There's a new post on one of my favorite topics: ER (endoplasmic reticulum) stress and ALS. If ER stress becomes chronic, as it does in many neurological diseases, it can cause proteins to misfold and accumulate in the cytosol, exactly what is found in ALS.

There are already drugs that target ER stress in ALS, for example Sephin1 also known as IFB-088 or icerguastat. https://inflectisbioscience.com/our-pipeline/

This new publication comes from an independent group in Finland.

One of the interesting aspects of this work is that they tested their drug candidate on 3 types of animal models (a fast TDP-43 model and a slow model, 1 SOD1). However, TDP-43 animal models are not commercial and it is therefore impossible to quickly reproduce their results. As usual with ALS animal models, the mice die quickly which does not reflect the human disease.

The authors used transgenic technology to produce brain dopamine neurotrophic factor (CDNF) in vivo. Activation of the transgene was as usual conditioned on the withdrawal of doxycycline in the diet. The method of administration was quite intrusive and would be difficult to replicate in human patients. A continuous infusion of 6 µg/day of CDNF or phosphate-buffered saline (PBS) as vehicle into the lateral ventricle of the brain (where the motor neurons are located).

Neurotrophic factors support the survival of dopamine neurons. Brain dopamine neurotrophic factor (CDNF) is a novel neurotrophic factor with strong trophic activity on dopamine neurons comparable to that of glial cell line-derived neurotrophic factor (GDNF). It is often cited in articles on Parkinson's disease. The CDNF protein is found primarily in the endoplasmic reticulum (ER) of cells. ER is an important cellular organelle primarily involved in the folding of approximately one third of all proteins in the cell. enter image description here The authors' claims are impressive: "We found that administering CDNF to ALS mice and rats significantly improved their motor behavior and stopped the progression of paralysis symptoms. The improvement in symptoms was reflected in an increased number of surviving motor neurons in the spinal cord. spinal cord of animals compared to rodents that did not receive “CDNF. Our experiments suggest that CDNF could rescue motor neurons by reducing the ER stress response and, consequently, cell death. Importantly, ER stress was present in all of our animal models, regardless of specific genetic mutations,” explains study lead author Dr. Francesca De Lorenzo.

However, if we read the text carefully, only one animal model (SOD1) showed benefits, and the progression was slowed by 8 days or about a year for a human, which is an impressive result.

  • In SOD1-G93A mice, the median survival time for females was 148 days for CDNF-treated mice and 140 days for PBS-treated mice, with an increase of 8 days. In males, median survival was 140.5 days for CDNF-treated mice and 132 days for PBS-treated mice, with an increase of 8.5 days. This likely corresponds to SOD1-G93A mice treated daily with riluzole in drinking water.

  • Based on the text and supplementary materials, it appears that there was no benefit in survival time for either TDP-43 mouse models.

Yet, and this is a bit worrying, the abstract states "We show that intracerebroventricular administration of brain dopamine neurotrophic factor significantly arrests disease progression and improves motor behavior in the TDP43-M337V and SOD1 rodent models -G93A amyotrophic lateral sclerosis."

Since most people only read the summary or popular science articles, they are misled.

With aging, T cells of the adaptive immune system are often exhausted and/or become senescent. People with dysfunctional T cells are at high risk of infections, cancer, chronic diseases, and possibly death.

A recently published text studies the relationship between inflammation, alterations in the immune system, and Alzheimer's disease (AD). While the common mindset is to wonder what causes diseases (beta-amyloids in the case of Alzheimer's disease), this text takes a more complex view. enter image description here There are many studies showing a link between the immune system and Alzheimer's disease.

Inflammation has been observed in postmortem brain scans of Alzheimer's disease patients, as well as the presence of amyloid plaques and neurofibrillary tangles.

The use of nonsteroidal anti-inflammatory drugs (NSAIDs) has been shown to have a lower risk of dementia or Alzheimer's disease in adults who use them periodically, although results from clinical trials with NSAIDs have been mixed.

There is also a link between cognitive changes and acute infections. Likewise, there is a link between chronic infections and long-term cognitive decline.

Human herpesviruses, particularly herpes simplex virus-1 (HSV-1) and human herpesvirus 6 (HHV6), are considered potential contributors to infection-related inflammation causing Alzheimer's disease.

Other pathogens such as Porphyromonas gingivalis, Chlamydia pneumoniae, and Toxoplasma gondii have been associated with the development of Alzheimer's disease due to their chronic nature.

Vaccinations against diseases such as influenza, shingles, and BCG have shown associations with decreased risk of Alzheimer's disease in various populations.

