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.

For once, we are going to talk about an article about Huntington's disease. Huntington's disease (sometimes called Huntington's chorea) is a rare hereditary disease that results in neurological degeneration causing significant motor, cognitive, and psychiatric disorders, and progressing to the loss of autonomy and then death. This disease occurs in adults aged between 35 and 50 on average. The progression of the disease follows a rhythm and a form that varies greatly from one individual to another.

The genetic abnormality that causes Huntington's disease is a greater than normal increase (20 times) of the repetition of three nucleotides (C, A, and G - called the CAG codon or triplet) within the HTT gene encoding the huntingtin protein. This blog focuses on three neurodegenerative diseases, ALS (sometimes called Charcot's disease or Lou Gehrig's disease), Parkinson's disease, or Alzheimer's disease. But in fact, it is only in books that these diseases are clearly categorized, in reality, we distinguish multiple subtypes to each of these categorizations and moreover, these diseases share characteristics both between themselves and with other neurodegenerative diseases.

A variant of ALS (C9orf72) closely resembles Huntington's disease in some aspects because it too is characterized by repeat expansions of a gene, C9orf72. Repeat expansions of the C9orf72 gene are responsible for about 40% of genetic ALS and 25% of genetic FTD.

The article we are discussing today focuses on the genetic and molecular mechanisms underlying Huntington's disease (HD), with a particular emphasis on the dynamics of CAG repeat expansions in the huntingtin (HTT) gene.

It explores the implications for the pathogenesis and therapeutics of HD. Although ALS is not cited by the authors, this paper has implications for that disease as well as for about 30 others.

An expansion of CAG triplet causes Huntington's disease repeats in the HTT gene. Normal alleles have 15 to 30 CAGs; disease-causing alleles have 36 or more. Longer CAG repeats correlate with earlier onset.

Scientists identified the progression of CAG repeat expansion with age by analyzing somatic mosaicism, or the variability in CAG repeat lengths between different cells within an individual. This variability increases over time, and the progression of CAG repeat length has been linked to cell-specific processes that cause expansions as individuals age.

The authors found that HTT alleles are not inherently toxic, but become harmful after somatic expansion exceeds approximately 150 repeats. This toxicity results in asynchronous and rapid neuronal decline, challenging the understanding of Huntington’s disease as a slowly progressive disease. They measured somatic repeat expansion over time in individual neurons from donors of different ages. They found that early-phase expansions (e.g., from 40 to 80 CAG repeats) were slow and stochastic, taking decades, while later expansions (e.g., from 80 to 150 repeats) occurred more rapidly. They then analyzed genetic markers and DNA repair mechanisms associated with repeat instability, such as those involving DNA mismatch repair (MMR) proteins (e.g., MSH3, PMS1). Variants in these genes have been shown to influence the rate of somatic instability. The progression of CAG repeat expansion is driven by errors in DNA replication, repair, and maintenance, particularly in neurons. Key mechanisms include:

Striatal projection neurons, the cells most affected by Huntington’s disease, exhibit higher levels of somatic instability than other cell types. This may be due to their unique transcriptional and metabolic profiles, which make them more susceptible to DNA damage and inefficient repair.

Expansion dynamics have been categorized into phases: - Phase A (36–80 repeats): Slow and stochastic over decades. - Phase B (80–150 repeats): Faster and more predictable. - Phase C (>150 repeats): Gene expression changes begin, leading to cellular dysfunction. Toxicity threshold: Neurons derepress other genes (e.g., CDKN2A/B) and eventually die.

These findings highlight how somatic mosaicism and age-related repeat expansions are central to the pathogenesis of Huntington’s disease and provide a framework for understanding similar processes in other repeat expansion disorders.

The somatic expansion mechanism may extend to other repeat expansion disorders, such as myotonic dystrophy or some forms of spinocerebellar ataxia.

