Les oligonucléotides antisens (ASO) sont de petites séquences d'ADN capables de réduire l'expression d'un gène cible au niveau post-transcriptionnel, ce qui les rend intéressants pour neutraliser les produits génétiques mutants ou toxiques. Les progrès réalisés dans la chimie médicinale des ASO ont amélioré leur profil pharmacodynamique, permettant ainsi une administration sûre et efficace au système nerveux central. Les thérapies ASO pour la SLA se sont rapidement développées au cours des deux dernières décennies, et les ASO ciblant SOD1, C9orf72 et ATXN2 sont actuellement en essais cliniques pour les formes familiales ou sporadiques de SLA.

L'injection directe dans le SNC permet à l'ASO de se distribuer dans tout le SNC, et les ASO ciblant SOD1 (Tofersen/Qalsody) ont démontré que l'administration intrathécale était une approche bien tolérée. De nouvelles approches d'administration, telles que la conjugaison des ASO à des nanoparticules lipidiques ou à des cholestérols, pourraient bientôt permettre une administration moins intrusive et pouvant être effectuée par davantage de professionels.

Les mutations du sarcome fusionné (FUS) sont à l'origine d'une forme rare et agressive de SLA, d'apparition précoce et souvent juvénile. FUS est une protéine de liaison à l'ARN essentielle à la réparation et au métabolisme de l'ADN, notamment à l'épissage et à la traduction de l'ARNm.

Alors que la plupart des formes de SLA présentent généralement une pathologie TDP-43, les tissus post-mortem de patients atteints de SLA présentent une agrégation intracytoplasmique en l'absence de pathologie TDP-43. Identifié par criblage in vitro, l'ASO ION363 développé par la société IONIS qui a aussi développé Tofersen, cible le 6e intron de FUS (SLA avec une mutation P525L). ION363 réduit les taux de protéines de liaison à l'ARN insolubles et insolubles associées aux agrégats, telles que hnRNPA1 et ralentit la neurodégénérescence des motoneurones lombaires et la perte d'innervation de la jonction neuromusculaire.

L'inversion de la neurodégénérescence et la réduction de la prolifération chez les souris P525L ont motivé une demande d'IND (« usage compassionnel ») pour des tests chez l'homme porteur de mutations. Une demande d’IND a été approuvée par la FDA pour l’utilisation d’ION363 chez un patient atteint de SLA porteur d’une mutation P525L (âgé de 26 ans).

Jaci Hermstad, une jeune femme de 25 ans originaire de l'Iowa, a reçu un diagnostic de SLA-FUS, huit ans après avoir perdu sa sœur jumelle, atteinte de la même maladie, à l'âge de 17 ans. La famille Hermstad a contacté Project ALS et le Dr Shneider, qui étudiait le potentiel des ASO dans le traitement des patients atteints de SLA-FUS, pour savoir s'il existait des thérapies susceptibles d'aider Jaci.

« L'histoire des Hermstad a immédiatement attiré l'attention de nombreuses personnes talentueuses et bienveillantes, d'Ionis et du Dr Shneider, expert du gène FUS, aux experts réglementaires bénévoles, aux fabricants et aux conseillers universitaires », a déclaré Valerie Estess, directrice de recherche du Project ALS. Le courage de Jaci, et le travail d'équipe qu'elle a inspiré, peuvent désormais porter leurs fruits pour tous les patients atteints de SLA-FUS.

Grâce au financement de l'ALS Association et du Projet SLA, le Dr Shneider et son équipe de Columbia ont pu proposer le jacifusen à dix patients supplémentaires atteints de SLA-FUS au cours des deux dernières années, tout en suivant en parallèle les données de sécurité du médicament et les biomarqueurs pertinents pour la maladie.

Cela a conduit la Chambre des représentants des États-Unis à adopter le projet de loi de Jaci, autorisant les médecins à administrer l'ASO avant de réaliser des tests toxicologiques sur des rongeurs. Selon sa nécrologie, Hermstad a reçu 12 injections du médicament, appelé Jacifusen, entre juin 2019 et mars 2020 avant de décéder de la SLA le 1er mai 2020.

