NINDS ALS Strategic Plan Workshop

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I watched the first day of NINDS ALS Strategic Plan Workshop, and unfortunately I can't attend the second day.

Here is my take on what I watched:

  • The introduction was interesting because it offered a large overview of the research effort. I noted than East Carolina university works on restoring homeostatsis as opposed to inhibiting or activating pathways. I will try to find a link to publications.

  • I do not know if it's a cultural bias (I am French) but everyone looked happy and were congratulating each other.

  • There were a lot of discussion, but few information provided.

  • I think that overall the purpose of this meeting was that NINDS needed to connect with organisations that could use some money.

The first day there were three main themes:

  • Accelerating Research on the Biology Behind ALS

1 Unlock sporadic ALS to identify new therapeutic targets across ancestries.

Basically what scientists said is that there is only one subject of discussion: Genetics behind ALS. For them even sporadic ALS is from genetic origin. No other subject was discussed even if scientists agree they do not understand what is causing ALS.

As usual for them ALS is indeed a disease of motor neurons even if one component of Relyvrio, the recent FDA approved drug is a bile acid synthesized in the liver.

2 Understand the molecular mechanisms underlying clinical heterogeneity in ALS.

Clearly there is no room for other domain than molecular biology, even if molecular biology was unable to provide any success in neurodegenerative and chronic diseases and limited ones in other diseases such as cancer.

3 Harness emerging technologies to uncover new disease mechanisms of ALS

There are new tools in molecular biology (things like two photon microscopy) and scientists want to play with them.

  • Translating Fundamental Research into Potential ALS Therapies

1 Establish a network of ALS Centers of Excellence to support ALS translational research

This is a call to network research centers which is probably a good idea.

2 Enhance and expand ALS biosample and data infrastructure

A call for more public databases, even if they are numerous today. In my opinion, public databases are only a tool for academics to make quick and cheap studies but they are not used for more useful goals.

3 Increase the biotherapeutic pipeline by enabling clinical trials and fostering academic/industry collaboration

A lot of words, but little content. It's well known that there is little connection between academics and industry and a general contempt of the later towards the former.

Optimizing ALS Clinical Research

There were three sub-themes, but basically it was a long and unclear discussion on the premise that ALS starts 10 years before diagnostic.

It looked to me as medieval debates about "How many angels can dance on the head of a pin?" Some scientists told it in a very polite way, when they stated that it was totally impossible and even dangerous to treat preventively people at risk, and anyway most people at risk will not develop any disease.

You can contact me through the link in the header of this page

Interplay between activation of endogenous retroviruses and inflammation as common pathogenic mechanism in neurological and psychiatric disorders.

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There is a bit weird observation about drugs that had a successful phase II in ALS: On third of those drugs can counter HIV.

Human Endogenous retroviruses (ERVs) are elements in the genome that closely resemble retroviruses. They comprise up to 5–8% of the human genome. They have repeatedly been implicated in the aetiology and pathophysiology of numerous human disorders, particularly in those that affect the central nervous system.

There is evidence that HERVs can be reactivated by viral infections, such as: 1) retroviruses – human immunodeficiency virus type-1 (HIV-1), human T-lymphotropic virus 1 (HTLV-1);

2) RNA viruses – influenza A virus, hepatitis C virus (HCV), severe acute respiratory syndrome coronavirus-2 (SARSCoV-2);

3) DNA viruses – herpes simplex virus type-1 (HSV-1), Epstein-Barr virus (EBV), human cytomegalovirus (CMV), Kaposi’s sarcoma-associated herpesvirus (KSHV) [66]

A growing number of studies links the induction and expression of these retroviral elements with the onset and severity of neurodevelopmental and psychiatric disorders.

Although these disorders differ in terms of overall disease pathology and causalities, a certain degree of chronic inflammation can be identified in all of them.

Based on these commonalities, the authors discuss in this new publication of the bidirectional relationship between ERV expression and inflammation and highlight that numerous entry points to this reciprocal sequence of events exist, including initial infections with ERV-activating pathogens, exposure to non-infectious inflammatory stimuli, and conditions in which epigenetic silencing of ERV elements are disrupted.

