Alzheimer may be a comorbidity of ALS

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As observed in other neurodegenerative conditions, mixed pathologies also exist in ALS. In similar fashion to TDP-43 pathology playing a role in Alzheimer disease, Shuangwu Liu, Chuanzhu Yan and colleagues suggest here that Alzheimer disease pathology also plays a role in ALS. Indeed they found alterations at early stage in the subiculum, which is located in the temporal lobe of the brain, a region different from the frontal lobe which hosts the motor cortex which is classically implicated in ALS.

enter image description here Source: Wikipedia. The temporal lobe is shown in green, while the motor area is in the frontal lobe in blue

ALS is now considered a multisystemic disorder in which almost half of patients present with varying degrees of cognitive deficits, yet unfolded TDP-43 aggregates in cytosol are found in most ALS cases.

TDP-43 pathology in ALS can be divided into four stages (Braak stages): it begins focally, and then spreads persistently in sequential and regional patterns that typically originate from the motor cortex and extend to the prefrontal cortex, thalamus and eventually, the hippocampus.

However neuroimaging studies of hippocampal volumes in patients with amyotrophic lateral sclerosis (ALS) have reported inconsistent results. The group of Chinese scientists from 10 institutions, aimed to demonstrate that such discrepancies are largely due to atrophy of different regions of the hippocampus that emerge in different disease stages of ALS and to explore the existence of co-pathology in ALS patients.

They used King’s clinical staging system for ALS to classify patients into different disease stages. The scientists then investigated in vivo hippocampal atrophy patterns across subfields and anterior-posterior segments in different King’s stages using structural MRI in 76 ALS patients and 94 health controls.

The thalamus, corticostriatal tract and perforant path were used as structural controls to compare the sequence of alterations between these structures and the hippocampal subfields.

In summary:

  • ALS patients at King’s stage 1, had lower volumes in the bilateral posterior subiculum and presubiculum;
  • ALS patients at King’s stage 2 exhibited lower volumes in the bilateral posterior subiculum, left anterior presubiculum and left global hippocampus;
  • ALS patients at King’s stage 3 showed significantly lower volumes in the bilateral posterior subiculum, dentate gyrus and global hippocampus. Thalamic atrophy emerged at King’s stage 3.

White matter tracts remained normal in a subset of ALS patients.

In the present study, the authors demonstrated that the earliest hippocampal alterations in ALS patients occurred in the posterior subiculum and presubiculum, and these alterations emerged at King’s stage 1. This indicates that subiculum atrophy occurs earlier and independent of TDP-43 pathology in ALS.

enter image description here Hagmann P, Cammoun L, Gigandet X, Meuli R, Honey CJ, et al. 

Taken together, their data suggest that patients with ALS have additional pathologies that are independent of TDP-43 pathology.

Increasingly, studies have shown that at least 20% of ALS patients present significant Alzheimer disease pathology of both Aβ and tau proteins. Recently, Gómez-Pinedo and colleagues showed that in ALS patients, the amyloid cascade of the amyloid precursor protein is activated in the hippocampus of ALS patients, and cytoplasmic Aβ peptide and pTDP-43 expression levels are moderately correlated.

Thus the motor cortex and subiculum seem to represent two independent centres of ALS during the early stages of the disease, which represent TDP-43 pathology and Alzheimer disease pathology, respectively, and these pathologies may converge as the disease progresses toward advanced stages.

If these findings are confirmed in further studies, they will have a profound effect on the understanding of the aetiology and pathogenic mechanisms underlying ALS and other neurodegenerative diseases.


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.

Another interesting article was published by Alzforum. Alzforum is a quality news website dedicated to Alzheimer’s disease and other neurodegenerative disorders. It is a subsidiary Fidelity Management & Research. enter image description here In Alzheimer disease, aggregation of Aβ42 peptide into amyloids is conceived as the pathogenic trigger of a cascade leading to tau accumulation into neurofibrillary tangles, neuronal loss, and clinical dementia. However, while most of the 40 anti-amyloid clinical trials over the past two decades have successfully reduced the burden of brain amyloid, corresponding benefits for the patients have never materialized.

Moreover, brain amyloidosis does not invariably predict dementia: by the age of 85, the prevalence of brain amyloidosis is approximately 60% whereas that of dementia is only of 10%.

