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

We decided to use a new post format in 2025. It would propose aggregated short news instead of dedicating a post per publication.

Scientists who publish on neurodegenerative diseases often ignore the fact that neuron-type cells comprise only half of cells in the central nervous system. So it's fresh air to read a review on Schwann cells involvement in ALS. Yet conceptually associating Schwann cells and ALS is not common, ALS is a disease of the central nervous system (upper motor neurons in the brain and spine) while Schwann cells are located in the peripheral nervous system (lower motor neurons with their bodies from the spine and terminating in muscles). This does not mean there are no relations between the two types of cells, and it's a common view now that neurons are not independent, self-sufficient entities and that they are cared for by a large number of other cell types.

In a similar vein, Uruguayan scientists were interested in astrocytes' health. Astrocytes are the main kind of motor neuron supportive cells, if they ill behave, motor neurons die and it happens that they can switch between several behaviors. The scientists thought that metabolic reprogramming could occur in astrocytes following damage, and it significantly influences the progression of ALS pathology. Metabolic reprogramming, which involves changes in mitochondrial activity, within glial cells may provide valuable insights for developing innovative therapeutic approaches to mitigate neuronal damage.

It's no new but another study finds common molecular features between ALS and Parkinson's diseases. This reinforces the idea that sporadic neurodegenerative diseases are not clearly delineated diseases as in medical books. On the contrary, these medical classifications just describe symptoms belonging to a spectrum shared by many sporadic neurodegenerative diseases and aging.

Scientists in Taiwan studied the effects of isofraxidin on motor performance changes in chemically induced (lipopolysaccharide) Parkinson's disease in mice.

Isofraxidin is isolated from Eleutherococcus senticosus. Eleutherococcus senticosus, as many berries, is itself loaded with chemical components and provokes adverse effects in some people. What makes them study this plant is not disclosed. Still, as often it's probably because it is used in traditional medicine, and there were some interesting scientific studies on its effects on neurological disease. Isofraxidin pre-treatment significantly improved lipopolysaccharide-induced motor dysfunction, as evidenced by better performance in the rotarod, pole-climbing, and beam-walking tests. Does this prove anything? I am not sure, there are many articles that isofraxidin protects against lipopolysaccharide-induced diseases, the scientists most probably knew that when they planned their experiment.

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.

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.

Here is a summary of an interesting article on how ALS clinical trials could be improved.

Introduction

Clinical trials typically proceed sequentially, through early, middle, and late phases, often referred to as Phases 1, 2, and 3. Phase 2 trials are generally designed to gather information about the safety, tolerability, and dosing of an experimental treatment, and to determine whether the therapeutic agent shows sufficient promise to warrant further study in a large, randomized, controlled Phase 3 study. In the field of amyotrophic lateral sclerosis (ALS), approximately several dozen drugs showed “promise” in phase 2 but failed in phase 3.

Much has been written about the many potential reasons why so many trials have led to so few effective treatments and how we might learn from this experience.

Duration

Historically, phase 2 trials in ALS have varied in duration, but a 6-month placebo-controlled phase followed by an open-label extension (OLE) seems to have become a common standard, for example the Healey Platform trial. The phase 3 VALOR study of tofersen in SOD1 ALS provides useful information on the length of time needed for a clinical trial in ALS. In this 6-month trial, significant reductions in CSF SOD1 protein levels (a marker of target engagement) and plasma neurofilament light chain (NfL) (a marker of axonal degeneration rate) were observed at 12 weeks. A meaningful clinical benefit did not emerge until 12 months in an integrated analysis of double-blind and open-label extension (OLE) data.

The long latency is notable given that the SOD1 ASO targets a biological mechanism that causes disease. This study showed that clinical benefits may take time to be detectable. Longer treatment periods may be required for clinical effects to become apparent for therapies that target more downstream biological mechanisms.

The VALOR study also showed that a significant reduction in NfL was detected over a shorter time period than meaningful clinical effects, providing an early confidence signal, later reflected in the FDA’s groundbreaking recognition of NfL as a “reasonable surrogate marker predicting clinical benefit in ALS” in its decision to grant accelerated approval to tofersen. The problem of a long latency to show clinical benefit is not unique to the ALSFRS-R.