The C9orf72 variant in ALS involves a hexanucleotide repeat expansion (GGGGCC) in a noncoding gene region. Although distinct from the CAG repeats in the Huntington’s disease coding region, there are notable parallels. As in Huntington’s disease, somatic instability of the repeat expansion has been observed in ALS C9orf72. The degree of mosaicism may influence disease onset and progression. C9orf72 expansions lead to toxic RNA foci and dipeptide repeat (DPR) proteins, leading to neuronal dysfunction and death. This reflects Huntington’s disease idea that toxicity only occurs after substantial repeat expansion. In ALS, motor neurons are selectively vulnerable. As in Huntington’s disease, the specific cell types affected may result from unique somatic instability dynamics.

Therapeutic potential: This work in Huntington’s disease suggests that modulation of DNA repair pathways (e.g., MSH3) may stabilize nucleotide repeats, thereby delaying toxicity.

It's a bit sad that scientists studying FTD think of themself as "dementia scientists" while scientists studying ALS or Parkinson's disease think they belong to a motor disorders category and motor neurons specialists for ALS scientists, while many neurodegenerative diseases share a lot of molecular and physiologic characteristics. At least these cases are often those of aged people and they involve mislocated and misfolded protein aggregates.

So many scientists from the Memory and Aging Center at the University of California, were motivated to study the impact of age on neurodegenerative diseases:

• They tell that age is the biggest risk factor for dementia, which is a way to present aging as a cause of neurodegenerative diseases, not simply a comorbidity.
• Most dementia cases (>75%) involve multiple types of brain pathologies, which implies again that those pathologies are not diseases in the same sense as communicable diseases where usually there is a single pathogen and removing this pathogen more or less (not always) restore health.
• Previous animal experiments showed that exchanging blood between young and old animals could affect brain aging (called "heterochronic blood experiments"). This is a controversial topic as some ultra-rich people already buy young blood of unclear origin. Identifying the detrimental substances and those that are beneficial would help human society as a whole.
• While individual blood factors had been identified in animal studies, their relevance to human disease wasn't well understood

This study involved the direct examination of persons in two cohorts: A longitudinal study of people with genetic frontotemporal dementia (FTD) and healthy controls. A cross-sectional study of people with sporadic Alzheimer's disease and controls.

• Discovery Cohort (ALLFTD Study): 119 people with FTD genetic mutations (37 MAPT, 33 GRN, 49 C9orf72) 78 healthy controls without mutations This was a longitudinal study (participants were followed over time) Participants had on average 3 annual evaluations (ranging from 1-7 visits) About half (52) of the mutation carriers were asymptomatic at the beginning of the study.

• Replication Cohort (Stanford ADRC): 35 people with Alzheimer's disease 56 clinically normal older adults This was a cross-sectional study (participants were NOT followed over time)

For both groups, the scientists collected: - Cerebrospinal fluid (CSF) through lumbar punctures - Comprehensive cognitive tests - Functional assessments (rated by caregivers) - Blood or CSF samples for NfL (a marker of neurodegeneration)

The scientists identified five specific proteins from previous animal studies: - Could cross the blood-brain barrier - Were measurable in human samples - Had shown effects on brain aging

These proteins included: Three "pro-aging" factors: CCL11, CCL2, B2M Two "pro-youthful" factors: CSF2 and BGLAP

They found that people with FTD mutations had lower levels of "rejuvenation proteins". Higher levels of these proteins were associated with slower disease progression The protective effect was seen across multiple cognitive domains. The effect was similar regardless of which specific FTD mutation people had

Similar protective associations were found in Alzheimer's disease. Higher levels of these proteins were associated with better cognitive performance and functional status. The effect was particularly strong for memory performance.

• CCL11 is a small cytokine belonging to the CC chemokine family. CCL11 selectively recruits eosinophils by inducing their chemotaxis, and therefore, is implicated in allergic responses. Increased CCL11 levels in blood plasma are associated with aging. Exposing young mice to CCL11 or the blood plasma of older mice decreases their neurogenesis and cognitive performance on behavioral tasks.
• CCL2, another cytokine, is implicated in pathogeneses of several diseases characterized by monocytes (a type of leukocyte or white blood cell) infiltrates, such as psoriasis, rheumatoid arthritis, and atherosclerosis
• B2M is a component of MHC class I molecules. MHC class I function is to display peptide fragments of proteins from within the cell to cytotoxic T cells. Systemic B2M accumulating in aging blood promotes age-related cognitive dysfunction and impaired neurogenesis. In addition, it promotes beta-amyloid aggregation and neurotoxicity in models of Alzheimer’s disease.
• CSF2 is a monomeric glycoprotein secreted by macrophages, T cells, mast cells, natural killer cells, endothelial cells, and fibroblasts, that functions as a cytokine.
• Osteocalcin, also known as (BGLAP), is a protein hormone found in bone. Numerous recent studies have revealed bidirectional crosstalk between the brain (and Alzheimer's disease) and bone health.

