If you have ever wondered how drugs are selected for clinical trials and assumed, as often described, that they must be selected after lengthy preclinical studies in animal models, here is an article that will disappoint you.

50 scientists in Scotland conducted a two-stage systematic review to select the first two drugs for evaluation in Motor Neuron Disease-Systematic Multi-arm Adaptive Randomised Trial (MND-SMART: NCT04302870).

Obviously this could only lead to drugs that were already tested either in preclinical studies or in drugs trials.

Indeed the repurposing of drugs reduces costs and barriers to clinical development because they have been assumed by someone else, this is for example the strategy used by Amylyx for AMX0035.

First, the authors reviewed clinical studies in Motor neuron disease, Alzheimer's disease, Huntington's disease, Parkinson's disease and multiple sclerosis, identifying drugs described in at least one Motor neuron disease publication or publications in two or more other diseases.

The authors scored and ranked drugs using a metric evaluating safety, efficacy, study size and study quality. In stage two, the authors reviewed efficacy of drugs in Motor neuron disease animal models, multicellular eukaryotic models and human induced pluripotent stem cell studies.

An expert panel reviewed candidate drugs over two shortlisting rounds and a final selection round, considering the systematic review findings, late breaking evidence, mechanistic plausibility, safety, tolerability and feasibility of evaluation in Motor neuron disease-SMART.

Curiously those experts eliminated Sodium phenylbutyrate which is one component of AMX0035.

We learn also they rightly eliminated drugs that were already trialed four times or more. As the saying tells: "Errare humanum est, perseverare autem diabolicum."

The seven candidate drugs remaining were memantine, acetyl-l-carnitine, simvastatin, ciclosporin, melatonin, fluoxetine and N-acetyl cysteine.

For future drug selection, the authors will incorporate automation tools, text-mining and machine learning techniques to the systematic reviews and consider data generated from other domains, including high-throughput phenotypic screening of human iPSCs.

This statement is in itself a bit bizarre, there are many AI tools for discovering drugs, some are open source, some are commercial, but in most cases they are of good to excellent quality. Drug selection with a literature review sounds like a process from the dark ages.

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Consuming a high fat diet causes various metabolic diseases including metabolic syndrome and type 2 diabetes by developing insulin resistance and even decreasing insulin production.

For example a good way to induce Parkinson's syndrome in rats is to feed them a very high fat diet. Alzheimer's disease has sometimes been referred to as type 3 diabetes.

A mystery is that of ALS (Charcot's disease) where we often have insulin resistance, but very rarely comorbid diabetes. It also seems that the existence of misfolded proteins in the cytoplasm of patients is linked to stress in the endoplasmic reticulum, a cell organ whose function is precisely to fold the proteins newly produced by the ribosomes, before they are sent to their destination in the Golgi apparatus.

Long-term exposure to saturated fatty acids (SAFAs) in pancreatic β cells causes desensitization and impaired insulin secretion.

For example, consumption for three months of a very high fat diet containing pork fat and sunflower oil (80% fat) reduced the insulin content of pancreatic islets in mice (50%), proinsulin mRNA (35%), insulin biosynthesis and secretion in response to glucose (50%), and glucose oxidation.

According to previous research, WFS1 (Wolfram syndrome 1) is involved in insulin synthesis and release, as well as mass preservation of pancreatic β cells. This Wfs1 gene was first identified by Wolfram and Wagener (1983) in patients with Wolfram syndrome (i.e. diabetes mellitus and optic nerve atrophy).

The WFS1 gene expresses a glycoprotein in the endoplasmic reticulum (endoplasmic reticulum) of pancreatic β cells, heart, placenta, lungs and brain.

Saturated fatty acids like palmitate induce endoplasmic reticulum stress. Studies have shown that there is a mutual relationship between oxidative stress and endoplasmic reticulum stress. It is found in palm oil, but also in all animal (butter, cheese, milk and meat) or vegetable fats and oils.

During endoplasmic reticulum stress, WFS1 expression increases to inhibit stress signaling and thus prevent apoptosis (one of the processes leading to cell death).