À l'autopsie, l'ION363 a été largement détecté dans les tissus du cerveau et de la moelle épinière, deux mois après la dernière perfusion. Les signes pathologiques de la SLA-FUS P525L ont diminué, notamment les inclusions cytoplasmiques neuronales positives, les agrégats insolubles de protéines de liaison à l'ARN et d'autres protéines, ainsi que la localisation nucléaire.

Un examen neuropathologique a été réalisé chez le premier participant, ainsi que chez un témoin non atteint de SLA et un patient atteint de SLA porteur de la mutation P525L n'ayant pas reçu de traitement. Par rapport au témoin atteint de SLA, le participant traité par ASO présentait moins de protéines totales et mutantes, y compris de protéines insolubles, dans la moelle épinière lombaire.

Shneider et son équipe à Columbia ont proposé du Jacifusen à dix patients supplémentaires atteints de SLA au cours des deux dernières années.

En juin 2021, Ionis a lancé un essai de phase 3 appelé ION, visant à traiter jusqu'à 77 patients dans le monde. Les participants sont âgés de 11 ans et plus, atteints de SLA causée par une mutation pathogène confirmée du gène ION363 et ne doivent pas être sous ventilation mécanique permanente au moment de l'inscription. Ils reçoivent des injections rachidiennes d'ION363 ou d'un placebo toutes les douze semaines, après une dose de charge à quatre semaines, pendant 61 semaines, suivies d'une prolongation en ouvert de 85 semaines. Le critère d'évaluation principal est l'évolution fonctionnelle selon l'échelle d'évaluation fonctionnelle de la SLA révisée et la durée de vie sans ventilation mécanique. Les critères d'évaluation secondaires incluent la qualité de vie, la fonction pulmonaire et musculaire, la survie et les modifications du biomarqueur des chaînes légères des neurofilaments. Réalisé à L'essai clinique, mené sur 24 sites en Amérique du Nord, en Europe, au Royaume-Uni, à Taïwan et en Corée, devrait se poursuivre jusqu'en juin 2026.

La deuxième partie de l'étude consiste en une période d'extension ouverte de 72 semaines au cours de laquelle tous les participants ont reçu du jacifusen.

Une caractéristique unique de cet essai est la mise en œuvre d'un « sauvetage ». Plus précisément, si un participant présente un déclin fonctionnel significatif au cours de la première partie, il sera transféré vers la deuxième partie/extension ouverte de l'étude. Cela semble suspect du point de vue statistique: L'étude ne conserve que les patients qui évoluent lentement!

Bien que la plupart des participants aient connu un déclin fonctionnel continu (mesuré par l’ALSFRS-R) après le début du traitement par jacifusen, l’un d’eux a présenté une récupération fonctionnelle objective sans précédent après 10 mois, et un autre est resté asymptomatique, avec une amélioration documentée des anomalies électromyographiques.

At Padiracinnovation, we face a paradox: despite the deluge of scientific publications on ALS, Parkinson's, and Alzheimer's disease, academic and industry scientists seem unable to develop effective drugs.

In fact, the incentive for academic scientists appears to be publishing a large volume of work, as this is nearly their only path to career advancement. Industry scientists publish infrequently, but their work primarily serves to promote their company to potential investors.

How can we differentiate the wheat from the chaff? There are several telltale signs:

• single author

• authors who publish more than two papers per year

• publishing outside of prominent journals, such as in conferences

• articles based on specific intuition without testing other hypotheses

• articles concerning a specific drug without explaining the rationale for its initial selection

• articles making bold claims based on queries to a public database without conducting further research to validate the results and without considering confounding factors

• articles making outrageous claims, such as "breakthrough in disease X."

In our field, additional indicators exist: a strong publication should report results from human trials, as animal models often prove to be completely ineffective.

Consequently, we find few publications to discuss, even as popular science news organisations report daily on significant advances made toward new drugs.