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Brain insulin resistance and cognitive function: influence of exercise.

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Exercise has systemic health benefits in people, in part, through improving whole-body insulin sensitivity. The brain is an insulin sensitive organ that is often underdiscussed relative to skeletal muscle, liver, and adipose tissue. While brain insulin action may have only subtle impacts on peripheral regulation of systemic glucose homeostasis, it is important for weight regulation as well as mental health. In fact, brain insulin signaling is also involved in processes that support healthy cognition.

Furthermore, brain insulin resistance has been associated with age-related declines in memory and executive function as well as Alzheimer's disease pathology. Herein, the authors provide an overview of brain insulin sensitivity in relation to cognitive function from animal and human studies, with particular emphasis placed on the impact exercise may have on brain insulin sensitivity. Mechanisms discussed include mitochondrial function, brain growth factors, and neurogenesis, which collectively help combat obesity-related metabolic disease and Alzheimer's dementia.

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Parkinsonism in a sample of patients with amyotrophic lateral sclerosis

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Numerous studies have suggested that the medical classification of many neurodegenerative diseases (Alzheimer's, ALS, Parkinson's, many dementias) is artificial because patients may have biomarkers involving up to four comorbidities.

The coexistence of amyotrophic lateral sclerosis (ALS) with clinical forms of Parkinson disease (PD), although uncommon, is found to a greater degree than one would expect by chance. The pathological mechanisms of ALS and Parkinson disease are still not understood, and the coexistence of these two diseases suggests that they could share mechanisms in common.

In this publication, authors from Colombia, Brazil, USA present a sample of patients with clinically definitive or probable ALS who were evaluated with single-photon emission computed tomography (SPECT/TRODAT) and compared with non-ALS controls. SPECT is a nuclear medicine tomographic imaging technique using gamma rays.

Dopamine is a neurotransmitter that modulates a variety of human functions such as motion, cognition, emotions, and the peristaltic reflexes in the gastrointestinal tract. The transport of this molecule at the neuron pre- and postsynaptic junctions is mediated by an axonal membrane dopamine transporter (DAT) that regulates dopamine levels within the synaptic cleft.

Development of various imaging ligands that specifically bind to DAT has been of interest to understand the functioning of these transporters and also to diagnose and monitor the treatment of Parkinson disease. TRODAT was shown to have a high sensitivity and specificity to measure the gradual loss of DAT in Parkinson disease patients.

Patients with clinically definite or probable ALS were assessed with the amyotrophic lateral sclerosis functional rating scale (ALSFRS) to define severity and had their demographic data collected. The TRODAT results of patients with ALS were compared with those of patients with a diagnosis of Parkinson disease with less than 10 years of duration, and with patients with a diagnosis of others movement disorders not associated with neurodegenerative diseases.

A total of 75% of patients with ALS had TRODAT results below the levels considered normal; that was also true for 25% of the patients in the control group without neurodegenerative disease, and for 100% of the patients in the Parkinson disease group. A statistically significant difference was found between patients with ALS and the control group without neurodegenerative disease in the TRODAT values < 0.05.

Conclusions: This study fits with the neuropathological and functional evidence that demonstrates the existence of nigrostriatal dysfunction in patients with ALS.

Sometimes ALS and Parkinson's are associated, for example in a unique neurodegenerative disease found on the island of Guam which is attributed to a toxin in cycad flour.

Progressive degeneration of functionally related groups of neurons occurs in certain infective, toxic, nutritional and genetically determined neurological diseases. It also takes place in normal aging, and several of the regions that undergo selective decay with the passage of time.

One (old) hypothesis that I like, is that features associated with Parkinson's disease, Alzheimer's disease, and ALS may be non-specific indicators of neuronal "disease", with certain morphological markers tending to appear more frequently in particular circumstances and particular regions associated with the pathology of particular diseases.

The association between beta-blockers and outcomes in patients with heart failure and concurrent Alzheimer's disease and related dementias.

