Neuroimaging is central to the diagnostic process in amyotrophic lateral sclerosis (ALS). Neuroimaging, particularly magnetic resonance imaging (MRI), is uniquely powerful in identifying tumors and other lesions of the brain, spinal cord, or nerve roots that can masquerade as ALS. High-quality MRI of these structures is widely available and most patients with suspected ALS have MRI scans of the brain and/or spinal cord, although this may not always be necessary. Prior to the advent of neuroimaging, there was limited scope for understanding the nature and importance of the cerebral lesions in ALS. The development of neuroimaging techniques in the past 30 years has permitted the detailed study of brain pathology in vivo, and has revolutionized the study of neurologic diseases more than any other single development. Conventional techniques that can be applied in almost all modern neuroimaging units include T1- and T2–weighted images, proton density-weighted images and fluid attenuated inversion recovery (FLAIR)-weighted images.
Amyotrophic lateral sclerosis (ALS), also known as Lou Gehrig's disease, is the most common motor neuron disease. The pathologic hallmark of ALS is the selective death of motor neurons in the brain and spinal cord that innervate skeletal muscles, with symptoms of progressive weakness, muscle wasting and spasticity. Genetic susceptibility is an important determinant of the risk for ALS. The rapid rise and subsequent fall of ALS incidence rates in the Western Pacific suggest that the cause may be an environmental agent that peaked after World War II and has declined, but not completely disappeared. The classic example of a neurodegenerative disorder caused by an environmental excitotoxin is lathyrism, a disease of upper motor neurons caused by excessive consumption of the chickling pea which contains an unusual amino acid that acts as a glutamate-like excitotoxin. The epidemiologic study of ALS and motor neuron diseases has spanned several recent decades and has undergone evolution over this time period.
During development of higher vertebrates, many types of neurons including spinal and bulbar motoneurons are generated in excess. When developing motoneurons become postmitotic, they grow out axons and make contact with their target tissue, the skeletal muscle. Subsequently, about 50% of the motoneurons are lost during a critical process, which is called physiological motoneuron cell death. This phenomenon has been the focus of research for about a century and has led to the identification of neurotrophic factors that regulate survival of motoneurons during this developmental period. Motoneuron cell death is also observed in vitro when these neurons are isolated from the embryonic avian or rodent spinal cord. These cultured motoneurons have been a useful tool for studying basic mechanisms underlying neuronal degeneration. Such studies have revealed insights into signaling pathways that modulate survival during development and that might be disturbed under pathophysiological conditions in neurodegenerative disorders such as amyotrophic lateral sclerosis (ALS). However, specific differences in mechanisms that regulate survival of developing and postnatal motoneurons have also been identified. These findings could help to develop new therapeutic strategies that could counteract the pathophysiological processes underlying ALS.
ABSTRACT Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease which leads to a progressive degeneration of motoneurons. Since the pharmacological options available provide only a slight increase in life expectancy, cell therapy is emerging as a promising therapeutic alternative for ALS. A growing body of evidence from studies using genetically engineered ALS animal models demonstrate the safety and efficacy of therapies based on different cell types such as mononuclear cells, neural progenitors, and mesenchymal stem cells. Despite the encouraging results in preclinical studies, cell therapy-based clinical trials for ALS have achieved only modest results so far, probably due to the genotypic variations seen among ALS patients, which is difficult to reproduce in animal models. The advent of induced pluripotent stem cells (iPSCs) has enabled the development of patient-specific cell lines, a valuable tool to investigate in vitro molecular mechanisms of the disease and therapies in different genetic backgrounds. The applications of ALS iPSCs and their future therapeutic potential are also briefly discussed in this chapter.
