More news about brain clearance

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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. enter image description here 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.

About obsolete knowledge in ALS scientific literature

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The level of interest and knowledge among scientists about human physiology and anatomy is appalling.

We know that higher primates (including humans) have a special corticospinal system for dealing with tasks that need high skills. Most animal models of ALS do not have this kind of corticospinal system. Another feature of this corticospinal system in higher primates is that the connection from upper motor neurons to lower motor neurons is done directly in some cases (for example the hands), while in most animals the interconnection is done with interneurons, which take in charge automatic and repetitive movements such as walking.

Yet publications are still written that discuss at length of interneurons' role in ALS. One such publication (a review) is interesting as it starts well, by stating the obvious, that as there were hundreds of unsuccessful clinical trials on ALS drugs, we must have missed something important. enter image description here Alas, the authors resort to an old hypothesis, one of the first about ALS etiology, which is the excitotoxicity hypothesis.

This old hypothesis postulates that increased activation of upper motor neurons spreads pathology to lower motor neurons in the spinal cord in the form of excessive glutamate release, which triggers excitotoxic processes. As the authors recall many clinical trials have focused on therapies that target excitotoxicity via dampening neuronal activation, but not one was effective.

On the contrary, the authors never mentioned that the only clinical trials that were successful were about mutations in some rare cases (SOD1). A few other clinical trials did better than the average but they were far from providing a cure, they addressed cellular stress. It seems obvious now that for the majority of ALS patients, the cellular stress response is defective.

The authors correctly state that the current evidence requires revision in the context of appreciating the complexity of the nervous system and the limitations of the neurobiological assays the scientists use to study it.

The authors ask for more research:

  1. Network activity: Assess the activity level of the affected networks, not just excitability.

  2. Individual neurons: Investigate how ALS pathology affects the function of individual neurons, including lower motor neurons and interneurons.

  3. Interneurons: Understand their role and how their activity changes in ALS.

Point 1. looks like we are still in the 1940' with the Nernst and Goldman equations.

Point 2. is about the function of individual neurons. That's weird, people are not made of individual neurons, neuron types are numerous and are not even the sole cell population, and there are many more non-neuronal cells than neurons in the CNS. All these cells type collaborate and compete in what we call "tissue".

Point 3. is weird, ALS strikes a special kind of muscle (skeletal muscles) and nerves (corticospinal). In most cases, the lower motor neurons that connect to these muscles are not themself connected to an interneuron.

What to conclude from this review? I assume the authors are in good faith, but by perpetrating obsolete ideas they slow any progress toward a cure for ALS

The corticospinal system and ALS

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Here is a summary of an educational article that will be of particular interest to people affected by ALS (Lou Gehrig in the USA/Charcot's disease in France).

Essentially the article explains that ALS is a disease specific to certain nerve formations that are absent in most mammals, except certain higher primates (and perhaps other mammals like the Degu). These formations being absent in rats and mice, we wonder what the purpose of preclinical trials on these rodents is. I think this is the main contribution of the article.

There are indeed key differences in the organization and function of the corticospinal system in primates compared to non-primates, such as rodents. enter image description here Cortico-motoneuronal projection is a late evolutionary development that is present only in dexterous primates, such as capuchins, macaques, great apes, and humans, but absent in adult rodents, carnivores, and many others. primates, such as marmosets.

Although tool use is not exclusive to advanced primates and humans with demonstrable cortico-motoneuronal connections, primates exhibit a wide range of tool-making and use behaviors. Why did the direct projection from the cortex to the α motor neuron appear so late in evolution? One possibility is that the cortico-motoneuronal system acts selectively on the motor apparatus of the upper limb to allow relatively independent finger movements. These movements are essential for performing all skilled manual tasks, including key human motor characteristics, such as gestures and tool use.