To understand how the peripheral immune system is altered, it is interesting to study an aging cohort at different stages of Alzheimer's disease development.

Jason M Grayson, Suzanne Craft, and their colleagues at the Winston-Salem School of Medicine therefore studied an aging cohort that had been evaluated for Alzheimer's disease pathology.

The authors observed major alterations in the peripheral innate immune system in the blood of members of the aging cohort. High-dimensional flow cytometry, amyloid PET imaging, and cognitive testing were used to identify changes in the innate and adaptive immune systems as amyloid pathology and cognitive symptoms developed.

Specific findings include differences in dendritic cell populations, T cell differentiation, and cytokine production in amyloid-positive participants, particularly those with mild cognitive impairment. enter image description here

Mature T cells are considered immunologically naive until they encounter the specific peptide in the context of a human leukocyte antigen (HLA) molecule that their receptor recognizes. Once antigen recognition occurs, cells receive a proliferative signal that leads to a marked expansion of antigen-specific T cells and an inflammatory response.

Although many of these T cells undergo apoptosis after the initial response, others are rescued from immune retraction and persist as memory T cells. Memory T cells can respond rapidly to a novel antigen-specific challenge and persist in blood circulation for a long time.

When the scientists examined the adaptive immune system, amyloid-positive participants, regardless of cognitive status, had an increase in their CD3 T cells. Further analyses of CD4 and CD8 T cells revealed that members of the aging cohort had increased numbers of T cells with a more differentiated phenotype, compared to those with normal cognition. That is to say that there was either or both a lower production of naive T cells and a strong presence of T cells having been in contact with pathogens.

When T cell function was measured, the authors observed that T cells from members of the aging cohort had increased IFN-γ production compared to other participants.

IFN-γ, or type II interferon, is a cytokine essential for innate and adaptive immunity against viral, bacterial, and protozoal infections. This is consistent with anti-microbial activity, which is one of the many roles of β-amyloids.

IFN-γ is an important activator of macrophages and an inducer of the expression of major histocompatibility complex class II molecules (HLA in humans). Aberrant IFN-γ expression is associated with several autoinflammatory and autoimmune diseases.

Several studies have observed an increase in IFNγ associated with slower symptomatic progression in Alzheimer's disease.

The authors explain that members of the aging cohort had a major increase in the number of T cells lacking cytokine production after restimulation and expressed increased levels of PD-1 and Tox, suggesting that these are exhausted cells.

Programmed cell death protein 1 (PD-1) is a protein found on the surface of T and B lymphocytes that plays a role in the immune system's response to cells in the human body by downregulating the immune system and promoting self-tolerance by suppressing the inflammatory activity of T cells.

PD-1 protein prevents autoimmune diseases, but unfortunately it also sometimes prevents the immune system from killing cancer cells. Given the many links between infection, inflammation, and Alzheimer's disease, these results suggest two models in which T cells could be a driving force in Alzheimer's disease.

  • In the first model, amyloid production is a response to latent infections in the periphery and brain by the multiple chronic pathogens that all humans carry. Individuals who have strong T cell functions control the replication of these pathogens and remain cognitively normal. This would explain why members of the aging cohort, who have the most functional T cells, still have high cognitive levels.

However in individuals who lose T cell function, chronic pathogens reactivate and overstimulate innate responses, particularly type I interferon production, potentially leading to cognitive impairment. The authors suggest that T cell rejuvenation by immune checkpoint inhibitors and other therapies could be a plausible ex vivo therapy for Alzheimer's disease. Indeed, testing of immune checkpoint inhibitors in the 5X FAD mouse model of Alzheimer's disease has yielded promising results.

  • An alternative model posits that the production of cytokines by T cells while participants are cognitively normal leads to the development of cognitive impairment. This idea is supported by a recent study by Jorfi and colleagues.

The study suggests that rejuvenating T cell function could be a potential treatment for Alzheimer's disease, particularly cancer therapies may suggest a possibility. For example, the patient's rare and/or dysfunctional T cells could be rejuvenated ex vivo once by pre-selected neurotransmitters and/or neuropeptides, tested, and reinoculated into the patient's body as it is currently administrated to some cancer patients.

Those of you who have bought an infrared helmet to attenuate your Alzheimer's disease might be interested in using it at night.

Photobiomodulation is a non-pharmacological approach based on the use of red or near-infrared light that has shown very promising results in the therapy of Alzheimer's disease in pilot clinical and animal studies. The Food and Drug Administration (FDA) recognizes photobiomodulation as safe.

It was recently discovered that photobiomodulation effectively stimulates lymphatic removal of wastes and toxins, including amyloid-β, from the brain.