The publication does not mechanistically explain these "pro-aging" and "pro-youthful" factors. It may suggest that it pays to have a low inflammation level and to be physically active. The results appear relatively reliable because the scientists found similar effects in two different types of dementia. The effects were seen across multiple measures (cognitive, functional, and biological markers).

This research could impact drug development in several ways: - It suggests targeting multiple proteins simultaneously might be more effective than single-target approaches - It identifies specific proteins that could be therapeutic targets - It demonstrates these effects in humans, making it more likely to translate into effective treatments - The proteins are measurable in the blood, which could make treatment monitoring easier and safer than the very intrusive CSF sampling.

While not directly studied, this research could be relevant to ALS because ALS shares some biological mechanisms with FTD (they're often considered part of the same disease spectrum).

The research suggests a new paradigm for treating neurodegenerative diseases by targeting multiple age-related factors simultaneously, rather than focusing on single disease-specific pathologies. This could be particularly relevant for diseases like ALS where multiple mechanisms contribute to disease progression.

Preclinical studies are performed on a number of organisms, which scientists call "animal models of the disease." This concept is very vague and can involve everything from immortalized cancer cells to nematodes or fish. The most serious work is done on several standardized and commercial mouse models. This makes it possible in theory to compare work between laboratories, although this remains difficult in practice. However, commercial mouse models of disease are expensive and are almost useless for diseases like ALS, because the nervous system of mice is very different from the human nervous system. However, in preclinical studies, scientists look for clues that a drug might be useful, but it is not yet possible to prove that a drug will be effective in humans. One of the best things they can do at this stage is to show that a drug has a positive effect on several unrelated commercial animal models. The endoplasmic reticulum (ER) is an important organelle in cells that is involved in protein conformation. This step occurs after protein synthesis by ribosomes and after conformation, the new protein will be sent to its final destination by the Golgi apparatus. Protein conformation requires energy, so when disease occurs, the ER may not be able to properly conform the new proteins.

The accumulation of unfolded proteins leads to ER stress, followed by an adaptive response via activation of the unfolded protein response (UPR). Since folded proteins require energy, the unfolded protein response significantly slows down the production of new proteins. This is a way to cope with temporary stressful events, but it is not sustainable, as a cell that does not produce proteins is in a kind of stasis and will die quickly. Indeed, prolonged cellular stress activates apoptosis signaling leading to cell death.

Several studies have shown that impaired endoplasmic reticulum (ER) proteostasis is a pathogenic feature of ALS/FTD. Several drugs targeting the UPR in ALS have been proposed (GSK2606414, ISRIB, Guanabenz, Sephin1, Trazodone, KIRA), but none seem to be effective in ALS at this point.

There are different strategies, one is to stop the prolonged deleterious UPR in the hope that somehow the stressor has disappeared and the cell is healthy again. Another, on the contrary, tries to force an unfolded protein response state on all cells in the hope that the cell will be able to clear the backlog of accumulated misfolded proteins. However, the involvement of the UPR and the mechanisms by which ER stress contributes to pathogenesis are not entirely clear and can have contrasting or even opposing effects. Contributing to this complexity is that the UPR is actually several mechanisms.

The transcription factor XBP1s has several roles, one of them being that of regulator of the unfolded protein response. In a new publication, scientists provide evidence of suboptimal activation of the UPR in mouse models of ALS/FTD under experimental ER stress.

They designed a genetic therapy so that nervous system cells in ALS/FTD mouse models express the active form of XBP1 (XBP1s). XBP1s expression improved motor performance and extended lifespan in SOD1 mutant mice, associated with reduced protein aggregation.