This new study makes the revolutionary hypothesis that high levels of natively-folded, soluble Aβ42 are associated with normal cognition in the setting of brain amyloidosis.

In a cross-sectional analysis of 598 brain amyloid-positive individuals participating in the Alzheimer's Disease Neuroimaging Initiative, higher levels of soluble Aβ42 were associated with normal cognition.

Higher soluble Aβ42 levels were also associated with better neuropsychological performance and larger hippocampal volume, with a larger effect size yielded by changes in soluble Aβ42 than in insoluble (brain amyloid) Aβ42.

“The main premise on which Alzheimer’s and all neurodegenerative diseases are conceived, is essentially the idea that proteins are toxic. It should end,” Alberto Espay, University of Cincinnati, told Alzforum.

Espay and Ezzat want their findings to inspire a paradigm shift on how we view neurodegenerative disease. “Our key message is that neurodegenerative diseases, in general, are associated with loss of protein,” said Espay. He contends that yes, aggregates accumulate, but total soluble protein goes down and that is what leads to disease. Tau protein levels falls in tauopathies, as synuclein in falls in Parkinson’s, Aβ in Alzheimer's disease, and progranulin in FDD/ALS.

The situation in Parkinson's disease mirrors what the scientists found in Alzheimer's disease. Most cases of Parkinson's disease have no specific known cause. A small proportion of cases, however, can be attributed to known genetic factors. Environmental toxins, herbicides, pesticides, and fungicides, as well as some medical and recreational drugs have been associated with the risk of developing PD. Vascular events such as stroke can cause Parkinson's disease. As for ALS, there are many conditions that look similar to Parkinson's disease. The motor symptoms of the disease result from the death of cells in the substantia nigra, a region of the midbrain.

For several generations of neurologists, the alpha-synuclein protein has been at the center of the Parkinson's disease universe. Alpha-synuclein is exists in the same form since prehistoric genomes. While the function of a protein molecule generally depends on its correct shape, wouldn't adopting an “incorrectly shaped” beta sheet aggregate make it impossible for it to function?

The central event was the discovery in 1997 that autosomal dominant Parkinson's disease was caused by a point mutation in the SNCA gene. Alpha-synuclein aggregates to form insoluble fibrils in pathological conditions characterized by Lewy bodies, such as Parkinson's disease, dementia with Lewy bodies and multiple system atrophy.

The elegant work of Braak and colleagues on the brains of patients under 50 with Parkinson's disease has shown that alpha-synuclein aggregates in a stereotypical pattern, conspicuously first appearing in the peripheral nervous system, then into the central nervous system.

As with the beta-amyloid protein in Alzheimer's disease, the elimination of alpha-synuclein in young mice makes no difference and actually protects them from the effects of MPTP, a mitochondrial toxin. Surprisingly, knockout mice, where the SNCA gene has been turned off, develop deficits when they get old!

One of the curious things about Lewy bodies is that the proportion of substantia nigra neurons containing Lewy pathology remains relatively constant regardless of how many neurons are already lost, which invalidates the classic belief that it is Lewy bodies that cause cell death in the substancia nigra.

Is it really the higher level of proteins, normal or mutated, that ultimately leads to neurodegenerative diseases?


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.

Mitochondria are organelles that have their own genomes, which are small and only encode 13 proteins, compared to around 20,000 for the genome of human cells. enter image description here By National Human Genome Research Institute - via Wikipedia

More than 1000 proteins are used by the mitochondria to perform their functions, the mitochondria therefore rely on the importation of proteins encoded in the nucleus of the host cell. The majority of mitochondrial proteins are synthesized in the cytosol and must be actively transported to the mitochondria, a process that occurs via a sophisticated system.

In many neurodegenerative diseases, there are dysfunctions in the management of proteins. This is called proteopathies. Proteopathies are found in diseases such as Creutzfeldt-Jakob disease and other prion diseases, Alzheimer's disease, Parkinson's disease, ALS and a wide range of other disorders.

Since proteins share a common structure known as the polypeptide backbone, all proteins have the potential to fold badly under certain circumstances. Mitochondrial defects might be responsible in part for those misfolded proteins that accumulate in the cytosol.