A short study duration therefore risks missing potential delayed clinical effects, increasing the likelihood of a false negative result. This risk can be partially mitigated by implementing an OLE (non-randomized extended drug availability), which allows time for delayed effects to become evident during the extension phase. A long OLE, however, cannot fully compensate for a short placebo-controlled period.

But the longer the OLE period, the more similar the groups become, diluting a potentially effective treatment effect and possibly increasing the risk of statistical error. The results of these studies are confounded by incomplete follow-up, differences between completers and non-completers, and selection bias in those eligible for treatment.

Outcome measures

The ALSFRS-R measures the patient's functional independence with a set of activities that reflect bulbar, fine motor, gross motor, and respiratory muscle function. It is a relatively subjective measure of patient functioning, and a slower rate of decline, or a higher score, correlates with longer survival. The heterogeneity in the rate of disease progression among patients, manifested by enormous variation in the rate of change in the ALSFRS-R, generally makes phase 2 trials that rely on the ALSFRS-R or similar subjective measures of insignificance. The use of the ALSFRS-R is preferable in phase 3 trials that aim to answer questions of clinical efficacy.

In addition, the selection of the ALSFRS-R as the primary outcome measure for a phase 2 trial suggests a desire to demonstrate clinical efficacy. An overreliance on the ALSFRS-R as the primary outcome measure may also lead investigators to seek drug approval based on a single phase 2 trial of small size, as was the case for AMX0035.

If the ALSFRS-R is to be used in phase 2 trials, these results need to be supported by biomarkers, such as baseline blood NfL and the ENCALS prediction score. Although much is not yet known about NfL, it is undoubtedly one of the most promising candidates to date to help select participants for a phase 3 study.

Missing Data

For both trial duration and primary endpoint selection, the question arises as to how best to deal with missing data, whether due to death, treatment interruption, or patient “evaporation.”

Strategies such as the last observation carried forward (LOCF) used in the masitinib phase 2/3 trials, the edaravone phase 3 trials, and the post-hoc analyses of the CENTAUR AMX0035 trial data are subject to bias given the assumption that the outcome is constant after treatment is stopped. This is difficult to justify for diseases such as ALS, which are progressive over time, particularly when instruments such as the ALSFRS-R are used to measure the outcome.

This problem was well illustrated in the FDA’s analysis of the CENTAUR trial data, where differential treatment of deaths with accompanying missing data showed a loss of statistical significance.

The Dangers of Statistical Manipulation

Multiplicity is an important consideration in the analysis of clinical trial data. It occurs when multiple significance tests are performed, for example, opportunistic and dishonest selection of different outcomes such as measuring outcomes at multiple time points, using multiple doses, or different study populations and subgroups. Performing a statistical test at p < 0.05 has a 5% chance of finding a false positive on one type of measurement, but increases to 40% for performing ten statistical tests.

Interpretation and communication

The lack of biological and mechanistic information on many failed drugs significantly limits the lessons that can be learned from them.

The absence of primary and secondary outcomes in the main study population, but the discovery of a “hit” in one (or more) exploratory outcomes in a subpopulation, even if pre-specified, especially when financial considerations are taken into account, leads to a real risk of over-optimistic interpretation and unbalanced (and dishonest) communication of results. The release of the results of several recent trials provides a useful recent example.

Not only is there a risk that the discovery of false positives will encourage large, necessarily costly, and time-consuming phase 3 trials, but also a demand from patients for expanded access programs (EAPs) based on the promise of new and hypothetical therapies. Moreover, the appropriation of significant funds by political personnel for such purposes, motivated by “advocacy” by patient organizations and manipulation of opinion via social media, can divert valuable research funds from more promising therapeutic candidates and clinical trials. There is also a risk that the ALS community will be given false hopes about the potential clinical benefits of these investigational compounds based on minimal data.

Although "post-hoc" analysis of phase 2 trial data can sometimes lead to the generation of new hypotheses that could be tested in a future study, a distinction must be made between phase 3 trials that are based on a hypothesis that was tested in phase 2 and a hypothesis that was generated on the basis of phase 2 data and is, therefore, more fragile because it did not benefit from preclinical testing.