Given the role of the WFS1 protein in maintaining endoplasmic reticulum homeostasis, it is expected that the expression of this protein is increased in the endoplasmic reticulum of β-cells, and its translocation to the cytoplasm is reduced. and leads to a decrease in pancreatic islet GSIS and insulin content.

Although many studies have investigated the effects of each very high fat diet and the involvement of WFS1 in insulin synthesis and secretion, no study has examined the interaction of very high fat diet and WFS1 in relation to insulin synthesis and secretion and therefore glucose homeostasis.

After weaning, the rats were divided into six groups and fed a normal diet and a very high fat (30%) diet for 20 weeks, followed by 4-phenyl butyric acid (4-PBA, an inhibitor endoplasmic reticulum stress) was administered. Note that this is one of the two components of the AMX0035.

After performing a glucose tolerance test, the animals were dissected and their pancreases removed for endoplasmic reticulum extraction, islet isolation, and GSIS evaluation. Additionally, pancreatic endoplasmic reticulum stress biomarkers.

This very high-fat diet decreased pancreatic protein WFS1 and GSH levels, and increased pancreatic catalase activity. As a result, it increased the levels of BIP, CHOP and WFS1 proteins in the ER extracted from the pancreas. In addition, the very high-fat diet caused glucose intolerance and decreased GSIS and insulin content of islets.

However, administration of 4-PBA restored previous levels. It therefore appears that consumption of very high fat diet by inducing pancreatic endoplasmic reticulum stress altered WFS1 expression levels, reduced GSIS and islet insulin content and ultimately impaired glucose homeostasis.

The administration of 4-PBA does not seem to me to be a solution to the problem of the stress of the endoplasmic reticulum, on the other hand it is certainly a means of mitigating a dramatic consequence of this stress: Cell death, which

Yet, administration of 4-PBA does not seem to me to be a solution to the problem of the stress of the endoplasmic reticulum, on the other hand it is certainly a means of mitigating a dramatic consequence of this stress: Cell death, which in the case of ALS most certainly affects the cells that consume the most energy, such as skeletal muscles and motor neurons.

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Caffeic acid is an organic compound. The structure of caffeic acid (aromatic core, conjugated double bond, and hydroxyl groups) allows it to function as an antioxidant.

Caffeic acid (50 mg/kg) reduces blood glucose levels in streptozocin-induced diabetic mice.

In depressed rats, caffeic acid (10 and 30 mg/kg) normalized noradrenalin and tryptophan levels in a dose-dependent manner.

BDNF, a neurotrophin that modulates neuroplasticity in the brain, is regularly decreased in depressed patients.Caffeic acid also increased the expression of brain-derived neurotrophic factor (BDNF) in stressed mice; the effect was mediated by 5-lipoxygenase inhibition [106].

The main components of plaques found in the brains of patients with Alzheimer’s disease consist of β-amyloid peptides and tau proteins. enter image description here The essential step for tau protein aggregation is tau phosphorylation which may also play a role in initiating β-amyloid toxicity. One of the kinases that phosphorylate tau protein is glycogen synthase kinase-3 beta (GSK3β); insulin signaling inhibits the activity of this kinase. Therefore, a hypothesis suggests that GSK3β deregulation in neurons may be a key point in developing Alzheimer’s disease.

In the brain of hyperinsulinemic rats, caffeic acid normalized superoxide dismutase (SOD) activity and glutathione levels, inhibited glycogen synthase kinase 3β (GSK3β) activity, and decreased the level of β-amyloid and phosphorylated tau protein.

Feeding hyperinsulinemic rats with caffeic acid (30 mg/kg b.w./day) for 30 weeks significantly improved their memory and learning impairments caused by a high-fat diet.

The concurrent effects of caffeic acid on atherosclerotic lesions and cognitive decline were explored in a new article by using the ApoE (Alzheimer) mice model.

A two months' administration of 20 mg/kg caffeic acid or saline was given once two days intraperitoneally to 5-month-old female ApoE mice.