However, it is still unclear whether mitochondrial defects appear as a consequence of neurodegeneration, or if they contribute to it, or both. Since the accumulated mitochondrial protein precursors can form toxic aggregates, host cells have a mechanism to respond to and cope with them properly.

In an excellent eLife publication, Urszula Nowicka and colleagues at the University of Warsaw hypothesized that mitoprotein-induced stress induces a general response to precursor proteins which then accumulate in the cytosol and this contributes to the onset and progression neurodegenerative disorders. In this study, the authors propose a new mechanism of proteostasis.

Studies have shown that specific mitochondrial proteins that are functionally related to oxidative phosphorylation are downregulated by transcription in Alzheimer's disease. In the present study, scientists at the University of Warsaw investigated why these proteins are downregulated.

They used yeast homologues of these proteins to show the consequences of this cytosolic accumulation as well as of C. elegans worms. They applied mutations to the import machines, overexpression of mitochondrial proteins and CCCP (a decoupler of oxidative phosphorylation). They studied two disease-relevant aggregation models - α synuclein and Amyloid beta aggregation.

They found that importation of compromised mitochondrial proteins caused overall changes in the levels of transcriptome and proteins, especially chaperones, including Hsp104 and Hsp42, ABC transporters and mitochondrial proteins, which can lead to growth defects. (yeast) and decreased motility (C. elegans).

This new hypothesis complements the recent findings very well that unprocessed (but imported!) Precursor proteins aggregate in the mitochondrial matrix and initiate an mtUPR-like response.

These proteins trigger a molecular chaperone response specific to the host cell that aims to minimize the consequences of protein aggregation. However, when this rescue mechanism is insufficient, these aggregates stimulate cytosolic aggregation of other mitochondrial proteins and lead to downstream aggregation of non-mitochondrial proteins.

The present study showed that a group of mitochondrial proteins that are downregulated in Alzheimer's disease (i.e. Rip1, Atp2, Cox8 and Atp20) can aggregate in the cytosol and that the overexpression of these proteins upregulates Hsp42 and Hsp104, two molecular chaperones. Cellular stress responses induced by mitochondrial proteins mitigate the danger.

Urszula Nowicka's findings indicate why and how metastable mitochondrial proteins can be downregulated during neurodegeneration to minimize the imbalance in cellular protein homeostasis caused by their poor targeting.

Several stress response pathways have recently been identified to counteract import defects in mitochondrial proteins. It is not known, however, whether they act independently or whether simultaneous actions of all of these stress responses are necessary to ensure balanced homeostasis of cellular proteins.

It is likely that the study of the mechanisms of protection against stress, whether at the cellular level or at the mitochondrial level, will make it possible to better understand neurodegenerative diseases and to develop drugs to treat them.


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.

Il a déjà été mis en évidence que les personnes diagnostiquées de SLA sont souvent atteintes de plusieurs comorbidités de type neurodégénérescence (Alzheimer, Parkinson). On soupçonne que c’est aussi le cas pour d’autres diagnostics ainsi que chez de nombreuses personnes âgées qui n’ont pas de diagnostic. enter image description here

Évidemment si cela est le cas, cela complique considérablement le travail des équipes qui cherchent des remèdes à ces maladies : Il ne suffirait pas de trouver un remède à une maladie diagnostiquée, tâche déjà considérable, mais il faudrait aussi soulager le malade des autres commorbiditées. Cela ouvre une perspective où les thérapies pour les maladies de types neurodégérescente seraient multi-maladies.

L’imagerie IRM est de plus en plus exploitée pour obtenir des renseignements in-vivo. Dans cette pré-publication Rosaleena Mohanty et ses collègues essayent de vérifier s’il y a une corrélation entre les pathologies diagnostiquées in-vivo grâce à l’IRM d’une part et d’autre part le diagnostic fait après autopsie. Mais les scientifiques différencient aussi ces atteintes sur le plan anatomique, ce qui est un changement rafraîchissant alors que les scientifiques généralisent souvent sans apporter de preuve, la portée de leurs trouvailles qui est limitée au tissu sur lequel ils ont opérés.

Les scientifiques ont sélectionné 31 personnes disposant : - d’une imagerie par résonance magnétique ante mortem évaluant l'atrophie cérébrale disponible dans les deux ans avant leur mort. - d’un diagnostic ante mortem de démence de la maladie d'Alzheimer ou de la maladie d'Alzheimer prodromique. - d’une confirmation neuropathologique post-mortem de la maladie d'Alzheimer.

