Il y a un lien complexe entre le métabolisme et la myéline lors de la SLA (maladie de Charcot).

Many ALS patients have noticed that their patients seem to share a particular skin type. Studies have shown that ALS patients often exhibit small fiber neuropathy in the skin, contributing to symptoms such as impaired thermoregulation, abnormal sweating, and sensory disturbances (e.g., numbness, and pain). Similar skin changes have been observed in diseases such as Parkinson's disease and Alzheimer's disease, suggesting that skin biomarkers could contribute to the early diagnosis and monitoring of ALS.

The article reviewed here is a review of this phenomenon, which rarely receives scientific attention. While the focus of the article is on early diagnosis of ALS, scientists, and physicians are not necessarily pleased that ALS is a disease far more complex than motor neuron disease, as this makes it difficult to conceptualize and makes the design of therapeutic strategies more challenging.

One factor that may explain this is that the skin and the nervous system share a common embryonic origin. The skin is composed of the epidermis, dermis, subcutaneous tissue, and appendages (such as sweat and sebaceous glands). In patients with ALS, the skin exhibits a soft, leathery texture, as well as a phenomenon called delayed return (DRP). In healthy individuals, after a deformation or pinching, the skin quickly returns to its original shape. In patients with ALS, this return is slower. This is called the delayed return phenomenon (DRP).

In the context of ALS, DRP has been associated with abnormalities in the dermal connective tissue, such as altered collagen composition. Microscopic examination reveals fewer and less organized collagen bundles and increasing gaps in the connective tissue. Electron microscopy shows the progressive deposition of fine materials in the dermal matrix, disrupting collagen fibers and connective tissue integrity. These changes reduce the skin's resilience and elasticity, making it softer and slower to regenerate.

ALS patients also exhibit decreased sweat gland nerve fiber density (SGND) and pilomotor nerve fiber density (PNF).

Histological studies show thickening of the walls of small dermal blood vessels, particularly in sporadic ALS (sALS). Electron microscopy reveals onion-like structures formed by β-amyloid deposits and basement membrane duplications, reducing the surface area of ​​the vascular bed. This vascular remodeling, particularly in the papillary layer, may be linked to changes in autonomic innervation and contribute to preventing pressure ulcers.

One of the culprits for this state of affairs could be MMP-9, which belongs to the matrix metalloproteinase (MMP) family. Metalloproteinases degrade extracellular matrix components such as collagen. Proteins of the matrix metalloproteinase (MMP) family are involved in the restructuring of the extracellular matrix in processes such as embryonic development, wound healing, learning, and memory, as well as in pathological processes such as asthma, arthritis, intracerebral hemorrhage, and metastases.

A clinical trial (NCT04866771) was conducted at the University of Illinois Chicago to investigate the effects of remotely supervised transcranial direct current stimulation (tele-tDCS) on ALS patients. By enabling patients to undergo treatment in the comfort of their own homes under remote supervision, tele-tDCS promises to minimize travel-related barriers.

Patients were stratified into two groups based on their ALS Functional Rating Scale (ALSFS) score progression rate. The intervention group received 72 sessions of tele-tDCS, while the delayed-start group received 36 sham sessions followed by 36 active sessions. Out of 70 individuals initially screened, 14 (7 males, 7 females) were enrolled but only 10 participants completed the study. The intervention group had full retention, while the delayed-start group had a 57% retention rate.

Assessments were conducted at six-time points: pre-testing (T0), up to three mid-testing sessions (T1), post-testing at 24 weeks (T2), and a follow-up at three months (T3). These evaluations included functional and neurophysiological tests, as well as clinical and scalp integrity checks.

Tele-tDCS was administered three times per week for 24 weeks, with a stimulation dosage of 2 mA for 20 minutes. The devices were preprogrammed to ensure consistency and prevent alterations by participants or caregivers.

All intervention sessions were facilitated via ZoomPHI, allowing the participant and the researcher to see each other throughout the process. A caregiver was required always to be present to start and stop the session as instructed, ensuring safety and proper operation. Training was provided to ensure correct headset placement and operation, and caregivers were required to assist in starting and stopping each session.