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Beta blockers, also spelled β-blockers, are a class of medications that are used to manage abnormal heart rhythms, and to protect the heart from a second heart attack after a first heart attack. They are also widely used to treat high blood pressure.

Patients aged ≥ 75 years who receive a beta-blocker after heart failure with reduced ejection fraction (HFrEF) hospitalization have significantly lower 90-day mortality and readmission rates.

Several studies have shown it may also be useful to diminish the risk of Alzheimer disease.

This study aimed to determine the association between beta-blocker use and outcomes among patients with reduced ejection fraction and Alzheimer's disease and related dementias.

Using a random 40% sample of Medicare Parts A, B, and D data the authors identified 357,030 patients with ≥1 hospitalization for reduced ejection fraction between 2008 and 2018. 12.7% of those patients had dementia.

Patients with reduced ejection fraction and dementia had higher 90-day and 1-year mortality compared to patients with reduced ejection fraction-only.

Discontinuing beta-blocker was associated with a 2.2-fold higher risk of 90-day mortality among patients with HF-only and a 2.- fold higher risk of 90-day mortality among patients with reduced ejection fraction + dementia.

Not starting a beta-blocker was associated with a 1.8-fold higher risk of 90-day mortality among patients with reduced ejection fraction-only and a 1.7-fold higher risk of 90-day mortality among patients with reduced ejection fraction + dementia. Similar risks were seen at 1 year.

In conclusion beta-blocker therapy was found to be associated with significantly lower short and long-term mortality rates among all patients with reduced ejection fraction.

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Community-based high-intensity cycling improves disease symptoms in individuals with Parkinson's disease

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Regular and long-term engagement in aerobic exercise protocols hold promise in slowing the progression of Parkinson's disease. It is recommended that people with PD participate in a minimum of 90–150 min of moderate to vigorous aerobic exercise per week.

Regular program attendance and pedalling at a relatively high cadence may be key variables in mitigating Parkinson's disease symptoms.

The aim of the project describe by authors of a new article, was to monitor exercise behaviour and evaluate its effect on disease progression over a 6 month period in 50 people with Parkinson disease. It was implemented at five community exercise facilities (two in northern Washington and three in central Colorado) from 2019–2020.

The Movement Disorders Society-Unified Parkinson's disease Rating Scale Motor III and other motor and non-motor outcomes were gathered at enrollment and following 6 months of exercise. Attendance, heart rate, and cadence data were collected for each exercise session. enter image description here

On average, people with Parkinson disease attended nearly two-third of the offered PFP classes. The MDS-UPDRS III significantly decreased over the 6-month exercise period and immediate recall significantly improved.

Other motor and non-motor metrics did not exhibit significant improvement. Participants who attended most available classes experienced the greatest improvement in MDS-UPDRS III scores.

Consistent attendance and pedalling at a relatively high cadence may be key variables to Parkinson disease symptom mitigation. Improvement in clinical ratings coupled with lack of motor and non-motor symptom progression over 6 months provides rationale for further investigation of the real-world, disease-modifying potential of aerobic exercise for people with Parkinson disease.

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Serial olfactory testing for the diagnosis of prodromal Parkinson's disease in the PARS study.

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The Parkinson Associated Risk Syndrome study was designed to evaluate whether screening with olfactory testing and dopamine transporter imaging could identify participants at risk for developing Parkinson's disease.

Hyposmia, a reduced ability to smell odors, has been associated with increased risk of Parkinson disease, but, taken alone, lacks specificity. The scientists in a new publication evaluated whether repeating olfactory testing improves the diagnostic characteristics of this screening approach.

The participants that they included in their study completed up to 10 years of clinical and imaging evaluations in the PARS cohort. Olfaction was assessed with the University of Pennsylvania Smell Identification Test at baseline and on average 1.4 years later. Multiple logistic regression and Cox proportional hazards regression were used to estimate the hazard of development of clinical Parkinson disease or abnormal DAT imaging.

DAT scan (Dopamine Transporter Scan) commonly refers to a diagnostic method to investigate if there is a loss of dopaminergic neurons in striatum.