Les sous-types basés sur l'atrophie antemortem ont été modélisés comme un phénomène continu en termes de deux dimensions: la typicité (allant de la maladie d'Alzheimer à prédominance limbique aux sous-types de la maladie d'Alzheimer épargnant l'hippocampe) et la gravité.

L'évaluation neuropathologique post-mortem comprenait des critères de jugement: - pathologies caractéristiques de la maladie d'Alzheimer de bêta-amyloïde et de tau. - les co-pathologies non liées à la maladie d'Alzheimer de l'alpha-synucléine corps de Lewy (habituellement associé à la maladie de Parkinson) et du TDP-43 (habituellement associé à la SLA). - et la concomitance globale entre ces quatre (co)-pathologies.

Des modèles de corrélation partielle et de régression linéaire ont ensuite été utilisés pour évaluer l'association entre les sous-types basés sur l'atrophie ante mortem et les résultats neuropathologiques post mortem.

Les scientifiques ont observé des associations globales et régionales (spécifiques à certains tissus) significatives entre la typicité ante mortem et les (co)-pathologies post mortem, notamment les corps tau, alpha-synucléine de Lewy et TDP-43. La typicité ante-mortem a démontré des associations régionales plus fortes avec la concomitance de plusieurs (co)-pathologies post-mortem par rapport à la gravité ante-mortem.

Les résultats des auteurs suggèrent les susceptibilités suivantes des sous-types basés sur l'atrophie : - la maladie d'Alzheimer à prédominance limbique vers une charge plus élevée de pathologies tau et TDP-43. - la maladie d'Alzheimer épargnant l'hippocampe vers une charge plus faible. - la maladie d'Alzheimer à prédominance limbique et la maladie d'Alzheimer typique vers un fardeau plus élevé de la pathologie à corps de Lewy à l'alpha-synucléine. -la maladie d'Alzheimer épargnant l'hippocampe et la maladie d'Alzheimer à atrophie minimale vers des fardeaux plus faibles.

L'étude des auteurs met en évidence l'importance de comprendre l'hétérogénéité dans la maladie d'Alzheimer en relation avec la concomitance de la maladie d'Alzheimer et d’autres pathologies.

Les résultats des auteurs permettent de mieux comprendre les vulnérabilités globales et celles affectant spécifiquement certains tissus, des sous-types biologiques du cerveau de la maladie d'Alzheimer vis-à-vis des (co)-pathologies.

L'implication relative à la fois des (co)pathologies caractéristiques de la maladie d'Alzheimer et de la maladie d'Alzheimer améliorera les connaissances actuelles sur l'hétérogénéité biologique dans la maladie d'Alzheimer et pourrait ainsi contribuer au suivi de la progression de la maladie et à la conception d'essais cliniques à l'avenir.

虽然星形胶质细胞通常有助于对抗 β-淀粉样斑块沉积,但持续的星形胶质细胞反应性可能导致星形胶质细胞营养不良、灰质萎缩和葡萄糖代谢减退。

enter image description here

这项新研究 中,伦敦帝国理工学院的科学家 Nicholas R Livingston、Paul Edison 和他们的同事使用新的咪唑啉受体 11C-BU99008 PET 示踪剂来检验星形胶质细胞反应性与神经变性。

他们发现有病理性淀粉样斑块(主要位于额叶、顶叶和枕叶区域)的患者的星形胶质细胞反应性增加的证据。 与阿尔茨海默病患者相比,轻度认知障碍患者的这些增加更大。



11C-BU99008 是一种新型 PET 示踪剂,可与 I2-BS 结合,I2-BS 的表达与星形胶质细胞的反应性有关。 咪唑啉受体主要分为三类:I1 参与抑制交感神经系统以降低血压,I2 的功能尚不清楚但与几种精神疾病有关,I3 调节胰岛素分泌。位于大脑中的 I2-BS 蛋白随着健康衰老而上调,并在阿尔茨海默病中进一步增加。

