Living with ALS (2024)

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1 Introduction and Study Context Amyotrophic lateral sclerosis (ALS) is a rapidly progressive, invari- ably fatal neurological disease for which there are no treatments that stop or reverse disease progression. At least 30,000 individuals in the United States are estimated to have a diagnosis of ALS at any given time, though as discussed in Chapter 6, this estimate may be an undercount (Mehta et al., 2023). The pathological hallmark of ALS is progressive degenera- tion of motor neurons in the brain, brainstem, and spinal cord that causes a gradual loss of motor functions. As upper motor neurons in the motor cortex deteriorate, there is scarring (sclerosis) along the length of the corti- cospinal tract. Death of spinal cord motor neurons and resulting denerva- tion of muscle underlie muscle wasting (amyotrophy). No two people living with ALS will experience the disease in the same way or have their disease progress at the same rate. Some people living with ALS have symptoms that progress slowly, while others progress rapidly. Some two-thirds of individuals with ALS initially experience effects in the muscles of the hands, forearms, calves, and feet. This form of ALS is called limb-onset ALS (Wijesekera and Nigel Leigh, 2009). The other one- third of patients first experience weakness in the muscles around the mouth and throat and develop what is called bulbar-onset ALS. Over time, these symptoms progress toward other areas of the body until all muscle groups are paralyzed. As a result, people with ALS often find motor tasks such as walking, eating, and interacting with objects increasingly difficult as their disease progresses (Jellinger, 2023; Simmons, 2015), and many then require assistance with day-to-day activities. Death usually results from respiratory failure when the muscles responsible for breathing become paralyzed. 17 

18 LIVING WITH ALS People living with ALS typically experience respiratory failure within 2 to 5 years of when symptoms first appear (Chiò et al., 2009; Wolf et al., 2014). A surgical procedure called a tracheotomy allows for artificial ven- tilation and breathing, and people living with ALS may undergo such a procedure to extend their lives. In doing so, people with ALS may live for many more years. For example, the famed astrophysicist Stephen Hawking lived for 55 years after his symptoms first appeared. Despite the progression of symptoms for this always fatal disease, most people living with ALS and who are not affected by frontotemporal dementia (FTD) retain cognitive function. However, ALS can also present with symptoms of cognitive impairment more frequently than in patients with other neuromuscular diseases (Ferrari et al., 2011; Jellinger, 2023). When cognitive impairment does occur in people with ALS, it is fre- quently associated with behavioral dysfunction similar to cognitive impair- ment observed in people with FTD (Ferrari et al., 2011). The spectrum of cognitive and behavioral dysfunction in persons with ALS is broad, ranging from mild cognitive decline to clinically confirmed FTD (Jellinger, 2023). FTD can cause dramatic behavior or personality changes, socially inappro- priate or repetitive behaviors, agitation, and an inability to use language. The reported frequency of cognitive impairment in persons with ALS varies greatly between 30 percent to 75 percent, with up to 45 percent of persons with ALS exhibiting clinically confirmed FTD (Jellinger, 2023). The cognitive and behavioral changes come with shared pathological and genetic features of these two diseases, which are often called the disease continuum or spectrum disease of ALS and FTD. The symptoms of ALS progress over the natural history of the disease. While these are widely recognized as hallmarks of ALS, ALS is a multisystem disease with a high prevalence of secondary symptoms including fatigue, pain, insom- nia, anxiety, depression, and dyspnea (Brizzi et al., 2020; Jaafar et al., 2021; Nicholson et al., 2018). The impact of secondary symptoms affecting quality of life is not as well recognized. For example, while ALS was once described as a disease characterized by “painless weakness,” it is now known that pain is a common secondary symptom affecting persons with ALS (Goutman, 2017). Most pain experienced by people with ALS is caused by tissue damage, although they can also experience other pain subtypes, such as pain caused by nerve dam- age (Chiò et al., 2017). Shoulder pain is a common example of pain affecting people with ALS, with an estimated prevalence of 23 percent in one population- based retrospective study involving 193 patients (Ho et al., 2011). EPIDEMIOLOGY ALS incidence increases with age and peaks around 60 to 79 years. Since there are approximately 30,000 people living with ALS, it is considered a rare disease, which the Orphan Drug Act of 1992 defines as a disease or 

INTRODUCTION AND STUDY CONTEXT 19 condition affecting fewer than 200,000 people in the United States (FDA, 2013). Although ALS is technically a rare disease, the lethality of the disease and the short lifespan greatly reduce the number of individuals alive with ALS at any one time. The number of new cases each year in the United States is approximately 5,000, compared to approximately 360 new cases of Duchenne muscular dystrophy and 10,000 new cases of multiple sclerosis annually. The number of people expected to develop the disease around the world in any given year is an estimated 1.68 per 100,000, though this varies slightly by region (Longinetti and Fang, 2019; Marin et al., 2017; Xu et al., 2020) and sex (Fontana et al., 2021). The number of new cases of ALS is expected to rise in the future (Arthur et al., 2016; Gowland et al., 2019). This is a result of demographic changes, such as the aging of the population and an increase in exposure to potential environmental risk factors. The Centers for Disease Control and Prevention (CDC) National ALS Registry data report a prevalence of 9.1 per 100,000 in 2018 (Mehta et al., 2023) in the United States, though as discussed in Chapter 6, this may be a significant undercount. ALS global crude prevalence is 4.42 per 100,000 but varies slightly by region and sex (Xu, 2020). The data from only a few countries are reliable, but the available data can show patterns and use- ful information about the prevalence of ALS outside of the United States (Blank et al., 2021). The highest prevalence of ALS is found in Australia (8.7), Belgium (8–12), Canada (8.1), Ireland (8), Italy (10.5), Japan (7–8), Nigeria (15), and the United Kingdom (7) (all per 100,000). The lowest prevalence of ALS can be found in China (1.23), India (4), Mexico (1.44), Pakistan (1.44), Russia (0.7–1.25), South Korea (3.43), and Tunisia (0.45) (all per 100,000) (Blank et al., 2021). STUDY TASK In response to the devastating nature of ALS for individuals and their families, Congress, as noted in the Consolidated Appropriations Act of 2022,1 directed the National Institutes of Health (NIH) to commission a study by the National Academies of Sciences, Engineering, and Medicine (the National Academies) to identify and recommend actions for the public, private, and nonprofit sectors to undertake that would make ALS a livable disease within a decade. The National Institute of Neurological Disorders and Stroke (NINDS) contracted with the National Academies to address the statement of task (see Box 1-1). 1 See House Report 117-96, originally accompanying Labor, Health and Human Services, Education, Agriculture, Rural Development, Energy and Water Development, Financial Services and General Government, Interior, Environment, Military Construction, Veterans Affairs, Trans- portation, and Housing and Urban Development Appropriations Act, 2022, H.R. 4502, as consolidated in Consolidated Appropriations Act of 2022, Public Law 117-103, 117th Congress (March 15, 2022). 

