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ALS is a brutal neurodegenerative disease (PC: York Rehab Clinic) ALS is a brutal neurodegenerative disease impacting the complete mobility of the affected individuals with extreme muscle weakness and loss of voluntary movement. The onset of ALS is a gradual process, and manifests as different stages of ALS based on the severity of the disease and the course of treatment. Let’s understand the different stages of ALS in this article and how it impacts the people living with ALS in this article.   Introduction to ALS What does ALS stand for? ALS, a progressive degenerative disease stands for Amyotrophic Lateral Sclerosis, severely impacting the mobility and muscle control, deteriorating the ability for elementary activities such as eating, speaking, and breathing. Decoding “Amyotrophic Lateral Sclerosis” further, Amyotrophic comes from the Greek language, with ‘myo’ referring to muscles, ‘trophic’ meaning nourishment and ‘A’ meaning without, thereby implying ‘no muscle nourishment’. The word ‘Lateral’ refers to the specific part of the spinal cord containing particular nerve cells responsible for signalling and muscle control. With degeneration of this region, the outcome is scarring or hardening of the specific region, known as ‘Sclerosis’.   Understanding the ALS disease ALS, also known as Lou Gehrig’s disease, has a gradual onset, with the early signs and symptoms mimicking several other neurodegenerative diseases or issues with the muscle, or spine, causing early ALS diagnosis difficult. Generally, ALS diagnosis takes about 12 – 15 months to confirm considering the gap for recovery and process of eliminating other diseases. With the average life span from onset to progressing through different stages of ALS till death is about 3 – 5 years ( 1 ) . This emphasizes the importance of early ALS diagnosis to manage ALS treatment for better life expectancy. While determining the exact cause of ALS is a complicated process, it involves genetic mutations and unusual environmental factors leading to sporadic cases of ALS without a clear cause. While the mechanisms are not clear, the occurrence of abnormal protein levels and neuron damage are observed in the progression of ALS disease. The journey of every patient living with ALS is unique, and the pace of progression can vary for each based on the onset, genetic factors and initiation of treatment.   Summarizing different stages of ALS (PC: ALS News Today) Different stages of ALS ALS onset may present differently for each  affected individual, and the different stages of ALS progression will also change according to the age, genetics, sex and lifestyle in certain cases. ALS diagnosis is typically confirmed once muscle weakness progresses beyond the more subtle preliminary signs. Usually, the average life expectancy of ALS patients is 2 – 5 years after diagnosis. (   2  ) However, with treatment and personalized care tailored to the progression of the different stages of ALS, quality of life can be improved significantly. The different stages can be categorized as early stages, advanced stages and end stages. The early stages of ALS consist of muscle weakness and twitching. The disease progresses with respiratory and motor impairments in the advanced stages, and ultimately leading to complete loss of motor function and respiratory failure in the end stages. Awareness of the different stages of ALS helps caregivers better understand the condition of the person living with ALS (pALS) and support them with informed care choices. Let’s take a closer look at the different stages of ALS and get an overview on managing ALS disease better.   Stage 1: Early Muscle Weakness and Twitching The early stages of ALS have common symptoms indicating muscle weakness and twitching mimicking other diseases. It starts subtly impacting the functioning of arms and legs with difficulty in fine motor tasks such as buttoning shirts. Muscle twitching, cramping, and frequent tripping is also observed in the early stages of ALS. The people living with ALS can also experience muscle stiffness increasing the discomfort and impacting mobility. Some of them can also have minor difficulty swallowing or slurred speech for patients whose bulbar muscles are affected in the early stages of ALS. While recognizing these early signs as ALS diagnosis is challenging, early intervention with medication and physical therapy can delay the disease progression.   Stage 2: Progressive Muscle Weakness The second stage of ALS worsens the muscle weakness and the individual affected finds doing the daily tasks hard. The people living with ALS are struggling with movement, balance, coordination and simple tasks to upgrade their difficulty level. The worsening muscle atrophy and losing strength makes mundane muscle tasks such as walking, standing, controlling hand movement difficult, and individuals can experience frequent falls. The quality of life can be improved by using assisting devices and making it possible to adapt to the changes in mobility. The caregivers need to make care choices considering muscle weakness and atrophy, communication and respiratory issues and decline in physical function.   Stage 3: Intermediate Functional Impairment Progressing through different stages of ALS, the intermediate functional impairment involves significant challenges. With severe muscle weakness and atrophy, mobility is limited, making walking and standing challenging without support. Further, the swallowing and speaking problems have aggravated with increased risk of choking. The people living with ALS may also have weakened muscles causing difficulty in breathing, which leads to exhaustion and shortness of breath doing mundane activities. The quality of life can be enhanced with assistance devices paired with medicine and physical therapy for easy management of ALS.   Stage 4: Advanced Functional Decline This is one of the stages of ALS where the people living with ALS can have independence in mundane and routine activities with assistive devices only. This phase worsens the ability to communicate which can be resolved with using speaking aids. The affected person would require breathing support with aids to manage needs, ensure comfort and safety. The progression of ALS disease can vary from person-to-person based on genetic factors and the age at which the first signs and symptoms appear. When going through the advanced stages of ALS, the assisted devices for mobility, communication and breathing are essential.   Stage 5: Advanced Medical Care One of the advanced stages of ALS, stage 5 requires definite attention of caregivers with advanced medical care for the person living with ALS to function. Beyond the ALS medication and physical therapy, this phase requires caregivers to render emotional support and psychological tapping to motivate the people living with ALS to fight through the brutal challenges of the disease and continue receiving medical care. At this stage, the patient might require feeding tubes to cope with complete chewing impairments.   Stage 6: Severe Impairment The sixth stage is the intermediate phase from advanced to end stages of ALS with severe impairment. The people living with ALS can barely move, with extremely minimal voluntary control, impacting the competence for most functions of the body. Eventually, this leads to muscle paralysis and severe breathing issues. This stage could last from a few weeks to months, based on the specific progression of the disease. The respiratory functioning is critically damaged, swallowing is also impossible, leading to complete dependence on feeding tubes. The people living with ALS might have cognitive function, but complete physical dependence on the caregivers with 24*7 intervention. The objective at this stage is to mentally support the affected patients and improve their quality of life.   Stage 7: End-Stage ALS The end stage of ALS remarks complete loss of mobility, leading to muscle paralysis and respiratory failure. The people living with ALS can only control eye movements for communication. The patients are completely dependent on life-sustaining support and interventions such as ventilators and feeding tubes. All the stages of ALS lead to the end-stage with life expectancy for ALS patients limited to a few months till complete respiratory failure causes death.   Conclusion ALS is a brutal neurodegenerative disease impacting the mobility of the affected people, taking away complete voluntary control with the declining progression of the disease. When ALS diagnosis is confirmed, it is crucial to understand the stages of the disease with the current condition for personalized care options. The early stages of ALS cause muscle weakness and twitching. The condition worsens in the advanced stages of ALS with respiratory and motor impairments, eventually leading to complete loss of voluntary functions, respiratory failure and muscle paralysis by the end-stage. The different stages of ALS require personalized intervention based on the gradual decline in health and response to treatment – physical therapy and ALS drugs. As ALS disease progresses further, assisted devices are required for communication, feeding, mobility and ultimately to support respiratory function.