过去的不同研究证实了星形胶质细胞反应性是阿尔茨海默病病理进展的早期事件的假设,发生在对早期淀粉样蛋白沉积的反应中,淀粉样蛋白沉积通常起源于额叶。 在早期阶段,反应性星形胶质细胞具有神经保护作用,有助于清除 β-淀粉样斑块。

在科学家研究的队列中,他们发现颞叶中 11C-BU99008 的结合较弱,这与淀粉样蛋白相关神经病理学的更大相对进展有关,即葡萄糖代谢减退和灰质萎缩。 科学家提出,这种颞叶区域 11C-BU99008 摄取减少反映了星形胶质细胞营养不良,这是由慢性促炎和神经毒性淀粉样蛋白诱导的星形胶质细胞表型引起的,导致糖酵解能力降低和损伤。继发性神经元代谢或细胞丢失。

科学家的研究有明显的局限性。 首先,只能检查少数科目。 第二个限制是横截面设计,科学家们认识到这一点。然而,死后病理学也有同样的局限性。 因此,作者的结果最好是描述性的解释,并建议一个假设模型,而不是一个可靠和独立的测试。

尽管如此,本研究和之前的 PET 11C-DED 研究中观察到的效应方向的一致性为所提出的模型提供了令人信服的支持,其中星形胶质细胞反应性发生在 β-淀粉样斑块的早期沉积中,有助于清除 β-淀粉样斑块,但随着时间的推移,星形胶质细胞变得具有神经毒性,导致与认知障碍相关的组织活动减少和细胞死亡。

While astrocytes normally help fight β-amyloid plaque deposition, sustained astrocyte reactivity could lead to astrocyte dystrophy, gray matter atrophy, and glucose hypometabolism.

enter image description here

In this new study, scientists Nicholas R Livingston, Paul Edison and their colleagues at Imperial College, London, used the new imidazoline receptor 11C-BU99008 PET tracer to test the hypothesis of a dynamic relationship between the reactivity of astrocytes and neurodegeneration.

They found evidence of increased astrocyte reactivity in patients with pathologically developed amyloid plaques, mainly in the frontal, parietal and occipital regions. These increases were greater in patients with mild cognitive impairment than in patients with Alzheimer's disease.

Further analyzes showed that the lower reactivity of astrocytes in patients with pathologically developed amyloid plaques was associated with both hypometabolism of glucose in the parietal, temporal and frontal lobes and gray matter atrophy in the frontal and temporal lobes.

However, greater deposition of β-amyloid plaques was associated with increased reactivity of astrocytes in primary cortical motor and sensory areas, but decreased reactivity of astrocytes in temporal regions.

11C-BU99008 is a novel PET tracer that binds to I2-BS, the expression of which is associated with the reactivity of astrocytes. There are three main classes of imidazoline receptors: I1 is involved in inhibiting the sympathetic nervous system to lower blood pressure, I2 has functions as yet unclear but is involved in several psychiatric disorders, and I3 regulates insulin secretion. The I2-BS protein located in the brain, is upregulated with healthy aging, and is further increased in Alzheimer's disease.

Different past studies have reinforced the hypothesis that astrocyte reactivity is an early event in the progression of Alzheimer's disease pathology, occurring in response to early amyloid deposition, which usually originates in the frontal lobe. In the early stages, reactive astrocytes have a neuroprotective role, aiding in the clearance of β-amyloid plaques.

In the cohort studied by the scientists, they found weaker binding of 11C-BU99008 in the temporal lobe, which was associated with greater relative progression of amyloid-associated neuropathology, i.e. glucose hypometabolism and gray matter atrophy. Scientists propose that this reduced uptake of 11C-BU99008 in the temporal lobe region reflects astrocyte dystrophy, caused by a chronic pro-inflammatory and neurotoxic amyloid-induced astrocyte phenotype resulting in reduced glycolytic capacity and impairment. secondary neuronal metabolism or cell loss.

There are obvious limits to the study of scientists. First, only a small number of subjects could be examined. A second limitation was the cross-sectional design, which scientists recognize; however, postmortem pathology has the same limitation. The authors' results are therefore best interpreted descriptively and suggesting a hypothetical model, rather than a solid and independent test.