A lymphatic network of transparent vessels

The Italian anatomist Mascagni discovered the lymphatic network of transparent vessels in the brain meninges of humans in the eighteenth century. The meninges are the three membranes that envelop the brain and spinal cord. However, for two centuries the dogma was that the cerebrovascular basement membrane which envelops blood vessels in the brain, was a key pathway for protein clearance from the central nervous system.

After 2014, when meningeal lymphatic vessels were re-discovered in the meninges of rodents and humans along the main cerebral veins and the middle meningeal artery, a growing number of results clearly showed that meningeal lymphatic vessels are tunnels for clearance of β amyloid protein from the brain. enter image description here

Photobiomodulation during deep sleep

Photobiomodulation during deep sleep may provide a better therapy for Alzheimer's disease than photobiomodulation during wakefulness. In a new publication, scientists studied why photobiomodulation during sleep would be more effective in Alzheimer's disease during sleep. Since the brain lymphatics vessels play an important role in the removal of β amyloid protein from the brain and this system is activated during sleep, the scientists tested their hypothesis that photobiomodulation can stimulate clearance of β amyloid protein from the brain via the lymphatics stronger during sleep vs. wakefulness. enter image description here The authors found the presence of β amyloid protein in meningeal lymphatic vessels after its injection into the hippocampus. As the hippocampus is at the center of the brain, it means the β amyloid protein was moved from the center of the brain to its periphery. These results confirm other data suggesting that meningeal lymphatic vessels are the tunnels for lymphatic transport of β amyloid protein.

To further prove that the injury of lymphatic vessels significantly alters β amyloid protein evacuation from the hippocampus in mice, the scientists photo-ablated meningeal mice's lymphatic vessels with 5-ALA. 5-ALA is usually used to selectively destroy tissues. After this operation, photobiomodulation was used to verify if it could heal mice's lymphatic vessels enter image description here

The evacuation of β amyloid protein from the hippocampus and its subsequent distribution in the meninges after photo-ablation of meningeal lymphatic vessels was higher in mice that received photobiomodulation during deep sleep than mice treated by photobiomodulation during wakefulness. These data clearly demonstrate that photobiomodulation-mediated restoration of brain lymphatic function contributing to the removal of β amyloid protein from the brain is more effective during deep sleep than in the waking state.

The photobiomodulation was performed with 3835 SMD LED (central wavelength 1050 nm and spectrum width of 50 nm). The LED was operated in continuous wave mode with an output power of 50 mW that was distributed over a 3.6 mm spot at the skull surface. The irradiance at the skull surface does not exceed 0.5 W/cm2. The dose for a single 17-minute procedure each day was 500 J/cm2.

Conclusion

Photobiomodulation as a non-invasive and safe approach has high prospects for implementation in clinical practice for the treatment of brain diseases associated with lymphatic disorders, such as Alzheimer's disease or Parkinson’s disease.

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Is there a connection between stroke, TDP-43 and ALS?

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Is there a connection between stroke, TDP-42 and ALS?

Amyotrophic lateral sclerosis (ALS or Lou Gehrig disease) is a representative neurodegenerative disease that affects upper and lower motor neurons. The mechanism of ALS is not fully understood, but mislocalization and aggregation of the TDP-43 protein in the cytoplasm play an important role. A stroke in the motor area could cause symptoms similar to those of ALS, with one big difference: a stroke is a sudden accident, and ALS is a disease that develops slowly.

A stroke in the motor area could cause symptoms similar to those of ALS

TDP-43 proteinopathy is thus associated with several chronic neurodegenerative diseases and is common in the elderly. We have known for several years that there is an association between TDP-43 and ischemic stroke.

The TDP-43 protein is normally expressed in the nucleus of cells, but under pathological conditions, it forms inclusions in the cytoplasm.

Historically, the prevalence of stroke in patients with ALS ranged from 1.6 to 8.0% in case-control studies, with inconsistent results.

Thus, in a study of 500 patients with ALS in Portugal, the prevalence of strokes (hemorrhagic and ischemic) did not differ from that of controls, regardless of the region of onset.

However, another study of 200 patients in Germany suggested that the prevalence of ischemic stroke was higher among patients in control groups.

On the other hand, previous ischemic stroke has been reported to increase the risk of ALS.

In a cohort study carried out in England, the relative risk of ALS was found to be 1.31 times higher than the expected number.

A new study in Korea

In a recent study published on MedRXiv, the authors studied the risk of developing ischemic stroke in Korean ALS patients compared to a control population using the Korean National Health Insurance Service (NHIS) database and to what extent. the degree of disability may influence TDP-43 proteinopathy.