This chapter introduces the reader to neurodegenerative diseases linked to dementia or movement disorders in which a protein or proteins containing mutations have been identified as causative factors of the disease. The specific mechanisms for those vulnerabilities are still unknown, but together they illustrate a variety of molecular pathways, triggered perhaps by aggregation of specific proteins, that lead to neurodegenerative syndromes. Mutation or overexpression of a-synuclein leads to cytoplasmic inclusions of presumably misfolded a-synuclein recognized histologically as Lewy bodies (LB). Tau is present in the brain in six major isoforms derived from alternative splicing of a single tau gene. The mutations in the tau gene that cause missense amino acid substitutions tend to cluster around the microtubule-binding domains of tau. Alzheimer's Disease (AD) is the most common neurodegenerative disease, with over 4 million Americans affected.
Amyotrophic lateral sclerosis (ALS) is a progressive, degenerative neuromuscular disease with limited treatment options. The diagnosis of ALS can be challenging for numerous reasons, resulting in delays that may compromise optimal management and enrollment into clinical trials. Several studies have examined the process and challenges regarding the clinical diagnosis of ALS. Twenty-one studies that were almost exclusively from the English literature published between 1990 and 2020 were identified via PubMed using relevant search terms and included patient populations from the United States, Canada, Japan, Egypt, and several countries in South America and Europe. Probable or definitive ALS patients were identified using El Escorial or revised El Escorial/Airlie House Criteria. Time to diagnosis or diagnostic delay was defined as mean or median time from patient-reported first symptom onset to formal diagnosis by a physician, as recorded in medical records. The typical time to diagnosis was 10-16 months from symptom onset. Several points of delay in the diagnosis course were identified, including specialist referrals and misdiagnoses, often resulting in unnecessary procedures and surgeries. Bulbar onset was noted to significantly reduce time to ALS diagnosis. Future interventions and potential research opportunities were reviewed.
Early detection of amyotrophic lateral sclerosis (ALS) is critical for better therapeutic outcomes. The median time from symptom onset to diagnosis of ALS is 11 months, with a range of 6-21 months. Given that the median life expectancy is three years, it is important to shorten the diagnostic journey, initiate therapies promptly, and facilitate clinical research participation. Biomarkers may be the key to enhancing early diagnosis, tracking disease progression, and testing target engagement of promising therapeutics. Clinically valid biomarkers for ALS are currently lacking, and research has been ongoing to identify appropriate biomarkers. Ideal biomarkers should be minimally invasive, such as blood. In this chapter, we review our current understanding of blood based biomarker research in ALS and discuss future directions.
Amyotrophic lateral sclerosis (ALS) is a relentlessly progressive neurodegenerative disease resulting in death in 2 to 4 years in most cases. There are several clinical subtypes of ALS depending on the degree of upper and lower motor neuron involvement, and recognition of these subtypes is important because certain subtypes have better prognosis. Without a reliable biomarker, ALS is a clinical diagnosis supported by laboratory investigations. The etiology of ALS remains unknown. However, mutations in certain genes cause ALS in about 5–8% of cases and understanding molecular pathogenetic pathways in these cases may pave a way for effective therapies. There is currently no cure or meaningfully effective therapy for ALS. Supportive and palliative measures in multidisciplinary ALS clinics are exceedingly important to maintain and improve the quality of life in patients with ALS. This chapter summarizes the clinical features and management of ALS.
Amyotrophic lateral sclerosis (ALS) is a rare and severe neurodegenerative disease affecting the upper and lower motor neurons, causing diffuse muscle paralysis. Etiology and pathogenesis remain largely unclear, but several environmental, genetic, and molecular factors are thought to be involved in the disease process. Emerging data identify a relationship between gut microbiota dysbiosis and neurodegenerative diseases, such as Parkinson's disease, Alzheimer's disease, and ALS. In these disorders, neuroinflammation is being increasingly recognized as a driver for disease onset and progression. Gut bacteria play a crucial role in maintaining and regulating the immune system, and changes in gut microbial composition can influence neural function by affecting neuro-immune interactions, synaptic plasticity, myelination, and skeletal muscle function. This chapter outlines the relationship between ALS and the human microbiota, discussing whether an imbalance in intestinal microbiota composition through a pro-inflammatory dysbiosis promotes a systemic immune/inflammatory response, and has a role in ALS pathogenesis, clinical features, progression, and outcome.
