Amyotrophic Lateral Sclerosis Spectrum Research Articles

Amyotrophic Lateral Sclerosis and Other Motor Neuron Diseases.

This article reviews the clinical spectrum of amyotrophic lateral sclerosis (ALS), its variant presentations, and the approach to diagnosis and management. This review includes a detailed discussion of current and emerging disease-modifying therapies and the management of respiratory and bulbar manifestations of disease. An updated review of ALS genetics and pathophysiology is also provided. This article also touches on several other important motor neuron diseases. A new set of simplified diagnostic criteria may help identify patients at earlier stages of the disease. A coformulation of sodium phenylbutyrate and tauroursodeoxycholic acid has been shown to have a significant benefit on disease progression and survival, leading to approval by regulatory authorities in the United States and Canada. An oral formulation of edaravone and an antisense oligonucleotide to a SOD1 gene variation (tofersen) have also recently been approved by the US Food and Drug Administration (FDA). Phase 3 trials of intrathecal mesenchymal stem cells failed to meet primary end points for efficacy. Updated American Academy of Neurology quality measures for the care of patients with ALS were published in 2023. There has been continued progress in ALS genetics, diagnosis, and disease-modifying therapies. However, we still lack a definitive biomarker or a treatment that can halt the progression or reverse the course of disease. The evolving understanding of the genetic and pathophysiologic underpinnings of disease offers promise for more effective and clinically meaningful treatments in the future.

Peripheral Nerve Ultrasound for the Differentiation between ALS, Inflammatory, and Hereditary Polyneuropathies.

Background and Objectives: Ultrasound (US) is a non-invasive tool for the in vivo detection of peripheral nerve alterations. Materials and Methods: In this study, we applied nerve US to assist the discrimination between the spectrum of amyotrophic lateral sclerosis (ALS, n = 11), chronic inflammatory demyelinating polyradiculoneuropathy (CIDP, n = 5), and genetically confirmed Charcot-Marie-Tooth disease (CMT, n = 5). All participants and n = 15 controls without neurological diseases underwent high-resolution US of the bilateral tibial nerve. The nerve cross-sectional area (CSA) and nerve microvascular blood flow were compared between the groups and related to cerebrospinal fluid (CSF) measures, clinical symptoms, and nerve conduction studies. The analyses are part of a larger multimodal study on the comparison between US and 7 Tesla (7T) magnetic resonance neurography (MRN). Results: The patients and controls were matched with respect to their demographical data. CMT had the longest disease duration, followed by CIDP and ALS. CSA was related to age, weight, and disease duration. CSA was larger in CMT and CIDP compared to ALS and controls. The blood flow was greatest in CIDP, and higher than in CMT, ALS, and controls. In ALS, greater CSA was correlated with greater CSF total protein and higher albumin quotient. The US measures did not correlate with clinical scores or nerve conduction studies in any of the subgroups. Conclusion: Our results point towards the feasibility of CSA and blood flow to discriminate between ALS, CIDP, and CMT, even in groups of small sample size. In ALS, larger CSA could indicate an inflammatory disease subtype characterized by reduced blood-nerve barrier integrity. Our upcoming analysis will focus on the additive value of 7T MRN in combination with US to disentangle the spectrum between more inflammatory or more degenerative disease variants among the disease groups.

Mills’ Disease Variant (P3-8.012)

Mills’ Disease Variant (P3-8.012)

Oxytocin in Huntington's disease and the spectrum of amyotrophic lateral sclerosis-frontotemporal dementia.

Neurodegenerative disorders (NDDs) such as Huntington’s disease (HD) and the spectrum of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) are characterized by progressive loss of selectively vulnerable populations of neurons. Although often associated with motor impairments, these NDDs share several commonalities in early symptoms and signs that extend beyond motor dysfunction. These include impairments in social cognition and psychiatric symptoms. Oxytocin (OXT) is a neuropeptide known to play a pivotal role in the regulation of social cognition as well as in emotional behaviors such as anxiety and depression. Here, we present an overview of key results implicating OXT in the pathology of HD, ALS and FTD and seek to identify commonalities across these NDDs. OXT is produced in the hypothalamus, a region in the brain that during the past decade has been shown to be affected in HD, ALS, and FTD. Several studies using human post-mortem neuropathological analyses, measurements of cerebrospinal fluid, experimental treatments with OXT as well as genetic animal models have collectively implicated an important role of central OXT in the development of altered social cognition and psychiatric features across these diseases. Understanding central OXT signaling may unveil the underlying mechanisms of early signs of the social cognitive impairment and the psychiatric features in NDDs. It is therefore possible that OXT might have potential therapeutic value for early disease intervention and better symptomatic treatment in NDDs.