20 LIVING WITH ALS BOX 1-1 Statement of Task An ad hoc committee of the National Academies of Sciences, Engi- neering, and Medicine will conduct a study to identify and recommend key actions for the public, private, and nonprofit sectors to undertake to make amyotrophic lateral sclerosis (ALS) a livable disease within a decade. The committee will consider the landscape of ALS therapeutic development, care, services, and supports, such as: • pathways for developing more effective and meaningful treatments and a cure; • interventions to reduce and prevent the progression and complica- tions of ALS; • challenges and obstacles for public, private, and nonprofit sectors to overcome to make ALS a livable disease within a decade; • the type and range of care and services people with ALS and their families need and how to ensure they receive comprehensive, quality care; • what care, services, and preventive measures people at-risk of ALS need; and • how to improve the quality of life, health, and well-being of affected individuals and families. The committee’s work will consider equity issues across the land- scape and build on priorities identified in the National Institute of Neu- rological Disorders and Stroke’s ALS Strategic Plan, the U.S. Food and Drug Administration’s Action Plan for Rare Neurodegenerative Diseases including ALS, and additional existing analyses and expert and public input. The committee will develop a report with its recommendations for key actions that federal agencies, the pharmaceutical industry, and non- governmental organizations can take, including identifying opportunities for collaboration. THE NATURE OF ALS AND ITS SYMPTOMS As discussed earlier, ALS is a neurodegenerative disease most commonly characterized by symptoms such as difficulty walking, breathing, and speak- ing; weakness in hands and limbs; and muscle twitching. Chapter 2 discusses these and other symptoms through the lens of care and management. How- ever, the course of ALS is variable; no two people with ALS will experience the disease the same way. Exposure to risk factors, age of onset, clinical phenotype, and developmental course all differ from person to person. 

INTRODUCTION AND STUDY CONTEXT 21 Risk Factors of ALS There are two main types of ALS. Sporadic ALS is the most common form, accounting for approximately 90 percent of all cases and occurs ran- domly in individuals without a family history of ALS. However, approxi- mately 10 to 15 percent of individuals with sporadic ALS have mutations in genes known to be associated with ALS cases (Chia et al., 2018; Goutman et al., 2022d). The term familial ALS refers to individuals with ALS who have a family history of the disease. Of those individuals with familial ALS, 70 percent are carriers of known gene mutations associated with ALS. Identifying risk factors for ALS has been a key component of research into the disease. It allows people to better assess their personal risk of ALS. Knowledge about the genetic components of ALS may help inform models of the disease’s development, while identifying environmental risk factors may help reduce risk by reducing exposure. Further discussion of ALS prevention can be found in Chapter 6. However, research into gene–environment interac- tions into ALS remains nascent, and further investigation is warranted. Genetic Risk Factors Genetics are thought to be a large component of risk in ALS, affecting both familial ALS and sporadic ALS. The most prevalent gene mutations related to ALS risk include C9orf72, SOD1, TDP-43, and FUS (Chia et al., 2018). However, research has identified close to 50 genes associated with ALS when mutated, with additional gene variants that are considered risk factors of ALS disease manifestation. Mutations can be either monogenic (occurring in one gene) or polygenic (occurring in many), though research into polygenic risk is ongoing (Dou et al., 2023). These gene variations often lead to a loss of function of the affected gene, which disrupts normal cellular processes and produces the physiological phenomena associated with ALS, such as neuronal or glial dysfunction. Known ALS genetic mutations vary in their frequency, penetrance, inheri- tance pattern, and associated phenotypes and pathology. Frequency refers to how common the mutation is in ALS populations, which can be further disaggre- gated by familial/sporadic ALS, race or ethnicity, and other demographic factors. Penetrance is how likely a carrier (i.e., someone with the gene) is to develop the disease. Higher penetrance means many carriers develop dis- ease, while lower penetrance means fewer carriers develop disease. Carriers who have yet to develop ALS are a genetically defined population of interest in many studies, especially those examining preventive strategies (Benatar et al., 2022a). Penetrance varies by ALS genetic mutation, and mutations to the most common, such as C9orf72 and SOD1, are often highly penetrant (Goutman et al., 2022d). Importantly, some genes related to ALS do not definitively cause the disease but instead confer risk. Some evidence further 