The scientists found that the caffeic acid treatment reduced the atherosclerotic lesions in the whole aorta and aortic sinus of the resulting 7-month-old ApoE mice by roughly 50%, compared with the saline control.

Meanwhile, the cognitive decline of treated mice were significantly alleviated, as measured by Y-maze and Morris water maze tasks. A reduced accumulation of β-amyloid in the hippocampus was also observed. These effects were associated with elevated serum HDL-c concentration, upregulated ABCA1 and ABCG1 mRNA levels, as well as decrease local inflammation and reduced levels of serum pro-inflammatory cytokines including TNF-α, IL-6 and MCP-1.

These obtained results suggested the preventive and therapeutic potential of caffeic acid against atherosclerosis and Alzheimer's disease during aging.

Free caffeic acid can be found in a variety of herbs of the mint family, especially thyme, sage and spearmint (at about 20 mg per 100 g), and in spices, such as Ceylon cinnamon and star anise (at about 22 mg per 100 g).

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There is growing evidence that patients with type 2 diabetes mellitus have an increased risk of developing Parkinson's disease and share similar dysregulated pathways. There is growing evidence that patients with type 2 diabetes mellitus have an increased risk of developing Parkinson’s disease and share similar dysregulated pathways, which suggests the presence of common underlying pathological mechanisms.

Type 2 diabetes develops from insulin resistance, leading to a variety of detrimental effects on metabolism and inflammation. Similar dysregulation of glucose and energy metabolism are early events in the pathogenesis of sporadic Parkinson's disease and to some degree in Alzheimer's disease as well as amyotrophic lateral sclerosis (Lou Gehrig disease). Trials of intranasal insulin administered to patients with mild cognitive dysfunction and early Alzheimer's disease led to improvements in verbal memory and cognition.

For example it is possible to induce a Parkinson disease like in rats, by feeding them with a high fat diet. enter image description here Scientists in a new publication, aimed to determine whether the risk of Parkinson disease increases as diabetes progresses among patients with type 2 Diabetes mellitus.

Using a nationally representative database from the Korean National Health Insurance System, 2,362,072 individuals with type 2 Diabetes mellitus who underwent regular health checkups during 2009-2012 were followed up until the end of 2018.

There is still no universal agreement on the optimal data needed to create a reliable diabetes severity measure, despite the presence of some diabetes-specific severity indices.

The diabetes severity score parameters included the number of oral hypoglycemic agents, diabetes duration, insulin use, or presence of chronic kidney disease, diabetic retinopathy, or cardiovascular disease.

Each of these characteristics was scored as one unit of diabetes severity and their sum was defined as a diabetes severity score from 0-6.

The scientists identified 17,046 incident Parkinson disease cases during the follow-up. Each component of the diabetes severity score showed a similar intensity for the risk of Parkinson disease.

Diabetes severity, as measured by diabetic complication status, treatment complexity, and duration of diabetes, was strongly associated with an increased risk for Parkinson’s disease. All characteristics indicative of diabetes severity had an additive association with the risk of Parkinson’s disease in patients with type 2 DM. The coexistence of conditions such as retinopathy, nephropathy, CVD, the complexity of diabetes treatments, or the long duration of diabetes was more strongly associated with Parkinson’s disease risk than the presence of a single condition alone. People with a diabetes severity score of 4 or higher had a more than doubled risk of Parkinson’s disease compared with those with a score of 0, and those with a score of 6 had a 2.78-fold increased risk of Parkinson’s disease. These associations became stronger for younger diabetic patients.

Compared with subjects with no parameters, HR values of Parkinson disease were 1.09 in subjects with one diabetes severity score parameter, 1.28 in subjects with two parameters, 1.55 in subjects with three parameters, 1.96 in subjects with four parameters, 2.08 in subjects with five parameters, and 2.78 in subjects with six parameters.

Diabetes severity was associated with an increased risk of developing Parkinson disease. Severe diabetes may be a risk factor for the development of Parkinson disease. Yet this was an observational study, so the association found between the stratification parameters and endpoints may not be causal.