Of 186 studied patients who were initially hyposmic, 28% reverted to normosmia on repeat testing. No initially normosmic subjects and only 2% of reverters developed DAT imaging progression or clinical Parkinson disease, compared to 29% of subjects with persistent hyposmia who developed abnormal DAT and 20% who developed clinical Parkinson disease. The relative risk of clinical conversion to Parkinson disease was 8.3 and of abnormal DAT scan was 12.5 for persistent hyposmia, compared to reversion.

Persistent hyposmia on serial olfactory testing significantly increases the risk of developing clinical Parkinson disease and abnormal DAT imaging, compared to hyposmia on a single test. Repeat olfactory testing may be an efficient and cost-effective strategy to improve identification of at-risk patients for early diagnosis and disease modification studies.

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La calycosine améliore les changements neurodégénératifs induits par les produits finaux de glycation avancée dans des modèles de la maladie d'Alzheimer liée au diabète.

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De plus en plus d'éléments suggèrent que la maladie d'Alzheimer est liée au diabète de type 2, qui a été décrit comme le « diabète de type 3 ».

Le diabète sucré est caractérisé par une hyperglycémie causée par un manque d'insuline ou une résistance à l'insuline. L'insuline est une hormone chargée d'aider le glucose des aliments à pénétrer dans les cellules pour être utilisé comme source d'énergie. Le diabete est donc familièrement associé à la perte de poids et un appétit vorace. Le diabete est associée au développement de complications secondaires. Des études récentes ont révélé un risque accru de développer un dysfonctionnement cognitif ou une démence chez les patients diabétiques. enter image description here Le diabète sucré est considéré comme un facteur de risque pour de nombreuses maladies neurodégénératives, dont la maladie d'Alzheimer. Des études ont en effet montré le dysfonctionnement de la signalisation de l'insuline dans le cerveau, c'est à dire que les cellules du cerveau sont affamés par manque de glucose.

Ce stress cellulaire entraîne une augmentation de la phosphorylation de la protéine tau (hyperphosphorylation), ce qui est un biomarqueur de la pathologie de la maladie d'Alzheimer. Ce stress cellulaire modifierait l'activité de la glycogène synthase kinase-3β (GSK-3β) et améliorerait la phosphorylation de tau.

Fait intéressant, plusieurs études in vivo avec des médicaments antidiabétiques oraux et un traitement à l'insuline dans le diabète ont amélioré la fonction cognitive et diminué l'hyperphosphorylation de tau.

La glycogène synthase kinase-3 (GSK-3) est une protéine phosphorylant et inactivant la glycogène synthase. Au contraire l'insuline stimule la glycogène synthase.

Les glycations se produisent principalement dans la circulation sanguine pour une petite proportion des sucres simples absorbés : glucose, fructose et galactose. Les produits finaux de glycation avancée (AGE) sont des protéines ou des lipides qui deviennent glyqués à la suite d'une exposition aux sucres. Certains produits de glycation sont impliqués dans de nombreuses maladies chroniques liées à l'âge, notamment les maladies cardiovasculaires (l'endothélium, le fibrinogène et le collagène sont endommagés) et la maladie d'Alzheimer (les protéines amyloïdes sont des sous-produits des réactions évoluant vers les AGE).

Dans cette étude, les auteurs de l'university Minzu en Mongolie intérieure, étudient les effets des produits finaux de glycation avancée sur les neurones comme modèles de la maladie d'Alzheimer. C'est peut-être une influence culturelle qui les a poussé à s'interroger sur l'intérêt de la calycosine dans la maladie d'Alzheimer. En effet un thérapeute de la cour mongole, Hu Sihui, sous le règne de la dynastie mongole Yuan en Chine, est connu pour son livre Yinshan Zhengyao (Principes importants de la nourriture et des boissons), qui est devenu un classique de la médecine chinoise et de la cuisine chinoise. Il a été le premier à découvrir empiriquement et à décrire clairement les maladies de carence.

La calycosine est une isoflavone O-méthylée. Elle peut être isolée de la racine de l'Astragalus membranaceus mongholicus ainsi que du trèfle rouge. L'Astragalus membranaceus, est une plante à fleurs de la famille des Fabacées et fait partie des 50 herbes fondamentales utilisées dans la médecine traditionnelle mongole.