22 LIVING WITH ALS suggests that penetrance of a genetic mutation may be related to other environmental exposures (Westeneng et al., 2021). Heritability for genetic mutations related to ALS varies. These genes are typically autosomal dominant, meaning that only a single copy of the muta- tion on a nonsex chromosome is sufficient to cause disease or modify risk. However, recessive inheritance, which requires inheritance of two mutated copies, occurs for some genes, as does sex-linked inheritance. Estimates of heritability in ALS-associated genes have ranged from 8.5 percent to 61 percent (Al-Chalabi et al., 2010; van Rheenen et al., 2016). ALS genes also impact onset age, phenotype, development of cogni- tive or behavioral involvement, rate of disease progression, and survival (Goutman et al., 2022d). For instance, mutations in the C9orf72 gene are strongly associated with the co-development of FTD. In many instances, the specific mutation to the ALS gene impacts all these characteristics (McCann et al., 2017). For example, a variant of the SOD1 gene with what is called the A5V mutation is very rapidly progressive. However, the full spectrum of genotype-phenotype relations in ALS remains incompletely known, particu- larly since new ALS genes and variants continue to be discovered. Environmental Risk Factors Research has linked contributions from environmental exposures to the development of sporadic ALS (Al-Chalabi and Hardiman, 2013; Chiò et al., 2018). The ALS “exposome” refers to the sum of environmental exposures and lifestyle habits that contribute to ALS risk (Goutman et al., 2023). Identifying environmental risk factors may allow for disease preven- tion in several ways. For example, exposure to known risk factors can be eliminated. When exposure cannot be fully eliminated, such as when it is related to home or occupational factors, it may still be possible to mitigate risk of ALS onset. Polluted areas could be cleaned up, and employees could use personal protective equipment when necessary. Finally, based on their genetic and environmental exposures, genetic carriers may benefit from prophylactic gene therapies currently being tested (Benatar et al., 2022b). Systematic reviews and meta-analyses have suggested multiple environ- mental risks (Newell et al., 2022; Wang et al., 2017). These include: • pesticides (Andrew et al., 2021a; Goutman et al., 2019; Su et al., 2016); • metals (Andrew et al., 2018; Figueroa-Romero et al., 2020; Peters et al., 2021); • air pollution (Myung et al., 2019; Nunez et al., 2022; Parks et al., 2022; Seelen et al., 2017); • electromagnetic exposure (Koeman et al., 2017; Luna et al., 2019; Peters et al., 2019); 

INTRODUCTION AND STUDY CONTEXT 23 • one’s microbiome (Boddy et al., 2021; Di Gioia et al., 2020; Hertzberg et al., 2022; Nicholson et al., 2021); • being a veteran, particularly when exposed to environmental toxicants or trauma (Cragg et al., 2017; McKay et al., 2021; Sagiraju et al., 2020); • working in certain occupations likely to encounter toxic environ- mental exposures (Goutman et al., 2022b), such as: 0 production (Goutman et al., 2022a); 0 agriculture (Filippini et al., 2020b); 0 mechanics (Andrew et al., 2017, 2021b); 0 painting (Andrew et al., 2017, 2021b); 0 construction (Andrew et al., 2017, 2021b); and 0 glass, pottery, and tile work (Peters et al., 2017). • exposure to repeated physical trauma (Andrew et al., 2021b; Filippini et al., 2020a; Pupillo et al., 2018); and • other variables (e.g., socioeconomic status, education, exercise, alcohol, smoking) (Goutman et al., 2022c; Henry et al., 2015; Peters et al., 2020; Westeneng et al., 2021). Investigators do not consider the link between these and the develop- ment of sporadic ALS to be conclusive, and genetic status may modify envi- ronmental risk (Westeneng et al., 2021). Concordance is not 100 percent across studies, and further investigation is needed to determine the role of genetics in modifying environmental risk. Age Age is one of the strongest known risk factors for ALS. Older onset age is more common, but, nevertheless, like presentation, is variable. Juve- nile (<25 years of age) and young-onset (<45 years of age) ALS are possible (Souza et al., 2024; Turner et al., 2012). Studies suggest that onset age varies with ALS subtype (see Table 1-1) as well as genetic mutation. Older onset age results in an older peak prevalence. In the United States, the National ALS Registry reports peak ALS prevalence between 60 to 79 years (Feldman et al., 2022). Development of ALS Pre-Symptomatic Phase Prior to disease onset, individuals are susceptible to ALS either by har- boring pathogenic mutations to ALS genes, by various risk-enhancing expo- sures, or through combined gene-exposure interactions (Benatar et al., 2022b; Goutman et al., 2023). Preventative strategies may be feasible during this phase, but research is still ongoing (Benatar et al., 2023). People with ALS 

24 LIVING WITH ALS TABLE 1-1 ALS Subtypes, Mean Onset Age, Median Survival, and Other Characteristics Approx. Approx. Mean Male to Proportion Percentage Mean Diagnostic Female Median Frontotemporal ALS Subtype of Cases Onset Age Delay Incidence Survival Dementia Spinal onset 30.3% 62.8 years 10.9 months 1.65:1 2.6 years 4% Bulbar onset 34.2% 68.8 years 9.8 months 0.98:1 2.0 years 9% Flail leg 13.0% 65.0 years 13.1 months 1.03:1 3.0 years 4.1% Flail arm 5.5% 62.6 years 12.8 months 4.00:1 4.0 years 1.4% Pyramidal 9.1% 58.3 years 15.9 months 1.04:1 6.3 years 2.5% Primary lateral 4.0% 58.9 years 15.9 months 0.98:1 13.1 years 3.8% sclerosis Progressive 2.9% 56.2 years 15.5 months 2.04:1 7.3 years 0% muscular atrophy Respiratory 1.1% 65.2 years 6.4 months 6.00:1 1.4 years 0% onset NOTE: Data are broadly representative and specific characteristics vary by ALS population. SOURCE: Generated by the committee with data from Chiò et al., 2011. first experience a pre-symptomatic phase lacking overt symptoms. This phase is further broken down into an earlier, clinically silent “pre-manifest” phase and a “prodromal” phase characterized by early symptoms. Some sensitive biomarker tests may detect evidence of the disease during the pre-manifest phase, although there is no clinically approved test. Blood or cerebrospinal fluid levels of a protein called neurofilament light chain, a marker of neuronal injury, may be promising (Benatar et al., 2018). During the prodromal phase, patients exhibit signs and symptoms not meeting the formal diagnostic criteria for ALS, such as mild motor, mild cognitive, and mild behavioral impairments, which may go unnoticed. Presentation and Subtypes of ALS Eventually, people with pre-symptomatic ALS enter a clinically manifest phase where diagnosis becomes possible, with subsequent disease progres- sion until death. This presentation is highly variable with several clinical subtypes (Feldman et al., 2022; Goutman et al., 2022e). One variable is the onset segment, meaning the part of the spinal cord and the cor- responding muscles that are first affected by the disease (see Figure 1-1, Part B). A second variable is motor neuron involvement; ALS presentation can involve lower and/or upper motor neurons (see Figure 1-1, Part A). 