It is important to note that AAV-XBP1 administration also attenuated disease progression in mouse models of TDP-43 and C9orf72 pathogenesis. As noted at the beginning of this text, most preclinical work in a single animal model is a bit suspect, especially when the animal model is not standardized but performed by administering a chemical that affects the nervous system.

ALS SOD1 disease is probably very different from TDP-43 and C9orf72 diseases. As SOD1 is an anti-oxidant, a mutated SOD1 protein probably protect less neurons from metabolism by-products. TDP-43 protein has many roles but one is to repair DNA in pluripotent stem cell-derived motor neurons. Most ALS patients have misfolded, aggregated fragments of TDP-43 in cell's cytosol which is weird as normally TDP-43 should be in cell's nucleus where it could repair DNA. C9orf72 is different again, in this disease the cellular ribosomes produce the wrong proteins from correct RNA, a so-called frameshift effect.

It is not clear how an XBP1s drug could benefit these three variants of ALS. However, if this is confirmed in humans, it would be good news because today, only one drug benefits ALS patients (Tofersen), but it benefits less than 1% of them. Having a drug that would benefit most patients would be extraordinary.

But we are not there yet, a first step would be to understand the mechanism of action of this drug in ALS

It's 2025, Happy New Year!

Since late 2018 this blog has comments on research on ALS, Parkinson's, and Alzheimer's diseases. My goal initially was to write a post every two days, with newly published research on Pubmed as input. This goal was impossible to reach because there is an immense activity but little valuable research on these topics.

Most articles are produced with an optic where quality is not important as long it's obscured by jargon. As publishing an article cost anywhere between $1000 and $4000, this is an incredible waste of money. Another aspect is that the articles about drugs' effects on immortalized cells, worms, or fishes, do not provide any hint that a drug might be useful for humans.

At a minimum such research to apply to humans must use animal models that are as large as humans and with a similar central nervous system. Only upper primates fit these requirements and the cost and ethics aspects are that kind of research almost never happen.

So I will try for a few months to write posts that briefly talk about publications that I feel have some merit.

Let's go!

• A medical case report recounts that an ALS patient was given a GLP1-inhibitor (a category of drugs including Ozempic). Indeed the "case" deteriorated quickly. Sometimes patients make bad encounters in white coats.

• Some good news came for ALS patients with a familial form. More than half of familial ALS cases are due to a nasty dysfunction in the mechanism that produces proteins. This study explores a novel approach to combat C9ORF72-linked amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) using a CRISPR-Cas13-based RNA-targeting system. C9ORF72 mutations contribute to those diseases through three mechanisms: loss of C9ORF72 protein function, RNA toxicity from repeat-containing transcripts, and toxicity from dipeptide repeat (DPR) proteins. Current therapies, such as antisense oligonucleotides (ASOs) and miRNAs, face limitations, including transient effects and suboptimal targeting. The researchers developed RfxCas13d, a compact CRISPR-Cas13 variant, to target and degrade the pathogenic G4C2 repeat RNA in cellular and animal models. When delivered to the brain of a transgenic rodent model, this Cas13-based platform curbed the expression of the G4C2 repeats without affecting normal C9ORF72 levels.

• Another study demonstrates the potential of a CRISPR-CasRx-based approach for targeting both sense and antisense C9orf72 repeat transcripts. ASOs for the G4C2 repeat RNA developed by Wave Life Sciences and Ionis Pharmaceuticals and Biogen failed to show a benefit in human trials. Though the exact reason for this remains unknown, these ASOs targeted only the G4C2 (sense) repeat RNA and were thus presumed to not affect the G2C4 (antisense) transcript. This last study has the same overall goal as the first one but it targets both sense and antisense C9orf72 repeat transcripts. Yet the First study's RfxCas13d is a multiplexable enzyme. Thus, it has also the capacity to simultaneously target both the G4C2 (sense) and G2C4 (antisense) repeat RNAs from a single vector. Indeed there is a long road to transform these findings into efficient drugs, but it's a step in the right direction.