Two FDA-approved small-molecule drugs, riluzole and edaravone, are currently available on the market; the antisense oligonucleotide tofersen was also recently approved. However, none blocks disease progression, making it crucial to investigate new therapeutic routes to overcome ALS.

Several products are known to slightly slow ALS progression, but they are not pursued by the pharmaceutical industry and academics because they lack patentability. One of the best-known among these products is TUDCA, while two lesser-known ones are Acetyl-L-Carnitine and Alpha-Lipoic Acid.

There are many forms of ALS, and each will likely require different therapeutics. Most forms are characterized by aggregates of misfolded TDP-43 fragments, an important protein. Various theories exist regarding how these aggregates form; one posits that they are a form of stress granules.

Numerous teams from diverse backgrounds collaborated to find a drug capable of dissolving these aggregates.

They screened many drug candidates and found that one, closely related to Alpha-Lipoic Acid, holds good prospects for future use as a drug. Indeed, it will likely be modified to enhance its bioavailability and thus could be patented.

The scientists screened a library of 1,600 small molecules to identify compounds that affect stress granule formation, using HeLa cells expressing FUS–GFP, a fusion protein that localizes to stress granules under stress. I remain cautious about findings from in vitro experiments, especially those involving immortalized cells of cervical cancer, whose biology often differs from that of normal cells. So consider yourselves warned, dear readers. The researchers specifically focused on molecules that could reduce or reverse stress granule formation, particularly those that act directly on stress granule proteins and may be useful as therapeutic agents. From the initial screening, lipoamide emerged as a novel, potent modulator of stress granules. Once lipoamide was identified as a hit, the researchers sought to determine its effects in cells regarding specificity, potency, intracellular localization, and its effects on other cellular condensates.

It's beneficial to understand the underlying mechanism of action, even if it's often challenging to achieve in biology. Thus, the authors evaluated the structure–activity relationships (SAR). Understanding which chemical features are critical for its function will assist in enhancing the potency of a future drug. The authors thus aimed to clarify its mechanism of action—whether it alters the physical properties of condensates, binds to specific proteins, or acts via redox chemistry.

Lipoamide was found to prevent stress granule formation when added before stress and to dissolve existing stress granules when added afterward.

Lipoamide's effect was also specific to stress granules, without impacting other cellular condensates or general protein synthesis. This specificity is crucial as it minimizes the risk of adverse effects.

Proteins stabilized by lipoamide are enriched in intrinsically disordered regions (IDRs) with high arginine and tyrosine content—characteristics typical of stress granule proteins. These effects suggest that lipoamide interacts with these IDR-rich proteins to modulate condensate behavior, likely through nonenzymatic redox interactions.

In conclusion, the authors identified lipoamide as a promising small molecule that selectively and reversibly modulates stress granule formation. It does so not through conventional binding to a specific target, but likely via redox-sensitive interactions with disordered proteins, altering the physical properties of condensates.

This may have therapeutic implications for ALS and other neurodegenerative diseases linked to stress granule dysfunction. However, this research is not yet at the pre-clinical trial stage, which we know unfortunately provides limited information about success in human trials. This study is in vitro with cells that possess biology mostly alien to living beings. These cells are not motor neurons, so it's somewhat odd to see so many references to ALS in the text; it's probably a bait for investors.

An unusual news today: Alchemab Therapeutics, a UK biopharmaceutical company, announced it has entered a collaboration with Lilly to discover novel therapeutic candidates to treat amyotrophic lateral sclerosis (ALS). There are a few similar announcements, so it means that Lilly knows that Alchemab's drug has a good chance of developing into a commercial drug. A similar partnership in the ALS field was Ionis with Biogen, which at the end provided Tofersen (Qalsody), which helped some ALS patients.