The risks associated with predicting phase 3 trials on the results of post-hoc exploratory analyses of phase 2 data are well illustrated by the experience with dexpramipexole, reldesemtiv, and NurOwn. Overreliance on clinical endpoints, short duration of placebo-controlled follow-up, and multiplicity, combined with overly optimistic reporting, have jeopardized the entry criteria and predictive value of phase 2 results for phase 3 outcomes. This problem was also clearly illustrated by the major negative phase 3 results for edaravone, AMX0035, and tauroursodeoxycholic acid. Each of these studies was preceded by positive clinical results in small, short trials, which were the primary drivers of the decision to proceed to phase 3.

Basing decisions on biological and mechanistic considerations could significantly reduce the risks of initiating Phase 3. While there is a risk that go-ahead criteria based on biological markers, such as NfL or other mechanistic markers, may not guarantee translation to clinically meaningful Phase 3 results, this approach could help to select better which drugs to test.

Premature Approval of Drugs

Regulatory approval of drugs based on Phase 2 data carries risks and benefits. It is certainly permissible for a company or group to advocate for early access to a drug with a favorable safety and tolerability profile while a confirmatory Phase 3 trial is underway, but approval of a drug based on limited evidence should not be confused with proof of efficacy.

My conclusion One development that seems likely to the author of this post is that future ALS clinical trials will address a smaller (and more homogeneous) population. This will ultimately make it even more difficult to conduct trials when the population with ALS available for trials is already very small.

In recent days, there has been a lot of talk on social networks and mainstream press about a surgical procedure that is being carried out in a Shanghai hospital by a team led by Li Xia from the Faculty of Medicine of Shanghai Jiao Tong University, which could slow the progression of Alzheimer's disease, or even allow a temporary regression, in half of the participants.

Five weeks after the operation, clinical assessments revealed an improvement in cognitive function: the Mini-Mental Status Examination score went from 5 to 7, and the Clinical Dementia Rating-sum of boxes test score went from 10 to 8. The Geriatric Depression Scale score went from 9 to 0. The PET scan examination provided objective proof of this improvement.

This recent increase of interest is quite curious because a publication was made in June of this year by the team that innovated with this technique.

This study presents a new surgical procedure, neck shunting to unclog the cerebral lymphatic systems, aimed at improving the elimination of waste accumulated in the glymphatic system of the brain to manage Alzheimer's disease. The glymphatic system facilitates the removal of harmful proteins such as beta-amyloid and tau, the accumulation of which is linked to Alzheimer's disease.

The surgical procedure uses lymphatic-venous anastomosis (LVA) to decompress the cervical lymphatic trunk, allowing cerebrospinal fluid (CSF) and residual proteins to flow more efficiently from the brain into the venous system.

It is an extracranial procedure and therefore less invasive and potentially safer than intracranial methods. The surgical treatment, which involves four small incisions in the patient's neck, has been performed on at least 30 patients in two public hospitals in China. Other much larger numbers of patients treated are circulating on the Internet.

Early results indicate that the procedure holds promise as an innovative strategy for the prevention and treatment of Alzheimer's disease.

This surgical technique has not been considered for the treatment of Alzheimer's disease, or even the brain in general, but has been used for some time for other diseases such as lymphedema.

The field of lymphedema surgery has seen enormous progress over the years and has been associated with the rapid growth of super microsurgery techniques. A lymphovenous bypass or lymphaticovenular anastomosis requires the identification of residual lymphatic channels and the creation of an anastomosis on a recipient venule, thus allowing the flow of lymphatic fluid and the improvement of a patient's lymphedema.

A technique similar to that of Chinese doctors has long been used in the context of hydrocephalus. The cause of this disease is a blockage of cerebral-spinal fluids which leads to an accumulation of these fluids in the brain. Treatment for hydrocephalus then involves creating a way to drain the excess fluid from the brain.

In the long term, some hydrocephalus patients require a permanent cerebral shunt. This involves placing a ventricular catheter (a silastic tube) into the brain's ventricles to bypass the flow obstruction and drain the excess fluid into other body cavities, where it can be reabsorbed. Most shunts drain fluid into the peritoneal cavity (in the abdomen), but other sites include the right atrium (heart), pleural cavity, or gallbladder.

Hydrocephalus is known to cause Alzheimer's disease. Normal pressure hydrocephalus is common in elderly patients. Curiously, as Western physicians consider this hydrocephalus to be independent of Alzheimer's disease they are reluctant to operate on these patients because they believe the benefits are small.