• In younger, healthy cells, the "normal" metabolic process is typically oxidative phosphorylation (OXPHOS), which occurs in the mitochondria. Healthy cells maintain a slightly alkaline intracellular pH (around 7.2 in the cytoplasm). However, during aging, cells may shift towards glycolysis (a process common in senescent cells), where the cytoplasm, not mitochondria consumes glucose to produce ATP with lactic acid as a side product. As neurodegenerative diseases are, in most cases, diseases of aged people, one layperson would expect that the cell shift in metabolism from mitochondria to cytoplasm and subsequent acidification are of the utmost importance. Unfortunately, it is not, and as usual, when scientists have no idea about something, they tell that this shift in aging metabolism is due to a combination of multiple factors. Joyal Xavier and colleagues wanted to understand the mechanisms associated with TDP-43 aggregation. TDP-43 expressing cell lines were exposed to either an acidic environment, a neutral environment, or sodium arsenate. Asparaginyl endopeptidase (AEP) has been implicated in the misfolding and aggregation of TDP-43 and other proteins implicated in neurodegenerative diseases because it is an enzyme that can cleave proteins in toxic fragments. They have observed the localization of TDP-43 in the mitochondria under normal pH conditions. However, under acidic conditions and after sodium arsenate exposure, they observed an increase in TDP43 levels in the mitochondria and nucleus. Alternatively, they observed a decrease in TDP43 in the mitochondria and nucleus following treatment with an asparaginyl endopeptidase inhibitor. My conclusion is that not much has been learned, yet it is a neglected research avenue that has some potential.

Les personnes qui présentent des problèmes de santé sont exposées à une stigmatisation, consciente ou inconsciente. La stigmatisation peut être ressentie ou effective. Dans le cas de la SLA/maladie dite "de Charcot", il y a une profonde dissonance entre la personne qui en général conserve toutes ses facultés mentales, mais subit une évolution si rapide de la maladie qu'il est difficile de s'y adapter et par ailleurs les interlocuteurs qui voyant un corps amaigri, sans force, assimilent la difficulté à parler, la bave et la tête penchante à des facultés intellectuelles défaillantes. Par ailleurs nos sociétés présentent incorrectement la santé comme étant l’état naturel, et donc est toujours accusatrice envers les malades qui auraient donc dilapidé leur « capital santé ». On trouve cela aussi chez les malades du cancer à qui bizarrement les médecins intiment sérieusement de « se battre » contre leur cancer comme si c’était de leur faute s’ils étaient malades et qu’il fallait qu’ils se battent pour obtenir une forme de rédemption.

La stigmatisation des patients atteint de la sclérose latérale amyotrophique/maladie du motoneurone (SLA/MND) augmente leur retrait social et réduit leur qualité de vie ainsi que l’utilisation des technologies et appareils d’assistance qui est si importante pour leur relatif confort et leur survie à long terme.

Je me rappelle un malade qui se plaignait avec humour du personnel médical qui haussait le ton pour lui parler comme s'il était sourd, quand il ne l'ignorait tout simplement pas et s’adressait à son accompagnateur pour lui demander comment lui, le malade, allait.

D'autres malades signalaient qu'ils étaient ignorés dans les conversations car inaudibles, jusqu'à ce qu'ils achètent un système d'amplification de la parole.

Par ailleurs, avoir la tête inclinée, baver, amène des regards insistants et dérangeants des personnes rencontrées quand elles ne sont pas des familiers du malade.

L'étude faisant l'objet de ce post rend compte de l'influence d'une série de ces facteurs sur la stigmatisation auto-perçue rapportée, si ces influences restent importantes au fil du temps et comment, le cas échéant, la stigmatisation varie au fil du temps. Elle est dérivée de l'étude Trajectories of Outcomes in Neurological Conditions-ALS (TONiC-ALS) au Royaume-Uni.

Les données collectées entre 2013 et 2019 ont été utilisées pour cette analyse afin d'éviter l'influence éventuelle de la pandémie de Covid sur les comportements. Les participants ayant complété un questionnaire de base étaient éligibles pour un suivi avec des questionnaires répétés à au moins 4 mois d'intervalle, avec un intervalle de 11 mois entre le début et le premier suivi. Les chercheurs ont suivi les participants sur 30 mois.