INTRODUCTION AND STUDY CONTEXT 25 FIGURE 1-1 Most common ALS subtypes, natural history, and multidisciplinary treatment. NOTES: (A) Lower (blue) and upper (red) motor neurons and spinal segments and cor- responding areas initially affected by bulbar versus spinal onset ALS. (B) ALS subtypes and lower and/or upper motor neuron involvement in color legend. ALS progression is variable and can be relatively constant (C) versus punctuated by plateau periods with- out progression (D). Treatment will differ for (E) bulbar versus (F) spinal onset ALS. For instance, bulbar ALS patients may require oral and nutritional care earlier in their disease course than spinal onset ALS patients. Conversely, spinal onset ALS patients may require mobility assistance earlier in their disease course than bulbar onset patients. SOURCE: Adapted from Feldman et al., 2022. 

26 LIVING WITH ALS Lower motor neurons connect the muscles to the spinal cord whereas upper motor neurons connect the spinal cord to the brain. “Spinal” and “bulbar” ALS are the two most common subtypes. Although the precise percentage varies across populations, generally, they each constitute about one-third of ALS cases (see Table 1-1). Bulbar ALS involves both upper and lower motor neurons and affects facial mus- cles; this often presents as difficulty speaking and/or swallowing. Spinal ALS involves both upper and lower motor neurons and causes muscle weakness in limbs. The cervical-onset spinal subtype first affects the arms, especially by causing hand weakness; lumbar-onset spinal subtype first impacts the legs, especially by causing foot weakness. However, muscle weakness eventually spreads to all limbs and spinal segments, including respiratory muscles. Besides spinal and bulbar ALS, the remaining third of cases present as flail leg (approx. 13% of total ALS), flail arm (approx. 5.5%), pyramidal (approx. 9%), primary lateral sclerosis (approx. 4%), progressive muscular atrophy (approx. 3%), respiratory onset (approx. 1%), or hemiplegic (rare) (see Table 1-1). Flail leg involves lower motor neurons and affects the legs, whereas flail arm instead affects the arms but also predominantly affects lower motor neuron (although progressive disease impacts some upper motor neurons). Primary lateral sclerosis is an upper motor neuron manifes- tation impacting limb and facial muscles, while progressive muscular atro- phy affects the same muscles as well as respiratory muscles but manifests with lower motor neuron injury. Primary lateral sclerosis and progressive muscular atrophy are sometimes considered distinct entities from ALS, but many ALS neurologists consider them to be part of the same disease spec- trum as ALS. Pyramidal ALS is like primary lateral sclerosis but eventually involves lower motor neurons. Respiratory onset ALS impacts both upper and lower motor neurons and initiates in the respiratory muscles. Finally, the rare subtype of hemiplegic ALS predominantly affects upper motor neurons but causes muscle weakness only on one side of the body. ALS Natural History and Survival Like phenotypic presentation, the progression rate of ALS and overall survival from the time of diagnosis is highly variable. Death from ALS typically occurs due to respiratory failure and generally occurs within 2 to 5 years from diagnosis (Feldman et al., 2022; Goutman et al., 2022e). However, about 10 to 20 percent of ALS patients survive longer than 10 years; this is typically seen in people with younger-onset ALS (Chiò et al., 2009). ALS subtype affects survival (see Table 1-1), as do genetics and cognitive involvement (Chiò et al., 2009; Feldman et al., 2022; Goutman et al., 2022d; McCann et al., 2017). Increasingly, environmental factors are 

INTRODUCTION AND STUDY CONTEXT 27 also being identified as influential on survival; factors investigated include exposure to persistent organic pollutants and holding occupations with hazardous occupational exposures, such as manufacturing occupations or occupational pesticides exposure (Goutman et al., 2019, 2024). ALS progression is assessed by the Revised ALS Functional Rating Score (ALSFRS-R). Staging systems have also been developed to describe the stage of disease, the further along in stage the shorter the remaining survival time (Feldman et al., 2022; Goutman et al., 2022d). Progression is not always linear, and the disease course can be punctuated with periods without progression called “plateaus” (see Figure 1-1, Parts C and D). A population-based study of 1,214 ALS cases suggests that about one out of six people with ALS experiences a plateau lasting at least 6 months, but some experience plateaus as long as 12 or 18 months (Vasta et al., 2020). In the study population, plateaus usually occurred earlier in the disease course and were more frequent in spinal onset ALS. There is no prognostic model in clinical practice to predict overall survival. However, the European Network for the Cure of Amyotrophic Lateral Sclerosis generated a personalized algorithm based on onset age, time to diagnosis, clinical progression rate, respiratory function, bulbar onset, confidence in the ALS diagnosis, cognitive involvement, and presence of C9orf72 mutations (Westeneng et al., 2018). Diagnosing ALS By the time symptoms become sufficiently evident for a clinical diagno- sis of ALS, the disease has already progressed at the molecular and cellular level, and motor neuron injury is already present. Even upon symptom onset, it sometimes takes 10 to 16 months to definitively diagnose an indi- vidual with ALS, although some subtypes with a more distinct presentation, such as respiratory and bulbar onset, have shorter times to a diagnosis (Richards et al., 2021) (see Table 1-1). There are several reasons for this diagnostic delay. First, ALS is a rare disease, so it may not occur to a general physician that they are presented with a case, which may delay referral to a specialist. However, a few core clinical factors and symptoms may prompt consideration of ALS, includ- ing family history of ALS or other neurodegenerative diseases, progressive difficulty talking or eating, limb weakness without sensory symptoms, unexplained weight loss, pseudobulbar affect, and cognitive or behavioral changes (Feldman et al., 2022). Conversely, predominantly sensory or auto- nomic, nonprogressive, or no-weakness manifestations should preclude ALS. The ALS Association launched the thinkALS tool to promote con- sideration of ALS based on core clinical and symptom presentations (ALS Association, 2021). 