Clinical and genetic spectrum of amyotrophic lateral sclerosis in a Tunisian series

Few studies looking at Amyotrophic Lateral Sclerosis (ALS) among African populations were published. Our aim was to describe clinical characteristics of Tunisian ALS patients and to explore the main candidate genes and their potential associations with ALS phenotype.

Mutation spectrum of amyotrophic lateral sclerosis in Central South China

To analyze the mutational spectrum of known ALS causative genes in China ALS patients. We comprehensively analyzed 51 ALS causative genes by combining different sequencing technologies in 753 unrelated ALS patients from Central South China. The mean age at onset (AAO) was 53.7±11.4 years. The AAO was earlier in the autosomal dominant (AD) ALS patients than in the sporadic ALS (sALS) patients. Bulbar onset was more frequent in females than in males. SOD1 was the most frequently mutated gene in the AD-ALS and the sALS patients, followed by the ATXN2 and FUS genes in the AD-ALS patients and the NEK1 and CACNA1H genes in the sALS patients. Patients with RDVs in the SOD1 or FUS genes had an earlier AAO than the mean AAO of all the patients, while the patients with RDVs in the NEK1 gene showed later onset. SOD1 gene was the most commonly mutated gene in ALS patients in China, followed by ATXN2 and NEK1. The phenotype might be determined synergistically by sex and genetic variants.

CSF sAPPβ, YKL-40, and NfL along the ALS-FTD spectrum.

To investigate the clinical utility of 3 CSF biomarkers along the clinical spectrum of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). We analyzed 3 CSF biomarkers: the soluble β-fragment of amyloid precursor protein (sAPPβ), YKL-40, and neurofilament light (NfL) in FTD (n = 86), ALS (n = 38), and a group of age-matched cognitively normal controls (n = 49). Participants with FTD with a CSF profile of Alzheimer disease were excluded. We compared cross-sectional biomarker levels between groups, studied their correlation with cognitive and functional scales (global cognitive z score, frontotemporal lobar degeneration Clinical Dementia Rating, revised ALS Functional Rating Scale, and ALS progression rate), survival, and cortical thickness. We found increased levels of YKL-40 and decreased levels of sAPPβ in both FTD and ALS groups compared to controls. The lowest sAPPβ levels and sAPPβ/YKL-40 ratio were found in the FTD group. In FTD, sAPPβ and the sAPPβ/YKL-40 ratio correlated with the disease severity. In the whole ALS-FTD spectrum, NfL levels and the NfL:sAPPβ ratio correlated with global cognitive performance (r = -0.41, p < 0.001 and r = -0.44, p < 0.001, respectively). In the ALS group, YKL-40 correlated with disease progression rate (r = 0.51, p = 0.001) and was independently associated with shorter survival. In both FTD and ALS groups, the sAPPβ/YKL-40 ratio showed a positive correlation with cortical thickness in frontotemporal regions. sAPPβ, YKL-40, and NfL could represent valuable tools for the staging and prognosis of patients within the ALS-FTD clinical spectrum. This study provides Class III evidence that CSF levels of sAPPβ, YKL-40, and NfL are useful to assess frontotemporal neurodegeneration and the progression rate in the ALS-FTD continuum.

Clinical Spectrum of Amyotrophic Lateral Sclerosis (ALS).

Amyotrophic lateral sclerosis (ALS) is primarily characterized by progressive loss of motor neurons, although there is marked phenotypic heterogeneity between cases. Typical, or "classical," ALS is associated with simultaneous upper motor neuron (UMN) and lower motor neuron (LMN) involvement at disease onset, whereas atypical forms, such as primary lateral sclerosis and progressive muscular atrophy, have early and predominant involvement in the UMN and LMN, respectively. The varying phenotypes can be so distinctive that they would seem to have differing biology. Because the same phenotypes can have multiple causes, including different gene mutations, there may be multiple molecular mechanisms causing ALS, implying that the disease is a syndrome. Conversely, multiple phenotypes can be caused by a single gene mutation; thus, a single molecular mechanism could be compatible with clinical heterogeneity. The pathogenic mechanism(s) in ALS remain unknown, but active propagation of the pathology neuroanatomically is likely a primary component.

Comprehensive rehabilitative care across the spectrum of amyotrophic lateral sclerosis.

Amyotrophic lateral sclerosis (ALS or Lou Gehrig's disease) is a neurodegenerative disease that results in progressive muscle weakness and wasting. There is no known cure and the disease is uniformly fatal. This review discusses current concepts in ALS care, from breaking the diagnosis to end-of-life care. People with ALS have several multidisciplinary needs due to a complex and dynamic disease process. They benefit from rehabilitation interventions that are individualized and have the goal of optimizing independence, function, and safety. These strategies also help minimize symptomatic burden and maximize quality of life. Patient-centered, multidisciplinary care has a significant impact on the life of people with ALS and is the current standard of care for this patient population.