The type and severity of disability are legally defined in Korea by the degree of disability recorded in the National Disability Registration System (NDRS) of the Ministry of Health and Welfare. Korean scientists defined and studied three groups, the control group, the group of ALS patients without disability, and that of ALS patients with disability.

Risk of ischemic stroke in the ALS group compared to the control group

During the follow-up period, 13 ischemic strokes were recorded in the ALS group and 204 in the control group. Incidence rates were 7.8/1000 person-years in the ALS group and 3.2/1000 PY in the control group. Incidence rates of ischemic stroke were similar in the disabled and non-disabled ALS groups.

There are several possible explanations for the increased risk of ischemic stroke not explained by vascular risk factors. First, ischemic stroke can be caused by paradoxical embolism.

Venous thromboembolism is common in ALS patients due to reduced mobility, and the risk of deep vein thrombosis is 3.2 times higher than in people without ALS.

This increased risk of thromboembolism in ALS may explain the higher risk of ischemic stroke. Second, increased systemic inflammation in ALS can lead to ischemic stroke.

The lack of expected effect of disability on the risk of ischemic stroke in ALS patients may be due to the small number of events.

Detailed clinical characteristics regarding the region of onset, disease duration, and medications for the treatment of ALS such as riluzole and edaravone, which may be neuroprotective in cerebral ischemia were not included in Analyses.

Our conclusion

This study, like most, leaves us wanting more. Making a causal link between strokes which would lead to TDP-43 inclusions which would ultimately cause ALS is attractive. The existence of stroke or TIA (micro/mini-stroke) is common as we age over fifty. For the cells concerned this is an enormous stress, that of no longer being supplied with oxygen and nutrients. We know that stressed cells sometimes develop proteinopathies.

However, this article does not further explore the causal link between stroke and proteinopathy.

Another article published in 2018 can serve as a complement to this recent article. Scientists studied the age-related expression of TDP-43 in neurons and glial cells and its role as a modulator of inflammation following ischemic injury. To do this, they created artificial strokes in wild-type and TDP-43 transgenic mice of different age groups.

These authors reported an age-related increase and formation of cytoplasmic inclusions of TDP-43 after artificial strokes. The dysregulation observed in TDP-43 expression patterns was associated with increased microglial activation and innate immune signaling.

The presence of aggregates of ubiquitinated TDP-43 and its cleaved fragments of TDP-35 and TDP-25a was markedly increased in mice aged 12 months, leading to larger infarcts and a significant increase in neuronal death.

Overexpression of cytoplasmic TDP-43 also drove the pathogenic NF-κB response and further increased the levels of pro-inflammatory markers and ischemic injury.

Regardless, the causes of ALS are probably multiple and, once neurons or muscles are lost, unfortunately, nothing currently known will be able to replenish them.

A recently published text discusses the application of electrical stimulation of the neuro-muscular system in combination with rehabilitation strategies based on the mirror neuron system (Mirror Neuron System) to improve the rehabilitation of function motor of the upper limbs and of the hand. enter image description here Motor dysfunctions of the upper limbs and hands have a significant impact on the daily lives of people with neurological diseases. Neuroplasticity is the ability of the nervous system to find other nerve circuits in response to external stimuli to activate specific muscles.

Electrical stimulation of the neuro-muscular system uses low-frequency electrical currents through surface electrodes to induce involuntary movements and facilitate motor rehabilitation. It is a common physiotherapy method, based on neuroplasticity and supposed to work by coupling between the sensory system and the motor system. We electrically activate a muscle (remember Volta's frog?), via a device controlled by the patient, the sensation of this activation reaches the brain through the sensory system, if this is not disturbed and the brain learns after numerous tests, there is a parallel path which activates this motor system. In a way it's similar to learning to drive a car, we activate different devices (brakes, accelerator, steering wheel, shifters), we have sensory feedback (the car accelerates, brakes, turns), and little by little these are maneuvers that we do instinctively.

Electrical stimulation of the neuromuscular system involves the use of electrodes placed on the skin over target muscles. These electrodes deliver controlled electrical impulses to the muscles, causing them to contract. Electrical stimulation of the neuromuscular system can be used to:

  • Muscle Activation: Electrical stimulation of the neuro-muscular system can activate muscles that are weak or paralyzed due to neurological problems or injuries. This is particularly useful when voluntary muscle activation is limited or impossible.

  • Build Strength and Endurance: Electrical stimulation of the neuro-muscular system can help strengthen muscles and improve endurance, which is important for regaining functional motor skills.

