des échantillons.

La spectroscopie Raman a déjà été utilisée pour identifier les biomarqueurs de la maladie d'Alzheimer dans le sérum sanguin et la salive et pour étudier les mécanismes d'agrégation de base des amyloïdes. Cependant, certaines limites concernant la sensibilité, le niveau de bruit / signal et la répétabilité ont mises en évidence.

L'objectif de l'étude qui nous occupe aujourd'hui était de mettre en évidence les différences spectrales dans la réponse spectroscopique SERS des larmes humaines chez des sujets atteints de la maladie d'Alzheimer, des sujets atteints de troubles cognitifs légers et des sujets témoins sains. Les larmes humaines ont été caractérisées par SERS couplé à une analyse de données multivariée. Trente et un sujets informés (Ctr, MCI et AD) ont été considérés.

Dix-huit sujets atteints de la maladie d'Alzheimer (7 femmes, 11 hommes et âge moyen 71 ± 10 ans) et sept sujets atteints de troubles cognitifs légers (3 femmes, 4 hommes et âge moyen 73 ± 9 ans) ont été inclus dans cette étude.

Alors que le spectre Raman ne fournit aucune information précieuse en dehors de caractéristiques très faibles, à l'inverse, le spectre SERS a mis clairement en évidence les diverses contributions des composants des larmes. Les mesures SERS ont été effectuées avec des verres de microscope standard revêtus d'un colloïde fait maison de nanoparticules d'or (GNP). Le traitement des données a été mis en œuvre à l'aide de routines logicielles (boîte à outils ondelettes). L'ensemble de données entièrement traité de tous les spectres moyens a été analysé par PCA et i-PCA pour le décrire en utilisant un ensemble de vecteurs propres orthogonaux tenant compte séparément des différentes sources de variance dans les données d'origine. enter image description here

Les différences entre les spectres SERS des larmes de sujets présentant des états cliniques différents sont parfois très subtiles et sont principalement localisées dans certaines plages spectrales spécifiques. Notamment, les auteurs ont constaté que la PCA réalisée sur toute la gamme spectrale ne différenciait pas les changements subtils qui se produisaient dans les spectres examinés. Pour mieux mettre en évidence ces différences et en profiter pour classer les spectres, les auteurs ont donc réalisé la PCA dans les intervalles (interval partial component analysis (i-PCA)).

Les spectres SERS moyens des sujets Ctr, MCI et AD ont mis en évidence des différences liées aux composants protéiques de la lactoferrine et du lysozyme. Des changements quantitatifs ont également été observés en déterminant le rapport d'intensité entre les bandes sélectionnées. Les scientifiques ont également construit un modèle de classification qui discrimine les sujets AD, MCI et Ctr. Ce modèle a été construit en utilisant les scores obtenus en effectuant une analyse en composantes principales sur des régions spectrales spécifiques (i-PCA).

Même s'il n'a pas été possible de discriminer des biomarqueurs spécifiques de la maladie d'Alzheimer, la réponse globale du SERS reflète des modifications petites mais intéressantes de la composition des larmes qui peuvent être attribuées à des niveaux modifiés de substances pathologiques spécifiques et stimulées par la maladie.

L'analyse des composantes partielles d'intervalle (i-PCA) des spectres par les auteurs a permis de distinguer les sujets atteints de la maladie d'Alzheimer des sujets sains et atteints de MCI. La précision de classification de la méthode construite était très encourageante avec des perspectives intéressantes pour les applications médicales comme support du diagnostic clinique et de la discrimination de la maladie d'Alzheimer des autres formes de démence.

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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.

Multiple studies have signaled brain atrophy in relationship with obesity, particularly in elderly cohorts. Initially, this relationship was shown in the Cardiovascular Health Study in 94 cognitively normal participants in their late 70s who remained cognitively normal 5 years after their brain MRI scan.

The findings of brain atrophy in relation to higher BMI were replicated in the separate Alzheimer's Disease Neuroimaging Cohort and then in a larger Cardiovascular Study Cohort. However, what makes the present study different from that work, is the focus on brain perfusion, that shows greater sensitivity and earlier changes related brain dysfunction than atrophy.