Nonetheless, the consistency of effect directions observed in this study and previous PET 11C-DED studies provide compelling support for the proposed model, where astrocyte reactivity occurs in response to early deposition of β-amyloid plaques, aiding in the clearance of β-amyloid plaques, but where after time the astrocytes become neurotoxic, contributing to reduced tissue activity and cell death associated with cognitive impairment.


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.

Alors que les astrocytes aident normalement à lutter contre le dépôt de plaques de β-amyloïdes, une réactivité soutenue des astrocytes pourrait entraîner une dystrophie des astrocytes, l'atrophie de la substance grise et l'hypométabolisme du glucose.

enter image description here

Dans cette nouvelle étude, les scientifiques Nicholas R Livingston, Paul Edison et leurs collègues de l'Imperial College, Londre, ont utilisé le nouveau traceur TEP du récepteur d'imidazoline 11C-BU99008 pour tester l'hypothèse d'une relation dynamique entre la réactivité des astrocytes et la neurodégénérescence.

Ils ont trouvé des indices d'une réactivité accrue des astrocytes chez les patients ayant un développement pathologique des plaques amyloïdes, principalement dans les régions frontale, pariétale et occipitale. Ces augmentations étaient plus importantes chez les patients atteints de troubles cognitifs légers que chez les patients atteints de la maladie d'Alzheimer.

Des analyses complémentaires ont montré que la réactivité plus faible des astrocytes chez les patients avec un développement pathologique des plaques amyloïdes était associée à la fois à un hypométabolisme du glucose dans les lobes pariétal, temporal et frontal et à une atrophie de la substance grise dans les lobes frontaux et temporaux.

Cependant, un plus grand dépôt de plaques de β-amyloïdes était associé à une réactivité accrue des astrocytes dans les zones corticales primaires motrices et sensorielles primaires, mais une réactivité des astrocytes diminuée dans les régions temporales.

11C-BU99008 est un nouveau traceur PET qui se lie à I2-BS, dont l'expression est associée à la réactivité des astrocytes. Il existe trois classes principales de récepteurs d'imidazoline : I1 est impliqué dans l'inhibition du système nerveux sympathique pour abaisser la tension artérielle, I2 a des fonctions encore incertaines mais est impliqué dans plusieurs troubles psychiatriques, et I3 régule sécrétion d'insuline. La protéine I2-BS localisée dans le cerveau, est régulé positivement avec le vieillissement en bonne santé, et est encore augmenté dans la maladie d'Alzheimer.

Différentes études passées ont renforcé l'hypothèse selon laquelle la réactivité des astrocytes est un événement précoce dans la progression de la pathologie de la maladie d'Alzheimer, se produisant en réponse à un dépôt amyloïde précoce, qui prend généralement naissance dans le lobe frontal. Dans les premiers stades, les astrocytes réactifs ont un rôle neuroprotecteur, aidant à la clairance de plaques de β-amyloïdes.

Dans la cohorte étudiée par les scientifiques, ils ont découvert une liaison plus faible du 11C-BU99008 dans le lobe temporal, qui était associée à une progression relative plus importante de la neuropathologie associée à l'amyloïde, c'est-à-dire l'hypométabolisme du glucose et l'atrophie de la matière grise. Les scientifiques proposent que cette absorption réduite de 11C-BU99008 dans la région du lobe temporal reflète une dystrophie des astrocytes, provoquée par un phénotype d'astrocytes chronique pro-inflammatoire et neurotoxique induit par l'amyloïde et entraînant une capacité glycolytique réduite et une altération secondaire du métabolisme neuronal ou une perte cellulaire.

Il y a des limites évidentes à l'étude des scientifiques. Premièrement, seul un petit nombre de sujets a pu être examiné. Une deuxième limitation était la conception transversale, que les scientifiques reconnaissent ; cependant, la pathologie post mortem a la même limitation. Les résultats des auteurs sont donc mieux interprétés de manière descriptive et suggérant un modèle hypothétique, plutôt qu'un test solide et indépendant. Néanmoins, la cohérence des directions d'effet observées dans cette étude et les études TEP 11C-DED antérieures fournit un soutien convaincant pour le modèle propos, où la réactivité des astrocytes se produit en réponse à un dépôt précoce de plaques de β-amyloïdes, aidant à la clairance de plaques de β-amyloïdes, mais où après un certain temps les astrocytes deviennent neurotoxiques, contribuant à une activité tissulaire réduite et à la mort cellulaire associée à une déficience cognitive.