A portable tDCS device (Soterix Medical 1X1 tDCS mini-CT Stimulator, NY) was used in this study. This device included a stimulator, a customized head strap for secure placement, and designated positions for active (anodal current over the lower limb motor cortex) and inactive electrodes (cathodal current over the contralateral supraorbital region).

It featured built-in programmable codes, allowing for controlled session-specific settings under the remote supervision of a researcher. The stimulation dosage of 2 mA for 20 min was preprogrammed into the device by research personnel before being provided to participants.

An interim analysis was conducted after six participants completed the study. The study would be halted for review if the mean ALSFS-score difference between groups exceeded two standard deviations. The "two standard deviations" rule is a way to check if the observed difference between groups is improbable. Participants were categorized as slow, intermediate, or fast progressors based on these rates.

ALSFRS-R scores at the beginning did not significantly differ between groups. Some people in the intervention group showed an astonishingly slower disease progression compared to the delayed-start group:

From pre-testing to post-testing at 24 weeks the intervention group mean change was 1.7 (only a little degradation in ALSFR), while in the delayed-start group, there was a 13.6 change. However it looks like the situation in the intervention group was not homogeneous at all, there were patients who reacted extremely well to the therapy, while others reacted extremely badly to the therapy.

Statistically results from a group of 14 people mean absolutely nothing, yet ALS is without cure and this result is much better than in any other ALS clinical trial.

As noted by the authors future studies may benefit from incorporating objective biomarkers such as NFL to assess the effects.

There are many articles on statins and ALS, and in general the results show that statin use does not influence the progression of ALS.

Statins are commonly used to manage cholesterol levels and reduce the risk of cardiovascular disease, but their safety in amyotrophic lateral sclerosis (ALS) has long been questioned by both patients and their caregivers. Since the mid-1990s, weight loss has been identified as a contributing factor for patients with ALS, leading to a 7.7-fold increased risk of death. Many individuals worry that statins may accelerate the progression of ALS or exacerbate symptoms, and reports from drug monitoring systems suggest a potential link between a diagnosis of ALS and statin use; however, these reports have yet to be validated in epidemiological studies. In contrast, findings from more recent studies indicate that high LDL cholesterol and elevated LDL/high-density lipoprotein ratios occurring well before the onset of ALS may be associated with an increased risk of developing the disease.

A new Norwegian study on this topic confirms that statin use does not impact the progression of ALS.

https://pubmed.ncbi.nlm.nih.gov/40034089/

The researchers analyzed data from four Norwegian health surveys spanning the years from 1972 to 2003. They linked these surveys to national registries to track ALS diagnoses, mortality, and medication use. Specifically, they examined whether statin use before and after an ALS diagnosis influenced survival time.

The researchers included 524 ALS patients in the analysis. They compared statin use before and after diagnosis and adjusted for various factors, including age, sex, smoking status, BMI, cholesterol levels, and use of riluzole (the main ALS drug).

Their work found no association between statin use and ALS survival. Interestingly, 21% of ALS patients stopped taking statins in the year before their diagnosis. This group had a poorer prognosis, perhaps because of worsening general health, but the fact they stopped using statins did not appear to have improved ALS survival.

The study therefore suggests that routinely stopping statins in ALS patients is not necessary. Since statins do not appear to have a negative impact on survival, stopping them solely because of an ALS diagnosis may deprive patients of their cardiovascular benefits.

Two recent studies highlight the complex interplay between metabolic dysregulation and ALS progression.

The first study investigated energy balance and glucose control in TAR DNA-binding protein 43 (TDP-43)Q331K mice, which serve as a model for ALS, during both the early and late symptomatic stages of the disease. It suggests the presence of compensatory mechanisms that regulate glucose metabolism differently in this form of ALS. Thus, targeting metabolic pathways, such as insulin signaling and oxidative stress, could provide new therapeutic approaches for ALS.