These changes have been demonstrated even in cognitively normal individuals, as well as persons with mild cognitive impairment and Alzheimer's disease. Regional cerebral blood flow has also been used to track obesity-related brain abnormalities. enter image description here

A SPECT scan monitors level of biological activity at each place in the 3-D region analyzed. Emissions from the radionuclide indicate amounts of blood flow in the capillaries of the imaged regions. Because blood flow in the brain is tightly coupled to local brain metabolism and energy use, the radionuclide is used to assess brain metabolism regionally, in an attempt to diagnose and differentiate the different causal pathologies of dementia. SPECT imaging is performed by using a gamma camera to acquire multiple 2-D images (also called projections), from multiple angles. A computer is then used to apply a tomographic reconstruction algorithm to the multiple projections, yielding a 3-D data set.

Recent studies have shown the accuracy of SPECT in Alzheimer's diagnosis may be as high as 88%. SPECT was superior to clinical exam and clinical criteria in being able to differentiate Alzheimer's disease from vascular dementias. This latter ability relates to SPECT's imaging of local metabolism of the brain, in which the patchy loss of cortical metabolism seen in multiple strokes differs clearly from the more even or "smooth" loss of non-occipital cortical brain function typical of Alzheimer's disease.

The authors have previously utilized SPECT functional neuroimaging to review and identify patterns of abnormality relevant to the diagnosis of traumatic brain injury, depression versus dementia classification , marijuana-related influences in the brain , omega-3 fatty acid associated improved cerebral blood flow , gender-related differences in the brain , and brain aging.

The purpose of their current article is to identify potential brain perfusion abnormalities in adults related to being overweight or obese.

A large psychiatric cohort of 35,442 brain scans across 17,721 adults were imaged with SPECT. ANOVA was done to identify patterns of perfusion abnormality in this cohort across BMI designations of underweight, normal weight, overweight, obesity, and morbid obesity.

With over 35,000 functional neuroimaging scans across more than 17,000 individuals, this study is one of the larger studies linking obesity with brain dysfunction, as evidenced here by quantifiable regional perfusion.

In particular, brain areas noted to be vulnerable to Alzheimer's disease: the temporal and parietal lobes, hippocampus, posterior cingulate gyrus, and precuneus were found to have reduced perfusion along the spectrum of weight classification from normal weight to overweight, obese, and morbidly obese.

While the work presented here focused on body tissue adiposity and cerebral perfusion in a large cohort, other studies have suggested a negative relationship between BMI, obesity, and the brain, particularly with neuroimaging as a proxy of structure or function.

Across adulthood, higher BMI correlated with decreased perfusion on both resting and concentration brain SPECT scans. These are seen in virtually all brain regions, including those influenced by AD pathology such as the hippocampus.

Perfusion is the passage of fluid through the circulatory system or lymphatic system to an organ or a tissue, it usually refers to the delivery of blood to a capillary bed in tissue. Cerebral perfusion may therefore warrant further study as a biomarker of caloric restriction in related efforts to improve brain health.

Overall, the scientists have found a strong set of relationships between being overweight and obese and brain hypoperfusion across a large adult cohort spanning young adults to late life.

The persistence of these abnormalities despite adjusting for demographic and psychiatric factors further highlights the need to address obesity as a target for interventions designed to improve brain function, be they Alzheimer's disease prevention initiatives or attempts to optimize cognition in younger populations.

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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.

More about infections and Alzheimer

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Flu (influenza) and pneumonia vaccinations are associated with reduced risk of Alzheimer's disease, according to new research reported at the Alzheimer's Association International Conference® (AAIC®) 2020.

Three research studies reported at AAIC 2020 suggest:

  • At least one flu vaccination was associated with a 17% reduction in Alzheimer's incidence.
  • More frequent flu vaccination was associated with another 13% reduction in Alzheimer's incidence.
  • Vaccination against pneumonia between ages 65 and 75 reduced Alzheimer's risk by up to 40% depending on individual genes.
  • Individuals with dementia have a higher risk of dying (6-fold) after infections than those without dementia (3-fold).