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Au cours du processus de vieillissement, il y a une augmentation de l'incidence de plusieurs maladies, y compris le déclin de la santé physique et mentale, qui ont un effet en cascade sur d'autres problèmes de santé. La démence et les troubles cognitifs font partie des maladies non transmissibles ou des problèmes liés à l'âge les plus importants. Bien qu'il n'existe actuellement aucun remède contre la démence, les stratégies non pharmaceutiques telles que l'activité physique ou les interventions d'exercice physique sont considérées comme essentielles pour prévenir l'apparition de la maladie. En particulier, la santé cardio-respiratoire s'est avérée être associée à une meilleure cognition et à un risque plus faible de démence.

Le santé cardio-respiratoire est définie comme la capacité des systèmes circulatoire, respiratoire et musculaire à fournir de l'oxygène pendant une activité physique soutenue. Elle est généralement évaluée en tant que pic de consommation d'oxygène (VO2peak). Cependant, pour obtenir une mesure exacte et précise du santé cardio-respiratoire, un test d'effort cardiopulmonaire incrémental (CPET) jusqu'à épuisement est nécessaire. La CPET comporte certains risques physiques et sanitaires, en particulier pour les personnes âgées, et nécessite l'utilisation d'équipements de haute précision et coûteux qui entravent sa mise en œuvre.

De plus, l'argument que les tests de santé cardio-respiratoire ne devraient pas être utilisé dans la pratique clinique de routine est obsolète. Kaminsky et al. ont récemment souligné que les unités commerciales d'épreuves d'effort métaboliques sont faciles à utiliser, fournissent une analyse en temps réel des échanges respiratoires et même un système d'électrocardiogramme intégré à des prix faibles. La mise en œuvre du CPET dans les hôpitaux doit maintenant être envisagée.

Cependant, bien que les tests de santé cardio-respiratoire ne soit pas couramment utilisé dans la pratique clinique, une alternative est l'utilisation d'estimations des tests de santé cardio-respiratoire. Plusieurs études ont déjà développé des ensembles d'équations basées sur des études de larges populationr et visant à construire des équations simple pour prédire les résultats des tests de santé cardio-respiratoire. On nomme l'ensemble de ces équations: eCRF.

Boots et al. ont montré que l'eCRF était aussi associé à la fonction cognitive, cependant, ce travail incluait seulement des personnes âgées de 20 à 70 ans, et ils utilisaient une équation qui n'était pas spécifique aux personnes âgées.

Par conséquent, les objectifs de cette nouvelle étude de Ana Carbonell-Baeza and David Jiménez-Pavón du Biomedical Research and Innovation Institute of Cádiz (INiBICA), étaient:

  • d'analyser la précision des équations existantes pour prédire les tests de santé cardio-respiratoire chez les personnes âgées et de développer de nouvelles équations pour prédire les résultats de tests de santé cardio-respiratoire (eCRF) dans ce groupe de population spécifique.
  • d'analyser les associations de santé cardio-respiratoire (mesurée objectivement par un test en laboratoire et estimée par les équations) avec un ensemble complet de tests de performance cognitive.

Cependant les auteurs de cette nouvelle étude ont constaté qu'aucune équation de eCRF existant, n'a permis d'obtenir un bon rapport de prédiction après application à leur échantillon d'étude.

Ils ont donc élaboré un nouvel ensemble spécifique d'équations eCRF pour les personnes âgées a été développé avec des valeurs prédictives allant de 74 à 87 % qui pourraient être utilisées en fonction des besoins, de la disponibilité de l'équipement, des ressources ou du contexte de mesure (c'est-à-dire, milieu clinique ou maison de retraite).

De plus, l'eCRF est positivement associé, de la même manière que les tests de santé cardio-respiratoire mesuré objectivement, aux performances sur le langage, la fluidité, la flexibilité cognitive, l'attention et la mémoire de travail, indépendamment du sexe, de l'âge et du niveau d'éducation.

Ainsi, l'augmentation du santé cardio-respiratoire pourrait être un facteur de protection contre la détérioration de la fonction cognitive associée au vieillissement chez les personnes âgées.