28 LIVING WITH ALS Second, even once a person with ALS has been referred to a specialist, the illness can mimic other conditions, so other more common causes must be ruled out before definitively diagnosing ALS. This is especially critical, since some conditions that mimic ALS are treatable. Nevertheless, due to its similar presentation and symptoms to other illnesses, ALS can be initially misdiagnosed. This may cause a person with ALS to incur unnecessary tests or cause them to miss tests that would have otherwise facilitated a more rapid diagnosis. A misdiagnosis also takes a significant emotional toll on an individual if the diagnosis is revised from a treatable condition to a terminal one, such as ALS. An accurate, timely, and earlier ALS diagnosis is the optimal scenario, since there is evidence to suggest that earlier treatment can improve out- comes. A large analysis of 4,778 ALS patients found that delaying riluzole initiation by 1 year may shorten median survival from disease onset by 1.9 months (Thakore et al., 2022). Evidence also suggests that multidisci- plinary care may improve outcomes for people with ALS across multiple domains (Miller et al., 2009). Furthermore, an earlier diagnosis would also offer ALS patients more time to contemplate and seek opportunities for clinical trial enrollment. It may also affect clinical trial eligibility. Eligibility criteria for many ALS trials exclude participants with more advanced dis- ease in order to evaluate effectiveness before molecular and cellular devel- opment of the disease. Finally, given the typical post-diagnosis survival of only 2 to 5 years, an earlier diagnosis would give people with ALS and their families more time to plan their future financial, legal, social, psychological, and spiritual well-being. Currently, ALS diagnosis continues to incur delays. Faster ALS diag- nosis may be facilitated by encouraging earlier consideration of ALS, such as with thinkALS. For future approaches, better coordination between pri- mary care centers and multidisciplinary ALS care centers could streamline referrals. Development of sensitive biomarker tests, especially for people exposed to genetic or environmental risk factors for ALS, might also help diagnosis of people with ALS in the pre-manifest phase. Treating ALS Individuals with ALS lack effective disease-modifying therapies. There are only two FDA-approved therapies that may marginally influence or alter the disease course. Riluzole, an antiglutamate agent, slows progression and increases survival by a few months. Edaravone, an antioxidant, is of uncertain efficacy and not been definitively established as broadly helpful for all people with ALS (Goutman et al., 2022d). The cornerstone of ALS care beyond these two therapies is multidisciplinary care, which is a com- prehensive plan to manage symptoms in ALS patients, including respiratory 

INTRODUCTION AND STUDY CONTEXT 29 and oral symptoms; nutrition and gastrointestinal symptoms; pain and symptoms secondary to muscle loss; and cognition, behavioral, and mood changes (Miller et al., 2009). Overall, ALS treatments must be dynamic and proactive as interven- tions that are useful early in the disease may be different than what is useful later. Multidisciplinary care contributes to making ALS a livable condition by alleviating symptoms, helping procure equipment, and helping the indi- vidual with ALS maintain some function to navigate their day-to-day life. For instance, a motorized wheelchair can provide an individual with ALS increased movement and independence. Multidisciplinary care also sup- ports the caregiver when the medical equipment needed to facilitate care is available. For example, an eye tracker or laser pointer can help an indi- vidual with ALS communicate with their caregiver. Timing of multidisciplinary care services will depend on the ALS sub- type. For instance, feeding tube insertion often occurs earlier in individuals with bulbar onset ALS, since facial muscles are the first to weaken. Another treatment element varying significantly across ALS cases is whether the individual suffers from cognitive and behavioral deficits. This has important implications for caregiving support and for the individual with ALS, who needs to make end-of-life decisions earlier in their disease course before cognitive impairment becomes too severe. Since ALS is a terminal illness, people with ALS will require palliative care in addition to supportive care, especially with progressive disease. Importantly, initiation of palliative care needs to be early in the disease course to ensure continued quality of life for individuals with ALS. Although palliative care in ALS can be delivered by a multidisciplinary team, it may need to be coordinated with local providers as individuals with ALS become less able to travel. STUDY APPROACH AND SCOPE The National Academies Study Process The National Academies established a committee of 18 volunteer experts with the experience and skills to accomplish the statement of task.2 The committee included individuals with expertise in these areas: neurology, rehabilitation, pulmonary and primary care; translational ALS and FTD research; health law and policy; ethics; health care financing; nursing and long-term care; and therapeutic development and regulatory pathways, 2 See https://www.nationalacademies.org/about for a detailed overview of the National Acad- emies and see https://www.nationalacademies.org/about/our-study-process for an overview of the National Academies’ study process (accessed June 10, 2024). 