"With the COVID-19 pandemic, vaccines are at the forefront of public health discussions. It is important to explore their benefit in not only protecting against viral or bacterial infection but also improving long-term health outcomes," said Maria C. Carrillo, Ph.D., Alzheimer's Association chief science officer.

"It may turn out to be as simple as if you're taking care of your health in this way — getting vaccinated — you're also taking care of yourself in other ways, and these things add up to lower risk of Alzheimer's and other dementias," Carrillo said. "This research, while early, calls for further studies in large, diverse clinical trials to inform whether vaccinations as a public health strategy decrease our risk for developing dementia as we age."

Seasonal Flu Vaccine May Reduce Incidence of Alzheimer's Dementia

Previous research has suggested vaccinations may have a protective factor against cognitive decline, but there have been no large, comprehensive studies focused on the influenza (flu) vaccine and Alzheimer's disease risk, specifically. To address this gap, Albert Amran, a medical student at McGovern Medical School at The University of Texas Health Science Center at Houston, and team, investigated a large American health record dataset (n=9,066).

Amran and team found having one flu vaccination was associated with a lower prevalence of Alzheimer's (odds ratio 0.83, p<0.0001), and among vaccinated patients receiving the flu vaccine more frequently was associated with an even lower prevalence of Alzheimer's (odds ratio 0.87, p=0.0342). Thus, people that consistently got their annual flu shot had a lower risk of Alzheimer's. This translated to an almost 6% reduced risk of Alzheimer's disease for patients between the ages of 75-84 for 16 years.

The researchers found the protective association between the flu vaccine and the risk of Alzheimer's was strongest for those who received their first vaccine at a younger age — for example, the people who received their first documented flu shot at age 60 benefited more than those who received their first flu shot at age 70.

"Our study suggests that regular use of a very accessible and relatively cheap intervention — the flu shot — may significantly reduce risk of Alzheimer's dementia," Amran said. "More research is needed to explore the biological mechanism for this effect — why and how it works in the body — which is important as we explore effective preventive therapies for Alzheimer's."

Pneumonia Vaccine May Reduce Alzheimer's Risk later in life.

Repurposing of existing vaccines may be a promising approach to Alzheimer's disease prevention. Svetlana Ukraintseva, Ph.D., Associate Research Professor in the Biodemography of Aging Research Unit (BARU) at Duke University Social Science Research Institute, and team, investigated associations between pneumococcal vaccination, with and without an accompanying seasonal flu shot, and the risk of Alzheimer's disease among 5,146 participants age 65+ from the Cardiovascular Health Study. The team also took into account a known genetic risk factor for Alzheimer's — the rs2075650 G allele in the TOMM40 gene.

The researchers found that pneumococcal vaccination between ages 65-75 reduced risk of developing Alzheimer's by 25-30% after adjusting for sex, race, birth cohort, education, smoking, and number of G alleles. The largest reduction in the risk of Alzheimer's (up to 40%) was observed among people vaccinated against pneumonia who were non-carriers of the risk gene. Total number of vaccinations against pneumonia and the flu between ages 65 and 75 was also associated with a lower risk of Alzheimer's; however, the effect was not evident for the flu shot alone.

"Vaccinations against pneumonia before age 75 may reduce Alzheimer's risk later in life, depending on individual genotype," Ukraintseva said. "These data suggest that pneumococcal vaccine may be a promising candidate for personalized Alzheimer's prevention, particularly in non-carriers of certain risk genes."

Infection Substantially Increases Mortality in People with Dementia

People living with dementia commonly experience other health conditions including viral, bacterial, and other infections. There is a growing trend in research to investigate whether infections might be worsening, more life-threatening or possibly causing dementia.

Janet Janbek, a Ph.D. student at the Danish Dementia Research Centre, Rigshospitalet and the University of Copenhagen in Denmark, and team, used data from national health registries to investigate mortality in Danish residents over age 65 (n=1,496,436) who had visited the hospital with an infection. They found that people with both dementia and such hospital visits died at a 6.5 times higher rate compared with people who had neither. Study participants with either dementia alone or infection-related contacts alone had a threefold increased rate. The rate of mortality was highest within the first 30 days following the hospital visit.