Leveraging Tofersen for SOD1 ALS treatment INTRODUCTION: The advancements in  ALS treatment particularly for genetic forms like SOD1 ALS have opened new avenues for disease stabilization and functional recovery. Tofersen, an antisense oligonucleotide therapy, is at the forefront of this transformation, showing promise in reducing neurofilament levels, slowing disease progression, and improving certain patient outcomes. Alongside pharmaceutical interventions, neuromuscular rehabilitation is emerging as a vital component of the care paradigm, potentially reshaping how we approach recovery in ALS. Through expert insights from leading clinicians at institutions like WashU, this article explores key questions around diagnostics, functional assessments, and whether therapies like Tofersen could revolutionize ALS treatment—not just for SOD1 but potentially for broader ALS populations as well. FEATURED QUESTIONS:  Are neurofilament levels routinely measured by neurologists in ALS clinics in the U.S., and should neurofilament testing be considered a standard part of ALS patient evaluation?  It’s not a standard of care at the moment. And, here in the neuromuscular lab under Dr. Robert Bucelli, we have been measuring serum neurofilament since 2021, and most of the attendings here have adopted it as a relatively good biomarker to use when patients come in for evaluation of ALS. There are some caveats, as it may not be elevated in all patients. And, so, it’s not a single test to be able to confirm ALS diagnosis. It needs to be taken in the context of the clinical exam, the clinical history of progression of weakness, excluding other diagnoses that can mimic ALS. I strongly advocate for testing for all my patients in the initial stages, as well during long-term follow-up as well.  Has there been any instance of a person with genetic forms of ALS, such as SOD1 or FUS mutations, who lost the ability to speak and then regained speech following successful treatment?  Not that I am aware of. None of our patients have significant speech changes. Some of the research studies conducted by EverythingALS highlight speech changes and I think some of the recent trials are including software or applications to do that. We haven’t heard of any patient living with ALS with an SOD1 gene receiving Tofersen with chewing or swallowing issues. Some with respiratory issues include the need  to be on non-invasive ventilation. This might not be a fair comparison, considering representation of the whole ALS population, but following the data, there are definite possibilities to improve functioning in patients living with ALS undergoing disease stabilization therapy.  What do you make of the recent data published from various Italian EAPs? While I am not familiar with this publication, there are several studies cited in our research papers that showed similar results of Tofersen in the clinical setting or real-world setting, which depicts significant reduction in the neurofilament levels, maintenance of function, with some patients potentially having continued progression at a slower rate, and some patients showing improvement. Nearly 20-25% of the patients show some degree of improvement. It is to be noted that all of our patients living with ALS have elevated inflammatory attributes (factors) in the spinal fluid. There is no clinical correlation for this, and there are no patients who have experienced severe side effects due to Tofersen. These include increased intracranial pressure, increase in the spinal fluid, radiculitis, or inflammation of the nerves or spinal cord.  When standardized (e.g., converted to Z-scores), do functional outcome measures like the ALSFRS-R and FIM show consistent effect sizes post-Tofersen treatment?  Yes. The sample size of participants was very small, estimated to be around 7. We lacked longitudinal data for one of the participants to report on. The studies were oriented to descriptive statistics over inferential statistics, implying that we are trying to present the data collected over making comparisons. So, FIM, as in functional independence motor score, has been leveraged in several ALS research studies. There is a correlation between FIM motor score and a decline in the ALSFRS overtime with disease progression. It has not been used to monitor for functional improvement in patients living with ALS undergoing disease stabilizing therapies. We are the first paper to present the possibility of using this as a measure in comparison to ALSFRS, and it seems to be more sensitive to patient improvement and functional independence than ALSFRS. The focus as a team is to conduct a larger study with funding.  I have SOD1 but no one in my family has ALS disease. It is interesting that 6 out of 7 in the study similarly had no family member with ALS. Can you explain why, since I was told by the genetic counselor that the mutation is dominant?  Yes, it is interesting that 6 out of 7 had no clear family history of ALS. The majority of the mutations in SOD1 are dominantly inherited. At some point, without a family history, it’s possible for an individual to be the first to develop the mutation. So, there is not much clarity as to why an individual would develop that specific mutation in SOD1. However, we are going to continue to learn more about genetics. The study we conducted highlights the potential of differential response, based on the type of genetic mutation. This highlights a need within ALS research to better identify which patients may or may not benefit from Tofersen, or may not need additional treatment options to fully stabilize their disease.  Given increased cardiovascular risk in ALS disease, how does your program take these risks into account, specifically the maximum heart rate to determine the exercise targets.  Typically, our programs start relatively conservatively and we use low-to-moderate intensity. Presently, the neuromuscular literature indicates between 50 – 70% of the heart rate reserve. Heart rate reserve is a calculation which is based on the individual’s resting heart rate and age, which generates an individualized baseline. We will start by using 50-70% of that maximum and also use the rate of perceived exertion. For individuals with higher respiratory involvement, we have a breathlessness scale for self-monitoring. Furthermore, there are continuous heart rate and oxygen monitors when capacity is measured. During the 10m walk and the 30 seconds sit-to-stand test, we are also monitoring physiologic response and administering a dose based on the tolerance levels, but in general, we have been starting folks conservatively in the 50-70% range. However,individuals have also progressed to the moderate-vigorous range (70-85%). Generally, we use the cardio or heart rate response as a gauge of neuroplasticity and neuromuscular control.  In the context of ALS clinical assessments which you shared, when performing the 10-Meter Walk Test (10mWT), is the test typically conducted with the participant wearing their orthotic devices, or without them?  Yeah, we have done a measure for both. It depends on the individual, and we try to make it a day-to-day activity in their real life. For the patients living with ALS wearing their orthotic devices, I highly encourage them and mention the same in prescriptions for improved safety and control. All the measures are a great gauge, but they are typically capacity measures. It helps us get a baseline, get a measure, help prescribe the activity, discuss safety recommendations such as orthotics, wear, and use. But, one area that can be specifically improved is getting performance measures and tracking activity outside of therapy to understand how the rehab is influencing those individuals outside of the measures we are seeing right in front of us.  What are the broader implications for other forms of ALS outside of SOD1? What is the perspective concerning drug development care paradigms as well as rehabilitation programs?  It’s kind of limited right now. There’s a minimal amount of information on how to do neuron muscle rehab for a patient with ALS whose disease has stabilized. The goal is for multiple drugs or treatments to be made available to help any patient with any form of ALS to reach disease stabilization. At that point, the question is how can we get the function back? I think it’s going to take a lot more than only treatment for patients to have recovery and live with ALS. And, so, we are building the foundational knowledge of what that would look like. It’s a pretty decent step in the right direction that patients on a disease stabilizing treatment like Tofersen right now can participate in neuromuscular rehab for extended periods of time and do it safely. We can progress them, whether that is through resistance exercise with different weights, or increasing their walking program using technology available to help mobility. There is a definite need for extensive research on this subject and hopefully when substantial treatment is available, we can implement the knowledge for patients living with ALS rather than waiting.  When we look at the biggest body of evidence right now within neuromuscular rehab, it’s typically within stroke rehab. We are observing that, with the right dosage of therapy, when patients are in a medically stable position, high intensity rehab can be greatly effective in improving motor function, even years after the initial stroke. This model gives us hope that we can change the current model from low-to-moderate, shifting focus from maintenance in ALS disease management to neuroplasticity and improvement of function.  During the sit-to-stand test in your protocols, is the use of arms to assist in pushing oneself up from the chair allowed or expected?  The standardized assessment is without upper arm assistance. However, there are some patients living with ALS who are unable to perform that, so we allow them to use arm assistance because that is expected as a means to get out of the chair for long-term, based on their current status.  Are the patients in your study just those who go to WashU’s clinic or do you get data from other hospitals (eg. Mass General Hospital)?  Presently, it is an internal study of patients only at WashU who recurrently follow-up in our clinic and are receiving the Tofersen dosing here. It’s unfunded right now. The ALS center and a bunch of other individuals who are highly devoted to seeing patients improve are actively working on the study. Our work with the patients is very goal-oriented and is focused on their routine activities, and we would like to expand this approach. We have submitted some grants to that end and we are still waiting for funding opportunities in the near future.  What was the time between first and second measurements of function?  With reference to the FIM score, we have been keeping all the functional measures for those we have been taking out on a monthly basis. The other ones shown in the slides with the graph consisted of the most recent Tofersen dose, and varied for all the patients over time. For instance, one patient living with ALS was on Tofersen for over 7 months and his FIM score improved from 86 to 89. Another patient living with ALS was on Tofersen for 30 months and had improvement from 86 to 89. So, we are seeing it in the short-term as well as analyzing the functional gains that are retained for a significant period of time.  I'm pre-symptomatic SOD1 L145F variant, which excluded my participation in ATLAS. Back when ATLAS was rolling out recruitment, I spoke to Dr. Bucelli and he mentioned that WashU was "looking at possibly doing a mirror study" of ATLAS. Are you aware of any recent new discussions of such a study? Yes. For the unversed, ATLAS is a study in presymptomatic individuals with SOD1 mutations. They have limited the ALS research study for certain variant mutations, that’s what the question was addressed to. When there’s a change in the neurofilament level, when it increases or if an individual becomes asymptomatic with weakness, it’s potentially starting very early Tofersen treatment in the hopes of delaying the onset of ALS disease or even preventing the onset. So, that ALS research study is still ongoing, and we are not yet able to share data publicly. Hopefully, the study will have promising results and there’s potential looking at the broader implications that – the sooner we confirm ALS diagnosis, especially the genetic form or hereditary, ALS treatment can be initiated promptly. During the time when symptoms of ALS start showing up, there could be a possibility that we can prevent the onset of ALS disease, which could be amazing.  I am not aware of any kind of mirror study, but I will definitely pass that along to Dr. Bucelli and let him know about the question.  Why can’t non gene mutation patients be offered the rehabilitation program at their own discretion?  [I wasn’t offered any PT during the first 3 years of a clinic setting but pursued a clinic setting that agreed to let me try! Can this not be a patient/clinic discussion and decision, not a blanket statement? Every good day is a joy, let us have our days]  We actually recommend rehab programs for all of our ALS patients we see. The difference in ALS treatment here is the dosage and how those programs are tailored. There is good evidence for low-to-moderate intensity exercise, but we really recommend working with individuals or therapists familiar with ALS disease progression, because it can be a tough balance to titrate those programs appropriately. There is a risk for muscle overuse and further muscle decline. The biggest thing is, when you are strengthening muscle, it can break down those muscle fibers. In healthy individuals, they typically grow stronger. For patients with ALS that are not on disease stabilizing medications, that poses a risk that we want to monitor. Exercise can still be appropriate, as long as it's dosed well and individualized to that person. Here at WashU, we do work with all of our patients living with ALS, it’s just the difference in the dosage. Basically, making sure the program that is prescribed for the patients is monitored and changed over time. We have individuals that come in monthly, 3 months, 6 months, or other frequencies to ensure that the program that they have been given is tailored to their needs. Ultimately, the ALS treatment approach is goal-oriented, and it’s personalized to what they want to be able to do, with the goal of enhancing their quality of life.  Do you have exercise programs for patients with ALS at different stages and fitness levels? What are recommendations for patients who don’t have access to your clinic? Yeah, a really good resource, free for clinicians and patients is the Academy of Neurologic Physical Therapy. It’s all neurologic-specialized physical therapists, and so there is literature and evidence-based practices for guidelines on low-to-moderate exercise. I still highly recommend working with a therapist who specializes in ALS so that they can test and measure patients with ALS for their functional capacity. There’s also another website called ‘Choose PT’ where you can search for a physical therapist  who specializes in ALS in your area Do you see Toferson being used prophylactically? The ALS research study conducted by ATLAS is hoping to answer whether it is possible to treat someone who has not yet developed the symptoms of ALS but has increased levels of neurofilament, and if so, to understand the potential clinical benefits. After the completion of the study, it will give us a lot more information on how to best use Tofersen in treatment of SOD1 ALS. There’s also some interesting research in sporadic ALS that SOD1 protein misfolds and contributes to the pathology of ALS. It would be interesting to study the use of Tofersen in non-SOD1 ALS patients and look for any prevalent benefits.  CONCLUSION: The growing clinical research studies around Tofersen and neuromuscular rehabilitation is signaling a critical shift in ALS treatment options. From proactive biomarker testing like neurofilament levels to individualized exercise protocols, care is becoming more patient-centered and precision-driven. While genetic therapies like Tofersen are currently specific to SOD1 ALS, the insights gained are paving the way for broader applications. The future of ALS treatment may lie in early detection, personalized rehab, and a multidisciplinary approach that combines medical and functional care. With continued research and collaborative innovation, there’s real hope for improved quality of life and recovery potential in patients living with ALS.