This chapter discusses non-amyotrophic lateral sclerosis (ALS) forms of motor neuron degeneration that have a genetic basis. The conditions covered include the spinal muscular atrophies (SMAs), the hereditary motor neuropathies (HMNs), Kennedy's disease and the hereditary spastic paraplegias (HSPs). SMA was first described independently by Werdnig and Hoffman in 1891. The term SMA encompasses a group of genetically determined pure lower motor neuron disorders. Nascent pre-mRNA transcripts are processed in the nucleus to produce mature mRNA by removal of introns. SMA with arthrogryposis and bone fractures is characterized by a pattern of weakness indistinguishable from SMA type 1, and congenital long-bone fractures. Distal muscle wasting in a scapuloperoneal distribution may be myopathic or neurogenic in origin. Patients frequently have mild androgen insensitivity, causing gynecomastia, testicular atrophy, oligospermia and erectile dysfunction. Clinical features of androgen insensitivity suggested a defect in androgen-reoeptor function.
This chapter examines the different methods of Motor unit number estimation (MUNE), their advantages and limitations. The concept of obtaining a motor unit number estimate is remarkably simple. A maximum compound motor action potential (CMAP) is recorded in response to supramaximal stimulation of the nerve innervating the muscle being recorded. A crucial assumption of the incremental method is that each response increment resulting from graded stimulation represents the addition of a single motor unit. The multiple point stimulation technique was developed to avoid the problem of alternation associated with the incremental technique. Brown and Milner-Brown in 1976 suggested stimulation at multiple locations along the nerve to obtain a more representative sample of motor units and more important to avoid the problem of alternation. An important assumption is that there is no bias in selection of motor units and that the sample is representative of the population of motor units.
Recent studies provide new insights into the molecular and cellular processes leading to selective motor neuron death in ALS. Proposed mechanisms of pathogenesis include glutamate toxicity, oxidative stress, apoptosis, cytotoxicity, protein aggregation and neuroinflammation. The excitotoxicity theory was first proposed in the early 1970s to describe neurodegeneration resulting from excessive exposure to excitatory amino acids. Riluzole was originally developed as an anticonvulsant. The drug inhibits the pre-synaptic release of glutamate and reduces neuronal damage in several experimental models. Riluzole had a significant effect on rates of survival and muscle strength deterioration. The safety concerns for riluzole are relatively few, with side-effects mainly confined to fatigue, nausea or vomiting, and very occasionally elevated liver enzymes, renal function impairment, vertigo or somnolence. Gabapentin Studies suggest that the anticonvulsant gabapentin may reduce glutamate activity, but its exact mechanism of action upon the glutamatergic system has not been fully elucidated.
Aging events establish the molecular and cellular contexts required for the development of motor neuron degeneration in Amyotrophic lateral sclerosis (ALS). Aging is a universal and inevitable biological process whose implications for human mortality have long fascinated biologists and artists alike. Aging can be defined as a process whereby cells and tissues of somatic lineage deteriorate with time, becoming progressively more vulnerable to environmental insults, eventually resulting in disease and death. Germline cells are not limited in their ability to divide, because the enzyme telomerase lengthens the telomere with each cell division. Pathologic states, such as oxidative stress, may increase rates of telomere loss. Genetic factors are also related to the aging process. Aging research has made remarkable discoveries in the past 10 years. Identification of genetic alleles that are under-represented in populations of aged individuals should reveal putative risk factors for those disorders.