En conclusion, les scientifiques ont démontré in vivo avec le nouveau traceur TEP 11C-BU99008 que la réactivité des astrocytes est augmentée dans les régions supposées représenter les premiers stades de la progression pathologique avec de faibles charges de dépôt de plaques de β-amyloïdes, et inversement relativement réduite dans les régions qui montrent des signes de progression plus avancée de la maladie avec un plus grand dépôt de plaques de β-amyloïdes et une atrophie.


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.

众所周知,接受手术的大约 10% 认知健康的患者在手术后会出现认知功能障碍的症状,但会很快康复。 他们中的百分之几会患上帕金森病。 众所周知,在手术后三个月内,高达 10% 的老年患者会出现持续程度的认知障碍。 没有大型研究研究过手术和麻醉对阿尔茨海默病的影响。

帕金森病与消化系统之间存在某种关系。 聚集的 α 突触核蛋白是帕金森病的病理特征。 它在帕金森病发病早期就在胃肠道中被发现。 关于阑尾切除术是否会增加帕金森病风险的报道相互矛盾。 阑尾切除术后患者发生帕金森病的总体相对风险 通常估计为几个百分点。

台北国立阳明大学的 Chih-Sung Liang、Mu-Hong Chen 当前研究 的目的是检查阑尾炎或阑尾切除术后患阿尔茨海默病 (AD) 和其他类型痴呆的风险 对于阑尾炎。

科学家们使用了台湾国民健康保险研究数据库中的索赔数据。 年龄≥45 岁的急性阑尾炎或因阑尾炎接受阑尾切除术的参与者入组并随访超过 15 年。

在随访期间,发生阑尾炎的患者和因阑尾炎接受阑尾切除术的患者阿尔茨海默病的发病率高于对照组。 Cox 回归分析表明,这些患者比对照组更容易患上阿尔茨海默病。

这些患者在所有类型的痴呆症(但不是通常与衰老相关的血管性痴呆症)方面的风险也高于对照组。 对照组痴呆诊断年龄为88.51岁; 然而,在阑尾炎后出现痴呆的人中,诊断时的平均年龄为 70.18 岁,而在阑尾炎后出现痴呆的时间为 5.84 岁。

阿尔茨海默病的病因是多因素的。 饮食、心血管疾病、低度全身炎症都与它有关。 所有这些因素都与胃肠道有一定的关系。

人们越来越关注阿尔茨海默病由感染引发的可能性,因为阿尔茨海默病大脑特征蛋白 β-淀粉样肽具有抗菌活性,因此 β-淀粉样肽可能是阿尔茨海默病的结果而不是原因。 阿尔茨海默病 几项观察性队列和病例对照研究表明,接种某些类型的疫苗后痴呆症发生率降低。 二十年前,Verreault 和他的同事报告说,疫苗暴露(白喉/破伤风、脊髓灰质炎、流感)与随后阿尔茨海默病的发展减少 25-60% 相关。

Klinger 及其同事已经证明,膀胱癌患者反复膀胱内注射卡介苗疫苗可显着降低患阿尔茨海默病的风险,尤其是在 75 岁以上的人群中。

Scherrer 和他的同事们发现,与未接种疫苗的人相比,接种破伤风、白喉、百日咳和带状疱疹疫苗的人患痴呆症的几率显着降低。



水痘-带状疱疹病毒(称为 VZV,用于水痘-带状疱疹病毒)是一种疱疹病毒,也称为 HHV-3(人类疱疹病毒 3),可引起水痘或带状疱疹。



在威尔士,从 2013 年开始进行全国带状疱疹疫苗接种,目标是为 70 岁的人接种疫苗,并为 70 岁未接种疫苗的人在 79 岁时进行补种。

直到 2018 年,威尔士唯一可用的带状疱疹疫苗是针对人类疱疹病毒 (Zostavax) 的减毒活疫苗。自 2018 年 6 月以来,一小部分威尔士人接种了重组带状疱疹疫苗(Shingrix)。