  • Prevent Atrophy: In cases of muscle disuse or atrophy, such as after surgery or during prolonged immobility, electrical stimulation of the neuro-muscular system can prevent muscle loss by maintaining muscle contractions.

*Improve blood flow: Electrical stimulation of the neuro-muscular system can promote blood circulation in the stimulated area, which facilitates tissue healing and recovery.

Although electrical stimulation of the neuro-muscular system has benefits, it is passive and can lead to limited patient engagement. The combination of electrical stimulation of the neuro-muscular system with active rehabilitation strategies or methods based on the mirror neuron system can improve the results.

The mirror neuron system plays an essential role in neuronal plasticity linked to motor learning. It is activated when a person performs an action but also when they observe a similar action. The mirror neuron system plays a crucial role in learning.

Various rehabilitation techniques, such as Action Observation Therapy (AOT), Mirror Therapy (MT), Motor Imagery (MI), and Virtual Reality (VR), are based on the system theory of mirror neurons and are widely used in neurological rehabilitation. The study described in this post uses functional near-infrared spectroscopy (fNIRS) to measure cortical activation patterns related to electrical stimulation of the neuromuscular system combined with strategies based on the mirror neuron system.

The study involved 66 healthy adults in various experimental tasks combining electrical stimulation of the neuro-muscular system with different mirror neuron system strategies, such as action observation, action execution, and action imitation.

The scientists used an fNIRS device with multiple channels to measure changes in blood oxygen levels in the brain during different tasks. This method is slower to acquire data than EEG, but it is also more reliable.

Results showed that combining electrical stimulation of the neuromuscular system with strategies based on the mirror neuron system activated brain areas, with active exercises showing the most significant activation. This suggests a potential for enhanced rehabilitation effects.

As our editorial policy concerns neurodegenerative diseases, among them ALS (Lou Gehrig's disease), we immediately consider which benefits a patient could derive from this technology.

Spinal cord injuries cause symptoms quite similar to those of ALS. Recently patients who had severed spinal cords have been able to walk again thanks to similar technologies.

The study suggests that brain-computer interface (BCI) systems based on fNIRS could be developed to aid rehabilitation, especially in cases where patients have lost the ability to perform active exercises.

Neuromuscular electrical stimulation (Electrical stimulation of the neuro-muscular system) may have some potential benefits for people with amyotrophic lateral sclerosis (ALS), but it is important to understand its limitations and consider it as part of an approach. comprehensive disease management. One would think that she might be of particular interest for the following points:

  • Muscle Preservation: Electrical stimulation of the neuro-muscular system may help slow muscle atrophy and maintain muscle function in people with ALS. This is particularly relevant when voluntary muscle activation becomes difficult or impossible.

  • Management of pain and spasticity: Some people with ALS may experience muscle pain and spasticity. Electrical stimulation of the neuro-muscular system can help alleviate these symptoms by promoting muscle relaxation and blood circulation.

In the future, one could even imagine that devices for electrical stimulation of the neuro-muscular system can be used as assistive devices to facilitate daily activities, such as grasping objects or walking, by stimulating specific muscle groups.

However, it is unlikely that this technology will be able to slow the progression of the disease: ALS is a progressive disease and, although electrical stimulation of the neuromuscular system can provide temporary relief and muscle preservation, it is unlikely to stop not the underlying neurodegenerative process.

There is also the problem of individual variability which is very broad in the context of ALS. ALS is more of a syndrome than a disease, each patient is unique which makes clinical trials terribly complicated, and in most patients, their health and motor skills evolve terribly quickly. As the response to electrical stimulation of the neuromuscular system can vary greatly among individuals with ALS, some may find it beneficial, while others may not benefit or may even experience accelerated deterioration.

Electrical stimulation of the neuromuscular system could be considered part of a comprehensive approach to managing ALS, which may include physiotherapy, occupational therapy, speech therapy, and medical treatments.

In summary, electrical stimulation of the neuromuscular system may be helpful in managing specific symptoms and preserving muscle function in people with ALS. However, this should be part of a broader, multidisciplinary approach to ALS care. The effectiveness of electrical stimulation of the neuromuscular system can vary from person to person, so it is crucial to work closely with healthcare professionals to determine the most appropriate interventions and therapies for individual needs and the stage of the disease.

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Often scientists claim to make breakthrough discoveries, while their "findings" are known for many years. This is unsettling for lay persons as most of us, as it questions the real value of scientific publications. Here is another example, it has been known at least for 15 years that microglia phagocytes synapses that this process is mediated with the protein MFG-E8 and that this process is dysregulated in Alzheimer's disease. enter image description here Now scientists are claiming to just have discovered that and their publication was accepted in a prestigious journal.

