scholarly journals Human Spinal Motor Neurons Are Particularly Vulnerable to Cerebrospinal Fluid of Amyotrophic Lateral Sclerosis Patients

2020 ◽  
Vol 21 (10) ◽  
pp. 3564 ◽  
Author(s):  
Stefan Bräuer ◽  
René Günther ◽  
Jared Sterneckert ◽  
Hannes Glaß ◽  
Andreas Hermann
Keyword(s):  
Amyotrophic Lateral Sclerosis ◽  
Cerebrospinal Fluid ◽  
Harmful Effect ◽  
Model Systems ◽  
Early Event ◽  
Human Patient ◽  
Sporadic Als ◽  
Golgi Fragmentation ◽  
Als Patients ◽  
Lateral Sclerosis

Amyotrophic lateral sclerosis (ALS) is the most common and devastating motor neuron (MN) disease. Its pathophysiological cascade is still enigmatic. More than 90% of ALS patients suffer from sporadic ALS, which makes it specifically demanding to generate appropriate model systems. One interesting aspect considering the seeding, spreading and further disease development of ALS is the cerebrospinal fluid (CSF). We therefore asked whether CSF from sporadic ALS patients is capable of causing disease typical changes in human patient-derived spinal MN cultures and thus could represent a novel model system for sporadic ALS. By using induced pluripotent stem cell (iPSC)-derived MNs from healthy controls and monogenetic forms of ALS we could demonstrate a harmful effect of ALS-CSF on healthy donor-derived human MNs. Golgi fragmentation—a typical finding in lower organism models and human postmortem tissue—was induced solely by addition of ALS-CSF, but not control-CSF. No other neurodegenerative hallmarks—including pathological protein aggregation—were found, underpinning Golgi fragmentation as early event in the neurodegenerative cascade. Of note, these changes occurred predominantly in MNs, the cell type primarily affected in ALS. We thus present a novel way to model early features of sporadic ALS.

scholarly journals Sterol auto-oxidation adversely affects human motor neuron viability and is a neuropathological feature of amyotrophic lateral sclerosis

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
James C. Dodge ◽  
Jinlong Yu ◽  
S. Pablo Sardi ◽  
Lamya S. Shihabuddin
Keyword(s):  
Amyotrophic Lateral Sclerosis ◽  
Motor Neuron ◽  
Cholesterol Homeostasis ◽  
Cholesterol Oxidation ◽  
Therapeutic Approaches ◽  
Cellular Survival ◽  
Sporadic Als ◽  
Human Motor ◽  
Als Patients ◽  
Lateral Sclerosis

AbstractAberrant cholesterol homeostasis is implicated in the pathogenesis of amyotrophic lateral sclerosis (ALS), a fatal neuromuscular disease that is due to motor neuron (MN) death. Cellular toxicity from excess cholesterol is averted when it is enzymatically oxidized to oxysterols and bile acids (BAs) to promote its removal. In contrast, the auto oxidation of excess cholesterol is often detrimental to cellular survival. Although oxidized metabolites of cholesterol are altered in the blood and CSF of ALS patients, it is unknown if increased cholesterol oxidation occurs in the SC during ALS, and if exposure to oxidized cholesterol metabolites affects human MN viability. Here, we show that in the SOD1G93A mouse model of ALS that several oxysterols, BAs and auto oxidized sterols are increased in the lumbar SC, plasma, and feces during disease. Similar changes in cholesterol oxidation were found in the cervical SC of sporadic ALS patients. Notably, auto-oxidized sterols, but not oxysterols and BAs, were toxic to iPSC derived human MNs. Thus, increased cholesterol oxidation is a manifestation of ALS and non-regulated sterol oxidation likely contributes to MN death. Developing therapeutic approaches to restore cholesterol homeostasis in the SC may lead to a treatment for ALS.

scholarly journals Cerebrospinal Fluid Chitinases as Biomarkers for Amyotrophic Lateral Sclerosis