30 LIVING WITH ALS as well individuals with ALS lived experience. The committee convened for three in-person meetings, five virtual meetings, three virtual public workshops, and numerous committee subgroup meetings during which they gathered information, reviewed evidence, and discussed findings, con- clusions, and recommendations.3 The committee’s public workshops are summarized in a Proceedings of a Workshop—in Brief, released publicly in November 2023 (NASEM, 2023). Study Context Within the ALS Ecosystem and Related ALS Activities and Initiatives This National Academies study ran in parallel with the launch or implementation of a broad range of new ALS initiatives focused pri- marily on enhancing funding and coordination for basic research and drug development, spurred by the 2021 Accelerating Access to Critical Therapies for ALS Act (ACT for ALS). These initiatives were mounted by a diverse range of groups, including NINDS, the U.S. Food and Drug Administration (FDA), and public–private partnerships such as the Critical Path for Rare Neurodegenerative Diseases. ACT for ALS initiatives primarily support expanded access to investigational therapies and accelerated development of therapeutic interventions for ALS. The committee developing this National Academies report was cognizant of these other parallel activities and its recommendations are intended to complement them. In fiscal year (FY) 2023, NIH spent $219 million on ALS research (NIH, 2024). NIH funds a broad portfolio of ALS research including: identifying the genetic and environmental contributions to both sporadic and familial ALS; characterizing cellular processes that cause motor neuron degeneration and may be targets for intervention; understanding disease heterogeneity and progression; developing new research tools and resources; discovering biomarkers for facilitating diagnosis or clinical trials; and optimizing cur- rent therapies and developing new therapies to slow, stop, or prevent ALS or to restore communication, mobility, and independence. Investigator-initiated research forms the foundation of NIH’s ALS research portfolio, but NIH also supports several large programs for ALS research, such as the Accelerating Leading-edge Science in ALS initiative, which supports multidisciplinary team science to advance our understand- ing of what triggers ALS and what drives the rapid progression of this disease, and The CReATe Consortium (The Clinical Research in ALS and 3 Information on the study process, committee meetings, and recordings of public sessions is available on the project webpage: https://www.nationalacademies.org/our-work/amyotrophic- lateral-sclerosis-accelerating-treatments-and-improving-quality-of-life (accessed June 10, 2024). 

INTRODUCTION AND STUDY CONTEXT 31 Related Disorders for Therapeutic Development), part of the trans-NIH Rare Diseases Clinical Research Network, which aims to accelerate the development of effective treatments by characterizing disease heterogeneity, improving existing clinical outcome measures for early- to mid-phase clini- cal trials, validating biomarkers as “fit for purpose,” and reducing barriers for patient participation in clinical research. Passage of ACT for ALS in 2021 and subsequent annual appropriations to NIH for implementing the ACT for ALS enabled the establishment of large clinical research programs for ALS. Section 2 of ACT for ALS authorized the expanded access research grant program to conduct scientific research and to provide access to inves- tigational therapies to people not otherwise eligible for clinical trials. The program is open to phase 3 or phase 2/3 clinical trial sites for investiga- tional drugs or biological products sponsored by a small business concern (HHS, 2023). Section 3 of ACT for ALS authorized the HHS Public-Private Partner- ship for Rare Neurodegenerative Diseases among NIH, FDA, and other eli- gible entities. NIH and FDA are collaborating to establish this partnership, which has three integrated components in the design and implementation phases during this project’s timeframe: (1) Critical Path for Rare Neurode- generative Diseases (CP-RND), (2) Accelerating Medicines Partnership in ALS (AMP ALS), and (3) Access for ALL in ALS Clinical Research Con- sortium (ALL ALS). Specific research activities within the public–private partnership are being guided by the NIH ALS Strategic Research Priorities, which were developed by the ALS community, including researchers, cli- nicians, advocates, and people with lived experience of ALS, to create a roadmap for research that will lead to effective therapies, prevention strat- egies, and improved quality of life (NIH, 2023). Developed by the ALS community, including researchers, clinicians, advocates, and people with lived experience of ALS, the priorities create a research roadmap for the ALS community and are being used by NIH to guide current and future investments. Congress appropriated $25 million in FY 2022,4 and $75 million in FYs 20235 and 20246 to NIH for implementing ACT for ALS. These funds are required to first be used to fund all expanded access research grants deemed meritorious by NIH peer review. If any funds remain, they are to be used to support the public–private partnership. 4Public Law 117-103. 5Public Law 117-328. 6Public Law 118-47. 

32 LIVING WITH ALS Critical Path for Rare Neurodegenerative Diseases (CP-RND) In September 2022 NIH and FDA announced that the Critical Path Insti- tute (C-Path) was selected to establish a public–private partnership involving FDA, NIH, persons with lived experience, advocates, researchers, and industry to advance research in ALS and other rare neurodegenerative diseases (FDA, 2024). The CP-RND efforts will focus on landscaping activities to inform research projects supported through the initiative, generation of standards, and creation of drug development tools such as biomarkers, digital health technolo- gies, trial simulation tools, biological disease classification, and novel clinical outcome assessments to accelerate ALS clinical trials (C-Path, n.d.). Accelerating Medicines Partnership in ALS (AMP ALS) The Accelerated Medicines Partnership (AMP) program through the Foundation for the National Institutes of Health (FNIH) consists of part- nerships between public- and private-sector partners intended to transform the current model for developing new diagnostics and treatments (FNIH, 2023). AMP ALS was convened by FNIH and is guided by input from people with ALS lived experience. During the project’s design phase, which was launched in June 2023, the steering committee was co-chaired by Dan Doctoroff, Target ALS; Stephanie Fradette, Biogen; and Amelie Gubitz, NINDS. Participants in the design phase included nine pharmaceutical companies, eight nonprofit organizations, federal partners (NIH, FDA), people with ALS lived experience, as well as FNIH and C-Path (ex officio). Following conclusion of the design phase, the AMP ALS implementation phase was launched in May 2024. AMP ALS has the goal of establishing a comprehensive strategy to expe- dite the development of effective new ALS treatments and seeks to achieve this goal through (1) establishing a central ALS Knowledge Platform for data sharing and analysis; (2) developing validated biomarkers for early diagnosis and treatment assessment; (3) improving clinical outcome assessments; and (4) discovering new therapeutic targets and risk factors (FNIH, 2024). The AMP ALS partners, in consultation with people with ALS lived experience, will direct research studies to achieve these objectives through the analysis of both existing and prospectively collected longitudinal clinical and biologic datasets as well as biospecimens collected from people living with ALS or at high risk of developing ALS. Key deliverables from AMP ALS include: • ALS Knowledge Platform—large-scale harmonized, longitudinal ALS clinical and molecular datasets comprising all stages of ALS, including pre-symptomatic familial ALS. The ALS Knowledge Plat- form will be a one-stop shop for academic and industry researchers to access high-value, deidentified clinical and molecular data. 