The etiology of ALS is complex, involving mechanisms such as neuroinflammation, protein aggregation, and energy metabolism dysfunction. The origin of hypermetabolism in amyotrophic lateral sclerosis remains unknown; however, metabolic perturbations in skeletal muscle may be a determining factor, including an increase in the expression of pyruvate dehydrogenase kinase 4 (PDK4), which plays a central role in regulating the oxidation of glucose.

Both sporadic and familial ALS cases commonly exhibit metabolic disturbances, including weight loss, increased resting energy expenditure, and hypermetabolism, which are associated with poorer disease outcomes. Interestingly, a higher body mass index (BMI) at disease onset is linked to increased survival, and high-calorie, high-fat diets have shown some benefits in ALS patients and mouse models, suggesting that metabolic interventions could influence disease progression.

Insulin resistance has been implicated in the progression of ALS. Some studies indicate that diabetes mellitus increases the risk of ALS, while others suggest that type 2 diabetes may delay the onset of the disease. This discrepancy highlights the need for further research into how energy homeostasis and insulin signaling are affected in ALS. Previous studies on SOD1G93A mice, a model of familial ALS, revealed increased energy expenditure and enhanced glucose uptake through insulin-independent pathways, along with glucagon intolerance.

The discrepancy between studies may stem from differences in tissue-specific glucose uptake, as ALS patients exhibit increased glucose uptake in denervated muscles but decreased uptake in the central nervous system.

Building on these findings, the first study investigated metabolic perturbations in the TDP-43Q331K mouse model, which mimics the neuropathological and metabolic hallmarks of human ALS, including TDP-43 pathology, a common feature in both familial and sporadic ALS.

TDP-43Q331K mice exhibited significantly increased daily energy expenditure (DEE) from the early symptomatic stages of the disease. This hypermetabolism was accompanied by a transient increase in food intake, which helped maintain fat mass initially but was insufficient in later stages, leading to fat mass reduction.

During the later stages of the disease, TDP-43Q331K mice showed improved glucose clearance, independent of insulin. Despite reduced circulating glucagon levels, these mice maintained normal fasting blood glucose levels, suggesting alternative mechanisms for glucose regulation.

Unlike SOD1G93A mice, TDP-43Q331K mice did not exhibit insulin or glucagon intolerance. Insulin sensitivity remained unchanged, and while glucagon levels were reduced, the mice maintained normal blood glucose levels, indicating the involvement of other regulatory mechanisms.

Consistent with other ALS models, TDP-43Q331K mice experienced a reduction in lean mass during both early and late disease stages. Regression analysis confirmed that the increased energy expenditure was independent of changes in body mass.

The TDP-43Q331K mutation drives significant metabolic changes, including hypermetabolism and altered glucose uptake, which are not observed with wild-type TDP-43.

The increased glucose uptake in later disease stages is insulin-independent, highlighting the activation of alternative metabolic pathways in response to the disease.

The ability of TDP-43Q331K mice to maintain fasting blood glucose levels despite reduced glucagon suggests the existence of compensatory mechanisms that regulate glucose metabolism differently in this ALS model.

• The second study, a phase 2a clinical trial, explored the pharmacodynamic response of trimetazidine, a partial fatty acid oxidation inhibitor, on oxidative stress markers and energy expenditure in amyotrophic lateral sclerosis. This publication highlights how it's difficult and inconclusive to conduct an ALS clinical trial as twenty-one participants received trimetazidine but only 19 completed the treatment period. While trimetazidine is a well known drug, usually well tolerated, the assessment of energy expenditure may have been uncomfortable. While there were 57 adverse events, the conclusion was, as usual, that the drug was well tolerated! While the publication recounts that trimetazidine was beneficial for patients (this is not a phase III trial), for me the results section does not show conclusive results. For example, the results improved only during the wash-out period.

The authors tell that the on-treatment period may have been too short, or the sample size too small to detect a disease-relevant change, if one exists. Moreover, in this study, they simply used the approved dose for angina pectoris. Therefore, it remains unclear whether dosing was appropriate and whether a different dose would have resulted in more substantial reductions. Finally, the response in the oxidative stress markers may also be explained by external factors that influence metabolism, such as concomitant medication use and smoking, which cannot be completely ruled out in this uncontrolled study.

