Here is a quick analysis of two recently published papers. One is about the controversial role of 40Hz signals in Parkinson's and Alzheimer's disease, the other is about brain clearance during sleep. Intriguing connections suggest that VIP signaling pathways and EEG activity patterns may contribute to the regulation of brain waste clearance mechanisms during sleep. Indeed further research is needed to explore these interactions comprehensively. The first text discusses the paradoxical activity observed in the brain during sleep, where the brain remains highly active despite the body's restful state.

Scientists from Washington University School of Medicine in St. Louis have discovered that during sleep, brain waves play a crucial role in flushing waste out of the brain. These brain waves, generated by coordinated neural activity, facilitate the movement of fluid through dense brain tissue, effectively cleansing it.

The research indicates that sleep serves as a critical time for the brain to initiate a cleaning process, eliminating metabolic waste and toxins that accumulate during wakefulness. This cleansing mechanism is essential for preventing neurological diseases such as Alzheimer's and Parkinson's, where excess waste buildup leads to neurodegeneration.

The authors demonstrated that neural networks synchronize individual action potentials to create large amplitude, rhythmic, and self-perpetuating ionic waves in the interstitial fluid of the brain. These waves are a plausible mechanism to explain the correlated potentiation of the glymphatic flow through the brain parenchyma. To demonstrate that the scientists showed that flattening these high-energy ionic waves largely impeded cerebrospinal fluid infiltration into and clearance of molecules from the brain parenchyma. Notably, synthesized waves generated through transcranial stimulation substantially potentiated cerebrospinal fluid-to-interstitial fluid perfusion. So their study demonstrates that neurons serve as master organizers for brain clearance.

This reminds us of the "40hz" publications that many scientists find controversial.

Funnily another article is published by some of the MIT scientists who told a few years ago that gamma stimulation at a frequency of 40 Hz can reduce Alzheimer's disease progression. The authors of The Picower Institute for Learning and Memory of MIT have now discovered that this stimulation prompts a specific type of neuron to release peptides, which in turn drive processes promoting amyloid clearance via the brain's glymphatic system. This mechanism suggests a potential avenue for treating neurological disorders through sensory stimulation.

The authors from MIT say the relation between the 40hz signals and brain clearance is through interneurons in the brain that express the VIP protein. While named Vasoactive Intestinal Peptide (VIP) because it is first was found to be an intestinal peptide that influences blood pressure and heart rate, it is also expressed in other tissues such as the brain's cortex and hypothalamus.

Brain Clearance and VIP

Vasoactive Intestinal Peptide (VIP) plays a role in modulating various physiological functions in the brain, including neurotransmission and circadian rhythm regulation. Similarly to its action in the intestine on heart and blood flow, studies suggest that VIP is involved in the regulation of cerebral blood flow and may have implications for brain waste clearance mechanisms.

VIP and EEG Brain Waves

VIP-expressing neurons are involved in the regulation of circadian rhythms and are particularly abundant in the suprachiasmatic nucleus (SCN) in the hypothalamus. The SCN exhibits rhythmic electrical activity, which influences sleep-wake cycles and may indirectly affect EEG brain wave patterns during sleep. So VIP-mediated signaling pathways may intersect with mechanisms regulating EEG brain waves and brain clearance processes during sleep. VIP's role in modulating neural activity and circadian rhythms may influence the generation of EEG patterns associated with sleep stages, which, in turn, could impact glymphatic clearance and waste removal in the brain.

As usual, don't expect fast progress if this therapy hits the market, months of chronic sensory gamma stimulation may be needed to have sustained effects on cognition.

This post is about an interesting hypothesis. Hypotheses abound, yet few a convincing.

Half of patients with Alzheimer's disease, Parkinson's disease, or ALS have insulin resistance. Obesity and diabetes have been linked to neurodegenerative diseases like multiple sclerosis (MS), Alzheimer's (AD), and Parkinson's (PD). This means the cells of their body cannot let the glucose enter them. Glucose is the main energy source as it is converted into ATP. Glucose is for short-term (day) energy needs. Another source of energy is lipids (fat). Lipids are even more dense than glucose energy-wise.

The body needs an enormous amount of energy. With all the lipids in the body of a healthy person, you could charge two Tesla cars! The brain (a part of the CNS) needs 20% of all energy intake.