Obstructive sleep apnea is highly prevalent but easily undiagnosed and is an independent risk factor for cognitive impairment.

However, it remains unclear how OSA is linked to cognitive impairment. In the present study, the authors found the correlation between morphological changes of perivascular spaces and cognitive impairment in OSA patients. Moreover, the authors developed a novel set of dynamic contrast-enhanced magnetic resonance imaging methods to evaluate the fluid dynamics of glymphatic drainage system.
The scientists here found that the inflow and outflow parameters of the glymphatic drainage system in patients with OSA were obviously changed, indicating impairment of glymphatic drainage due to excessive perfusion accompanied with deficient drainage in OSA patients. Moreover, parameters of the outflow were associated with the degree of cognitive impairment, as well as the hypoxia level. In addition, continuous positive airway pressure enhances performance of the glymphatic drainage system after 1 month treatment in OSA patients.
The scientists here proposed that ventilation improvement might be a new strategy to ameliorate the impaired drainage of glymphatic drainage system due to OSA-induced chronic intermittent hypoxia, and consequently improved the cognitive decline.

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Parkinson's disease is the second most prevalent neurodegenerative disease of the central nervous system, with an estimated 5,000,000 cases worldwide. Parkinson disease pathology is characterized by the accumulation of misfolded α-synuclein, which is thought to play a critical role in the pathogenesis of the disease.

Animal models of Parkinson disease suggest that activation of Abelson tyrosine kinase plays an essential role in the initiation and progression of α-synuclein pathology and initiates processes leading to degeneration of dopaminergic and nondopaminergic neurons.

Four drugs, nilotinib, dasatinib, bosutinib and ponatinib are src tyrosine kinase inhibitor used for the treatment of chronic myelogenous leukemia. Given the potential role of c-Abl in Parkinson disease, a c-Abl inhibitor library was developed to identify orally bioavailable c-Abl inhibitors capable of crossing the blood-brain barrier based on predefined characteristics, leading to the discovery of IkT-148009.

IkT-148009, a brain-penetrant c-Abl inhibitor with a favorable toxicology profile, was analyzed for therapeutic potential in animal models of slowly progressive, α-synuclein-dependent Parkinson disease.

In mouse models of both inherited and sporadic Parkinson disease, IkT-148009 suppressed c-Abl activation to baseline and substantially protected dopaminergic neurons from degeneration when administered therapeutically by once daily oral gavage beginning 4 weeks after disease initiation.

Recovery of motor function in Parkinson disease mice occurred within 8 weeks of initiating treatment concomitantly with a reduction in α-synuclein pathology in the mouse brain. These findings suggest that IkT-148009 may have potential as a disease-modifying therapy in Parkinson disease.

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Nervonic acid is recommended to pregnant and nursing women as it can speed up the development in infants. It is particularly abundant in the white matter of animal brains and in peripheral nervous tissue. Yet there are very few studies on it in the realm of neurodegenerative diseases. enter image description here In this study, the authors applied behavioral, transcriptomic and metabolomic approaches to analyze the neuroprotective effect of nervonic acid and its molecular mechanism in Alzheimer's disease model mice.

They shown that nervonic acid improved motor skills and learning and memory abilities of mice at the behavioral level.

To further understand the specific pathways involved in this protective effect, the authors applied the metabolomics and transcriptomics profilings and focused on the expression patterns of genes that nervonic acid might alter, particularly those related to the accumulation of metabolites in the brain.

In lipopolysaccharide (LPS) induced Alzheimer's disease mice, pathways related to neuroinflammation (two imprecise notions) are significantly increased compared with the normal control, and pathways related to neuronal growth and synaptic plasticity are significantly downregulated.

When nervonic acid was used for protection in this mice model of Alzheimer, these signaling pathways induced by LPS were partially reversed. At the same time, compared with the Alzheimer's disease model group, upregulation of arachidonic acid metabolism, purine metabolism, and primary bile acid biosynthesis and downregulation of amino acid metabolic pathways were particularly pronounced in the nervonic acid treatment group.

Nervonic acid improved the spatial and learning behavior of the mice impaired by LPS administration.