The researchers also found that for people living with dementia the mortality rates remained elevated for 10 years after the initial infection-related hospital visit, and mortality rates from all infections (including major infections like sepsis to minor ear infections) were higher compared with people without dementia or without an infection-related hospital visit.

"Our study supports the need to investigate these relations even further; to find out why infections are linked to higher mortality in people with dementia, specifically which risk factors and biological mechanisms are involved. This will help advance our understanding of the role of infections in dementia," said Janbek.

"Our study suggests that the health care system — as well as relatives of people with dementia — should have increased awareness of people with dementia who get infections, so they get the medical care they need. People with dementia require more specialized treatment even when their hospital visits are not directly due to their dementia but to what might appear to be an unrelated infection," Janbek added.

Chronic neurodegenerative disorders, such as Alzheimer's disease and cerebrovascular disease, are common conditions in older people. The treatment of these conditions is aggravated by the relatively high prevalence of systemic comorbidity, which is detected in more than half of patients over 65 years of age in several surveys.

Coexisting neuropathological markers of Alzheimer's disease and cerebrovascular disease are found at autopsy in the majority of brains of many cohorts of patients clinically diagnosed with Alzheimer's disease.

A recent study, of over two hundred participants, showed the association of image markers of cerebrovascular disease, including cortical cerebral microinfarctions, with an increased risk of cognitive decline and atrophy in patients diagnosed with Alzheimer's disease.

Notably, clinical signs of the interaction of Alzheimer's disease and cerebrovascular disease can be attributed to the archetypal study Nun. A longitudinal study of aging and Alzheimer's disease of nuns was initiated in 1986 by Snowdon. The homogeneous lifestyle of the nuns makes them an ideal study population. The convent archives were made available to the investigators as a resource on the history of the participants. The study included the administration of memory and cognitive tests to nuns (some over 100 years old) and the post-mortem examination of their brains. The results of this study showed that the coexistence of rare markers of Alzheimer's disease with minor ischemic damage was associated with exacerbated dementia compared to patients diagnosed with only one or the other of the conditions.

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The hippocampus, one of the only cerebral structures, is one of the first structures affected in Alzheimer's disease, which explains the memory problems and disorientation that characterize the appearance of this neurodegenerative pathology. People with severe damage to the hippocampus are likely to suffer from different types of amnesia.

Scientists from the Instituto de Biofisica da UFRJ in Rio de Jaeiro, have developed an in vitro model of cerebrovascular disease co-morbid with Alzheimer's disease. This model involves organotypic cultures of the hippocampus, combining subtoxic oxygen-glucose deprivation (OGD) with exposure to subtoxic concentrations of amyloid oligomers (AβO).

This approach was designed to simulate early subclinical conditions that may precede the diagnosis of mild cognitive impairment, assuming that such subclinical conditions may be associated with minor vascular insufficiency and / or low AβO levels.

Scientists have developed an in vitro model of comorbid cerebrovascular disease / Alzheimer's disease applied to organotypic cultures of hippocampi, by combining subtoxic oxygen-glucose deprivation with exposure to also subtoxic concentrations of amyloid oligomers (AβO) Alzheimer's disease, toxins that build up in the brain and are believed to trigger synapse damage and cognitive impairment in Alzheimer's disease.

Using this experimental model, the scientists then studied in more detail the roles of glutamate receptors, which have been implicated in many approaches to cerebrovascular disease and Alzheimer's disease.

These results revealed a hitherto unappreciated synergy between subtoxic oxygen-glucose deprivation and AβO, and unveiled the complex roles of glutamate receptors on neurodegeneration in the hippocampus under conditions that mimic early and early cerebrovascular disease. comorbid / Alzheimer's disease. The results thus showed that:

  • subtoxic insults by oxygen-glucose deprivation and AβOs synergize to induce marked reductions in synaptic proteins in the absence of cell death.
  • the effects of glutamate receptor antagonists in the combined presence of subtoxic oxygen-glucose deprivation and AβO are complex and rather distinct from previous reports of their effects on experimental models of cerebrovascular disease or Alzheimer's disease alone .