The Chinese approach is the opposite. She believes that this accumulation of cerebrospinal fluid in Alzheimer's disease should be treated because, at the very least, it can temporarily relieve about two-thirds of patients. This pragmatic approach considers the patients and does not seek to demonstrate whether or not this accumulation causes Alzheimer's disease.

In a series of videos posted last month on social media, Cheng Chongjie, a doctor in Chongqing who adopted the technique following his colleagues, said the operation was effective in more than half of his patients.

"Two national medical centers have performed hundreds of LVA operations, and their results show that this procedure is effective in 60 to 80 percent of patients.

Spinal muscular atrophy (SMA) is a disease whose manifestations have some similarities with ALS, however, it has a well-identified genetic origin (SMN1 gene) and as a result, several drugs have been approved. These drugs improve the health of patients but have various drawbacks.

This rare disease causes the loss of motor neurons and progressive muscle atrophy. It is usually diagnosed in early childhood and, if left untreated, it often leads to death. It can also appear later in life and in this case the disease progresses more slowly.

The common feature is a progressive weakness of voluntary muscles, with the muscles of the arms, legs and airways being affected first. Associated problems can include poor head control, difficulty swallowing, scoliosis, and joint contractures. Although there is a large literature on the split hand phenomenon in ALS, knowledge remains limited for other motor neuron diseases, including SMA.

Early in ALS it is common for the thenar muscles (thumb muscles) to be affected and lose their usual volume, visually dividing the palm into two sections. This is oddly described as the split hand phenomenon or monkey hand phenomenon.

This phenomenon reflects the selective vulnerability of motor neurons characteristic of the disease. Conditions such as ALS, while also affecting motor neurons, tend to present with the classic split hand pattern, highlighting the differential pathophysiological mechanisms at play. However, the explanations for why these muscles are affected early in the disease are no clearer than in ALS. Furthermore, age-related atrophy can also present with the split hand phenomenon, complicating the diagnosis of ALS in older patients.

Muscle disuse is a common cause of muscle atrophy. The rate of muscle atrophy due to disuse is about 0.5% of total muscle mass per day. Older adults are most vulnerable to dramatic muscle loss with immobility. In SMA, as in ALS, loss of motor neuron function leads to muscle atrophy. A new study compared these losses in ALS and SMA.

To assess muscle loss in motor neuron diseases, the number of motor units is studied. A motor unit includes a motor neuron and all the skeletal muscle fibers innervated by the neuron's axon terminals, including the neuromuscular junctions between the neuron and the fibers. Groups of motor units often work together as a motor pool to coordinate the contractions of a single muscle.

The number of motor units per muscle can change due to aging, disease, or injury.

Motor unit number estimation (MUNE) is a technique that uses electromyography to estimate the number of motor units in a muscle.

Motor unit number estimation (MUNE) methods, such as MScanFit MUNE, provide accurate results. This study uses MScanFit MUNE to compare patterns of motor unit loss in SMA, ALS, and healthy controls. Key findings include:

Patients with SMA had more severe degeneration of the hypothenar muscles compared to the thenar muscles. The authors call this: The reverse split-hand phenomenon, in reference to the split-hand phenomenon in ALS. Patients with ALS had a traditional split-hand phenomenon, with more severe involvement of the thenar muscles.

Reinnervation in SMA: Evidence of compensatory nerve sprouting in the ADM muscle has been noted in SMA but not in ALS, highlighting distinct pathophysiological mechanisms in these two diseases.

For SMA, the APB muscle has emerged as an optimal biomarker to monitor disease progression and therapeutic response due to its resistance to degeneration.

Curiously, although the authors confirmed the correlation between MScanFit MUNE neurophysiological parameters and disease severity in SMA patients, they did not find convincing correlations between MUNE neurophysiological parameters and clinical variables in ALS patients, particularly with the ALSFRS-R scale. On this issue, although several studies have reported the correlation between MUNE values ​​and the ALSFRS-R scale, others have not confirmed it.

Limitations and future directions The small cohort of AMS in the study and the lack of longitudinal data (over a period of several years) limit the conclusions. Future research should examine whether the reverse split hand phenomenon is exclusive to SMA and clarify why certain hand muscles are more vulnerable.