A new paper argues that cells shift their metabolism from glucose to lipids under stressors. It tells that one notable distinction between glucose and lipid metabolism is in the quantity of oxygen required to generate each ATP molecule. Lipid metabolism needs two times more oxygen than glucose metabolism. The result is two times more damaging ROS (a by-product of metabolism). Studies have shown that oxidative stress and endoplasmic reticulum stress are correlated and can lead to protein misfolding (Abramov et al., 2020). Accumulation of misfolded proteins causes cellular damage and mitochondrial dysfunction and is associated with a range of neurodegenerative diseases, including ALS (misfolded SOD1, TDP-43, C9orf72) (McAlary et al., 2020), Parkinson's disease (misfolded α-synuclein) and Alzheimer disease (misfolded Aβ and Tau) (Abramov et al., 2020).

It explains also the accumulation of iron in patients' brains: To transport oxygen the blood cells need iron, and as the glucose in the blood is not absorbed in cells, it induces a change in microbiota.

It's also well known that SCFAs (including butyrate) have a positive effect on neurodegenerative diseases by their action on microbiota. SCFAs help to restore glucose as the preferred energy substrate. Authors say there are other means to restore glucose as the main source of energy.

What to think about this paper? First, some authors belong to a biotech so we can expect they want to promote their drug: Mitometin. Second, this is a review, this is not even a pre-clinical study, yet some of the authors were involved in pre-clinical studies on this topic. Other groups have written on this topic. What to make of this? Acetyl-CoA carboxylase might be of interest as they produce malonyl-CoA which inhibits the CPT1 gene that regulates lipid metabolism. B7 vitamin is known to convert acetyl-CoA to malonyl-CoA for fatty acid synthesis.

Scientists are never short of new hypotheses about the cause and even the nature of diseases. For example, some of them now believe that “inflammation” is the underlying cause of many neurodegenerative diseases.

The human immune system is made up of different subsets of extreme complexity. The main mode of action is quite brutal, as the cells renew themselves quite quickly (from a few days to a few weeks), any slightly suspicious cell is deliberately killed by one of the agents of the immune system.

The central nervous system is composed of cells that have a probable lifespan of a hundred years or more, and they do not renew themselves through division, so this mode of operation is impossible. Therefore the central nervous system is kept isolated from the rest of the body through the blood-brain barrier and it has its own immune system.

Breaks in this barrier and the invasion of the CNS by the body's immune cells have sometimes been suggested as being able to cause diseases such as ALS, and now Alzheimer's. A new article aims to show that in the case of Zika viruses, the terrible consequences that an infection causes are not due to the infection of cells by the virus, but by the invasion of the CNS by immune cells from the rest of the body.

The article incriminates CD8+ T cells which function like NK cells, formidable killers.

Antibody depletion of CD8 or blockade of NKG2D prevented ZIKV-associated paralysis.

Of course, this article is based on an experiment with mouse models of a disease, so it is quite risky to draw conclusions for humans.

In any case, once the damage is done, it is too late, as the neurons do not reproduce. Yet it is possible to have a form of damage mitigation, either thanks to neurogenesis in certain rare cases, or even to a sort of mutual aid mechanism between neurons, which causes a surviving neuron to try to take over the work of the dead neurons. This is what causes us to become clumsy as we age.

Therapy is therefore not to be expected quickly, the best is to maintain a healthy blood-brain barrier, that is to say, to follow the precautions recommended for cardiovascular diseases.

The TCA cycle (Krebs cycle) is the primary mechanism for ATP synthesis in brain cells, operating within the mitochondria's matrix. Additionally, glycolysis contributes to ATP production, particularly during heightened energy demands or glucose scarcity. Insulin plays a crucial role in regulating glucose metabolism and maintaining neuronal function.

Mitochondria, akin to tiny microbe-like structures, are strategically located within cells to provide energy where needed, including neuronal terminals. Synthesized primarily in the soma, the central part of the neuron, mitochondria must undergo transport to distant neuronal terminals. Maintenance of mitochondrial health is crucial as damaged mitochondria can induce oxidative stress, necessitating fusion with healthy counterparts for repair or elimination. Thus, ensuring mitochondrial integrity is paramount for neuronal function.

In both processes -glycolysis and the citric acid cycle- during oxidative phosphorylation (OXPHOS) glucose and other substrates are metabolized, generating the synthesis of ATP.

A new text using the detrimental effects of S-nitrosylation on TCA cycle function, provides insights into potential therapeutic interventions.