A growing body of research now challenges this assumption, with evidence that a strong link exists between amyotrophic lateral sclerosis (ALS) and frontotemporal lobar dementia (FTLD). A neuropsychologic and neurobehavioral evaluation provides clear confirmation of the presence of frontotemporal dementia or other dementia processes. The evaluation also can identify the more subde cognitive and behavioral abnormalities that may be present. Functional imaging studies provide support for the neural mechanisms for these cognitive and behavioral abnormalities, documenting cerebral abnormalities that extend well beyond the primary, secondary and sensorimotor cortices. Pathologic study of cognitively normal and abnormal ALS patients also supports the continuum hypothesis of the syndrome. A substantial literature exists regarding how clinical depression affects attention span, memory, executive function, social behavior and inhibition. Repeated assessment of depression level in the clinic is essential also to ensure proper identification of this potentially treatable problem.
This chapter reviews the current evidence supporting the involvement of mitochondria in amyotrophic lateral sclerosis (ALS) and discusses the potential implications in the pathogenesis of this neurodegenerative disease. Morphologic and ultrastructural abnormalities of mitochondria have been observed in autopsies of patients with sporadic disorder (SALS). In eukaryotic cells, superoxide is a normal byproduct of aerobic respiration and it is produced by oxidative phosphorylation in the mitochondria. A development in the field that has helped in shedding some light on the mechanisms of mitochondrial dysfunction caused by mutant SOD1 is the finding that a proportion of SOD1 is localized in the mitochondria. A number of toxic effects of mutated SOD1 have been proposed, including impairment of mitochondrial energy metabolism and apoptosis. Mitochondria are the site of initiation of the intrinsic apoptotic pathway, which is activated by the release of pro-apoptotic factors from mitochondria and can be either caspase-dependent or caspase-independent.
Amyotrophic lateral sclerosis is a fatal adult-onset neurodegenerative disease characterized by progressive muscular weakness and atrophy. The primary feature of amyotrophic lateral sclerosis is the selective loss of motoneurons in the brain and spinal cord. However, changes in synaptic transmission and motoneuron excitability are among the first events that take place during development and accompany the relentless deterioration of motor circuitry. This chapter aims to summarize the current understanding of defects in intrinsic electrophysiological properties of motoneurons, local GABAergic and glycinergic inhibitory as well as cholinergic modulatory interneuron networks, and long-range glutamatergic excitatory input neurons that can precede disease onset or occur during the progression of the disease. We summarize evidence that therapeutic options that target synaptic transmission and intrinsic features of motoneurons might represent novel effective strategies for patients with amyotrophic lateral sclerosis.
Since neurons have long neurites, especially axons, the transport of essential mRNAs, and their translation locally in axons, are essential to maintain the shape and function of the neurons. The RNA-binding protein TDP 43 (transactive response DNA binding protein 43) plays a crucial role in the transport and translation of mRNAs in neurons. In amyotrophic lateral sclerosis (ALS) and frontotemporal lobar degeneration (FTLD), TDP-43 and other RNA-binding proteins are mis-localized and abnormally deposited in neurons. Mutations of genes regulating these proteins have been identified in clinical cases. Impaired mRNA transport system may be a contributing factor of neurodegeneration in ALS/FTLD. In this chapter, we outline the role of RNA-binding proteins, with emphasis on TDP-43, in axonal transport and local translation of mRNAs in ALS/FTLD.
The roles of different members of the team will vary as the disease progresses - and the problems faced by the person and their family changes. The diagnosis of Amyotrophic Lateral Sclerosis (ALS) is often a shock to both patient and family. It may be unknown to them all, and may lead to particular fears and concerns. The recent interest and high-profile court cases, regarding euthanasia and physician-assisted suicide, have engendered increased fears about ALS, as there is discussion of the 'distress' of the disease and its progression. The insertion of a feeding tube - either a percutaneous endoscopic gastrostomy or a radiologically inserted gastrostomy — should be considered early and insertion arranged before respiratory function has deteriorated too much, as there is increased risk if the forced vital capacity is less than 50% of expected. Dyspnea is a problem faced by up to 85% of those with ALS and may be helped by opioids.