Alchemab's approach is data-oriented. Instead of trying to find molecules that are causative of a disease and to deactivate them, they search individuals with unusually slow rates of disease progression, or at risk of developing a disease but still healthy, to identify antibodies associated with resilience. Such individuals could be patients with years of survival with typically untreatable cancer, very long-lived, healthy individuals without chronic diseases, or patients with susceptibility to neurodegenerative disease that do not progress (it happens). If you want to know more about their methods, here is a link: https://www.mlsb.io/papers_2023/Enhancing_Antibody_Language_Models_with_Structural_Information.pdf

Alchemab believes these antibodies, which are not found in disease progressors, could present therapeutic opportunities. This is complicated reasoning. Why would antibodies be useful in non-transmissible diseases in general? Why not an approach like those of Ionis, which uses ASO to prevent proteins from being produced by the cell in the first place? And this is too simplistic to my taste, but apparently Lilly thinks otherwise. Alchemab deliberately uses agnostic approaches because it is not tainted by bias or misunderstanding of underlying biology.

Once data-driven approaches find an antibody candidate, it must be modified to be stable and safe for the host. Then it must be tested in pre-clinical studies on animal models, and if successful, in clinical trials involving humans.

Alchemab already has several candidate drugs in its pipeline, and there is one for ALS. The drug is named ATLX-1282, and it targets the protein UNC5C. This protein belongs to the UNC-5 family of netrin receptors. The UNC-5 family of receptors mediate the repellent response to netrin. Netrins are secreted proteins that direct axon extension and cell migration during neural development. They are bifunctional proteins that act as attractants for some cell types and as repellents for others, and these opposite actions are thought to be mediated by two classes of receptors.

So, at least there is some logical connection between the drug and the disease; this is not the case for most drugs (unsuccessfully) tested against ALS. Yet there are thousands of molecules associated with ALS, and it is not disclosed what makes UNC5C a good target in ALS. In addition, netrins apparently act during neural development, yet most ALS patients are at the opposite end of the life span.

Here are some publications on the relation between axon guidance and ALS, but it's not because some scientific publications assert something that it is necessarily true or useful.

https://pubmed.ncbi.nlm.nih.gov/24918638/

https://pubmed.ncbi.nlm.nih.gov/25177267/

https://pmc.ncbi.nlm.nih.gov/articles/PMC2175528/

The only publication I found by Alchemab about ALS and UNC5C is this one: https://www.alchemab.com/wp-content/uploads/2023/12/Society-for-Neuroscience-Posters.pdf I am not sure it proves anything about a link between ALS and UNC5C or even netrins.

Since we still don't know the causes of ALS and several other sporadic neurodegenerative diseases, it's interesting to find potential biomarkers associated with these diseases. Furthermore, since most clinical trials are negative, the pharmaceutical industry is seeking to change the definition of a successful trial by substituting biomarkers for clinical signs, as they are said to be more reliable. While there is some truth in this approach, it still seems highly questionable from an ethical perspective: The sole purpose is to validate clinical trials, even if there is no improvement in patient symptoms.

Researchers are therefore currently working to find biomarkers for neurodegenerative diseases, as the market for these tools appears immense and lucrative. The ideal biomarker would be an inexpensive blood test.

Researchers from Thomas Jefferson University examined two American GEO databases that collect blood samples (plasma and serum). https://www.ncbi.nlm.nih.gov/geo/info/overview.html

The Gene Expression Omnibus (GEO) is a public repository that archives and freely distributes comprehensive microarray, next-generation sequencing, and other forms of high-throughput functional genomics data submitted by the scientific community. These are digital data provided by microbiology tools and are therefore presumed to be reliable, but the associated metadata (provided by humans) may not be of high quality. Furthermore, some datasets submitted to GEO may have been contaminated.

Scientists focused on the small RNA fragments present in these samples. They focused on small non-coding RNAs because these molecules are stable and abundant in blood fluids such as plasma and serum.

These molecules were classified as follows:

• isomiR: slightly altered versions of microRNAs

• tRF: fragments from transfer RNA

• rRF: fragments of ribosomal RNA

• yRF: fragments of another type of RNA, Y RNAs

• And a residual group, called "not-itrs," for sequences they initially could not categorize.

The scientists found that these small types of RNA do not appear in sufficient quantities in ALS patients as in healthy people.

Some of these differences were related to the patients' survival time, even after taking into account factors such as age, sex, and whether or not they were taking riluzole (a common treatment for ALS).