Amyotrophic Lateral Sclerosis (ALS), also commonly known as Lou Gehrig’s disease, is a gradual neurodegenerative disease which causes the nerve cells in the brain to deteriorate. Initially impacting the arms and legs or having changes in speech, ALS disease causes extreme muscle distress and severely affects mobility, speech, swallowing, breathing, and muscle control, leading to progressive physical disability. Let’s take a closer look at the process of ALS diagnosis, highlighting the tests, symptoms, and key procedures.  What Is ALS and Why Is Diagnosis Important? ALS is a brutal neurodegenerative disease that gradually strips away the ability to eat, speak, move, and breathe, casting a dark shadow with its fatal prognosis. Overview of Amyotrophic Lateral Sclerosis (ALS): ALS disease can have a debilitating impact on physical health by damaging the motor neurons in the brain and spinal cord, which manage voluntary movements and muscle control (balancing relaxation and contraction). ALS causes progressive deterioration and death of these motor neurons, thereby causing the brain to cease the initiation and controlling of muscle movement. This impacts the ability of the person living with ALS (pALS) to chew, swallow, speak, and breathe. ALS symptoms appear gradually, and manifestation of symptoms can vary from person to person. Initially, ALS often begins with muscle twitching, which could appear as difficulty grabbing a pencil, lifting a water bottle, or changes in speech. This leads to progressive weakness in limbs, trouble swallowing, and difficulty in speech. The average life expectancy for people living with ALS is typically between 2 – 5 years after diagnosis, but some may live for  5 – 10 years or longer, depending on the progression of the disease.  The Importance of Early and Accurate ALS Diagnosis In many cases, people living with ALS are diagnosed after the disease has progressed to advanced stages. This often means they experience functional impairment and may miss the opportunity to benefit from treatment that could potentially improve their life expectancy of ALS. Although there are no specific diagnostic tests, ALS diagnosis typically follows a certain process, based on clinical symptoms and comprehensive evaluation to enable early intervention.  According to studies in the U.S., the duration from the first ALS symptom to a confirmed ALS diagnosis takes about 11 - 15 months. This timeline includes a process of elimination, with a minimum of 3 - 4 consultations with different healthcare professionals, which may include orthopedic surgeons, spinal specialists, chiropractors, and neurologists, which eventually lead to an ALS specialist. With timely ALS diagnosis, there is a higher quantity of healthy motor neurons in the spinal cord and brain, providing a window of time to modify ALS disease progression with experimental drugs and other novel treatment options. With early ALS diagnosis, people living with ALS tend to maintain better motor function, while the underlying cause of the disease is investigated. Early intervention also supports caregivers and families by easing some financial and emotional burden.  Common Symptoms Leading to ALS Diagnosis Although ALS diagnosis can take significant time, documenting and evaluating the early symptoms can accelerate the treatment process.  Signs and Symptoms of ALS Generally, ALS symptoms may differ among individual cases, based on the nerve cells impacted. It often begins with muscle weakness which progressively worsens, leading to a complete loss of mobility as the disease progresses through its stages. Some of the early signs and symptoms of ALS are as follows: Difficulty walking or doing routine activities. Stumbling and falling during movement. Experiencing weakness in the feet, legs or ankles. Weakness in the arms or hands, causing clumsiness. Difficulty swallowing and slurred speech.  Changes in thinking and behavioral patterns. Lack of control while laughing, yawning, or crying.  Muscle cramps and muscle twitching, especially in the arms, shoulders, feet, and tongue.  Early symptoms of ALS can sometimes be isolated to the feet, legs, hands, or arms. As the different stages of ALS progress, it starts affecting other organs in the body. ALS continues to worsen, eventually leading to an inability to do basic activities such as chewing, breathing, and speaking. The disease is so brutal that the person living with ALS can be paralyzed at advanced stages.  ALS symptoms leading to ALS diagnosis (PC: ALS News Today) When to Seek Medical Evaluation for ALS Symptoms If you are experiencing consistent muscle weakness, cramps, unusual exhaustion, or frequent dropping of objects during physical activity, it is important to seek medical evaluation. Prompt evaluation is critical to early ALS diagnosis, which may allow pALS to benefit from treatment, to ensure timely interventions for ALS treatment with required drugs or medication and other forms of therapy. The gradual progression of ALS disease may aggravate conditions with worsening symptoms, causing progressive muscle atrophy, extreme muscle distress, and weakness. If you, or someone you know, is experiencing muscle weakness, difficulty with everyday tasks, or changes in speech or ability to eat,  please seek medical evaluation.  Next steps after ALS diagnosis (PC: ALS News Today) Tests for ALS Diagnosis ALS diagnosis can be a difficult process, as early symptoms can resemble other neurodegenerative diseases. The following tests may be given as part of a comprehensive medical evaluation for early ALS diagnosis are: Electromyography  This test involves inserting a thin needle through the skin into specific muscles. Electromyography predicts ALS diagnosis by documenting the movement of muscles during contraction and relaxation. The records can help determine if the person has any nerve or muscle damage, as well as the specific location and intensity.  Nerve conduction study Nerve conduction study evaluates the ability of the nerves to issue signals to the muscles, helping to determine nerve conditions within different organs. ALS diagnosis can be confirmed with prevalent nerve damage. Generally, both electromyography and nerve conduction study are conducted together with samples from limb,  bulbar, and thoracic locations.  MRI Magnetic Resonance Imaging (MRI) scans offer intricately detailed and structured images of the spinal cord and the brain. With advanced MRI techniques, such as diffusion tensor imaging (DTI), it is possible to analyze very miniscule changes, such as white matter integrity, particularly in the corticospinal tract. This test may detect ALS diagnosis even before the other clinical signs. The MRI can detect tumors in the spinal cord, presence of herniated disks in the neck, and other changes in the body which indicate ALS symptoms or other neurodegenerative diseases. Blood and urine testing With a series of blood and urine tests, it is possible to rule out other conditions which share common ALS symptoms. ALS diagnosis can be detected through blood tests which show high levels of neurofilament light (NfL). The rise in NfL levels implies rapid degeneration of the neurons, making it a valuable biomarker for diagnosis of ALS disease. Spinal tap The spinal tap, or lumbar punction test involves extracting spinal fluid for laboratory testing. During the test, a small needle is inserted between two bones situated in the lower back, and spinal fluid is collected through the needle. Usually, the cerebrospinal fluid (CSF) of people living with ALS does not contain specific abnormalities that confirm ALS diagnosis. The CSF usually appears normal or has minimal changes, so lumbar puncture or spinal tap cannot directly confirm ALS disease, but examining CSF can indicate other conditions or diseases which are similar to the ALS disease. Test results can vary, sometimes showing a rise in protein concentration or an increase in albumin or IgG levels, which suggests a potential blood-brain barrier damage in ALS disease.  Nerve and muscle biopsy Nerve and muscle biopsies are not recommended for preliminary ALS diagnosis, but can help in the process of eliminating other conditions. During the procedure, small pieces of nerve/muscle tissue are collected for further laboratory analysis. These tests are generally ordered when clinicians suspect a muscle or nerve disorder, particularly with unusual weakness, pain or high levels of creatine kinase (CK).  Genetic testing Genetic testing plays a crucial role in ALS diagnosis, as it can identify mutations linked to familial ALS. The test involves collecting a blood sample and analyzing it using techniques, such as next-generation sequencing, which allows for the  simultaneous analysis of multiple genes related to ALS. The key genes tested for ALS diagnosis include C9orf72, SOD1, FUS, and TARDBP, and some other genes may be examined, according to clinical assessment, family history and ethnicity.  Conclusion  ALS is a brutal neurodegenerative disease which impacts voluntary movement and muscle mobility of the person, with gradual onset varying according to the intensity of the deteriorating neurons. The progression of the ALS disease can vary across individuals, and symptoms of ALS may manifest differently according to the different stages of ALS. ALS diagnosis is a complex process, which often involves a combination of different tests, from clinical evaluation, neurological tests, and other lab assessments. Early and accurate diagnosis is essential for timely intervention, effective management, and improved quality of life for people with ALS. Digital biomarkers studied by EverythingALS aim to simplify the diagnostic process, potentially enabling earlier intervention and improved outcomes.