INTRODUCTION AND STUDY CONTEXT 33 • Multimodal molecular analyses of longitudinal biofluid samples and post-mortem tissue, including whole genome, gene expression, targeted and untargeted proteomics data. • New biofluid-based and digital biomarkers to aid in early diagno- sis, monitor disease progression, as well as response to treatment. • New clinical outcome assessments, including patient-informed clinical outcome assessments (C-Path, 2024). Access for All in ALS Clinical Research Consortium (ALL ALS) In October 2023, NINDS announced initial awards for ALL ALS (NINDS, 2023a). The consortium will provide a large, scalable clinical research infrastructure with the goal of facilitating research aimed at obtaining mechanistic insights into ALS heterogeneity and identifying thera- peutic targets and biomarkers (NINDS, 2023b). ALL ALS will undertake a comprehensive longitudinal natural history study, collecting a wealth of longitudinal clinical data and associated biospecimens that will be shared through the ALS Knowledge Platform and established NIH biorepositories, respectively. The planned natural history study will include individuals with symptomatic ALS, asymptomatic gene carriers, and controls. To increase outreach to potential participants, the consortium will develop community engagement strategies to reach a broad population of people living with ALS or at high risk for developing ALS, and deploy decentralized clini- cal research methodologies to allow individuals to remotely enroll and be monitored in research studies. The AMP ALS steering committee and NIH will guide the implementation of ALL ALS. An AMP ALS working group will closely collaborate with ALL ALS to provide input on the various study protocols. Collaboration The initiatives described above are each applying their unique lens to the work and their collaboration, as well as to the ALL ALS network, to identify the best opportunities to develop effective drug development tools. The ALL ALS consortium will be the space where the drug development tools and approaches developed by CP-RND and AMP ALS will be tested and refined. At the time of this report’s writing, each initiative was just get- ting underway and moving beyond the design phase. To highlight one piece of work, as part of the landscaping effort to identify unmet needs, CP-RND reviewed more than 70 ALS datasets in the United States and around the world, including information on the data collected and the architecture of the data system. CP-RND is in progress to finalize 18 agreements that would allow the extraction and curation of datasets. Sharing this information with 

34 LIVING WITH ALS AMP ALS, the goal is to ensure that the creation of any new data infrastruc- ture is appropriately building on what has been done and is truly address- ing an unmet need (C-Path, 2024). In early 2024, CP-RND and AMP ALS began the process of bringing in datasets from a variety of industry and other databases for harmonization into an ALS Knowledge Platform, which will be broadly accessible for research purposes. Another ongoing effort of CP-RND is to evaluate opportunities to improve the ALSFRS (the widely used tool for measuring ALS disease progression) to measure outcomes that are most meaningful to persons with ALS. Centering on ALS Lived Experiences The committee centered this study around the lived experience of those affected by ALS. This includes people living with ALS, caregivers, and at- risk genetic carriers, and the committee included several people with such perspectives on its roster. In addition, members of the ALS community and others shared public comments with the committee during public workshops and via a public email address. The committee also received feedback from six consultants with lived experience who responded to some of the committee’s draft report text and recommendations to consider their relevance to the ALS community. Box 1-2 lists these lived experience con- sultants. The lived experience of ALS is discussed throughout this report, particularly in Chapter 2, and the committee based much of its analysis on the perspectives that people living with ALS provided. The contributions of the committee members with lived experience, speakers, and consultants, as well as the ALS community, were invaluable to this study. Overarching Goals of the Report The primary goal of this report in the short term is to ensure that all individuals suffering from ALS have access to affordable, state-of-the art multidisciplinary treatment and services. The longer-term goal is, as speci- fied in the committee’s statement of task, to make ALS a livable disease in 10 years. What that means is laid out in more detail in Chapter 2 but, in summary, it means to significantly increase both survivability and quality of life for everyone affected by this disease, including people living with ALS, people at genetic risk of developing ALS, and their families and caregivers. Despite the heroic efforts undertaken at ALS clinics every day across the country, many people living with ALS experience significant delays in diagnosis and never receive the multidisciplinary care they need. Black indi- viduals with ALS experience a 50 percent longer delay in receiving an ALS diagnosis even though Black individuals living with ALS, in one study, were found to live closer to a multidisciplinary ALS center than White people 

INTRODUCTION AND STUDY CONTEXT 35 BOX 1-2 Lived Experience Consultants The National Academies and the committee thank these individuals, who served as volunteer lived experience consultants, for sharing their perspectives with the committee. The consultants reviewed select por- tions of the committee’s draft report text and recommendations. Michael Cosgray is a presymptomatic genetic carrier of the C9orf72 mutation that can cause ALS. Michael lost multiple family members to ALS and saw the impact of the disease on his mother, who was a fast progressor and died on April 11, 2004. Michael made the decision early in life not to have children to avoid the risk of passing down this devastat- ing mutation to future generations. Desiree Galvez Kessler was diagnosed with ALS at age 28 shortly after giving birth to her daughter. Desi is a volunteer member of a support organization, Her ALS Story. The group seeks to raise awareness of the impact ALS has on young women diagnosed before age 35 and provide a community for them to connect, learn from each other, and find support so they can live their best lives. Bernadine A. Okeke was diagnosed with ALS in 2019 at age 63. She is a volunteer member of the Many Shades of ALS Community Team at I AM ALS, a nonprofit advocacy organization. The Community Team brings attention to, and provides resources for, the mental, physical, and social health of people of color living with and affected by ALS. Ann Oliff is a caregiver for her spouse, Layne Oliff, who was diag- nosed with primary lateral sclerosis in 2017 and then ALS in 2020 after lower motor neuron symptoms emerged. Ann retired from her career as a nurse and massage therapist to provide full-time care for Layne. She previously served on a pharmaceutical company patient advisory board related to her experience as an ALS caregiver. Kristin Rankin was diagnosed with ALS at age 38. She is a sup- portive mom to three daughters—ages 15, 12, and 10—who provide inspiration to live life to the fullest and remain hopeful. Since 2022, she has served as a volunteer with the Community Outreach Team of I AM ALS. Kristin continues to work part time for the University of Illinois at Chicago School of Public Health, where she previously taught epidemiology methods and currently studies maternal and child health issues. Julian (Jules) Rodriguez is a 38-year-old husband and father who was diagnosed with ALS in 2020. Jules receives full-time care from his wife and partner, Maria Aleandra. Along with their son, Skyler, the Rodriguez family lives by the mantra and motto, “Right Here, Right Now,” as they weather the multitude of challenges (emotional, physical, mental, and spiritual) that ALS brings. 