Their results unveiled the complex roles of glutamate receptors on neurodegeneration in the hippocampus under conditions that mimic early and co-morbid cerebrovascular disease / Alzheimer's disease.

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Les troubles neurodégénératifs chroniques, tels que la maladie d’Alzheimer et les maladies cérébrovasculaires, sont des pathologies courantes chez les personnes âgées. Le traitement de ces affections est aggravé par la prévalence relativement élevée de la comorbidité systémique, qui est détectée chez plus de la moitié des patients de plus de 65 ans dans plusieurs enquêtes.

Des marqueurs neuropathologiques coexistants de la maladie d’Alzheimer et des maladies cérébrovasculaires sont retrouvés à l’autopsie dans la majorité des cerveaux de nombreuses cohortes de patients diagnostiqués cliniquement avec la maladie d’Alzheimer.

Une étude récente, de plus de deux cents participants, a montré l’association des marqueurs d’image des maladies cérébrovasculaires, y compris les micro-infarctus cérébraux corticaux, avec un risque accru de déclin cognitif et d’atrophie chez les patients diagnostiqués avec la maladie d’Alzheimer.

Notamment, les signes cliniques d’interaction de la maladie d’Alzheimer et des maladies cérébrovasculaires peuvent être attribués à l’étude archétypale Nun. Une étude longitudinale du vieillissement et de la maladie d'Alzheimer de religieuses a été initiée en 1986 par Snowdon. Le style de vie homogène des religieuses en fait une population d'étude idéale. Les archives du couvent ont été mises à la disposition des enquêteurs en tant que ressource sur l'histoire des participants. L'étude comprend l'administration de la mémoire et des tests cognitifs aux religieuses (certaines de plus de 100 ans) et l'examen post mortem de leur cerveau. Les résultats de cette étude ont montré que la coexistence de marqueurs rares de la maladie d’Alzheimer avec des lésions ischémiques mineures, était associée à une démence exacerbée par rapport aux patients diagnostiqués avec seulement l’une ou l’autre des conditions.

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L'hippocampe, une des seules structures cérébrales, est une des premières structures atteintes dans la maladie d'Alzheimer, ce qui explique les problèmes de mémoire et de désorientation qui caractérisent l'apparition de cette pathologie neurodégénérative. Les personnes subissant de graves dommages à l'hippocampe sont susceptibles de souffrir de différents types d'amnésie. L'hypoxie (la privation d'oxygène), les encéphalites et les épilepsies du lobe temporal peuvent résulter de lésions au niveau de l'hippocampe.

Des scientifiques de l’Instituto de Biofisica da UFRJ à Rio de Jaeiro, ont développé un modèle in vitro de maladies cérébrovasculaires comorbides de la maladie d’Alzheimer. Ce modèle implique des cultures organotypiques d’hippocampe, en combinant la privation subtoxique d’oxygène-glucose (OGD) avec une exposition à des concentrations subtoxiques d’oligomères amyloïdes (AβO).

Cette approche a été conçue pour simuler des conditions subcliniques précoces susceptibles de précéder le diagnostic d’une déficience cognitive légère, en supposant que de telles conditions infracliniques peuvent être associée à une insuffisance vasculaire mineure et/ou à de faibles taux d’AβO.

Les scientifiques ont développé un modèle in vitro de maladies cérébrovasculaires comorbides / maladie d’Alzheimer appliqué aux cultures organotypiques d’hippocampes, en combinant la privation subtoxique d’oxygène-glucose avec une exposition à des concentrations également subtoxiques d’oligomères amyloïdes (AβO), des toxines qui s’accumulent dans le cerveau de la maladie d’Alzheimer et sont censés déclencher des dommages aux synapses et des troubles cognitifs dans la maladie d’Alzheimer.

À l’aide de ce modèle expérimental, Les scientifiques ont alors étudié plus en détail les rôles des récepteurs du glutamate, qui ont été impliqués dans de nombreuses approches des maladies cérébrovasculaires et de la maladie d’Alzheimer.