As ALS research continues to evolve further to offer different treatment options, the ALS clinical trials play an important role to present innovative choices for ALS therapy and patient-care. Let’s delve deeper into understanding ALS disease and clinical trials. Understanding ALS & the Importance of Clinical Trials  What is ALS? Amyotrophic Lateral Sclerosis, or ALS, is a brutal neurodegenerative disease which disrupts the functioning of nerve cells from the brain and spinal cord. ALS disease is very challenging to diagnose, as there are no specific biomarkers associated with the condition. It leads to severe muscle weakness, impacting mobility, and extreme difficulty in speech, leading to paralysis and eventually respiratory failure. The average survival time s  after ALS onset is approximately three years, with very few treatment options available. Raising awareness of the disease is critical to driving progress and increasing ALS life expectancy. What are Clinical Trials? Clinical trials, a type of clinical research study, are interventional and focus on assessing new treatments and the efficacy of drugs to determine their potential to cure or manage specific diseases. According to the U.S. FDA guidelines, any new drug or treatment must be evaluated through a series of large-scale clinical trials to ensure it meets established standards for safety and efficacy. The FDA reviews the data and outcomes from clinical trials to determine whether to approve or reject a drug or treatment. Why do Clinical Trials Matter in ALS Research? Clinical trials support the treatment of people living with ALS (pALS) by providing therapeutic options specific to the progression and stages of ALS.  The key focus of researchers is to investigate the safety and efficacy of the drugs or treatment options, with the goal of extending and improving the quality of life for pALS. The discovery of new therapies through clinical trials can benefit people living with ALS by slowing the disease progression or extending survival. Through rigorous testing phases with patient-centric approaches, clinical trials accelerate the path from research to real-world treatment. Relevance of ALS Clinical Trials for ALS treatment (PC: ALS Center/University of Miami) What are ALS Clinical Trials? ALS clinical trials can be classified into two broader categories – novel approaches for ALS treatment and studies that help uncover ALS disease. Typically, clinical trials consist of several phases to determine the best dose, evaluate any potential side effects and analyze the drug’s efficacy. Clinical trials typically proceed through the following phases: Pilot trial: This is a preliminary study on a small scale to understand details concerning the safety and side effects of the ALS drug, find any biomarkers relevant to ALS disease or examine the design to be plotted for larger clinical trials. Pilot trials involve patients with ALS to test drugs priorly approved for other conditions. Phase 1: The objective of Phase 1 clinical trials is to initiate investigational treatments in humans. This involves administering the drug to a very small group, typically around 20 people. The researchers monitor all participants for any side effects or adverse reactions. During the study, if the drug appears to be too harmful, the trial is stopped immediately and the drug is withdrawn from any further clinical trials. Phase 2: Once the safety of the drug is tested on a small scale, the researchers look for the most effective dose, route of administration (oral, intravenous, intranasal, etc.), and the frequency and timing of doses. Phase 2 assesses the efficacy of the treatment to enhance the motor functioning for people living with ALS. This phase will help determine if the treatment can be effective for patients living with ALS. Phase 2 involves no more than 100 people living with ALS, but studies concerning investigational treatments need to include a larger group of people. Phase 3: Phase 3 of ALS clinical trials involves a large number of participants, which are adequate to confirm the treatment efficacy. With hundreds of participants, the study analyses the effect of the drug in pALS with different  stages of ALS, and varying life expectancy for ALS. Once Phase 3 of ALS clinical trials is complete, the results are submitted to the FDA so they may review the data and consider whether to approve the treatment. Phase 4: This is the final phase of the ALS clinical trials and involves ongoing monitoring of the drug’s safety and efficacy of the ALS drug its approval by the FDA. How to Find and Join ALS Clinical Trials Navigating the world of ALS clinical trials begins with regularly checking the status of ongoing clinical trials and understanding the outcomes of those that have been completed. Several reliable platforms provide up-to-date information on trials, including eligibility criteria, locations, and enrollment status, which we’ll explore here. Where to Search for ALS Clinical Trials: ClinicalTrials.gov : This U.S. government database provides information on all registered clinical trials worldwide. The website can be easily searched for ALS clinical trials by entering the condition (ALS), or other details like location, phase, and by adding filters or other criteria.  ALS Trial Navigator: This website is managed by the ALS Therapy Development Institute, and it provides up-to-date information on ALS clinical trials. This tool helps pALS and families find clinical trials suited to their personal medical history and disease progression. National ALS Registry: Managed by the Centers for Disease Control & Prevention (CDC), the National ALS Registry is another credible website with more information about ALS clinical trials. It connects the patients living with ALS in the U.S. with research opportunities and also offers valuable public health data. In addition, EverythingALS also conducts several research studies to analyze the different stages of ALS using digital biomarkers to provide better clarity on the progression of ALS disease and life expectancy. Join our ALS research here  and be a part of one or more ongoing ALS research studies.  Who can Participate in Clinical Trials? Clinical trials for different diseases and conditions are designed with specific eligibility criteria to ensure patient safety and accurate data. Some of the common eligibility criteria, especially for ALS disease, are as follows: Age: Many clinical trials specify an age window, often between 18 and 65 years, to target appropriate populations and reduce age-related risks.  Disease characteristics: Eligibility often varies according to the type and different stages of ALS. For instance, some clinical trials require a “definite” or “probable” ALS diagnosis, and may specify whether participants have sporadic or familial ALS. Other factors may include the duration of the disease and progression, and some trials may exclude patients with very advanced disease or slow progression. Genetic markers: Certain clinical trials focus on patients living with ALS with specific genetic mutations linked to ALS, such as  SOD1  or  C9orf72 , to test targeted therapies. Respiratory function: Measures like forced vital capacity (FVC) or slow vital capacity (SVC) are often used to assess lung function, with minimum thresholds (typically 50-65%) required for participation. Overall Health and Prior Treatments:  Participants generally must be in a healthy state to participate in clinical trials safely. They may be excluded if they have had a recent occurrence of certain cancers, tracheostomy, or use of assisted ventilation. Concurrent use of other investigational drugs is usually prohibited. Steps to Enroll in a Clinical Trial Eligibility Criteria and Screening: ALS clinical trials’ enrollment begins with a thorough screening process to ensure that participants meet specific eligibility criteria designed to protect their safety and maintain the scientific integrity of the study. These criteria often include age, disease stage, genetic markers, respiratory function, and overall health status. During screening, study staff will review your ALS history, medical background, medications, and perform baseline assessments such as blood work, neurological exams, and respiratory tests. It’s important to know that many trials exclude a significant portion of ALS patients—on average, about 60%—but newer trials are working to broaden inclusion criteria to be more accessible. Questions to Ask Before Participating: Before agreeing to participate in a clinical trial, it is crucial to ask the research team key questions in order to fully understand what participation entails. Key questions include: What is the purpose of the study? Have similar studies been done, and what were their outcomes? Who is funding the trial? How will my privacy and medical information be protected? What are the possible risks and benefits? Will I receive a placebo, and if so, how is that managed? How long will the study last, and what will be required of me? Can I continue my current medications during the trial? What support is available if I experience side effects or harm? Discussing these questions with your doctor or ALS care team  can help you make an informed decision about participation. It is important that all participants have informed consent by understanding the complete trial process and make a choice of participation aligning with the ALS clinical trials.  Support from ALS Care Teams and Networks Enrolling in a clinical trial doesn't mean you're on your own. In fact, you’ll have support at every stage: Neurologists and specialists  can help evaluate your eligibility and explain how a trial fits into your care plan. Trial coordinators  will assist with paperwork, scheduling, and transportation logistics. Patient advocacy organizations like EverythingALS provide community support, education, and guidance on trial selection and participation.   Current and Promising ALS Clinical Trials ALS clinical trials are testing a range of innovative approaches to slow disease progression, manage symptoms, and work toward a cure. These include gene therapies targeting mutations like SOD1  and C9orf72 , stem cell treatments to protect motor neurons, and drug trials using small molecules or repurposed medications. Observational studies collect real-world data to guide future research, while adaptive and platform trials allow for more flexible and efficient testing. Notable Ongoing and Upcoming Trials 1. AP-101 (AL-S Pharma) Type: Intravenous monoclonal antibody targeting SOD1 activation Phase: IIa Status: Active, recruiting (Primary completion June 2024) Description: Evaluates safety, tolerability, pharmacodynamics, and pharmacokinetics in familial and sporadic ALS patients. Targets SOD1 mutations to reduce toxic protein effects. 2. RAPA-501 (Rapa Therapeutics) Type: Autologous T cell therapy (epigenetically reprogrammed regulatory T cells) Phase: II/III Status: Actively recruiting (Primary completion July 2025) Description: Designed to reduce neuroinflammation by enhancing anti-inflammatory T cell populations, potentially protecting motor neurons. 3. ALN-SOD (Regeneron Pharmaceuticals) Type: RNA interference (RNAi) gene therapy targeting SOD1 mutation Phase: I Status: Actively recruiting (Started August 2024) Description: Aims to reduce toxic SOD1 protein production in familial ALS patients with SOD1 mutations. 4. SNUG01 (Peking University Third Hospital) Type: AAV vector-based gene therapy Phase: Early Phase I Status: Actively recruiting (Started October 2024) Description: Uses viral vectors to deliver therapeutic genes to motor neurons to slow ALS progression. 5. Renzumestrocel (Corestemchemon) Type: Autologous bone marrow-derived mesenchymal stem cell therapy Phase: III Status: Active but not recruiting Description: Stem cell therapy aimed at slowing disease progression by delivering neuroprotective factors. 6. Healey ALS Platform Trial (Massachusetts General Hospital) Type: Adaptive platform trial testing multiple investigational drugs Phase: Ongoing Status: Actively recruiting Description: Tests multiple therapies simultaneously using shared placebo groups to accelerate drug development. 7. RESTORE-ALS (Cytokinetics) Type: Small molecule drug CNM-AU8 Phase: III Status: Ongoing Description: Evaluates whether CNM-AU8 can improve survival and slow disease progression in ALS patients. These trials represent a range of therapeutic approaches including gene therapies, cell therapies, monoclonal antibodies, and small molecules, reflecting the dynamic progress in ALS research. For detailed eligibility and enrollment information, visit ClinicalTrials.gov  and the ALS Trial Navigator .  How Participation Advances ALS Research Participation in ALS research is vital to advancing treatment options and improving patient outcomes. When pALS and their caregivers take part in clinical trials, observational studies, or data collection efforts, they directly contribute to the development of new treatments and diagnostic tools. Their involvement helps researchers better understand disease progression, identify patterns, and fine-tune therapies based on real-world experiences. Caregivers also provide essential insights into daily challenges and care needs, making research more patient-centered and impactful. EverythingALS is leading several innovative, remote-friendly studies that anyone in the U.S. can join. These include voice and speech analysis to detect early signs of ALS, movement tracking through wearables and smartphones, digital biomarker development, and caregiver-focused surveys to improve support systems. Our studies are designed to be inclusive, accessible, and easy to participate in from home. Join an ongoing study here  or download  the EverythingALS app to contribute to the future of ALS research. CONCLUSION ALS clinical trials are at the forefront of advancing new discoveries, offering hope to people living with ALS and families. By participating in research, individuals help accelerate treatments and bring us closer to a cure. From gene therapies to digital studies, opportunities are expanding across the U.S. Every contribution matters—whether through trials, data, or advocacy. Stay informed, get involved, and be part of the future of ALS research. Frequently Asked Questions Are ALS clinical trials safe? Yes, clinical trials follow strict ethical guidelines and regulatory oversight to ensure participant safety. When participants are registered for the study, they are clearly informed about the risks during informed consent, with continuous monitoring throughout the study.  What are trusted websites to access updates on recent ALS clinical trials? The most preferred website to access ALS clinical trials information is https://clinicaltrials.gov/ . Other websites include https://www.alsnavigator.org/  (ALS Trial Navigator, ALS TDI), and https://www.cdc.gov/als  (National ALS Registry, CDC) What is the newest ALS treatment approved by the FDA? The newest ALS treatment approved by the FDA is Tofersen (Qalsody). Tofersen is specifically designed for SOD1 gene related ALS.