Le trèfle rouge, est une plante à fleurs, elle aussi de la famille Fabaceae.

Les isoflavones sont des dérivés substitués des isoflavones, un type d'isoflavonoïdes naturels, dont beaucoup agissent comme phytoestrogènes chez les mammifères. Les isoflavones sont produites presque exclusivement par les membres de la famille Fabaceae (égumineuses).

Les résultats in-vitro que les scientifiques rapportent ici révélent que la viabilité des cellules PC12 induites par les AGE augmente lorsqu'elles sont traitées avec de la calycosine.

La lignée cellulaire PC12 est souvent utilisée pour obtenir des d'informations sur les maladies du cerveau. Elle a été utilisé dans la recherche sur l'hypoxie et aussi pour trouver quels fragments de protéine prion causent un dysfonctionnement neuronal.

Les scientifiques ont également observé que les capacités d'apprentissage et de mémoire de rats atteints de la maladie d'Alzheimer, liée à la diabète sucré induite par l'AGE, s'amélioraient dans ces conditions.

L'analyse de ces résultats indique donc que la calycosine peut réguler efficacement à la baisse l'activité de GSK-3β, qui inactive la glycogène synthase, ce qui améliore les effets du diabète.

On peut en déduire que la calycosine peut potentiellement présenter d'importantes propriétés thérapeutiques pouvant être exploitées lors du traitement de la maladie d’Alzheimer, notamment quand elle est liée à un diabète sucré.

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Gut-oriented disease modifying therapy for Parkinson's disease.

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Neuropathology studies have shown that the Parkinson's disease, one of the most common neurodegenerative disorders, may start from the gut enteric nervous system and then spread to the central dopaminergic neurons through the gut-brain axis.

Metabolomic analysis revealed different gut microbiomes and gut metabolites in patients with Parkinson disease compared with unaffected controls.

Currently, although dopaminergic treatments and deep brain stimulation can provide some symptomatic benefits for motor symptoms of the disease, but as the disease progresses, these medications become less effective, while at the same time amplifying Parkinson's symptoms (tremor, hallucinations).

Patients whose disease begins in the gut may benefit most from interventions that target the gut microenvironments. In this review, the authors summarize the currently available evidence for targeting the gut microbiota in Parkinson disease.

This includes:

  • Probiotics such as Lactobacillus rhamnosus GG, Bifidobacterium animalis lactis, Lacobacillus plantarum PS128 , Clostridium butyricum, Bifidobacterium bifidum, L. fermentum, Lactobacillus reuteri, lactis Probio-M8, and Lactobacillus acidophilus. Nota Bene: L. acidophilus, B. bifidum, L. reuteri, L. fermentum reduced gene expressions of inflammatory markers (IL-1, IL-8, TNF-α) and increased expressions of TGF-β and PPAR-γ in the blood of participants. Abnormal insulin-related signaling pathway was observed in people with Parkinson disease and PPAR-γ plays a vital role in the regulation of many signaling pathways, including regulating insulin sensitivity, carbohydrate and lipid homoeostasis and mitochondrial biogenesis.

  • Prebiotics: Prebiotics are non-digestible food ingredients, generally attributed to dietary fibers, that selectively stimulate the growth or activity of some genera of microorganisms to beneficially affect the host's health. One recent open-label clinical trial with 87 participants showed improvement of non-motor symptom scores, reduced fecal inflammatory marker of calprotectin and increased fecal butyrate in patients with PD who received prebiotic supplement with resistant starch compared to those without prebiotic intervention.

  • Fecal microbiota transplantation: Indeed it's hard to identify the characteristics of a "good" fecal microbiata in the case of Parkinson. Increased abundance of Blautia and Prevotella and lower abundance of Bacteroidetes may be of some interest.

  • Live biotherapeutic products: Two gut bacterial strains, Parabacteroides distasonis (MRX0005) and Megasphaera massiliensis (MRX0029) may help patients. Genetically modified strains are studied on animal models

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