Interestingly, some "non-itrs" sequences did not match human DNA, but rather the ribosomal DNA of bacteria (Burkholderiales) or fungi. Some of these foreign sequences were also linked to patient survival. This is a worrying claim.

What should we make of these claims of non-human RNA discovery in patients? Initial contamination is a plausible explanation for the detection of small non-human RNAs (sncRNAs), and it is a known concern in studies of low-input samples such as plasma and serum. But this contamination would also be apparent in samples from people without ALS.

The tools used in microbiology use short reads that are algorithmically reassembled. These short reads are likely to match multiple genomes by chance, increasing the risk of false positives during alignment, particularly if the databases are large and noisy. Here too, contamination would be apparent in samples from people without ALS.

Another explanation is that the presence of non-human genomes in humans is completely normal: our skin, mucous membranes, and internal organs harbor an extensive variety of microorganisms. We don't live in a vacuum. What we do know is that these populations of microorganisms respond to the host's health, sometimes with significant variations. For example, it has been shown that in Alzheimer's disease and, more generally, in aging, the dental microbial population is very different from that of healthy people.

So what can we conclude? There's probably no reason to worry; ALS is probably not caused by specific microbes or microscopic fungi. But that doesn't change the fact that we know that certain cyanobacteria cause a disease similar to ALS.

Abnormal protein aggregation within cells is a recurring phenomenon in Parkinson's disease (PD), Alzheimer's disease (AD), and amyotrophic lateral sclerosis (ALS). Current approaches use antibodies to target these aggregates, but this is a rudimentary approach, as little is known about the causes of their formation, or whether they are the cause or consequence of the disease.

Cells are an incredibly crowded environment, and their molecules undergo Brownian motion, which thwarts their biological function. Making the cell less dense and more soluble would certainly alleviate some molecular problems. There are various approaches, including those that use phase transitions.

Recent research sheds surprising light on the dynamic relationship between mitochondrial activity, ATP levels, and neuronal cytoplasmic fluidity, all of which play a critical role in controlling protein aggregation.

The researchers used mouse giant goblet cell cultures to analyze presynaptic viscosity using real-time confocal microscopy. These cells are characterized by large glutamatergic nerve terminals, ideally suited for real-time imaging. Rather than focusing on individual proteins, the team took a holistic approach, using a technique called fluorescence recovery after photobleaching (FRAP) of soluble green fluorescent protein (cGFP) to assess the overall viscosity of the axonal cytosol.

Cytosolic viscosity can reflect the extent of protein aggregation; Greater aggregation means less free diffusion of cGFP, indicating a more "solidified" cytosol.

Synapses are hotspots for mitochondria, which provide the ATP needed for neurotransmission. By labeling active mitochondria and comparing their location to cGFP mobility, the study revealed that regions with greater mitochondrial activity exhibited higher cytosolic fluidity. This suggests a direct link between ATP production and the maintenance of a more soluble and functional presynaptic environment.

To further investigate this, the team inhibited mitochondrial function using FCCP and other mitochondrial blockers. As ATP production decreased, cGFP diffusion decreased sharply, suggesting that the cytosol was becoming more viscous due to protein aggregation. It is important to note that this effect was specific to mitochondrial inhibition: blocking glycolysis had little effect.

Even components of the synaptic release mechanism, such as synaptic vesicles (SVs) and active zones (AZs), exhibited reduced mobility under mitochondrial stress, reinforcing the idea that energy depletion disrupts the fluid phase of the cytoplasm.

To test whether ATP could restore the altered cytosol state, the researchers administered ATP directly to neurons. They found that ATP not only restored cGFP diffusion but also reduced the size and number of protein aggregates. To test whether enhancing endogenous ATP production could mitigate the protein aggregation linked to mitochondrial dysfunction, the researchers turned to NMN, a molecule known to boost NAD⁺ levels and support mitochondrial health.

They treated neurons with NMN and observed the following key outcomes:

Partial restoration of cytoplasmic fluidity: In neurons with compromised mitochondrial activity (such as those derived from PARK2 or TDP-43 mutant patients), NMN treatment significantly improved the diffusion of soluble proteins like cGFP. While not as dramatic as direct ATP infusion, NMN nonetheless reduced cytosolic viscosity.