Nutritional Considerations in ALS: Role of nutrition in ALS treatment and cure Introduction: For people living with ALS, optimizing nutrition plays a key role in terms of enhancing care and slowing progression of the disease. (The session begins with an introduction highlighting the progress in ALS research and the importance of nutrition in managing the disease. The hosts invite participation in ongoing speech and gene carrier studies to improve ALS diagnosis and prognosis. The session, led by Dr. Terry Heiman-Patterson, Dr. Ikjae Lee, and Dr. Gina Tripicchio, highlights the progress in ALS research and the importance of nutrition in managing the disease.  The discussion explores whether optimizing nutrition can improve care, slow disease progression, and enhance survival for people living with ALS. The presenters outline the metabolic changes in ALS, such as hypermetabolism and weight loss, and emphasize the need for better nutritional strategies tailored to ALS patients.  I moved some of the phrasing from this part after the introduction to the presenters. Featured Questions Would a state of hypermetabolism have any protective effects on tissue preservation, particularly in the context of elevated blood glucose levels? Hypermetabolism basically means that one is losing a lot of energy, even without exercising or being active. For example, in a trial, attempts were made to help ALS patients gain weight. They had to consume 150% of their expected calories to actually gain weight. This implies that if one is consuming a regular amount of food, this will lead to weight loss due to energy use. How do the nutritional considerations in ALS support maintaining an active lifestyle and adequate energy intake for physically active patients? Absolutely. However, it is important to maintain energy intake and weight. Exercise has been an age-old question in ALS disease; whether it is good or not. Usually, it is recommended for patients to be active, if they are not getting exhausted and are able to maintain their weight. This includes daily activities, lightweight exercise, aerobic exercise, and stretching. However, weight training is not recommended as the muscles would only get stronger when they are connected to nerves. When the nerves are degenerating, it is hard to make the weak muscles strong. So, it is important to stay active as a means to keep the muscles conditioned, but don’t overdo it, and make sure to drink and eat adequately before and after exercising.   If there is limited energy storage for patients with ALS in weakened muscles, is fat the only alternative storage site? Are there any alternative storage areas which can be targeted via diet? When losing muscle, patients with ALS are also losing fat tissue. That’s because when the muscles get denervated, they lose the connection to the nerves. They actually get very greedy and take a lot of glucose to regenerate or reconnect to the nerves. When there isn’t enough glucose, they utilize fatty acids, breaking down fat from storage, probably near subcutaneous fat. So, when the muscle diminishes, the fat tissue also goes away. When the person has excess fat, it spares the muscle breakdown. In cases when the person is lean, there is less fat reserve, thereby impacting the muscles.   What types of dietary fats should be prioritized according to nutritional considerations in ALS, and how do they impact brain health? This is a common question and relates to the evidence we presented on glycemic load. The evidence to date shows that polyunsaturated fat (PUFAs) and omega-3s are the sources of fat which are ideal for consumption. Foods such as fatty fish, avocados, nuts and seeds, or equivalents of those, like nut butters or other things that can be pureed or mixed into other things. These are probably the primary sources of fat to prioritize, as they provide calories, in addition to the antioxidant and anti-inflammatory capacity that comes with them. The glycemic index data is compelling, and we would like to analyze it along with the EverythingALS Nutrition Module. There are still a lot of studies to be done. Metabolism is very complex and intertwined. Our body is a well-designed hybrid model. For instance, a car can run on gasoline, diesel, or electricity all at the same time, and it just interchanges between the modes as the available sources change. Similarly, the human body uses glucose but also uses fat, and also uses protein if there’s no glucose or fat. So, I think eating fat would have a similar effect as glucose, although it is less effective because it does not directly stimulate insulin, which is a signal for the body to know if it is in producing mode or storage mode. But, fat does have impact on insulin to a certain degree and can also be converted to glucose. PUFAs have an important role in membrane, or as a signaling molecule, for antioxidative effect. There is a lot of literature building up stating that PUFAs might have a beneficial effect. It is important to eat high calories, which includes some degree of high glycemic carb. You can eat fat as well as protein and supplement it with PUFAs. Integrating high quality fats with some of the high glycemic foods does map on to the template of Mediterranean diet. The diet also promotes a lot of grains and pastas, along with high-quality sources of fat, fruits, and vegetables. Generally, the perception of Mediterranean diet includes olives, polyunsaturated fatty acids or fruits, but in reality, the Mediterranean diet also has a big component of carbs and it’s a good example of a combination of beneficial ingredients that includes carbs and PUFAs. Another common question patients have is about consuming protein supplements. I’m a little cautious about protein. When you try to lose weight, you eat a lot of protein. You think protein might go to the muscles, but that’s conditional. Protein might go to muscles after extensive exercise when there’s a muscle tear which needs recovery. The muscle might get stronger during the recovery process and in that situation, protein would be beneficial. But if you’re just eating protein, it might make you lose weight. It has a significant thermogenic effect, meaning protein is commonly used for generating heat instead of making fat. We still don’t know whether eating more protein is beneficial or not, but eating more protein usually doesn’t cause weight gain. Carbs and fat do cause weight gain.   What role does a cholesterol-rich diet (high in dairy fat, butter, cream, etc.) play in protecting the brain? I don’t think we know too much about that. Cholesterol is a very important molecule and acts as a backbone of membranes of hormones. So, it’s absolutely essential for the body. But, I don’t know whether eating a lot of cholesterol is beneficial or not.   A patient living with ALS has gained 20 lbs since being diagnosed a year and a half ago. He wants to return to my normal weight, but the clinic discourages weight loss. What is the best way to achieve a healthy weight while feeling happy and healthy? It’s best to keep the weight on. This is a common question for many patients living with ALS. Honestly, losing weight makes all of us feel better, and we feel bad when gaining weight. So, it is kind of torture to tell patients to gain 10-15 pounds more, because that’s usually not well accepted and people don’t like it. In cases when one gains weight due to lack of exercise or inactivity, it is recommended to keep it steady for a while and see how disease is progressing. I have seen patients who try to lose weight through GLP-1 drugs like Ozempic and it didn’t end well. I have seen some rapid progression with that, so my only recommendation is to not try to lose the weight rapidly. If you want to lose weight very slowly and your ALS progression is also slow, that may be okay, but don’t try to lose weight very quickly.   Is flaxseed oil recommended for pALS? If so, how much? What about vitamin A – Is there a role for vitamin A in ALS? Flaxseed is part of the Mediterranean diet and certainly has good fats. There is not much known about Vitamin A. However, there are several studies on Vitamin E. Regarding Vitamin A, it is important to be cautious about toxicity. If you supplement Vitamin A, it can be really hard on the liver. Generally, vitamins and minerals are good, but we always recommend their intake through food. The same goes for flax. It would be much better to have ground flax seed, because that actually makes the flax readily available as opposed to the whole seeds or the oils because all those things, especially the oils, go through different levels of processing. So, it’s always better to consume the food sources. There is adequate intake of Vitamin A through fruits and vegetables, and you should not prioritize any of the supplements because it can be hard on the liver.   I have continued to lose weight and have a low BMI. My main problem is dysphagia, and I experience stomach pain about 1-2 hours after eating. It feels like my stomach is too small to eat more. What foods help with dysphagia, and what else can help? The discomfort after eating could relate to GI dysmotility, which can be part of autonomic involvement in ALS. There are some medications that can help with gastric emptying and GI motility. They are not that great, but things like Reglan and smaller, frequent meals can help. You could consider a feeding tube when losing weight, but it might also result in discomfort if you’re given excess quantity of food through the food pipe and there are some motility problems. It is essential to review other medications prescribed to ensure they are not affecting GI motility, like anticholinergic agents used for saliva. This is actually a common problem among patients and shows that there are a lot of hurdles even if they try. For example, issues while swallowing, limitations because of hand weakness, lack of appetite, stomach not digesting food, etc. Several issues are not easy to solve, leading us to figure out the most efficient way to help so we don’t have to deal with bulk. Maybe, if the key ingredients are known, they can be used in small amounts and still adequately help the patients to be stable.   Is it important to tailor dietary strategies to different stages of the disease? For example, might ketogenic diets be more beneficial in early ALS when there is a need to reduce oxidative stress and neuroinflammation? Well, that’s going to require studying across the continuum of the disease. With biomarkers like inflammatory markers and oxidative stress markers, the problem is lack of consistent findings. It is important to know the targets and check what happens with different diets longitudinally, in all corners in all stages, and then refine if it looks like there are differences. It’s going to be a very difficult situation until we have better ways to determine what mechanisms are operating at any particular time in the course of the disease. It’s going to help more after starting to follow longitudinally, and we can do cross-sections at different stages, which might provide some clues. It is important to observe differences in distinct phases of the disease and, depending on the phase, it might be cross-sections at early, mid, and other stages.   What are the nutritional considerations in ALS for daily protein intake? What are some good protein sources to focus on? Is a ketogenic diet sufficient for meeting protein requirements? A keto diet with low carbs and high fat involves a significantly higher amount of protein consumption. When considering high protein sources, salmon providesomega-3 and polyunsaturated fats, which are good for Mediterranean diet. It is nice to eat well-balanced meals. The priority is more high-quality sources of glucose and fats. Most people across the board are getting enough protein with consumption of high sources of fat. When eating beans, nuts, seeds, meats, or fish in your diet, the protein and fat intake is balanced. So, I don’t think additional protein should be added to every meal. Given the evidence we have right now, it is more important to focus on the high-quality sources of fat and the quality carbohydrates. In doing that you’ll probably be eating enough protein.   What should be done to manage Type 1 and 2 diabetes? Should patients raise their target glucose to achieve a desirable result? Any special recommendations when planning their food intake? The people with diabetes are in a tough spot, because diabetes and high blood sugar are not good for several things, including nerves. Also, diabetes can impact blood vessels and controlling blood sugar helps with reducing long-term cardiovascular risks, like strokes and heart attacks. When considering ALS patients with diabetes, the risks to benefit analysis is important. When consuming high quantity of carbohydrates, it might help the muscles but simultaneously raise the blood glucose levels and impact the vessels adversely. In cases when the hemoglobin A1C is not really high, i.e. falls in the range of 7 or below, it’s not very dangerous to eat some carbs and then try to control glucose with diabetic medications or insulin delivered into the tissues.  Insulin is needed, especially for Type 1 diabetes, along with increased carb intake. For Type 2 diabetes, reducing the insulin resistance through medications like metformin or GTA inhibitors might compensate for what is eaten. It is not recommended to lower the glucose excessively to reduce the cardiovascular events likely to happen 5-10 years later, because ALS is an immediate threat. Keep in close contact with the endocrinologist and make sure to monitor sugar levels and A1C. Diet is important, but don’t let sugar levels get too high; A1C 9 or 10 is not good.   Conclusion: The conclusion of the talk underscores the critical role of nutrition in ALS management, particularly in addressing hypermetabolism and weight loss, which are linked to faster disease progression. The experts highlight the importance of maintaining body mass index (BMI) and fat stores to improve survival outcomes. Early, personalized nutritional interventions and multidisciplinary care can improve patient outcomes and quality of life. The nutritional considerations in ALS broadly include having a high calorie food for ALS patients with a diet rich in carbs, fats with balanced intake of protein. It is important to track meals for people living with ALS and understand the impact of nutrition in recovery. The new 'Nutrition Module' in the EverythingALS app is designed to empower patients to manage their nutrition more effectively.