While the study was limited by its short duration and lack of a control group, the findings suggest that trimetazidine may help mitigate the hypermetabolic state in ALS and improve disease outcomes. Larger, randomized controlled trials are needed to confirm these results and determine the optimal dosing regimen.

These findings suggest that targeting metabolic pathways, such as insulin signaling and oxidative stress, could offer new therapeutic avenues for ALS. Future research should focus on understanding the underlying mechanisms of metabolic dysregulation, exploring the potential of antidiabetic agents, and conducting larger clinical trials to evaluate the efficacy of metabolic modulators like trimetazidine in ALS patients.

SUMO (Small Ubiquitin-like Modifier) proteins are a family of small proteins that are attached to and detached from other proteins in cells to modify their function. This process is called SUMOylation. SUMOylation is to signal to other cellular mechanisms that the protein attached must be processed. There are at least 4 SUMO isoforms in humans; SUMO-1, SUMO-2, SUMO-3, and SUMO-4. SUMO proteins are involved in a variety of cellular processes, such as nuclear transport, transcriptional regulation, apoptosis, and protein stability. Transactive response DNA-binding protein 43 (TDP-43) is a nuclear RNA binding protein (RBP) involved in RNA metabolism. TDP-43 has a high propensity to aggregate because of its low solubility in cells and in vitro. The aggregation propensity of TDP-43 is increased by ALS/FTD-linked mutations and upon exposure to stress and has been observed in patients with C9orf72 hexanucleotide repeat expansion, the most common genetic cause of sporadic and familial.

Stress conditions trigger the accumulation of TDP-43 in cytosolic stress granules. The role of stress granules in modulating TDP-43 aggregation is ambiguous. Functionally, SUMO2/3-ylation has been shown to maintain stress granules in a dynamic state: SUMOylation inhibition impairs stress granule disassembly, but the underlying mechanism is still unknown.

In this paper, the authors report that upon oxidative stress (induced by sodium arsenite), TDP-43 becomes modified by SUMO2/3 protein chains and moves from the nucleus to cytoplasmic stress granules. This conclusion is probably also valid for other stress conditions, so this study is of great interest. When researchers blocked SUMOylation, TDP-43 became less mobile within the cell, stress granules took longer to disassemble, and TDP-43 was more likely to form insoluble aggregates. Yet this is not a study on humans, the authors used various immortal cell lines, motor neuron cells, and Caenorhabditis elegans worms. Furthermore, the authors used genetic therapies to infect cells to express or repress PIAS4. This is easy to do in vitro but most probably hard to achieve in a seriously ill patient.

Because TDP-43 aggregation is central to familial and sporadic ALS, approaches aimed at preventing TDP-43 aggregation hold promise for future treatments. How cells control TDP-43 aggregation is poorly understood. Modifiers of TDP-43 solubility include molecular chaperones and posttranslational modifications. Besides ubiquitination, which is a key posttranslational modification required to clear aggregation-prone proteins, phosphorylation of TDP-43 is emerging as a protective response to counteract its misfolding. Phosphorylation of TDP-43 decreases its assembly into condensates and suppresses TDP-43 aggregation and toxicity.

Under normal growth conditions, cells prefer to modify proteins with SUMO1, while during cellular stress, SUMO2 and SUMO3 are usually conjugated in the form of SUMO2/3 chains (referred to as SUMO2/3-ylation). TDP-43 when SUMO1-ylated stays in the nucleus, does not aggregate in the cytoplasm, and its splicing activity is modified.

Using experiments in cells, the authors show that conjugation of TDP-43 with SUMO2/3 coincides with stress granule assembly. Pharmacological inhibition of TDP-43 SUMO2/3-ylation triggers TDP-43 aggregation inside stress granules.

E3 SUMO-protein ligase PIAS4 is one of several protein inhibitors of activated STAT (PIAS) proteins. PIAS proteins act as transcriptional co-regulators with at least 60 different proteins to either activate or repress transcription. The transcription factors STAT, NF-κB, p73, and p53 are among the many proteins that PIAS interacts with. PIAS4 has been shown to recruit proteins to the site of the DNA damage and promote repair.