Comprehensive rehabilitative care across the spectrum of amyotrophic lateral sclerosis

Comprehensive rehabilitative care across the spectrum of amyotrophic lateral sclerosis

Variability and prognostic relevance of different phenotypes in amyotrophic lateral sclerosis — Data from a population-based registry

ObjectivesThe clinical spectrum of amyotrophic lateral sclerosis (ALS) is characterized by a considerable variation. Different phenotypes have been described by previous studies. We assessed clinical variability and prognostic relevance of these phenotypes in a prospective, population-based cohort of ALS patients in Rhineland-Palatinate, Germany. MethodsIncident ALS cases, diagnosed between October 2009 and September 2012, were prospectively enrolled and classified according to established ALS phenotype classification (bulbar, classic, flail arm, flail leg, pyramidal, respiratory). Survival probability was described using Kaplan–Meier method. Moreover, the influence of an additional frontotemporal dementia (FTD) was analysed. ResultsPhenotypes of all 200 patients were determined. Bulbar and classic phenotypes accounted for 75% of all cases. Deterioration of functional impairment during disease progression was lowest in flail leg and pyramidal variants, and most pronounced in bulbar and classic phenotypes. A poor survival prognosis was observed for bulbar, classic or respiratory phenotypes. Patients with an additional FTD showed an even worse outcome. ConclusionsResults suggest that ALS is a heterogeneous disease, as ALS phenotypes differ in disease progression and survival time. Patients classified as suffering from bulbar, classic and respiratory ALS, as well as those with an additional FTD, show a marked reduction of survival time.

Seipin/BSCL2 mutation screening in sporadic adult-onset upper motor neuron syndromes

Sirs,The ability to distinguish between sporadic presentationsof hereditary spastic paraparesis (HSP) and primary lateralsclerosis (PLS) is important in terms of prognostication andgenetic counseling, but clinical differentiation is problem-atic [6]. Primary lateral scherosis is a sporadic disorder ofprogressive spino-bulbar spasticity and may be part of theclinical spectrum of amyotrophic lateral sclerosis (ALS)[10]. Hereditary spastic paraparesis is a clinically andgenetically heterogeneous group of disorders characterizedby a slowly progressive spastic paraparesis [8, 12].To date, 15 genes and more than 20 additional loci havebeen identified for autosomal dominant (AD), autosomalrecessive and X-linked forms of HSP [5, 7]. The spastingene (SPG4) mutation is the most frequent cause of ADHSP (around 40% of families) and is also frequent insporadic HSP (13%), but not in PLS [3]. We recently foundpathogenic paraplegin gene (SPG7) mutations 11% ofpatients with sporadic HSP [4]. The role of other HSP genesin sporadic upper motor neuron (UMN) syndromes islargely unknown. Two known mutations (c.263G [A/p.N88Sand c.269C[T/p.S90L) in exon 3 of the seipin/BSCL2 gene(SPG17) can cause a range of AD (mixed) upper and lowermotor neuron disorders, including Silver syndrome (HSPwith amyotrophy of the hands), variants of Charcot–Marie-tooth disease type 2, distal hereditary motor neuropathy typeV(dHMNV),butalsopureandcomplicatedformsofHSP[1,13, 14]. Because of incomplete penetrance, the seipin/BSCL2 mutation can manifest as a sporadic disease [14].To investigate whether these two seipin/BSCL2 muta-tions are present in patients with sporadic HSP and PLS,we screened exon 3 of the seipin/BSCL2 gene in 86 Dutchpatients with a sporadic adult-onset UMN syndrome.Inclusion criteria were a gradually progressive UMN syn-drome, adult-onset, disease duration [6 months and anegative family history. Exclusion criteria were lowermotor neuron loss meeting the revised El Escorial criteriafor clinically definite, clinically probable or probable lab-oratory-supported ALS [2] and evidence of other causes ofa UMN syndrome based on a battery of laboratory inves-tigations, including serum biochemistry (including thyroid-stimulating hormone, angiotensin converting enzyme,vitamin B12, folate and vitamin E), analysis of very longchain fatty acids in plasma, serology (syphilis, borreliosis,human T cell lymphotrophic virus type 1 and humanimmunodeficiency virus) and bile alcohol analysis in urine,and cerebral and spinal magnetic resonance imaging(MRI). The presence of the SPG4 and SPG7 mutations wasexcluded in all patients. The study was approved by themedical ethics review board of the University MedicalCenter in Utrecht, and written informed consent wasobtained from all patients.Mutation screening of the seipin/BSCL2 gene was per-formed using automated forward and reverse directsequencing of exon 3. The BSCL2 exon 3 was amplified byPCR using intronic primers (primer sequences available onrequest), and the PCR products were loaded on an Applied