Fast-Tracking Discovery in ALS Research Introduction: Advancements in ALS research are increasingly driven by open science, cross-disciplinary collaboration, and patient-centered innovation. As the complexity of ALS demands multifaceted exploration—from genetic pathways to immune system dynamics—researchers, clinicians, and advocacy groups are collectively reshaping how discovery and development are approached. With an emphasis on early diagnostics, personalized treatment strategies, and real-world data collection, the landscape is evolving rapidly. This session with Dr. Merit Cudkowicz highlights emerging therapies, cutting-edge technologies, and the pressing need for inclusive, accessible clinical trials that accelerate progress and bring tangible hope to those impacted by ALS. Featured Questions What are your thoughts about the potential benefits of Spinogenix SPG 302? What stage is the trial at? I like the biology and I put it in the repair category. It helps make new dendrites, so there are new connections between neurons. They are in early stages of study development and have completed a phase 2A study in Australia. They have not reported the results yet, but I believe the study had 24 participants for up to 6 months, with focus on identifying biomarkers. Furthermore, the study also analyzed the effectiveness and functional capacity of the drugs, e.g. increase of synapses, which can be measured through electrophysiology and other methods. Recently, they have announced a compassionate use study while they continue to work on the design of their phase 2B study.   What are your thoughts on IL-2 in MIRACALS ALS research study? Firstly, it’s exciting their results were finally published. They had shared the results publicly, but it took them a long time to publish. I think it’s positive. The theory behind IL-2 is that it increases the good T-regulatory cells, which are anti-inflammatory in nature. The study reveals that from a subset of participants, the people who did not have super high neurofilament levels are people who are not super-fast progressors. This includes nearly 80% of the population which showed an effect on longevity. The reason why it didn’t work with people with a high neurofilament level is not very clear, but I do think they saw a fairly large subset that responded and showed that their drug increased T-regs so it did what its’s supposed to do. I didn’t know what the next step is because it’s a marketed drug for cancer, and, sometimes, it is possible to change the label of the drug based on new data. If you have a positive study, the FDA can review the data to determine whether there’s enough evidence to change the label and officially approve it as a marketed drug for ALS. Alternatively, the FDA or the other regulatory groups may want an additional study. In this case, the company provided the drug and it was an investigator-initiated study. Will the Healey Center engage in NU9 clinical trials and are there any plans for it? I think Akava would be a good example for an ALS research study, but they need to first do their Phase 1 study by testing their drug in people without any illness. For safety purposes, the study could administer either single dose or multi-dose. But, when they are ready for the next stage in people with ALS, the Healey centre Center would be perfect for the kind of a perfect setting for a Phase 2A study, to ensure the drug is administered to the target and right target population.   COYA is working to launch a Phase II trial this quarter for a combination of compounds. Does it include IL-2? Yes. COYA includes IL-2 and another drug called Abatacept. So, it’s tackling two parts of the immune system that seem to be wrapped up in people with ALS. Dr. Appel has led major parts of the study and published on the first four patients, where he observed good safety and good response. And, now, they’re planning to launch an early Phase II trial, but the start date is not shared publicly. What’s the difference between ALL ALS PREVENT and the Atlas Study? The Atlas study is a therapeutic study in people who are gene carriers for SOD1, and will be administered the Qalsody drug to observe its mechanism, whether it can prevent the onset of illness. Whereas, ALL ALS PREVENT is following people with any gene that might cause ALS without any focus on the therapeutic intervention. It’s about following people with different outcome measures, whether they’re digital or fluid and try to understand the earliest changes that happen in ALS for not only improving the diagnosis, but also helping to design other prevention trials in those other forms of genetic ALS. Are there any preliminary results for PrimeC Phase 3? No, the Phase 3 trial for PrimeC hasn’t happened yet. So, PrimeC, developed by NeuroSense Therapeutics, is a combination of two drugs; Ciprofloxacin and Celecoxib. They have completed a Phase 2 study and reported positive biomarker data, safety, along and also with alpha measures, and they are gearing up for a Phase 3 trial.  Is there a known pathway by which COVID or COVID vaccinations could cause ALS? There are some researchers working on this subject, especially Dr. Avi Nath at the National Institutes of Health (NIH). Although, a direct link has not been established, there is a compelling rationale for deeper study. One leading hypothesis suggests that viral infections may trigger inflammation or an immune response in individuals who are genetically predisposed to ALS or related conditions. Individuals who suspect a temporal link between their ALS onset and COVID infection or vaccination are encouraged to reach out to Dr. Nath, who is currently collecting blood samples for  his research. Do you have an opinion on the Phase 2 trial of ROCK (Rho-associated protein kinase) inhibitor Bravyl, and when the results of the study are anticipated? I think it’s a good pathway, but I haven’t seen any results of it yet. But, I think it’s a good idea. Any results from the Fasudil study? I don’t think anything is published about the study yet. What are your thoughts on the ALS research study at Sunnybrook involving the opening of the blood brain barriers to deliver medications? This is conducted using focus ultrasound, where it is possible to briefly open up the blood brain barrier and release drugs in. This is a major problem for developing drugs for the brain. It could be very helpful for drugs to be administered once or twice. But, it may not work smoothly for drugs to be administered every day because it is not possible to get the focused ultrasound daily. But, for gene therapy, right now the drug could be injected in the spinal fluid or in the ventricles in the brain. The process is a little complicated, but if one could do it in the blood, and open up the blood brain barrier with the focus ultrasound for a couple of minutes, get in there, and then it shuts back down, it could be a game changer for gene therapy delivery for all forms of ALS. As we study people with ALS, is research finding that most types of ALS have a genetic component? I think it is. When I analyze the findings of Dr. Brown and Ammar Al-Chalabi, they talk about the twin studies where they have followed 25-30 pairs of identical twins to observe if they one or both twins develop ALS. They have concluded that about half of the cause of ALS is probably genetic. It’s not very simple with inheriting one gene from a parent that causes the illness. It’s probably complex genetics with multiple different gene changes that increase the risk. So, that’s the current number, with 50 % of the cause attributed to genetics, and the rest is attributed to environmental factors. Any chance that the two-year mark to reject patients into trials will be removed at some point soon? I don’t think so. I think we have to find other ways so that everybody has options. I think we are seeing more and more trials go earlier. For example, in the platform trial, we went earlier from 36 to 24. The reason is two-fold; one is some studies showing us better effects earlier, and if you take people who are up to 3 years, you are enriching for people who are slow progressors, which is great, we want everybody to be a slow progressor, but in a trial of 6 months or 9 months, it means someone might not change in that time period, and makes it much harder to conclude if the drug is functional or not. The goal of the trial is to confirm the drug’s efficacy with the fewest number of people so you can get it on the market for everybody. Also, the Prilenia trials are moving to to 18 months from symptom onset. So, I think there should be options for people who have passed the two-year or the 18 months mark. And that would be that compassionate use option, so that people can still have access to the drug and the therapy and be monitored safely. But, you are using the data from the people earlier in the illness to figure out if the drug works or not so then you can do a shorter trial to get that answer. Can patients with Bulbar ALS also participate in the ALS research activities? What is the registration link? Yes. All studies enroll people with bulbar ALS onset, whether that’s the ALL ALS, Natural History Database or the current clinical trials. I don’t have a specific link, other than finding the clinical trials at government website – clinicaltrials.gov . But, there’s also ALS TDI with a good website for clinical trial finding. You can also refer to the website of I AM ALS. Why are the Canadian neurologists not prescribing Vitamin B12 – Methylcobalmin in the same way as it’s been given elsewhere? While I can’t speak for the Canadians, but it’s approved in Japan. There were two studies – the first one was with a broad population, which did not see benefit, but they saw in a post-hoc analysis that there was a very big response if it was started early in the illness, between 12-15 months of first symptom. The second study was about adjusting people in the initial 12 months and observed a similar effect. These two studies have led to approval in Japan. However, it is not approved in Canada or in the US. This is not due to rejection by Health Canada or the FDA, but the company has not filed for approval. My guess is they are not prescribing it because it is not an approved drug. What focus areas and orgs are doing the most exciting work leveraging AI for ALS research? I think it’s going to be really helpful for the subgrouping of people for ALS research studies. I think we now have lot of data through Answer ALS and other groups on the biology from samples from people with ALS that we could start to subgroup people. There are some phenomenal scientists at UCSF, MIT, Hopkins and in our group who are real experts in AI trying to mine this data. I know Vision 2030 is very focused on AI and supporting that type of work with Everything ALS. You mentioned PET scan to identify a neuroinflammatory process. Can this be indicated for a newly diagnosed ALS patient to indicate possible response to steroids? Well, we can definitely do it in people who are newly diagnosed, and a lot of centers integrate a PET scan. It’s a protein called TSPO (18-kDa translocator protein). You could look at responses to steroids with it. There have been studies of steroids in people with ALS and they have not worked. So, I am not sure if it would be the best anti-inflammatory approach, but, other anti-inflammatory drugs could be used and PET scan to observe if the neuroinflammation decreases. What are your thoughts on testosterone, and the role that it plays in ALS onset in men? Do you think there is a connection and if so, would that impact the ALS treatment options? I don’t think there is adequate research about the connectivity. However, with respect to clinical understanding, if the testosterone is low, it should definitely be replaced.  