Diagnostics ◽  
2021 ◽  
Vol 11 (7) ◽  
pp. 1210
Author(s):  
Júlia Costa ◽  
Marta Gromicho ◽  
Ana Pronto-Laborinho ◽  
Conceição Almeida ◽  
Ricardo A. Gomes ◽  
...  
Keyword(s):  
Amyotrophic Lateral Sclerosis ◽  
Cerebrospinal Fluid ◽  
Motor Neurons ◽  
Neurological Diseases ◽  
Disease Diagnosis ◽  
Enzyme Linked Immunosorbent Assay ◽  
Progression Rate ◽  
Therapeutic Trials ◽  
Als Patients ◽  
Lateral Sclerosis

Amyotrophic lateral sclerosis (ALS) is a neurodegenerative neuromuscular disease that affects motor neurons controlling voluntary muscles. Survival is usually 2–5 years after onset, and death occurs due to respiratory failure. The identification of biomarkers would be very useful to help in disease diagnosis and for patient stratification based on, e.g., progression rate, with implications in therapeutic trials. Neurofilaments constitute already-promising markers for ALS and, recently, chitinases have emerged as novel marker targets for the disease. Here, we investigated cerebrospinal fluid (CSF) chitinases as potential markers for ALS. Chitotriosidase (CHIT1), chitinase-3-like protein 1 (CHI3L1), chitinase-3-like protein 2 (CHI3L2) and the benchmark marker phosphoneurofilament heavy chain (pNFH) were quantified by an enzyme-linked immunosorbent assay (ELISA) from the CSF of 34 ALS patients and 24 control patients with other neurological diseases. CSF was also analyzed by UHPLC-mass spectrometry. All three chitinases, as well as pNFH, were found to correlate with disease progression rate. Furthermore, CHIT1 was elevated in ALS patients with high diagnostic performance, as was pNFH. On the other hand, CHIT1 correlated with forced vital capacity (FVC). The three chitinases correlated with pNFH, indicating a relation between degeneration and neuroinflammation. In conclusion, our results supported the value of CHIT1 as a diagnostic and progression rate biomarker, and its potential as respiratory function marker. The results opened novel perspectives to explore chitinases as biomarkers and their functional relevance in ALS.

A-151 Cognitive Impairment in Amyotrophic Lateral Sclerosis

2021 ◽  
Vol 36 (6) ◽  
pp. 1205-1205
Author(s):  
Etiane Navarro ◽  
Charles J Golden
Keyword(s):  
Amyotrophic Lateral Sclerosis ◽  
Cognitive Impairment ◽  
Literature Review ◽  
Cognitive Impairments ◽  
Empirical Literature ◽  
Sporadic Als ◽  
Neuropsychological Assessments ◽  
Familial Als ◽  
Als Patients ◽  
Lateral Sclerosis

Abstract Objective Amyotrophic Lateral Sclerosis (ALS) is a progressive neurodegenerative disease caused by degeneration of the upper and lower motor neurons. This literature review examines the recurring etiology of cognitive impairments in ALS through empirical literature. The current study explores ALS across different subtypes and potential cognitive impairments. Two classifications are primarily examined ALS, and ALS with frontotemporal dementia (ALS-FTD). Involving three categories: familial inheritance pattern, genetic mutation, or sporadic. Neuropsychological studies affirm cognitive impairments in individuals diagnosed with ALS and ALS-FTD. Data Selection Data was culled from the American Psychological Association (PsycInfo), PubMed, Google Scholar. Terms used in this literature review include cognitive impairment in ALS and ALS-FTD, executive function deficiencies in ALS, neuropsychology in ALS, neuropsychological deficits in ALS, neuropsychological assessments for ALS, cognitive impairments in familial ALS, genetic ALS, and sporadic ALS, familial ALS, sporadic ALS, genetic mutations involved in ALS. Search dates December 20–23 of 2020 and March 3–4 of 2021. A total of 40 studies were examined. Data Synthesis ALS-patients demonstrate a significant cognitive impairment. However, influencing comorbidities accompanying the disease may be contributing to these impairments. Researchers employed neuroimaging and neuropsychological batteries to further understand influencing factors involved in ALS and cognition. Conclusions Researchers now understand ALS as a multi-symptomatic disorder and acknowledge the presence of cognitive impairments at various encased levels. There are limitations in neuropsychological batteries that accommodate for executive dysfunctions observed in ALS patients. Future studies should explore neuropsychological assessments that accommodate for motor deficits and dysarthria when assessing cognitive impairment in ALS patients.