Au total, 1059 personnes atteintes de SLA/MND ont contribué à cette analyse. Avec un âge moyen de 65 ans, la durée moyenne depuis le diagnostic était de deux ans. Les deux tiers des malades étaient des hommes. La plupart des patients étaient mariés ou vivaient avec leur partenaire. Plus de la moitié étaient à un stade avancé de leur maladie. Un quart d'entre eux avait une maladie caractérisée par début bulbaire.

Le questionnaire portait sur les sujets suivants.

• La capacité physique, la fatigue, l'essoufflement.
• Les symptômes évidents comme la spasticité, les spasmes musculaires. Les crampes, la tête tombante, la bave ;
• La stigmatisation ressentie et effective.

Près de la moitié des personnes interrogées ont indiqué avoir éprouvé un essoufflement plus ou moins important. La plupart des participants ont également évoqué une raideur musculaire et une fatigue intense.

Plus de 80% des personnes ont indiqué avoir subi une forme de stigmatisation liée à leur maladie. Elles se sont senties gênées par leurs limitations physiques et ont parfois eu l'impression que les autres les jugeaient. Cette stigmatisation était particulièrement marquée chez les femmes, les personnes plus jeunes et celles dont la maladie avait débuté au niveau bulbaire.

La stigmatisation touche une grande partie des personnes atteintes de SLA/MND. Plus de 80% des participants ont déclaré en avoir souffert à un certain degré. Les rires et pleurs incontrôlés, les spasmes musculaires ou les troubles de la parole augmentent le risque de stigmatisation. Les patients plus jeunes présentant un début bulbaire et sans partenaire sont plus vulnérables. À l'inverse, un âge plus avancé et le fait d'être en couple peuvent réduire cette stigmatisation.

De plus, l'estime de soi joue un rôle crucial. Plus l'estime de soi est faible, plus la stigmatisation est élevée.

Durant les 30 mois de l'étude il a été observé que le niveau de stigmatisation pouvait varier au fil du temps.

Les chercheurs ont identifié trois groupes de personnes :

• Un groupe important (plus de 70%) : Ces personnes ont un niveau de stigmatisation élevé dès le début de l'étude et celui-ci a tendance à augmenter avec le temps. Elles ont généralement une moins bonne santé et une estime de soi plus faible.
• Les deux autres groupes : Ces personnes ont soit un niveau de stigmatisation faible et stable, soit un niveau qui évolue différemment.

L’étude comporte évidemment des limites. L’étude actuelle se limite au Royaume-Uni et concerne principalement des patients caucasiens.

En conclusion, la stigmatisation ressentie et effective est fréquemment perçue par les personnes atteintes de SLA/MND. Les personnes plus jeunes et celles présentant un début bulbaire, ainsi que celles présentant une labilité émotionnelle, de la fatigue et de la spasticité ou des stades cliniques plus avancés sont plus à risque de cette stigmatisation.

Introduction This is a well-done study of ALS patients, but it will not provide new information to specialists in the field.

The survival time of patients after a diagnosis of ALS is variable, although death generally occurs about 2 to 5 years after the onset of symptoms, with a mean survival of 20 to 50 months, and only about 5 to 10% of those affected survive 10 years or more. In addition, earlier age at symptom onset and diagnosis, spinal onset, higher initial ALSFRS-R score, or higher body mass index (BMI) have been associated with longer survival. In contrast, older age, bulbar onset, cognitive impairment or depression, and poorer nutritional status are associated with shorter survival.

Although several authors have described the clinical and epidemiological characteristics and factors related to the survival of patients with ALS, few studies have been conducted in the Spanish population. This study is therefore one of the few to evaluate the epidemiological and clinical characteristics and prognostic factors of ALS in Spain, and it provides similar results to previous population studies.

A population-based registry data analysis over a long study period provides up-to-date, representative, and complete information on patients with ALS, which is useful for planning the necessary resources for affected individuals and their families. Therefore, this study aimed to determine the incidence and prevalence of patients with ALS, as well as their main characteristics, and to analyze the factors associated with the evolution and survival of these individuals using information from the Rare Disease Registry in the Region of Murcia (RM), located in the southeast of Spain.