I don’t think we should give it if testosterone levels are normal, but if it is low, we should give it a try. However, there should be more research studies about it. Are there any recent results from Ibudilast study? The previous results in 2020 were negative. Not yet. I think it was supposed to finish in April. I don’t know if they have actually finished enrolling and then it will be about a year from when the last person enrolled. So, I don’t think we are going to know for a while. The previous study on a small scale was open label and it was looking at the PET scan. We were looking at those measures of inflammation and we did not see any change in inflammation or in neurofilament. It was a small study, with 35 participants over a six-month period. The current study is much bigger, and they are looking at different outcome measures, but I don’t think we’ll know the results until 2026, unfortunately. How soon will treatments have FDA approval, based on all the information discussed and the current pipeline? I hope there will be some approvals in 2026. The approval process and the timeline are only known to the FDA. I hope we are going to have the flexibility that we had with the prior administration. Presently, they are very short-staffed and things are taking longer to get back from them, but hopefully, that will settle out. So, I think it is less likely to have something new this year. I think if Eisai filed for Vitamin B12, it might get approved quickly, but I don’t know that for a fact. Do you have ALS patients with neurofilament levels that remain normal throughout their disease? Yes. It tends to be in people who have a very slow or isolated form of ALS. For example, for some people, only the arm or leg area is impacted and progression is very slow. It might be that the damage is so minor that it does not leak into the blood, but we definitely see it. I take it as a good sign when people have that.   Conclusion: The path to meaningful breakthroughs in ALS research is rooted in open collaboration, scientific rigor, and a commitment to patient equity. By leveraging new biomarkers, repurposing existing drugs, integrating AI, and investing in preventative frameworks, the research community is making strides toward transforming how ALS is understood and treated. Continued support for open science initiatives, compassionate trial designs, and real-time data sharing will be essential in ensuring that discovery is not just fast-tracked, but also impactful and inclusive. Together, these efforts are paving the way for a more hopeful and effective future in ALS care. For any other questions on ALS research, you can download the Everything ALS app on Google Play Store  or Apple App Store  and learn more from our Chatbot.

Introduction On April 16, 2025, EverythingALS hosted a deeply informative Expert Talk titled “ALS Natural History: How to Turn Real-World Experience into Real Progress in ALS Research.” The session featured Dr. David Walk, Professor and Head of the Neuromuscular Division at the University of Minnesota. Dr. Walk addressed a wide range of audience-submitted questions spanning genetics, clinical trials, disease modeling, and international collaboration. This conversation shed light on how long-term, real-world patient data—known as natural history studies—can accelerate ALS research and drive more targeted, impactful treatment options for patients worldwide. Featured Questions  I’m an ATN X2 gene carrier. How can I find more information about this? What are the other genes being worked on for ALS Research? There’s a study about intervening taxin-2, which is a complicated gene, and its impact on ALS is a little different than many other genes. The clinical trials, both observational and interventional, are listed on clinicaltrials.gov . EverythingALS also lists the major clinical trials. More research is being done with taxin-2 with respect to the genetic component.             What is a disease model, and how would the model inform treatment paths? Modelling the progression of ALS has particular utility in terms of biostatistics and clinical trial design. Whether that’s designing a large trial and maximizing the likelihood of showing a benefit, or designing a futility study in a pragmatic trial focusing on a specific compound with minimal investments without integrating placebo, these models provide critical guidance to streamline this kind of research. For instance, around 200 people can be modelled with a specific drug without giving a placebo. Modelling can be done in advance by analyzing the difference between the outcomes anticipated versus the outcomes visible and concluding if the specific drug should be pursued further or not.   What if the disease has no connection with specific known genes? How can participating in a natural study help that? This is not about a genetics study. This is about ALS and everything defined as ALS, that includes people at genetic risk. Although we've worked with all ALS, to be sure we are not doubling up and we are using the resources appropriately, our inclusion criteria include PLS, people at genetic risk for ALS, Kennedy's disease, and other motor neuron disorders. Although, Kennedy’s disease is genetic, and we believe that most of ALS is not mono-genetic. Studies have only begun to divulge the role of genetic susceptibilities for any disease.   Is it possible that a natural history dataset might be more likely to address specific set of questions, for example, why there is a higher rate of ALS occurrence in the state of Michigan? I think we are less good at that than other epidemiological surveys, like what the CDC is doing. There’s someone Michigan who can speak to that much better than I, that is Steve Goutman. But we have the disadvantage of being specific to individual clinics.     How many patients are there in the database now, and how large would you like the ALS research database to grow? We do have data on approximately 3,000 individuals going on for around 10-11 years. I believe there are around 1,100 who are presently contributing data to the dataset. We are adding a few sites each year and it’s a little bit complex, because what I am leading is fortunate to have received is FDA funding and there are some sites that have been brought on that are not part of the FDA project. We are adding a couple of them per year and as long as we have the money to fund those sites, we are bringing them on to get the best numbers we can.   Is it possible to get any trial drugs outside the US, specifically Turkey? Are there any updates on international collaborations and given all the changes in the world? I know very little about access in Turkey or in much of the rest of the world.  I will say that I have not seen a change in the collaborative spirit of clinicians and scientists and there are some barriers, but let’s hope that we can continue to move forward.   Is there any more information on expanded use of treatments such as Tofersen? Tofersen is only being used in individuals with SOD-1 variants, although there are certain variants with some controversy about pathogenicity. There may be a role of SOD-1 in certain other individuals or more broadly in ALS, but I’m not sure how compelling the information is. The real-world evidence with Qalsody for people who have SOD-1 mutations is continuing to be remarkably good. So, there’s people whose diseases are stabilizing and really doing quite well. There are rare cases of inflammatory and autoimmune reactions like idiosyncratic causes. Some people also get infected with aseptic meningitis or myelitis, which is an inflammation of the spinal cord. These are very serious conditions and treatable with steroids. There are some recent studies to navigate the severity and the treatment process with steroids. But, the experience with Qalsody as a treatment for SOD1 is, so far, better than the expectations of the people from the clinical trial data. Further, it is extremely important that people undergo genetic testing at the time of diagnosis as there are emerging or experimental antisense nucleotides or other rare ALS genetic forms. And, it’s a directly targeted backdoor to potentially effective therapy for those individuals. The objective is to not let anyone miss out on being a candidate for antisense therapy, whether it’s the one approved by FDA, or others that might come along.   What can be done for folks who have been diagnosed with ALS for years? What needs to be tested? How should the folks who have been diagnosed with ALS for years navigate through? Expanded Access Programs, or EAPs, are a good example because some individuals with ALS will benefit in EAPs. There are ways to impact somebody’s care, regardless of the duration of the disease. And, one of the things that might be challenging, as a clinician, is knowing somebody over a period of 5 – 10 years or more in the clinic, it’s easy to get fooled and think that things are not moving much, but as a matter of fact they are. And, if the clinician is not looking at their, examination, symptoms, or the scores, he or she can miss subtle changes. Even treatments that offer modest or slow benefits can be meaningful. For instance, if someone has been living with the disease for 5 to 10 years, and a therapy can help them walk for an additional 2 years instead of just 6 months, that’s a significant impact. In other diseases like HIV or traumatic brain injury, researchers learned a lot by studying people who progressed slowly, like those who had HIV for a decade but never developed AIDS, or boxers who were punched in the head for years and never developed traumatic brain injury. The objective was to understand what was different about them. The probable answer lies in efforts like natural history studies, which collect clinical information systematically. With reference to gene testing, some studies suggest that a specific gene might be protective and more common in people with slowly progressing ALS who have a particular mutation. This redirects the focus towards new therapeutic targets. The only way to uncover this is by collecting data from people with slow and long-progressing ALS in a rigorous and coordinated way. For example, generating neurons from people with PLS and people with ALS, and specifically making spinal motor neurons to see if they have some kind of protective factors that people with ALS should have. Conclusion Dr. Walk’s insights emphasized the critical role of collaborative ALS research, genetic testing, and patient participation in shaping the future of ALS care. From exploring gene-based therapies like Tofersen to understanding slow disease progression in long-term patients, the conversation reinforced that every patient’s data matters. Continued global participation in natural history studies and clinical trials not only informs current treatments but opens new possibilities for the ALS community. As research advances, so does the hope for more effective, personalized care and ultimately, a cure. Link for the YouTube video: https://www.youtube.com/watch?v=nTjUjZmQmgw