scholarly journals Beyond the Traditional Clinical Trials for Amyotrophic Lateral Sclerosis and The Future Impact of Gene Therapy

2021 ◽  
Vol 8 (1) ◽  
pp. 25-38
Author(s):  
Marisa Cappella ◽  
Pierre-François Pradat ◽  
Giorgia Querin ◽  
Maria Grazia Biferi
Keyword(s):  
Gene Therapy ◽  
Clinical Trials ◽  
Amyotrophic Lateral Sclerosis ◽  
Muscular Atrophy ◽  
Monogenic Disease ◽  
Sporadic Als ◽  
Pathological Mechanism ◽  
Huge Impact ◽  
Als Patients ◽  
Lateral Sclerosis

Amyotrophic lateral sclerosis (ALS) is a devastating and incurable motor neuron (MN) disorder affecting both upper and lower MNs. Despite impressive advances in the understanding of the disease’s pathological mechanism, classical pharmacological clinical trials failed to provide an efficient cure for ALS over the past twenty years. Two different gene therapy approaches were recently approved for the monogenic disease Spinal muscular atrophy, characterized by degeneration of lower MNs. This milestone suggests that gene therapy-based therapeutic solutions could be effective for the treatment of ALS. This review summarizes the possible reasons for the failure of traditional clinical trials for ALS. It provides then a focus on the advent of gene therapy approaches for hereditary forms of ALS. Specifically, it describes clinical use of antisense oligonucleotides in three familial forms of ALS, caused by mutations in SOD1, C9orf72 and FUS genes, respectively.. Clinical and pre-clinical studies based on AAV-mediated gene therapy approaches for both familial and sporadic ALS cases are presented as well. Overall, this overview highlights the potential of gene therapy as a transforming technology that will have a huge impact on treatment perspective for ALS patients and on the design of future clinical trials.

Incidence and Characteristics of Spinal Decompression Surgery after the Onset of Symptoms of Amyotrophic Lateral Sclerosis

Neurosurgery ◽  
2005 ◽  
Vol 57 (5) ◽  
pp. 984-989 ◽  
Author(s):  
Daniel Yoshor ◽  
Arnett Klugh ◽  
Stanley H. Appel ◽  
Lanny J. Haverkamp
Keyword(s):  
Amyotrophic Lateral Sclerosis ◽  
Symptom Onset ◽  
Spinal Surgery ◽  
Foot Drop ◽  
Spinal Decompression ◽  
Sporadic Als ◽  
Number Of Patients ◽  
Als Patients ◽  
The Impact ◽  
Lateral Sclerosis

Abstract OBJECTIVE: The high incidence of spondylosis in patients at the mean age of onset (55.7 yr) of amyotrophic lateral sclerosis (ALS) can make recognition of ALS as a cause of weakness difficult. METHODS: To assess the impact of this diagnostic dilemma on neurosurgical practice, we performed a retrospective analysis of a database of more than 1500 patients with motor neuron disease. RESULTS: Of 1131 patients with typical, sporadic ALS, 47 (4.2%) underwent decompressive spinal surgery after the onset of retrospectively recognized symptoms of ALS. Among 55 operations in 47 ALS patients, 86% yielded no improvement, 9% produced minor improvement, and only 5% provided significant benefit. Cervical decompression was performed in 56%, lumbar in 42%, and thoracic in 2%. Foot drop was a symptom prompting surgery in 11 patients, and in 10, this finding was subsequently attributed solely to ALS. No differences between ALS patients who underwent spinal decompression and other ALS patients were noted regarding age at symptom onset, severity of impairment at time of diagnosis, or rate of disease progression. Not surprisingly, patients who had spinal surgery tended to have a longer interval between retrospectively recognized symptom onset and diagnosis of ALS. CONCLUSION: A small but significant number of patients with unrecognized ALS undergo spinal surgery that in retrospect may be inappropriate. The possibility of ALS must be considered in the evaluation of patients with weakness even in the presence of radiographic evidence of spondylosis and nerve root or spinal cord impingement.