Reduction in aggregate burden: In both mouse neurons under mitochondrial stress and hiPSC-derived human neurons from neurodegenerative disease patients, NMN treatment lowered the accumulation of insoluble protein aggregates.

Improved ATP levels: NMN supplementation helped increase intracellular ATP concentrations, presumably by enhancing mitochondrial NAD⁺-dependent enzymatic activity, which supports oxidative phosphorylation.

These results suggest that NMN supports the same protective pathway as ATP, but indirectly, by restoring mitochondrial capacity to generate ATP and maintain a more fluid intracellular environment.

The mechanism appears to be biophysical rather than biochemical: ATP acts as a hydrotrope, a molecule that keeps other proteins dissolved and prevents them from forming aggregates.

The researchers then examined whether this principle held true for specific proteins involved in neurodegenerative diseases, including:

• α-synuclein (mutant SNCA and SNCA-A53T), PARK2 – Parkinson's disease

• APP, Amyloid, Tau – Alzheimer's disease

• TDP-43 – ALS

These purified proteins were able to undergo liquid-liquid phase separation (LPS) and form condensates in vitro. ATP was able to dissolve many of these condensates in a concentration-dependent manner, although mutant or misfolded versions (e.g., SNCA-A53T) required higher ATP concentrations to dissolve.

When the aggregates were left to incubate for longer, some (notably SNCA-A53T) began to form protofibrils, elongated, fibril-like structures similar to those observed in real-life pathology. Here again, ATP could reverse this phenomenon, but with reduced efficiency.

Even under crowded conditions (mirrored by the addition of PEG), ATP retained some ability to prevent or dissolve aggregates, although the effect was less potent.

The team then studied neurons derived from Human induced pluripotent stem cells (hiPSCs) from patients with Parkinson's disease (PARK2 mutation) and ALS (TDP-43 mutation). These neurons exhibited reduced cytosolic fluidity, lower ATP levels, and greater protein aggregation than healthy controls.

This supports the idea that ATP deficiency and mitochondrial dysfunction contribute to the condensation of pathogenic proteins in human neurodegenerative diseases.

Implications for Drug Development

This research redefines our approach to therapeutic targets in neurodegenerative diseases. Instead of seeking to eliminate aggregates after their formation, we could:

• Target mitochondrial function to preserve ATP production at synapses.

• Use small molecules that mimic the hydrotropic effects of ATP to maintain cytoplasmic fluidity.

• Develop drugs that prevent the formation of LPS (lipoproteinases) of key disease proteins by improving their solubility.

ATP itself is not a drug molecule in the traditional sense, but these results open new avenues for small molecules capable of acting like ATP to maintain protein solubility or prevent aggregate formation at an early stage.

Conclusion

Neurodegenerative diseases are often viewed from a genetic or protein perspective, but this study provides a biophysical perspective: the physical state of the cytosol itself is crucial. If cells cannot maintain a fluid and soluble environment, primarily due to energy deficiency, aggregation may become inevitable.

This is not just about treating symptoms or even eliminating aggregates afterward. It is about preserving the cellular environment so that neurons can withstand stress and maintain their function. As the field continues to explore how biophysical properties such as viscosity, solubility, and phase separation interact with disease, the role of ATP may prove central, not only as a fuel, but also as a key regulator of neuronal health.

Researchers are currently very interested in finding biomarkers for the early detection of many neurodegenerative diseases. The market for these technologies is likely to be quite large. Detecting weakened cerebral rigidity before the onset of irreversible damage could pave the way for early intervention in Alzheimer's disease and related disorders. This could be achieved using a device that has now become relatively common: MRI. The hippocampus, a small, seahorse-shaped structure buried deep within the brain, is best known for its role in memory formation and learning. It is an exceptionally vulnerable structure, with perfusion deficits often observed in diseases related to learning and memory. However, a brain affected by Alzheimer's disease tends to exhibit at least moderate cortical atrophy, including in the precuneus and posterior cingulate gyrus. It should be noted that the posterior cingulate gyrus is adjacent to the hippocampus.