The authors found that PIAS4 helps attach SUMO2/3 to TDP-43. - PIAS4-mediated SUMO2/3-ylation increases the solubility of TDP-43 and prevents its aggregation in the cytoplasm. - Depleting PIAS4 leads to TDP-43 aggregation In motor neurons from the human spinal cord in familial ALS cases with TDP-43 and C9orf72 mutations, reduced cytoplasmic PIAS4 correlates with increased TDP-43 aggregates.

RNA binding appears to compete with SUMOylation: When cells are not subjected to stress, TDP-43 is mainly localized inside the nucleus, binding with high affinity to RNA. When TDP-43 is bound to RNA, it's less likely to be SUMOylated. When cellular RNA levels are low, there's increased SUMO2/3 modification This suggests SUMOylation may be a protective mechanism when TDP-43 isn't bound to RNA

The authors conclude that modification with SUMO2/3 chains maintains the solubility of RNA-free TDP-43 during stress.

There are many studies on reducing TDP-43 aggregates in ALS, but this one looks much more sophisticated than the previous ones. Yet this is mostly an in-vitro study. Long pre-clinical studies must be conducted on mammals to verify if a simple and safe agonist of PIAS4 (which does not exist today) could improve the health of ALS patients.

A few years ago I tried to model the course of ALS using SBML, a systems biology tool now abandoned by scientists.

At the time there was no model of ALS, but since then there have been very interesting attempts, for example, this one:enter link description here

However, few scientists and almost no doctors use models based on differential equations today, we live in an era where statistical models are all the rage. In addition, biology as it is practiced is essentially qualitative, which makes it not very suitable for modeling and which attracts the mockery of "soft science", because by nature it is not capable of making consistent predictions. One only has to look at the colossal failure rate of clinical trials to be convinced of this.

The publication reviewed in this post focuses on understanding the regulatory dynamics of amyotrophic lateral sclerosis (ALS) using the widely used SOD1-G93A transgenic mouse model.

ALS is a multifactorial disease, and previous studies have often focused on isolated aspects rather than its complex and interconnected nature.

The study suggests that ALS regulation may be hypervigilant, meaning that the system overcorrects in response to stress, leading to damaging oscillatory behavior that contributes to disease progression. The study uses an innovative and integrative framework to model the regulatory dynamics of wild-type (WT) and SOD1-G93A ALS mice. The models are based on first-order ordinary differential equations (ODEs) that describe how the system output evolves over time. The research uses dynamic meta-analysis to synthesize experimental data from the literature and parameter optimization based on genetic algorithms to infer missing data. Indeed, to build a model, data are needed and here these are obtained from results reported in the literature on SOD1-G93A ALS mouse models.

The study shows that SOD1-G93A mice with ALS exhibit unstable physiological regulation, characterized by oscillatory behavior due to hypervigilant regulation. This instability intensifies near disease onset and worsens with progression.

Computational models of the physiological dynamics of wild-type (WT) and transgenic SOD1-G93A mice were constructed: a WT mouse model to simulate normal homeostasis and a SOD1-G93A ALS model to simulate the dynamics of ALS pathology and their response to treatments in silico. The model simulates the functional molecular mechanisms of apoptosis, metal chelation, energetics, excitotoxicity, inflammation, oxidative stress, and proteomics using data curated from published SOD1-G93A mouse experiments. Time-course measures of disease progression (rotarod, grip strength, body weight) were used to validate the results from the literature.

The health of untreated SOD1-G93A ALS mouse models cannot be maintained due to oscillatory instability. The onset and magnitude of homeostatic instability corresponded with disease onset and progression. Oscillations are associated with high feedback gain due to hypervigilant regulation.