Ces résultats ont révélé une synergie jusqu’ici inappréciée entre la privation subtoxique d’oxygène-glucose et l’AβO, et dévoilé les rôles complexes des récepteurs du glutamate sur la neurodégénérescence dans l’hippocampe dans des conditions qui imitent les maladies cérébrovasculaires précoces et comorbides / maladie d’Alzheimer. Les résultats ont ainsi montré que : * les insultes subtoxiques par privation d’oxygène-glucose et AβOs synergisent pour induire des réductions marquées des protéines synaptiques en l’absence de mort cellulaire; * les effets des antagonistes des récepteurs du glutamate en présence combinée de privation subtoxique d’oxygène-glucose et d’AβO sont complexes et plutôt distincts des rapports précédents de leurs effets sur des modèles expérimentaux de maladies cérébrovasculaires ou de la maladie d’Alzheimer seule. Leurs résultats ont dévoilé les rôles complexes des récepteurs du glutamate sur la neurodégénérescence dans l’hippocampe dans des conditions qui imitent les maladies cérébrovasculaires précoces et comorbides / maladie d’Alzheimer.

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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.

The theory of infectious origin of the Alzheimer's disease

The hypothesis that Alzheimer's disease has an infectious origin, has a long and controversial history. The data at the origin of this hypothesis are contradictory and mainly associative in nature, without it being possible to demonstrate a causal link. Interest in this theory has been renewed, however, by several recently published observations. In the section Viewpoint de la revue Nature Reviews Neurology, Ben Readhead, a researcher at the Biodesign Institute's ASU-Banner Center for Research on Neurodegenerative Diseases, joined several distinguished colleagues to discuss the idea that bacteria, viruses or other infectious pathogens can play a role in Alzheimer's disease.

A hypothesis that has never been favored by researchers

This hypothesis may have been rejected too quickly. For example, microorganisms do not only cause acute illnesses, in fact certain microorganisms can hide in the body for decades in latent form, causing damage intermittently or after long periods of silence.

In addition, being infected does not necessarily mean being symptomatic. For example, out of the millions of people infected with Mycobacterium tuberculosis, only about a tenth of them will develop tuberculosis. Likewise, most people infected with HSV1 do not develop cold sores so it is possible that asymptomatic carriers of this virus were often mistakenly included in the control groups. It should also be noted that many viruses of the Herpes family (HSV1, HSV2, VZV) live preferentially in neurons.

A role for an infectious agent - in particular the herpes simplex 1 virus (HSV1) - in Alzheimer's disease (Alzheimer's disease) was proposed about 30 years ago based discovery of HSV1 DNA in the brain tissue of a large proportion of the elderly, followed by evidence that e the virus confers a high risk of disease to carriers of the ε4 allele of the gene apolipoprotein E (APOE * ε4).

Shortly after the detection of HSV1 DNA, two different species of bacteria, Borrelia burgdorferi and Chlamydia pneumoniae, were implicated in Alzheimer's disease, and a third species, Porphyromonas gingivalis, was recently added to the list.

Doubts remain, however

Nevertheless, it is known that an acute end-of-life infection, such as pneumonia, can cause a dramatic increase in the amount of microorganisms in the brain. They will then be detected post-mortem but that does not mean that these microorganisms are at the origin of the Alzheimer's disease. In addition, the issue of reverse causation is never really addressed: For example, clinical Alzheimer's disease can lead to poor dental hygiene and, therefore, damage to the oral microbiome.

Indeed, there are many challenges to prove the theory of microbial origin of Alzheimer's disease. A potential challenge is that each drug has a relatively narrow spectrum of antimicrobial activity. However, since a large number of microorganisms have been associated with Alzheimer's disease by a range of researchers, it would be difficult to interpret what a negative result in a clinical trial would mean, which would necessarily use a specific antimicrobial.

Another problem is the duration of the disease. We know that the underlying pathology of Alzheimer's disease begins 20 years or more before the onset of symptoms. So, how to prove that an infectious process that occurred decades before the onset of symptoms, really contributed to the disease process?

One may also wonder why bacteria or viruses would escape the innate innate immune defense mechanisms, which are responsible for protecting the brain against such an invasion.

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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.

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