在这份新的预印本 中,Christian Schnier、Janet Janbek、Richard Lathe 和 Jürgen Haas 在一项使用国家健康的观察性队列研究中分析了 2013 年至 2020 年威尔士接种疫苗的人群中接种带状疱疹疫苗与痴呆症的关联追溯收集的数据。 此外,他们分析了这种关联是否是由诊断出的带状疱疹的减少所介导的,以及这种关联在阿尔茨海默病和血管性痴呆中是否有不同程度的影响。

接种疫苗的人在接种疫苗后被诊断出患有痴呆症的风险降低了 39%。 这种关联与 Scherrer 及其同事发表的结果接近,他们发现接种带状疱疹疫苗的人痴呆症减少了 43%。

与阿尔茨海默病相比,血管性痴呆患者在接种疫苗后痴呆症的减少略显着。 如果属实,他们的结果表明带状疱疹疫苗接种与脑血管疾病之间存在关联,而不是疫苗接种与大脑中有毒蛋白质(如 β-淀粉样肽和 tau 蛋白)的病理性积累有关。

然而,他们的结果应该谨慎解释,因为那些接种疫苗并随后被诊断为带状疱疹的人的总随访时间很短,导致估计的置信区间很宽。 接种带状疱疹疫苗的人因癌症以外的所有原因死亡的风险较低,这一发现可能表明接种带状疱疹疫苗具有非特异性作用。


这种解释得到以下支持: (i) 当感染一种病原体可以减轻由第二种无关病原体引起的疾病时,有记录的交叉免疫保护, (ii) 有报道称免疫佐剂(明矾)可延缓阿尔茨海默病的发展, (iii) 有效的佐剂疫苗(卡介苗芽孢杆菌)降低了膀胱癌患者阿尔茨海默病的发病率这一事实。

然而,这些关于水痘带状疱疹病毒疫苗接种与痴呆症之间负相关的理论应该与其他潜在理论一起考虑。事实上,他们的结果可能来自选择偏差。事实上,Simonsen 及其同事在疫苗功效的观察性队列研究中已经描述了疫苗的非特异性作用,例如较低的死亡率,他们将这种关联归因于脆弱性的选择偏倚。

为了控制衰弱的选择偏差,爱丁堡大学和哥本哈根大学的科学家调整了 65 至 70 岁之间的衰弱、养老院居住情况以及构成查尔森合并症指数的多种疾病。

作者不能肯定地排除未接种疫苗的人的健康预期寿命可能较低。 Zostavax 疫苗效力研究的结果支持这一观察结果,该研究表明,接种疫苗的人和服用安慰剂的人之间的死亡率没有显着差异。

此外,虽然他们的研究人群很大并且代表了威尔士人群,但平均随访期相当短,因为该疫苗于 2013 年被引入全国运动,这提供了最长的随访时间。大约 6 岁(最高 76 岁)。

This is another paper using light for targeting β-amyloid in Alzheimer disease with light in a very interesting strategy. It's known that it's possible to desegregate β-amyloid with near-infrared light. The scientists from China start from the premises that UV could be used to successfully target β-amyloid. Indeed UV does not penetrate past a few millimetres under skin, so there is no hope to reach the brain where resides much β-amyloid plaques.

Yet Mengmeng Ma and colleagues observed that there is no need to reach the brain, as removing β-amyloid in the blood stream makes it been removed from the brain. It's a phenomenon called "Peripheral clearance".

While β-amyloid deposition is located in the brain in Alzheimer disease, peripheral clearance of β-amyloid may possibly also lower brain levels. The kidney, the skin, the gastrointestinal tract, and the liver contribute to peripheral β-amyloid clearance. β-amyloid could be detected in urine of humans. Recent evidence suggested that hepatic clearance of β-amyloid is impaired in liver cirrhosis. There is some evidence that patients with chronic liver diseases have an increased risk for Alzheimer disease.

So it the idea that targeting β-amyloid on a peripheral artery is very attractive. But indeed the scientists from China could not use UV light to target any large artery because its very low penetrance. So they used a proxy: An engineered peptide which when illuminated with IR, restitues this energy as UV.

The authors say that was useful in a mice model of Alzheimer. Indeed this must be taken with a grain of salt as 1. desegregation of β-amyloid plaques seems to have no impact on Alzheimer disease in humans and 2. successful trials on mice models of neurodegenerative diseases are rarely successful on humans.

Nevertheless it's a very interesting article exploring new ideas.


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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