Corticospinal neurons located in the motor areas of the cerebral neocortex project axons onto the spinal network. The corticospinal system of primates has a wider cortical origin than in other animals and a wide range of fiber diameters, including thick, rapidly conducting axons. Direct cortico-motoneuronal projections from the motor cortex to motor neurons of the arm and hand are a recent evolutionary feature, well developed in dexterous primates and particularly in humans. This system is involved in the control of skilled movements, performed with the splitting of the distal extremities and at low levels of force. During movement, corticospinal neurons are activated in a very different way from “lower” motor neurons, and there is no simple or fixed functional relationship between a so-called “upper” motor neuron and its target lower motor neuron, whereas in other mammals there is an interneuron which makes the junction between an upper motor neuron and a lower motor neuron.

During the development of ALS, there is a selective loss of rapidly conducting corticospinal axons and their synaptic connections, which is reflected in responses to noninvasive cortical stimuli and measures of corticomuscular coherence.

A given muscle can be used in different ways, and one of the key features of the cortico-motoneuronal system is the recruitment of particular, task-specific muscle groups. There is task-specific flexibility between the activity of a cortico-motoneuron and its target motoneurons. This is lost when the cortico-motoneuronal projection is dysfunctional and, as would be expected, there will then be deficits in skill as well as muscle strength.

The well-known weakness and loss of motor units in the hand muscles of ALS patients is more pronounced in the thenar (thumb) muscles than in the hypothenar (little finger) muscles. Although several different factors are known to contribute to lower motor neuron (spinal) dysfunction, these particular changes are due to the greater loss of the cortico-motoneuronal system on the thumb muscles compared to the little finger muscles.

This particular vulnerability of muscle groups heavily used during ALS is not limited to the hand. This includes studies on “split elbow,” “split foot,” and “split ankle.” In all three syndromes, the most profound weakness was seen in muscle groups that, in healthy controls, are known to receive relatively strong cortico-motoneuronal projections.

Along with the corticospinal projection from the cortex to the spinal cord, there is a significant corticobulbar projection to the motor centers of the brainstem, which is essential for actions such as speaking, chewing, and swallowing.

It is important to clarify that the corticospinal system is multifunctional and concerns not only movement but it also has somatosensory, autonomic, and trophic functions. When preparing for and executing the movement, it does not work in isolation, but in concert with other motor systems in the brainstem and spine.

In conclusion, because in rodents, corticospinal projections from the sensorimotor cortex primarily avoid the ventral horn and have limited direct effects on motor control, the pyramidal neurons giving rise to these projections are not considered similar "higher motor neurons." to those of primates, it is therefore not a good model for studying the effects of potential drugs on ALS. A small number of carefully designed studies in higher primates remain needed to advance the understanding and treatment of ALS.

For a patient, participating in a clinical trial is complicated to organize, in addition, the drugs tested are very rarely effective in the field of neurodegenerative diseases. However, it seems that there are unexpected benefits to volunteering for a clinical trial.

Clinical trials in neurodegenerative diseases are often disappointing, there are probably many reasons for that situation. A core aspect of clinical trials is that the population who received the treatment should be representative of the general population. For logistic reasons, biotechs that have few employees have to subcontract clinical trials. Principal investigators and subcontractors have every reason to select patients who present a textbook-like disease.

Suspecting that the clinical trial population is not representative of real-life patients, an international team wanted to characterize the progression of Parkinson's disease using real-world data to guide the design of clinical trials and identify subpopulations.

The increasing availability of real-world data, and recent advances in natural language processing, particularly large language models, allow for an easier and more granular comparison of populations than before.

This study includes two research populations and two populations derived from real-world data.

The research populations are the Harvard Biomarkers Study (935 patients), which is a longitudinal biomarker cohort study with structured in-person study visits, and finally Fox Insights (36,660 patients), a research study based on the Michael J. Fox Foundation online self-survey.

The real-world cohorts are Optum Integrated Claims electronic health records (157,475 patients), representing large-scale linked medical and claims data and de-identified data from Mass General Brigham (Mass General Brigham, 22,949 patients), a University Hospital.

Structured, anonymized data from Mass General Brigham's electronic health records is augmented using natural language processing with a large language model to extract measures of Parkinson's disease progression. This extraction process is manually validated to verify accuracy.