Relevance of brain health for ALS treatment Introduction: While comprehensively analyzing the diagnostic approaches and treatment for ALS, brain health plays a very significant role in decoding the gradual progression of the disease. Amyotrophic Lateral Sclerosis (ALS) is a complex and devastating neurodegenerative disease that primarily targets motor neurons, leading to progressive loss of voluntary muscle control. Despite decades of research, its precise mechanisms and effective ALS treatment strategies remain elusive. Here are some insights on some of the most pressing questions surrounding ALS, ranging from selective neuronal vulnerability and the role of upper motor neurons, to updates on promising treatments like NU-9 and Tofersen. This further delves into emerging concepts such as prion-like transmission, brain-computer interfaces, personalized medicine, and the potential of neuroplasticity in late-stage ALS. Featured Questions 1. Why aren’t sensory neurons impacted in ALS? Not all neurons will be impacted in all diseases. ALS primarily affects the motor neuron circuitry due to  selective vulnerability  and differences in gene expression and function between motor and sensory neurons. Sensory neurons have distinct molecular profiles and are not part of the motor circuitry targeted in ALS. Other diseases (e.g., sensory neuropathies) specifically affect sensory neurons, highlighting this selectivity. As the disease progresses further, the sensory neurons might become affected, but the primary impact remains on the motor neuron circuitry.   2. What is the relationship between upper motor neurons (UMNs) and non-motor neurons? There are many types of non-motor neurons, such as callosal projection neurons, which are also excitatory, similar to pyramidal neurons. Although they are smaller than corticospinal neurons, they are born at the same time, migrate together, and reside typically in layers 1 or 2. In ALS, the callosal projection neurons remain relatively healthy but corticao-spinal neurons feel the burden. The reason could be due to the projection field, as the callosal projection neurons project to the other side of the cortex while corticospinal neurons go to the spinal cord. Differences in gene expression profiles may also play a role. UMNs integrate inputs from  diverse non-motor neurons  (e.g., excitatory, inhibitory, sensory) to initiate voluntary movement. While ALS primarily targets motor neurons,  non-motor neurons  (e.g., cortical interneurons) may contribute indirectly to UMN dysfunction as the disease progresses.   3. Recent updates on the development and experimental testing of NU9? There are on-going investigations on ALS models along with ALS FTD and Alzheimer’s disease models. With the funding from the Cure SPG foundation, the team is studying various pre-clinical models of several diseases and analyzing how specific compounds may help address their underlying causes.   4. A case-related question – “A’s mother currently has ALS, and her aunt has dementia. The mother’s uncles died of Alzheimer’s, Parkinson’s, and dementia. A is also diagnosed with ALS and does not yet have the results of the SOD1 test. A wants to use QALSODY for treatment immediately to avoid wasting any time. If SOD1 test results are negative in the future, can this drug potentially cause any harm if A does not have any genetic inheritance? Firstly, it is important to consult clinicians and doctors before beginning any treatment. Tofersen is an ASO with anti-sense oligonucleotide designed to silence the mutation. If A does not have this mutation, there’s nothing to target and the treatment may not be effective.   5. What is the potential for Tofersen to stabilize ALS and potentially reverse it? Are there any records of the undoing of ALS, stabilization or reversal? Tofersen was given approval after a 60-day clinical trial. However, the nature of the disease and its impact needs to be gauged better, and given further evaluation from experts.   6. What about prion-like transmission? There are several studies indicating prion-like transmission, especially in the context of mutated proteins. For instance, if the protein has one mutation, it introduces a kink and the structure of the protein changes. When this mutated protein interacts with another wild protein, it also becomes mutated, even though there was no specific mutation. The reason – one of them has structural change. This causes a chain reaction, impacting other proteins. According to several theories, the SOD1 mutation may have a prion-like progression or some kinds of TDP pathologies. Theoretically, it could be possible. Also, the location of the mutation is also important because not all mutations are the same. With the SOD1 gene, how many mutations have been detected, for example, 89, 90 or 100, as there is not a single mutation, but multiple mutations. The same is also true for TDP, and the location is also important.   7. How would you place the sensor array in a brain computer interface? Would more than one site be better? There are ongoing tests for several cases, where the sensors are placed in the motor cortex to modulate, excite, or read and transmit brain’s activity together with another edit machine or reader. Furthermore, one of the problems in ALS is degeneration of apical dendrites. When the degeneration is to the extent that apical dendrites don’t receive input, the sensors are positioned in the surface over the cell body and deep layers, making it harder for them to respond to each other. Healthy apical dendrites are essential. Modulation would be more effective at the early stages of the disease as opposed to the later stages of the disease. Some of the brain computer interfaces are biodegradable and some of them may be transplanted. There are ongoing studies conducted on large mammals, including primates, focusing on the vertical placement into the motor cortex.   8. Currently, is there any way to determine the underlying cause of the disease of ALS? Every patient’s serum and plasma can be subjected to proteomic, lipidomic, RNA sequencing and metabolomic tests and used for ingenuity pathway analysis or large data management toolboxes. The data can be compiled to further determine the upstream regulator, the converging path, the canonical pathway, and gradually, the main cause. Each patient carries the relevant information within them, based on findings in the serum, plasma, CSF, urine or other biological fluids. It is important to not only compile the data, but also derive insights from this data to inform our understanding of ALS. For example, if someone has gene ABC up down, and gene ABC and D are working together on the axon transport pathway, there would be three genes that are upregulated, downregulated, but they are all in the axon transport pathway. This can signify that the axon pathway may be the most affected. There is a rising need to develop personalized medicine approaches for the disease. 9. Oncology routinely uses multiple compounds to treat all the different types of cancers. How about the potential of combining NU-9 and Riluzole and an immunomodulator for treatment purposes? Yes. The field of cancer research is ten years ahead of neuroscience. There is awareness about selectivity and different tumors based on cell-type specificity. Cancer research is forming a strong prototype for neuroscience solutions. In the current landscape of medical research and FDA drug development, the cure is not focused on specific diseases like Alzheimer’s or Parkinson’s, but instead on the mechanism that drove disease progression, with the goal of overcoming the burden of mechanistic dysfunction. For example, clinical trials are conducted to improve the health and integrity of mitochondria. If XYZ is the best mitochondrial drug discovered in the process trials would enrol patients whose disease developed through mitochondrial dysfunction. This is a game-changer as we understand that ALS is a heterogenous disease, unlikely to be cured by one single drug. Researchers are recognizing that only specific subpopulations, sometimes as small as 10-20 people, may benefit from a given treatment.   10. Have studies determined if NU-9 has any effect on neurofilaments or if its clinically significant? Within the ongoing research, NU-9 has been administered to SOD1 mice and TDP mice for a period of 60 days. Then, the brain is isolated for specific tests like proteomics, and the plasma from the blood is collected to analyze changes following treatment. In addition to neurofilaments, there are many other proteins that come up. Pro-neuro filaments are important, but especially when it comes to motor neurons, other proteins come up as well.   11. Can this protein help with UMNs that already have been damaged? Is there any reversal that’s possible? The treatment process was started at P60 or postnatal day 60, which is a specific time when these mice models begin to show symptoms. Furthermore, with P60, it is possible to detect that at the cellular level, a significant amount of corticospinal motor neurons are already degenerated, and the degeneration process is ongoing. Generally, it is assumed that death happens overnight, but in reality, death is a process. Everyday, we are dying by one more day, and neurons which are vulnerable to degeneration feel the complete burden in the process leading to death. But, once the underlying issues are addressed, neurodegeneration is either slowed or stopped, providing an opportunity to contemplate the path of neurodegeneration and opt for the pathway of neuro-integration. With a 60-day treatment, the ongoing neurodegeneration can be changed to neuro-integration by resolving issues in the process.   12. How can the community support ALS research? Community building is really important and attending meetings like the Expert Talks is also really important. Fellowships can help us to train the young generation of scientists. Furthermore, networking with key philanthropists or drug companies who are interested in this research is helpful. 13. Is there anything we should be eating to maintain the health of our neurons? Typically, problems with sleep are very common in patients with neurodegenerative diseases. So, maybe, to help ourselves, we really need a good amount of sleep, because the brain secretes all the toxins and dirt into the biological fluid, CSF, which is cleaned during sleep. The human body has around 850 ml of CSF. During sleep, the heartbeat becomes regular and the CSF is cleaned. When the person does not have good quality sleep, or has sleep apnea, then the CSF is not cleaned. When the CSF is not cleaned for 5 years, 9 years, 10 years etc., it leads to protein accumulation, sporadic cases of neurodegeneration, and no mutation. So, to keep our brain healthy, we have to sleep well, as it will help the brain take a deep breath and function better. Also, oxygen levels must be high, which is helped by exercise. 14. Even in a patient with complete loss of function, not all motor neurons are lost and the remaining ones can take over the function of the others. This idea was based on a few patients who have recovered on their own. Considering the concept of neuroplasticity, can AKV-9 have an effect on a patient who’s completely lost their functions? Are there any ongoing investigations about neurofilament biomarker improvements with AKV9? There must be experiments conducted in such a way that the treatment begins at P-90 or at a different time point, exploring how late we can go to see the effect. However, at present, there are very few studies on this subject. The role of neurofilaments needs to be further explored in clinical trials, with Phase 2 studies offering a deeper investigation. Conclusion: The insights shared during the Expert Talk underscore the multifaceted nature of ALS and the growing importance of a personalized, multi-pronged approach to treatment. Advances in molecular profiling, brain-computer interfaces, and targeted therapies such as NU-9 and Tofersen highlight the potential to not only slow disease progression but, in some cases, to reverse damage and support neuronal recovery. The community’s role—through advocacy, research funding, and public awareness—remains crucial in accelerating these breakthroughs. While challenges persist, the combination of scientific innovation, cross-disciplinary collaboration, and patient-centric care continues to drive the field forward, offering renewed hope for meaningful change in the treatment and understanding of ALS. Link to the full YouTube video - https://www.youtube.com/watch?v=BLy60jGNDeI