In summary, authors' results show that in LPS mice model, nervonic acid can significantly ameliorate neuroinflammation and deterioration of learning and memory, and exerts a neuroprotective function through regulation of multiple gene transcription and metabolism pathways.

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It is generally accepted that dynamic changes resulting from the death of cells in the substantia nigra, a region of the midbrain, that lead to a dopamine deficit, underlie Parkinson's disease. enter image description here Deep brain stimulation of the subthalamic nucleus is a well-established treatment for the motor symptoms of Parkinson's disease, but it is still poorly understood how subthalamic stimulation modulates the state dynamics of the brain's motor network. A biological network represents systems as complex sets of relationships between various biological entities.

To investigate this, the authors of a new paper acquired functional resting-state magnetic resonance imaging time series data from 27 drug-free patients with Parkinson's disease who had brain stimulation electrodes. deep deployed in the subthalamic nucleus, in activated and deactivated states of stimulation. Sixteen matched healthy people were included as a control group.

In this paper, scientists adopted a modeling approach known as the hidden Markov model, to highlight the emergence of recurrent activation patterns of interacting motor regions via the oxygen level-dependent signal in blood detected in resting-state functional magnetic resonance of all participants. The hidden Markov model includes the dynamics of distinct states of the whole-brain motor network, including frequency of occurrence, duration, fractional coverage, and their transition probabilities between different states.

Notably, subthalamic stimulation reshapes network expression and stabilizes state transitions. In addition, subthalamic stimulation ameliorates motor symptoms by modulating transition trajectories between network states.

This modulating mechanism of subthalamic stimulation appears to have three significant effects: recovery, slowing, and remodeling effects. Significantly, recovery effects were correlated with improvement in subthalamic stimulation-induced tremor and postural symptoms.

Additionally, subthalamic stimulation was found to restore a relatively low level of functional connectivity fluctuation in all motor regions that is at a level close to that of healthy participants.

The authors' findings provide mechanistic insight and explanation of how subthalamic stimulation modulates motor symptoms in Parkinson's disease.

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The risk of dementia is higher in women than in men. enter image description hereThe metabolic consequences of the decline in estrogen during menopause accelerate this neuropathology in women. However, the use of hormone replacement therapy gives contradictory results in the prevention of cognitive decline.

Hormone replacement therapy (HRT) is usually used to treat symptoms associated with female menopause. Within 10 years of menopause, hormone replacement therapy may reduces all-cause mortality and the risk of coronary heart disease, osteoporosis and dementia. But after 10 years, the beneficial effects on mortality and coronary heart disease are no longer apparent.

In this new publication, the authors study the modulating role of APOE genotype and age at the start of hormone replacement therapy on the heterogeneity of the cognitive response to hormone replacement therapy.

The analysis used baseline data from participants in the European Alzheimer's Dementia Prevention Cohort. Covariate pattern analysis was used to test the impact of APOE genotype and hormone replacement therapy on certain cognitive tests, such as MMSE, RBANS, score counting, the Four Mountain test, and the of the supermarket trolley, as well as the volumes of the medial temporal lobe by MRI.

APOE4 hormone replacement therapy users had the highest RBANS Delayed Memory Index score compared to APOE4 HRT non-users and APOE4 non-carriers, with entorhinal and amygdala volumes 6-10% greater important. Earlier initiation of hormone replacement therapy was associated with greater right and left hippocampal volumes only in APOE4 carriers.

Thus the introduction of hormone replacement therapy seems to be associated with delayed memory improvement and greater brain volumes only in in APOE4 carriers.

This may represent an effective targeted strategy to mitigate the higher lifetime risk of Alzheimer's disease in this large at-risk population subgroup. Confirmation of the results of a fit-for-purpose RCT with prospective recruitment based on APOE genotype is needed to establish causation.

We should remember that some studies on hormone replacement therapy seem to show that the risks could outweigh the benefits. It has been suggested that many of the positive perceptions of hormone replacement therapy may be due to the efforts of pharmaceutical companies including by publishing biased scientific publications.

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