Study population

An observational study was conducted on patients with a confirmed or probable diagnosis of ALS according to the El Escorial criteria and registered in the Rare Disease Information System (SIER) of the RM from January 2008 to December 2021. The data collected from each patient included the following:

• Data include gender, country of birth, date of birth, death of the patient (yes/no) and date of death.
• Family history of the disease, i.e. those including a family member with a diagnosis of ALS. The associated genetic mutation was collected in patients who underwent genetic study.
• Characteristics included year of diagnosis, date of symptom onset, and initial disease presentation (bulbar, spinal, bulbospinal, or respiratory). Time from symptom onset to diagnosis (years) and from symptom onset to death (years) were also recorded.
• Initial clinical manifestations collected were: muscle weakness (cervical, upper limbs, lower limbs, or both), dysarthria, dysphagia, dyspnea, gait alteration and clumsiness, muscle atrophy (upper limbs, lower limbs, or all limbs), muscle cramps, loss of dexterity, fasciculations (lingual, upper limbs, lower limbs, mixed), spasticity, and emotional lability (Citation35).
• Information on riluzole treatment, family support, palliative care, and the patient's last wishes were obtained. Finally, data were collected on the recognition of disability and/or dependency.

Statistical analysis

Demographic, genetic, and clinical characteristics of people with ALS were summarized using descriptive statistics. In addition, different hypothesis contrast tests were used depending on the type of variables and the normality of their data distribution. Survival was calculated from the age of symptom onset to the age of death (end event) or until December 31, 2021, or until loss to follow-up.

Results

781 cases of ALS were recorded in the SIER, 508 were of which were classified as confirmed or probable cases, including 374 incidents from 2008 to 2021.

The standardized incidence rate (SIR) was approximately 2/100,000 person-years. It was higher in men than in women. An increase in incidence was observed with age, with a maximum of data between 75 and 84 years, followed by an overall decrease. However, in men, the highest incidence was in the 65-74 age group. Throughout the study, incidence rates ranged from 2/100,000 person-years in 2008 to 2.77/100,000 in 2021), with the latter year being the year with the highest incidence recorded.

There was a family history of the disease in 28 patients (7.5%). Among patients for whom information on the causative genetic mutation was available, 55.5% were associated with the C9orf72 gene, 22.2% with the FUS gene, and the remaining 22.2% with other genes.

According to the site of onset, spinal ALS was predominant in half of the patients, followed by bulbar ALS in one-third of the cases. Dual pathologies (bulbar and spinal) were considerably less frequent and cases where the onset of the disease was characterized by respiratory symptoms were rare. In the remaining 8.3% of the cases, this information was not available.

The more frequent site of onset in men was spinal ALS, while in women it was bulbar ALS but less clearly. In analyses by age group, spinal onset predominated up to 74 years, after which bulbar onset had the highest incidence.

The mean time from symptom onset to diagnosis was less than 1 year, with no significant differences between the sexes. However, when analyzed by site of onset (bulbar or spinal), the diagnostic delay was slightly shorter for bulbar ALS.

Overall, the most common clinical manifestations at disease onset were muscle weakness (71.1%), followed by fasciculations (66.0%), muscle atrophy (61.2%), and gait alteration/clumsiness (53.0%). Patients with bulbar ALS had more dysarthria and dysphagia as their initial symptom (over 80% in both cases), while those classified as spinal ALS had mainly muscle weakness, atrophy, fasciculations, and gait alteration/clumsiness.

Interestingly, only 9 out of 10 patients were treated with riluzole, and more distressingly, less than half of the cases had their disability recognized. The average time from diagnosis of ALS to recognition of disability was one year, and the average time to dependency was one and a half years.

Half of the patients received palliative care, three-quarters of them had family support, and more than a third recorded their last wishes. Among these, most of them refused to receive palliative measures but accepted final sedation, while 15% of them on the contrary accepted any measure that could have prolonged their life.

During the study period, 297 people died (8 out of 10), half of them were men, and the average age at death was 70 years, without significant differences between genders.

The mean number of years between the onset of symptoms and death was 2.6 and the median was 2 years (there were more early deaths than deaths after these two years). 85% of patients survived more than 1 year after diagnosis, 12% more than 5 years, and 1% more than 10 years, which is lower than the 5 to 10% reported by other authors.