The scientists compared in-vitro isogenic wild-type and Alzheimer's disease mutant human induced pluripotent stem cell (hiPSC)-derived cerebrocortical neurons (hiN) and found evidence of dysfunctional processes in mitochondria. This aberrant S-nitrosylation is documented not only in hiN cells but also in postmortem human Alzheimer's disease brains versus controls

Detailed analyses showed significant inhibition of metabolic flux at various steps of the TCA cycle in hiN. It suggests that deficiencies in TCA cycle function were associated with a shift towards compensatory glycolysis, suggesting an adaptive response to impaired oxidative phosphorylation. In particular, supplementation with dimethyl succinate, a substrate bypassing the inhibited step in the TCA cycle, suggests a potential therapeutic strategy to mitigate mitochondrial dysfunction in Alzheimer's disease. Dimethyl succinate (DMS), a membrane-permeant form of succinate, could serve as a pro-drug to provide substrate to the next enzymatic step in the TCA cycle, succinate dehydrogenase (SDH).

Those findings are not entirely surprising and the motivation of the scientists seems more to test a new mass spectroscopy technique than finding a drug. Anyway, it may add to the incentive to make pre-clinical trials of dimethyl succinate in rat Alzheimer's disease models.

Usually, Dimethyl succinate is sometimes used as a solvent. Yet dimethyl succinate is an irritant and an explosive product.

Unfortunately, after decades of research and hundreds of unsuccessful phase III clinical trials, it's clear that the pharmacological industry and a cohort of academic laboratories are unable to create drugs that slow significantly the progression of neurodegenerative diseases.

Some courageous scientists interrogate basic hypotheses or design longer, more complex better clinical trials. For example, Alzheimer's disease can't seriously be attributed to any molecular dysfunction, as it would mean that a lot of cerebral functions would be affected, not only memory issues, and anyway, memory issues in Alzheimer's are much more complex than described in textbooks: They did not simply vanish: The patient looks to be living today in the context of the past. Sometimes the patient can discuss simultaneously at two levels: In the context of the past (when they were infants) and in the context of today.

Others are currently busy breaking the thermometer. If the clinical diagnosis makes it impossible to validate current clinical trials, then change the way success is defined: Abandon clinical criteria and use molecular criteria. They did it recently for Alzheimer's disease and now they propose it for Parkinson's disease..

The immediate consequence will be a flurry of successful clinical trials, even if patients get no improvements, as they did for Aducanumab.

There will also be false positives, people will be diagnosed sick because of the presence of a molecule but without any clinical signs.

Quelques jours avant que mon père décède, j'ai demandé à son médecin quelles pouvaient être les actions médicales à mener pour améliorer son état. Le médecin m'a répondu "si on arrive à améliorer ses constantes, il ira mieux".

Outre le fait que le médecin ne me répondait pas vraiment en terme d'actions à mener, cette lapalissade enseigne quelque chose de fondamental au sujet de l'approche de la santé par la médecine.

Les médecins sont conscients qu'en fait ils ne peuvent peuvent pas vraiment soigner, ils ne peuvent qu'améliorer un dysfonctionnement d'un corps qui autrement doit être en bonne santé. Ce corps, si on l'aide, va retrouver sa bonne santé.

Au contraire, une personne atteinte de comorbiditées a une chance de survie très faible, c'est de la statistique élémentaire. Si un malade a trois problèmes de santé ayant chacun une chance de survie de l'ordre de 80%, la résultante n'est que de 51%. Il est donc illusoire de penser que quand la physiologie est sévèrement compromise, on pourra restituer la santé avec une pilule ou une injection miracle.

Cette limitation de la médecine actuelle, n'est pas compris par les scientifiques. Ceux-ci s'obstinent à penser qu'en agissant sur une composante infinitésimale de notre physiologie, la santé sera, comme par magie, restituée. Cet aveuglement s'explique par le fait que la quasi totalité des scientifiques oeuvrant dans la recherche médicale, n'ont qu'une notion vague de la physiologie humaine et des interactions entre ses multiples systèmes.

Cela explique pourquoi je ne présente pas les multiples articles qui apparaissent tous les jours et qui annoncent une découverte majeure, alors que le plus souvent il s'agit de travaux mineures sur une souris, ou pire encore sur une lignée de cellules dénaturées immortelles.

Outre le fait qu'un scientifique doit publier pour être crédible, et donc qu'on a une avalanche de papiers au style ampoulé mais sans valeur, beaucoup se demandent pourquoi les souris semblent si bien répondre aux traitements, alors que quand ces traitements sont testés sur des humains, ils échouent à améliorer l'état des malades.

La réponse est complexe, mais un point essentiel est celui-ci: La tenue de l'expérience est soit confiée à des étudiants (masters, doctorants), des salariés (postdocs) ou à un organisme de sous-traitance de la recherche (CRO). Dans ces différents cas de figure, les personnes à qui sont confiées ces souris ont intérêt à ce que l'hypothèse faite par le professeur donneur d'ordre soit avérée. or on sait que la santé d'une souris est fortement dépendante à des caresses ou à un nettoyage de la litière (ce qui d'ailleurs influence le microbiome intestinal)...