Motor and cognitive progression scores change more rapidly in the Mass General Brigham than in the Harvard Biomarkers Study (median survival to H&Y scale: 5.6 years versus more than 10 years); median decline to mini-exam of mental status 0.28 versus 0.11. In real-world populations, patients are diagnosed more than eleven years later! After diagnosis, in real-world cohorts, treatment with Parkinson's drugs is initiated 2.3 years later on average than for patients in clinical trials.

This study provides a detailed characterization of Parkinson's disease progression in various populations. It delineates systemic discrepancies between patient populations enrolled in research settings and real-world patients. enter image description here The study shows systematic differences and potential directional biases between research and real-world datasets. Patients in research populations are diagnosed much earlier, start levodopa and other Parkinson's medications earlier, and show slower changes in clinical scales of motor and cognitive progression. Real-world-based populations are diagnosed at older ages, start medications later than research cohorts, and experience more rapid changes in clinical scales.

These discrepancies are likely due to a combination of selection bias, but exact attribution of causes is difficult using existing data. This study emphasizes the need to diligently consider potential biases when planning a clinical trial.

Targeting 14-3-3θ-mediated TDP-43 pathology in mice

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Every day brings its share of scientific articles announcing the imminent arrival of drugs for neurodegenerative diseases.

However, we are unable even to diagnose these diseases with certainty. The diagnosis is made by exclusion and sometimes gives rise to several different diagnoses. We would be better off talking about the spectrum of neurogenerative diseases. The only thing we know for certain is that these diseases are characterized by malformed protein aggregates in inappropriate places in cells.

These diseases are currently differentiated by scientists by the type of protein involved, but in fact, all of these malformed proteins are present to varying degrees in all of these diseases. The recent trend to generalize diagnosis based on molecular markers only recognizes our incompetence and only serves the pharmaceutical industry.

Amyotrophic lateral sclerosis (ALS) and/or frontotemporal dementia (FTD) are most often characterized by the cytoplasmic deposition of nuclear TAR-binding protein 43 (TDP-43). But this is rarely of a rare and deleterious protein form. Although the cytoplasmic localization of TDP-43 aggregates is commonly associated with ALS/FTD, it is unknown what causes the dysfunction, although different hypotheses have been posed such as cellular stress, for example (but not only) due to to a significant change in metabolism.

In a recent article, scientists from Macquarie University in Australia reported their work concerning the interaction between the proteins 14-3-3θ and TDP-43, which regulates the nuclear-cytoplasmic shuttle.

The 14-3-3θ protein, like many other proteins, is associated with several neurodegenerative diseases.

Similar work was carried out in the past (2016) which consisted of creating a peptide by attaching the M1 section of TDP-43 to a TAT peptide which gives a peptide: YGRKKRRQRRRAQFPGACGL, which repatriates the aggregates poorly localized in the nucleus of the cells.

This work does not seem to have given rise to recent developments in the field of neurodegenerative diseases. In any case, this 2016 work did not explain why these aggregates appeared. They only provided a mechanism to get them back into the cell's nucleus. It is not clear how this would have formed them correctly since this happens in a cellular organ called "endoplasmic reticulum" which is located in the cytoplasm.

In addition, forming proteins requires energy, but we know that the cells of many patients are in a state of "hibernation" called the cellular stress response, with activity reduced to the minimum necessary to survive. Furthermore, any genetic therapy only "infects" a fraction of cells, which reduces its interest. And these genetic therapies are not without side effects.

This new article presents a slightly different mechanism but does not further answer the questions above. The 14-3-3θ protein belongs to a family of proteins called 14-3-3, known to regulate other proteins by binding to them and they play a role in various cellular processes, including signaling, survival, and cell differentiation. This family includes more than 200 members. The authors found that neuronal levels of 14-3-3θ were increased in mouse models of ALS and sporadic FTD with TDP-43 pathology. As we already know, 14-3-3θ is associated with several neurodegenerative diseases. Scientists believe that the interaction of deleterious TDP-43 alleles with the 14-3-3θ protein results in cytoplasmic accumulation, insolubility, phosphorylation, and fragmentation of TDP-43, which resembles the pathological changes caused by these diseases in humans. enter image description here What is interesting is that 14-3-3θ seems to interact preferentially with pathogenic TDP-43 versions but not with the usual version of TDP-43. This suggests that reducing the production (or increasing the degradation) of 14-3-3θ would reduce the production of pathogenic TDP-43. Scientists have therefore sought to reduce the amount of this 14-3-3θ protein in cells through genetic therapy.