Multiple virtual treatments combined were able to stabilize the dynamics of SOD1-G93A ALS mice to near-normal WT homeostasis. However, treatment timing and effect size are critical for stabilization to match therapeutic success. The most common unidirectional stabilizing treatment was pro-proteomics, while the most common bidirectional stabilizing treatment was energy consumption and anti-apoptosis. The authors cite anti-apoptosis factors such as caspase-9 inhibitor, caspase-3 inhibitor, Bax inhibitor, and Bcl-2 homolog BCL-XL.

A major drawback is that this type of ALS only affects less than 2% of ALS cases and if it is still largely overrepresented in the literature, it is because the association of this type of mutation with ALS is historically the first to have been discovered during the boom in genetics and for almost 15 years no other association has been found.

Another important point is that we do not know what mechanisms cause this disease, or even if it is a single disease. Models of this type therefore make many assumptions and their results are less robust than they appear.

The study highlights the multifactorial nature of ALS, which involves various molecular mechanisms, such as apoptosis, bioenergetics, excitotoxicity, inflammation, oxidative stress, and proteomics. These mechanisms are interconnected, and their dysregulation contributes to disease progression.

The study also explores the potential of combination therapies to stabilize the regulatory dynamics of ALS. Previous studies focusing on single therapeutic targets have often been inadequate, but combination treatments have shown success in the management of other complex diseases such as cancer, COVID-19, and HIV. The study suggests that precisely timed combination therapies targeting multiple pathways may be necessary to achieve meaningful results in ALS.

Code and data are not available at the indicated Github address.

The authors acknowledge that first-order feedback models may not fully capture the complexity of biological systems, including phenomena such as bistability and hysteresis. But for now, we are still in the prehistory of biological systems modeling, the field needs to be developed before focusing on its imperfections.

I fear that this publication will go way over the heads of health professionals working in the field of ALS.

Usually, I strive to find articles that have some interest in patients. This means eliminating the countless articles about cell culture that bring little new knowledge in basic science and have zero interest in pre-clinical research.

Yet here is one about cell culture that may retain some interest. It's about a type of karyopherin that transports protein molecules from the cell's cytoplasm to the nucleus. It does so by binding to specific recognition sequences, called nuclear localization sequences (NLS).

Upon stress, several karyopherin proteins stop shuttling between the nucleus and the cytoplasm and are sequestered in stress granules. Everyone interested in ALS knows this is an important topic in neurodegenerative diseases. Neurodegenerative proteinopathies are characterized by progressive cell loss that is preceded by the mislocalization and aberrant accumulation of proteins prone to aggregation in the cell's cytoplasm. Despite their different physiological functions, disease-related proteins include tau, α-synuclein, TAR DNA binding protein-43, fused in sarcoma, and mutant huntingtin. Recent advances into the underlying pathogenic mechanisms have associated mislocalization and aberrant accumulation of disease-related proteins with defective nucleocytoplasmic transport and its mediators called karyopherins. These studies identified karyopherin abnormalities in amyotrophic lateral sclerosis, frontotemporal dementia, Alzheimer’s disease, and synucleinopathies including Parkinson’s disease and dementia with Lewy bodies, that range from altered expression levels to the subcellular mislocalization and aggregation of karyopherin α and β proteins.

In addition to their classical function in nuclear import and export, karyopherins can also act as chaperones by shielding aggregation-prone proteins against misfolding, accumulation, and irreversible phase-transition into insoluble aggregates. Karyopherin abnormalities can, therefore, be both the cause and consequence of protein mislocalization and aggregate formation in degenerative proteinopathies.

A new study suggests that the upregulation of two karyopherins might improve cell health in C9orf72.

Hexanucleotide repeat expansions in C9orf72 are the primary genetic mutation associated with amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD), collectively referred to as C9-ALS/FTD. The resulting dipeptide repeat (DPR) proteins, such as poly(proline-arginine) (polyPR), generated from G4C2 repeat expansions, have been shown to be highly toxic.

To investigate the cellular localization of PR20, a polyPR protein, it was labeled with fluorescein isothiocyanate (FITC). Notably, several cell lines survived PR20 treatment by sequestering it in the cytoplasm. However, treatment with JQ-1 or Ivermectin (Iver) translocated PR20 into the nucleus, leading to cell death.