La moralité de tout ceci est que pour un patient il faut essayer de faire fonctionner normalement son corps et son esprit autant que possible: Conserver une certaine activité physique, conserver une activité intellectuelle, s'informer à des sources fiables, avoir une sécurité financière, combattre les problèmes cardio-vasculaires, notamment l'hypertension artérielle, et lutter contre le diabète notamment en limitant la plage horaire où l'on ingère de la nourriture, conserver des contact sociaux notamment parce que celà oblige à faire attention à soit-même, combattre le tabagisme et dormir convenablement.

Cela est plus facile à écrire qu'à mettre en oeuvre.

2023 was marked by two events that I find regrettable: The marketing authorization of a drug (lecanemab) after an almost unsuccessful phase III clinical trial and dangerous side effects, and the proposal to redefine the disease of Alzheimer's disease based on molecules that are probably not biomarkers of this disease to facilitate obtaining marketing authorization.

Fortunately, there are more disinterested researchers, who are working on other hypotheses on the causes of Alzheimer's disease than those of amyloid plaques. The text discussed here, by Jennifer Erichsen and Suzanne Craft particularly highlights the link between insulin sensitivity, metabolic dysregulation, and inflammatory processes in the context of Alzheimer's disease.

It is well known that people with diabetes are at greater risk (1.6 times) of decline in cognitive function. The prevalence of moderate cognitive impairment in patients with diabetes is high (45%). This is presumably because, unlike most organs, brain functions require a constant supply of glucose as an energy source, so the brain is more sensitive to abnormalities in glucose metabolism.

The role of insulin is to trigger an intracellular signal that regulates the entry of glucose into our cells. Insulin resistance is one of the characteristics of diabetes but also of neurodegenerative diseases, as well as aging. It de facto leads to a sort of brain starvation.

There is a clear link between insulin and amyloid plaques: insulin is also involved in the clearance of beta-amyloid, a protein that forms the plaques characteristic of Alzheimer's disease. The authors believe that an impaired blood-brain barrier allows immune cells from the body to pass through, which leads to the activation of microglia in the central nervous system. Scientists point out that immune processes intensively consume energy, therefore glucose, and therefore insulin resistance slows down immune processes.

The progression of insoluble tau to neurofibrillary tangle pathology correlates with the progression of Alzheimer's disease symptoms. Insulin metabolism has been closely linked to tau protein. Pathological accumulation of tau leads to brain insulin resistance.

The main suggestion of the authors is to combine therapeutic interventions of different natures and to minimize side effects. This is certainly an important reflection which nevertheless does not seem to be common.

They cite for example that insulin delivery with specialized devices can quickly and directly transport insulin to the central nervous system, bypassing the peripheral nervous system to avoid hypoglycemia and other adverse systemic effects. A phase II clinical trial has shown some effectiveness with a specific device.

They also cite SGLT2 inhibitors, a class of drugs commonly used in diabetes, which reduce the risk of dementia by 42% in people with type 2 diabetes.

In conclusion, researchers believe that the elimination of amyloid is insufficient to stop, much less reverse the course of Alzheimer's disease and that significant risks accompany it.

They therefore propose researching adjuvants to improve efficacy and safety. They hope this next promising and essential step in the therapeutic pathway for Alzheimer's disease will begin quickly. ​

It's been known for more than 20 years that neprilysin inhibitors such as sacubitril could foster Alzheimer's disease. Yet in 2015, Novartis decided to ask the FDA to authorize Entresto (sacubitril/valsartan) for heart failure. A clinical trial was set up and failed to meet the primary objective (heart failure), nevertheless (usual story) the drug was authorized by FDA.

At that time it was well known that this drug could foster Alzheimer's disease, so the FDA mandated that another clinical trial was also designed (PERSPECTIVE; NCT02884206) to test if there was a risk to cognitive functions. There were also other clinical trials with the same goal, for example in Korea. These clinical trials didn't show any aggravation of cognitive functions.

More recent studies have suggested that this class of drugs (neprilysin inhibitors) could have both positive and negative effects on the development of Alzheimer's disease. . (source: Naif H. Ali and Hayder M. Al-Kuraishy)

A re-analysis of the results of another clinical trial by scientists from the University of Gothenburg, in collaboration with colleagues from the University of Glasgow, is less optimistic about the effects of sacubitril on cognitive functions.

There are many other drugs to manage heart failure and it is not even clear if Entresto brings substantial benefits to the patients. Why was Entresto authorized in the first place in 2015, and why is it still prescribed given the abundant literature about the effects of sacubitril on Alzheimer's disease?