36 LIVING WITH ALS living with ALS (Horton et al., 2018). ALS clinical trials often struggle to identify participants that meet eligibility criteria and therefore some trials are insufficiently enrolled and incapable of providing meaningful data. There is no comprehensive national registry of ALS, precluding meaning- ful assessment of overall trends in the health of people with ALS. Progress in therapeutics has been inconsistent and halting, and there is little to offer genetic carriers who are watching the clock on their own symptoms, often while caring for close relatives dying of the disease. Frustrated by the lack of significant progress, many individuals and families experienc- ing one of the most devastating diseases known to humankind are calling for major change. There are bright spots in the national picture. The committee heard many times about the value of care and supports for people with ALS within the U.S. Department of Veterans Affairs (VA) system. In the short term, everyone living with a devastating progressive disease such as ALS deserves, at a minimum, what the VA provides—care that frees an individual and their families from financial devastation because of the need to pay for ventila- tors, accessible vans, and home modifications; care that proactively delivers the interventions and equipment one needs before or just when needed; and care planning and services landscape navigation that includes partnering with caregivers and family members who will be at the side of the individual with ALS. The committee recommends actions that Congress, the Centers for Medicare & Medicaid Services (CMS), private insurers, ALS nonprofits, and patient-serving associations can take quickly to remove barriers for people with ALS to receive care and services that improve quality of life. These steps, while crucial, are not sufficient to make ALS a livable disease. Success requires significant advances in basic science, clinical care, and population health. Looking to the longer term, the committee appre- ciated the progress made in cancer and cystic fibrosis, based on a strong platform of sustainable, integrated, and coordinated systems of care and research. People living with ALS, caregivers, and genetic carriers deserve such a system too. To this end, the committee recommends that research and clinical care be coordinated across ALS community, regional, and comprehensive centers. As a condition for enhanced funding every clinical center should facilitate access to a meaningful national patient registry and allow patients access to research studies, including clinical trials. The com- mittee recommends actions Congress, NIH, CMS, ALS multidisciplinary care leaders, and community-based providers can take to build an inclusive and integrated care and research system, improve racial and ethnic equity in ALS care and research, align reimbursement to achieve the goals of the new system, and bolster VA clinical care, research, education, and informat- ics resources to further improve the comprehensiveness and reach of care for veterans. 

INTRODUCTION AND STUDY CONTEXT 37 The committee also makes recommendations for basic and translational research. The ACT for ALS research strategy holds enormous promise, and the committee believes realizing the full potential of the ACT for ALS ini- tiatives underway is necessary to achieve the goal of making ALS a livable disease in 10 years. As this report describes, an integrated and adequately funded ALS care and research system will be the foundation for introducing the new therapies these ACT for ALS initiatives are working to accelerate. The committee recognized that some of its recommendations are not unique to ALS and could apply to a broader range of diseases. For example, barriers that people living with ALS and their caregivers face in obtaining appropriate and affordable care are the same barriers experienced by many patients with other chronic and devastating diseases who are having dif- ficulties getting excellent care and negotiating with insurance companies. These recommendations are needed for ALS and could serve as a model or proof of concept for other disease areas. The committee believes that no single entity can have ultimate account- ability for coordinating all the recommendations in this report. However, entities to whom specific recommendations are directed should see this as a challenge to act. These entities can be the impetus for transforming the landscape of ALS care on which others can build. It will be incumbent on the ALS advocacy community working with people living with ALS, care- givers, genetic carriers, and more to push forward the committee’s recom- mendations and create the momentum for change. The committee hopes the ALS advocacy community will work collaboratively and build a set of expectations around the recommendations in this report and how they need to be addressed. This will ultimately involve the ALS advocacy community working with Congress, CMS, NIH, FDA, researchers, health systems, clini- cians, industry (drug developer and technology companies), and the people who are impacted by ALS every day. REFERENCES Al-Chalabi, A., and O. Hardiman. 2013. The epidemiology of ALS: A conspiracy of genes, environment and time. Nat Rev Neurol 9(11):617–628. Al-Chalabi, A., F. Fang, M. F. Hanby, P. N. Leigh, C. E. Shaw, W. Ye, and F. Rijsdijk. 2010. An estimate of amyotrophic lateral sclerosis heritability using twin data. J Neurol Neurosurg Psychiatry 81(12):1324–1326. ALS Assocation. 2021. thinkALS™ for Faster Diagnosis. https://www.als.org/thinkals (accessed May 1, 2024). Andrew, A. S., T. A. Caller, R. Tandan, E. J. Duell, P. L. Henegan, N. C. Field, W. G. Bradley, and E. W. Stommel. 2017. Environmental and occupational exposures and amyotrophic lateral sclerosis in New England. Neurodegener Dis 17(2–3):110–116. Andrew, A. S., C. Y. Chen, T. A. Caller, R. Tandan, P. L. Henegan, B. P. Jackson, B. P. Hall, W. G. Bradley, and E. W. Stommel. 2018. Toenail mercury levels are associated with amyotrophic lateral sclerosis risk. Muscle Nerve 58(1):36–41. 

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