Mechanistically, the interaction between KPNA2/KPNB1 and PR20 in the cytoplasm prevented PR20 from entering the cell nucleus. Genetic silencing of KPNA2/KPNB1 converted PR20-resistant cells into PR20-sensitive cells. Specifically, JQ1 treatment decreased KPNA2/KPNB1 protein levels, allowing PR20 to enter the nucleus.

Conversely, overexpressing KPNA2 or KPNB1 effectively blocked cell death induced by co-treatment with JQ-1 and PR20. The authors' findings suggest that the upregulation of KPNA2/KPNB1 protects cells from PR20 toxicity.

Pharmacological targeting of karyopherins represents a promising new strategy for therapeutic intervention in neurodegenerative diseases. Yet by the time patients are diagnosed, a significant number of neurons are already lost, while the remaining functional ones are doomed to degenerate over time due to the lack of efficient treatments. So, it's important not to exaggerate the benefits of drugs in those diseases.

Several compounds targeting karyopherins are already in clinical trials to treat specific forms of cancer and viral infections, so it might be less costly to retarget these drugs toward neurodegenerative diseases than it is for entirely new drugs.

One of the most devastating for of amyotrophic lateral sclerosis (ALS) is the loss of control of the muscles involved in speech and swallowing, which is called "bulbar onset". Early detection of changes during or after an ALS diagnosis could pave the way for interventions that improve quality of life, but conventional assessments often rely on subjective observation.

Indeed, surface electromyography observes the reaction of muscles that are excited by an electric current. This observation is subjective, it involves interpreting electrical signals by identifying patterns that are not obvious because they are fleeting and non-standardized. This observation depends heavily on the placement of the needles, but above all, from this observation the practitioner deduces the good or bad functioning of the lower and upper motor neurons. I am not a doctor, just a retired engineer, but I find that these deductions of the functioning of motor neurons from surface electromyography make absolutely no sense, no logic. Yet the majority of ALS diagnoses are made this way!

Furthermore, this approach is poorly adapted to bulbar involvement. Also, a slightly more standardized method of interpreting surface electromyography adapted to bulbar involvement would be welcome. A recent study renovates surface electromyography by automatically recording and interpreting the electrical activity of jaw muscles. The authors focused on three key muscles involved in jaw movement (the anterior temporal, the masseter, and the anterior belly of the digastric) by recording their activity while participants performed speech tasks. By applying the principles of network morphology, they showed that these subtle disturbances in the flow of communication between jaw muscles created a map of how these muscles coordinate with each other.

The study looked at three groups: ALS patients with overt bulbar symptoms, those in an earlier “prodromal” phase without overt symptoms, and healthy controls. Using sophisticated graph-based analysis, the researchers examined how muscle connectivity differed between these groups and whether these changes could serve as early warning signs of bulbar dysfunction.

The results were striking. Even for prodromal patients, this method highlights subtle disruptions in the flow of communication between jaw muscles. As the disease progressed, some features of the network continued to deteriorate, while others appeared to stagnate. Crucially, these network features correlated with measurable changes in jaw movement, reinforcing the idea that ALS changes not only the strength of muscles but also how they work together.

To further their findings, the researchers used machine learning models, and training algorithms to distinguish ALS patients from healthy individuals based solely on their muscle networks. The models performed well, suggesting that the technique could one day serve as an objective, data-driven tool to diagnose ALS earlier and more accurately than current methods.

However, moving this research from the lab to clinical practice will require several steps. Larger, more diverse studies are needed to confirm that the method reliably identifies ALS while distinguishing it from other speech-impairing conditions. To be widely used, the method must also be accepted by practitioners, who like many specialists are gradually being replaced by more reliable tools. To avoid being devalued, they will need to shift their service offerings toward greater personalization and the ability to interpret not raw results, but more sophisticated information.

Nevertheless, the study represents a significant step forward. By listening more closely to the hidden rhythms of muscle coordination, researchers have found a new way to detect muscle changes in ALS, which could help clinicians stay ahead of a disease that so often eludes early diagnosis.