Alzheimer's disease (AD) is a neurodegenerative condition characterized by cognitive decline and the presence of abnormal protein aggregates in the brain, namely amyloid-β (Aβ) plaques and phosphorylated tau tangles. The accumulation of toxic forms of Aβ and tau contributes to synaptic loss, which is a major factor in AD-related cognitive decline. However, there are currently no effective treatments to prevent synapse degeneration in humans.

Recent research suggests that glial cells in the brain, specifically astrocytes and microglia, play a role in the removal of synapses, a process known as synaptic pruning.

Microglial cells are the main innate immune cells in the complex cellular structure of the brain. These cells respond rapidly to pathogens and injury and accumulate in regions of neurodegeneration, producing a wide variety of inflammatory mediators. Microglia respond to each disruption of homeostasis by rapidly changing form and function. The main physiological function of microglial cells is phagocytosis.

Microglia can adopt multiple phenotypes with unique characteristics depending on their environment. However, the M1 and M2 phenotypes are the most studied to date. The M1 phenotype is considered pro-inflammatory and represents the first line of defense of the innate immune system. Alternatively, M2 microglia are considered anti-inflammatory, with potential functions in tissue repair and remodeling. Microglial involvement has been implicated in many diseases like schizophrenia, Parkinson's disease, Alzheimer's disease, prion diseases and multiple sclerosis.

The study examined human brain tissue from individuals with AD and found that astrocytes and microglia contained more synaptic material in AD brains compared to healthy controls. This effect was more pronounced near Aβ plaques and in individuals with the APOE4 risk gene. In laboratory cultures, both mouse and human glial cells ingested synapses from AD patients more than those from healthy individuals. Inhibiting the interaction of a protein called MFG-E8 reduced this excessive synapse removal by glial cells, suggesting a potential target for therapy.

A milk membrane glycoprotein, MFG-E8 [milk fat globule-EGF (epidermal growth factor) factor 8], is expressed abundantly in lactating mammary glands. But as most of the time with proteins, it has multiple roles. In the peripheral immune system, macrophages secrete Milk Fat Globule Factor-E8 (MFG-E8) that recognizes phosphatidylserine "eat me" signals expressed on the surface of apoptotic cells. MFG-E8 then acts as a tether to attach the apoptotic cell to the macrophage and trigger a signaling cascade that stimulates the phagocyte development, allowing the macrophage to engulf the dying cell. When this process becomes disrupted, inflammation and autoimmunity can result. MFG-E8 resides in the brain as well as in the periphery, and microglia express MFG-E8.

The findings suggest that glial cells in AD patients may be responsible for the excessive removal of synapses, which is associated with cognitive decline. This insight could lead to the development of treatments aimed at preserving healthy synapses in AD patients, potentially improving cognitive function.

How the gut microbiome influences insulin resistance.

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Alzheimer's disease, Parkinson's disease, ALS, and FT Dementia share many biomarkers and comorbidities. One of them is insulin resistance which is found in half of patients.

Indeed insulin resistance is also a consequence of diabetes and aging. Scientists from Japan explore in a recent article how the gut microbiome influences insulin resistance. enter image description here Previous studies have explored the role of gut microbiota in metabolizing nutrients in insulin resistance. This research aims to uncover the mechanisms underlying this relationship using a multi-omics approach. The study analyzes data from 306 individuals without diabetes, focusing on insulin resistance as defined by HOMA-insulin resistance scores.

The researchers used various techniques, including metabolomics, metagenomics, transcriptomics, and clinical data, to profile how the gut microbiome contributes to insulin resistance.

They found that certain carbohydrates in the feces, particularly those accessible to the host, are elevated in individuals with insulin resistance. These carbohydrates are linked to microbial carbohydrate metabolism and host inflammatory cytokines. Specific gut bacteria are associated with insulin resistance and insulin sensitivity, each displaying distinct carbohydrate metabolism patterns. In a mouse model, bacteria linked to insulin sensitivity demonstrate the potential to improve insulin resistance traits.

The study also involves analyzing metabolic syndrome (MetS) and its associations with fecal and plasma metabolites. Using human fecal cultures, the researchers discovered that Bacteroidales, a type of gut bacteria linked to insulin sensitivity, have a unique metabolic profile. These bacteria are efficient consumers of certain carbohydrates, affecting the production of fermentation products.

To explore causality, the researchers test the effects of seven candidate bacteria associated with insulin sensitivity on mice fed a high-fat diet. Several strains, notably Alistipes indistinctus, show promising results in reducing postprandial blood glucose levels and improving insulin resistance. These strains also impact body mass, lipid accumulation, and glucose intolerance.