A recent study shows a relationship between blood flow and mechanical stiffness (an MRI concept) of the hippocampus. Researchers sought to understand how these physical properties interact in a healthy brain and what this might reveal about early brain changes in neurodegenerative diseases. The researchers used two advanced MRI techniques—magnetic resonance elastography (MRE) and arterial spin labeling (ASL).

Using these tools, the researchers measured: * Tissue stiffness (the resistance of an area to physical deformation) * Perfusion (blood flow at the tissue level)

Seventeen healthy adults were examined by the researchers at two different MRI intensities (3T and 7T), allowing for a cross-comparison between the two magnetic field strengths. They found that the hippocampus had the highest blood flow among the deep gray matter structures, followed closely by the caudate nucleus and putamen.

A strong positive correlation was observed between blood flow and stiffness in the hippocampus, but not in the caudate nucleus, although both regions are highly vascularized. This indicates that good brain health appears to be linked to good blood flow, manifested by the good stability (stiffness) of the tissue.

In a subgroup of ten subjects, it was found that higher blood flow resulted in larger tissue pulsations, suggesting that the dynamics of blood supply physically influence the hippocampus.

These results suggest a previously underestimated link between the physical characteristics of well-perfused brain tissue and its metabolic needs. This connection is not entirely surprising, as the macroscopic characteristics of tissue depend on the well-being of its constituent cells.

Although not mentioned in the article, one might wonder about the relationship between this mechanical property—rigidity—and beta-amyloid (Aβ), the signature protein implicated in Alzheimer's disease.

Beta-amyloid plaques begin to accumulate in the brain well before the onset of symptoms. These plaques can form: * Extracellularly: outside neurons, interfering with cell-to-cell communication and nutrient supply; * Intracellularly: inside neurons and other nerve cells, disrupting protein production.

Based on current knowledge, beta-amyloid likely appears before physical changes in tissues. It emerges early, sometimes decades before cognitive symptoms, triggering a cascade of tissue changes. Mechanical stiffness, as measured by MRE, is more likely a result of these changes than a cause.

Interestingly, numerous MRE studies have observed brain softening, particularly in the hippocampus and cortex, in Alzheimer's patients and those with mild cognitive impairment. This supports the perspective that stiffness decreases due to beta-amyloid pathology and its effects on brain tissue structure.

As fascinating as these findings are, it is important to acknowledge the limitations of the study, which suggest future research directions.

With only 17 participants, the study lacks statistical power, making it vulnerable to false positives or exaggerated effect sizes.

All subjects were young adults (22–35 years old) who were generally healthy, limiting the relevance of the results to aging populations or those at risk for Alzheimer's disease.

The sample did not include key groups, either clinical or high-risk individuals, such as APOE4 gene carriers or those with mild cognitive impairment (MCI).

The study was cross-sectional, capturing a single snapshot in time. We do not yet know how stiffness or perfusion might change over time or in response to pathology.

No cognitive data were collected; therefore, the relationship between hippocampal mechanics and actual memory performance remains unexplored.

There are considerable interpretation challenges: Stiffness, measured by magnetic resonance elastography (MRE), reflects a complex array of biological factors: neuronal density, inflammation, vascular integrity, etc. It is a valuable signal, but not biologically specific. Indeed, perfusion can vary depending on common physiological factors (e.g., hydration, stress).

Because the study did not include beta-amyloid PET scans or fluid biomarkers, the link between mechanical findings and Alzheimer's pathology remains hypothetical.

The analysis focused on the hippocampus and a few other deep gray matter structures. Key cortical regions involved in Alzheimer's disease (such as the entorhinal cortex or precuneus) were not examined.

The emerging link between perfusion and mechanics, and how this relationship deteriorates in the presence of beta-amyloid, could help us uncover subtle clues that precede cognitive decline. Ultimately, measuring something as simple as brain "firmness" could help us identify those at risk and determine when to act.

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.