The authors designed multiple versions of a peptide they called CTx1000, each version of which is tailored to reduce one of these deleterious forms of TDP-43. This reduction is mediated by degron of pathogenic TDP-43. A degron is a part of a protein that plays an important role in regulating protein degradation rates. In mice that underwent this gene therapy, functional deficits and neurodegeneration decreased, including when they were already symptomatic at the time of treatment. This incidentally matches many studies that, contrary to consensus, show that motor neurons do not die in ALS.

The university's press kit is, as usual, dithyrambic and the authors' statements resounding: "This new research is incredibly promising in slowing the progression of MND and FTD for the vast majority of our patients. I'm extremely hopeful that it will soon be available to our patients at the Macquarie University Hospital MND Clinic." This type of press kit is not aimed at patients and their loved ones, but rather at potential investors.

In conclusion, we can think that just as the therapy proposed in 2016 did not allow the development of a drug eight years later, it will probably be the same for this one, because it does not answer basic questions: Quid patients (the majority) who do not present a mutated form of TDP-43? What causes these protein clumps? Where can cells find the energy to be permanently “reactivated” from cellular stress response so that the therapy can do its work? How can we ensure that all of the targeted cells can receive the therapy, without side effects?

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). enter image description here 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.

Expression of C9orf72 regulates IL-17A signaling in mice blood

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No one knows how to define what ALS is, its diagnosis is made by exclusion. Efforts are underway to define ALS based on molecular markers, but clearly, this would primarily be in the interest of the pharmaceutical industry.

If we do not know how to define what constitutes ALS rather than, for example, extreme cases of myasthenia gravis, it is difficult to find the cause(s).

The hypothesis of infection or poisoning is old, but apart from the case of BMAA, a neurotoxin produced by a cyanobacterium, this type of hypothesis has never been confirmed.

A peripheral hypothesis to that of infection is that of inflammation, either intraCNS or resulting from infiltration across the blood-brain barrier. There are countless studies on this subject but none are compelling.

What exactly does “inflammation” mean? Human immune systems are among the most complex systems in terms of physiology. To summarize, there are two strictly separated areas in our body: The central nervous system and the rest of the body. The CNS immune system is poorly understood. In the rest of the body, we could say that there are two kinds of subsystems, the innate nervous system which is the only one to protect us from our birth until the development of the acquired immune system. It is also the only one to protect us when the acquired immune system atrophies from the age of fifty. But these two systems interfere and the separation is only clear in medical textbooks.

Between these two systems, there is a sort of messaging system comprising many molecules with varied roles, including the famous cytokines.

One of them is called Interleukin-17A (IL-17A). A few studies have linked it to ALS since 2010, but hundreds of molecules have been associated with ALS. enter image description here The paper we are discussing today, like most of them, does not present a major discovery, but it has some interest.

The scientists used a mouse model with a mutation in the C9orf72 ORF that impairs blood cell production. We are far from ALS, except for the C9orf72 ORF which is associated with the majority of cases of familial ALS.

They found, among other things, that this C9orf72 mutation interacts with the immune system by increasing the production of IL-17A and CD80, which is associated with autoimmune diseases such as psoriasis or multiple sclerosis.

Using an IL-17A antibody they were able to improve the condition of the mice. But usually, scientists use hyperboles very extensively. For example, one of the authors does not hesitate to say; "Our research indicates that IL-17A blockade may be quickly repurposed to treat ALS patients to slow down the progression of their disease or possibly stop ALS from ever occurring."

It's very unlikely, but who knows?

What seems surprising about this study and these claims is that the impact is not studied on the CNS immune system. The reasoning is done by analogy ("Patients with C9ORF72-related ALS similarly showed CD80 enrichment in spinal cord microglia."). Reasoning by analogy, although common in scientific publications, should be banned, you can "prove" anything this way.

Activated CD8+ T cells may mediate neuropathology during viral infection

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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. enter image description here 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.


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