Mechanistically, the researchers find that A. indistinctus administration reduces carbohydrate oxidation in mice, possibly due to decreased host-accessible carbohydrates in the intestine. This is supported by altered caecal metabolites, including reduced monosaccharides like fructose.

In conclusion, the study employs a comprehensive multi-omics strategy to investigate the relationship between gut microbiota and insulin resistance. It identifies specific bacteria associated with insulin resistance and sensitivity and highlights the potential of A. indistinctus in ameliorating insulin resistance in mice. However, further research is needed to understand the precise mechanisms and potential therapeutic implications of these findings.

Radiation therapy for Alzheimer's disease

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Hormesis is a characteristic of many biological processes, namely a biphasic or triphasic response to exposure to increasing amounts of a substance or condition. Within the hormetic zone, the biological response to low exposures to toxins and other stressors is generally favorable.

Hormesis has been observed in a number of cases in humans and animals exposed to chronic low doses of ionizing radiation. enter image description here A new publication by Korean researchers discusses the current state of treatment for Alzheimer's disease, focusing on pharmacological and non-pharmacological approaches. It mentions that only four drugs (donepezil, rivastigmine, galantamine, and memantine) have been available to Alzheimer's patients. Yet, the improvement in neurological function is almost 0%, and it only slows the rate of cognitive deterioration. A new drug called aducanumab, targeting Aβ plaques, has been approved by the U.S. FDA, but its efficacy and accessibility are debated due to unclear clinical results and high costs.

An alternative approach, low-dose radiation therapy has gained attention after a case report described significant improvement in a patient with advanced Alzheimer's disease who underwent computed tomography (CT) scans of the brain five times. Recently, several preclinical studies based on mouse models revealed a significant reduction in Aβ plaques with low-dose radiation therapy, and low-dose radiation therapy induced the upregulation of pre-and post-synaptic molecules in the brains of Alzheimer's disease mouse models.

For example, a recent study showed that low-dose radiation therapy seems to reduce the levels of pro-inflammatory cytokines in animal models of Alzheimer's disease. Therefore, several pilot studies or clinical trials investigating the effect of low-dose radiation therapy on humans have been launched. Most recently, researchers at Virginia Commonwealth University (VCU) published positive pilot study results showing that four of five patients diagnosed with early Alzheimer's disease experienced improved or stable cognition after treatment with low-dose radiation therapy.

The Korean scientists describe an ongoing clinical trial aiming to explore low-dose radiation therapy as a treatment for Alzheimer's disease. The trial involves evaluating the safety and effectiveness of this therapy and determining appropriate dose schedules. The clinical trial is multicenter and randomized, with patients being divided into different treatment groups.

The study involves rigorous screening tests, including neurological examinations, cognitive function tests, and various imaging and laboratory tests. Eligible patients will receive low-dose radiation therapy in either 6 fractions of 4 cGy or 6 fractions of 50 cGy, while a control group will receive sham irradiation.

The clinical trial aims to evaluate cognitive improvement of at least 5% as an effective response. This would be a huge improvement over existing medications for Alzheimer's disease.

Brain implant to vocalize thoughts

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For ALS patients, failing to access a cure, it is important to overcome certain important problems. Alas a chair that can be controlled by gaze, telemanipulation arms, intelligent ventilation, and a device for vocalizing by thought, will not be marketed for another decade or two.

The press echoed two recent articles about devices for vocalizing through thought. One acquires the data via a deep cranial implant, the other via a surface cranial implant. enter image description here I analyze below the first article because the data and programs to implement this experiment are publicly available. Which is apparently not the case for the second.

I asked one of the authors if it was possible to use his program with an EEG helmet. We'll see what his answer will be, but I anticipate that the results of this course of action will be very disappointing.

The study focused on understanding how facial movement and speech production are organized in the motor cortex at the level of individual neurons. Neural activity was recorded from microelectrode arrays implanted in the brain of a participant with amyotrophic lateral sclerosis (ALS) who had limited facial movements and an ability to vocalize but not produce intelligible speech.

The results indicated neural solid agreement on various facial movements in a region of the brain called area 6v, and this activity was very distinct for different movements. In contrast, area 44, traditionally associated with speech production, appears (in this experiment) to contain little information about facial actions or speech.

The ventral premotor cortex, which is located in the middle of the upper part of the brain has been involved in motor vocabularies in both speech and manual gestures. A recent prospective fMRI study demonstrated adaptation effects in the ventral premotor cortex to repeating syllables.

Broca's area, is a region in the frontal lobe of the dominant hemisphere, usually the left, of the brain with functions linked to speech production.

The researchers developed a decoder using a recurrent neural network (RNN) to translate neural activity into speech. The participant attempted to speak sentences and the RNN decoded the predicted words in real-time, achieving a word error rate of 9.1% for a vocabulary of 50 words and 23.8% for a vocabulary of 125 000 words. This demonstrated the feasibility of decoding speech attempts using neural signals.

The neural representation of speech sounds in the brain was analyzed, showing that the activity patterns reflected the articulatory features of the phonemes. This suggests that even after years of paralysis, the detailed articulatory code of phonemes remains preserved in the brain.

The study also discussed design considerations for improving the accuracy of speech brain-computer interfaces (BCIs), including vocabulary size, number of electrodes used, and size of the training data set. The researchers noted that while their results were promising, there was still room for further optimization and improvements in the technology.

Overall, the study presented a proof of concept for a speech BCI that could potentially enable people with severe motor impairments to communicate more effectively by translating their intended speech into text from neural signals.

Grafting muscles to heal from ALS?

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Scientists tell that ALS is a disease striking upper motor neurons, which in a cascade effect, affects the lower motor neurons and muscles. Yet this does not match the patient's experience. enter image description here For them, symptoms often start with weakness, unreliability, and thinning of the thumb or calf, and with time the disease progresses to other (skeletal) muscles.

Scientific approaches are focussing on healing upper motor neurons (with a complete lack of success, which hints that we understand nearly nothing in this area) or replacing them (there are still no clinical studies).

For most scientists, it would be meaningless to try to replace muscles in ALS patients, as the upper motor neurons are dead (despite evidence they are not) new muscles would never be usable and therefore waste and die quickly.

And anyway grafting muscles on neuromuscular junctions is an extraordinarily difficult problem.

Yet there are contrarians: Scientists have recently unveiled an approach to address the devastating effects of amyotrophic lateral sclerosis (ALS), on muscle weakness. Their research introduces a novel technique involving a combination of grafted replacement motor neurons and optical nerve stimulation.

By employing a two-pronged strategy—grafting modified motor neurons and using light-based nerve stimulation—the researchers managed to rejuvenate muscle function, marking a tiny step toward devising effective therapies for ALS.

Led by Dr. Barney Bryson, the team of scientists had shown potential in restoring muscle denervation in a mouse model by utilizing optical nerve stimulation. This method hinged on grafting replacement motor neurons that were engineered to be light-sensitive, enabling their activation through an external light source.

In this latest study, the initial objective was to ensure the survival of donor motor neurons during the grafting process, overcoming potential immune system rejection. After determining that conventional immunosuppressive drugs were not viable for ALS mice, the researchers experimented with a specific antibody known as H57-597, which successfully prevented graft rejection and began reconnecting nerves to target muscles. Despite these positive outcomes, the force generated by muscle contractions was relatively weak, prompting the team to further refine their strategy.

Recognizing that neuromuscular junctions—the connection points between nerves and muscles—are influenced by regular stimulation, the scientists introduced a wireless optical stimulation system to enforce consistent muscle contractions for an hour each day. Astonishingly, after 21 days of this optical stimulation training, the mice exhibited an astonishing 13-fold enhancement in muscle contraction force. That would be nearly three years of rehabilitation therapy in humans.

These findings carry immense significance, demonstrating that even in the advanced stages of ALS, affected muscles remain amenable to reinnervation by healthy replacement motor neurons.

The strategy suggests the feasibility of a treatment that could potentially be universally applied to all ALS patients regardless of the kind of ALS they have (familial or sporadic).

More significantly, it tells that the model of ALS progression which was derived from stroke ~150 years ago and mostly never questioned since all these decades, is simply wrong.

However, significant challenges remain before this approach can transition to clinical use. Subsequent studies are necessary to confirm the efficacy of the grafting procedure with human motor neurons and to evaluate whether it can genuinely enhance patients' quality of life. Furthermore, the technique's applicability to other forms of MND, particularly those with longer life expectancies, must be investigated to ascertain its long-term effectiveness.

In conclusion, the study's senior author, Linda Greensmith, emphasizes that the findings underline the robustness of replacing motor neurons to reinnervate muscles even in advanced ALS stages. Should this approach successfully translate to ALS patients, it holds the potential to revolutionize treatment by employing a single type of motor neuron for various muscles, simplifying the therapy and making it more widely accessible. The introduction of this approach could be a game-changer in the ongoing battle against ALS and other related neuromuscular conditions.


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