scholarly journals Rare CYLD Variants in Chinese Patients With Amyotrophic Lateral Sclerosis

2021 ◽  
Vol 12 ◽  
Author(s):  
Xiaojing Gu ◽  
Yongping Chen ◽  
Qianqian Wei ◽  
Yanbing Hou ◽  
Bei Cao ◽  
...  
Keyword(s):  
Amyotrophic Lateral Sclerosis ◽  
Rare Variants ◽  
Chinese Patients ◽  
Causative Gene ◽  
Missense Variants ◽  
Whole Exome ◽  
Sporadic Als ◽  
Als Patients ◽  
Lateral Sclerosis

Background: CYLD Lysine 63 Deubiquitinase gene (CYLD) was recently identified to be a novel causative gene for frontal temporal dementia (FTD)-amyotrophic lateral sclerosis (ALS). In the current study, we aimed to (1) systematically screen the mutations of CYLD in a large cohort of Chinese ALS patients, (2) study the genotype–phenotype correlation, and (3) explore the role of CYLD in ALS via rare variants burden analysis.Methods: A total of 978 Chinese sporadic ALS (sALS) patients and 46 familial ALS (fALS) patients were sequenced with whole-exome sequencing and analyzed rare variants in CYLD with minor allele frequency <0.1%.Results: In total, seven rare missense variants in CYLD have been identified in 7 (0.72%) patients among 978 sALS patients. Two (4.3%) rare missense variants were identified among the 46 fALS cases, in which one patient was diagnosed as having comorbidity of ALS and progressive supranuclear palsy (PSP). Moreover, the burden analysis indicated no enrichment of rare variants in CYLD among patients with ALS.Conclusion: In conclusion, our study extended the genotype and phenotype of CYLD in ALS, but the pathogenicity of these variants needs to be further verified. Moreover, burden analysis argued against the role of CYLD in the pathogenesis of ALS. More studies from different ethnicities would be needed.

Chitotriosidase (CHIT1) is increased in microglia and macrophages in spinal cord of amyotrophic lateral sclerosis and cerebrospinal fluid levels correlate with disease severity and progression

2017 ◽  
Vol 89 (3) ◽  
pp. 239-247 ◽  
Author(s):  
Petra Steinacker ◽  
Federico Verde ◽  
Lubin Fang ◽  
Emily Feneberg ◽  
Patrick Oeckl ◽  
...  
Keyword(s):  
Spinal Cord ◽  
Amyotrophic Lateral Sclerosis ◽  
Cerebrospinal Fluid ◽  
Disease Progression ◽  
Underlying Disease ◽  
Therapeutic Trials ◽  
Sporadic Als ◽  
Jakob Disease ◽  
Diagnostic Sensitivity And Specificity ◽  
Lateral Sclerosis

ObjectivesNeurochemical markers of amyotrophic lateral sclerosis (ALS) that reflect underlying disease mechanisms might help in diagnosis, staging and prediction of outcome. We aimed at determining the origin and differential diagnostic and prognostic potential of the putative marker of microglial activation chitotriosidase (CHIT1).MethodsAltogether 316 patients were included, comprising patients with sporadic ALS, ALS mimics (disease controls (DCo)), frontotemporal lobar degeneration (FTLD), Creutzfeldt-Jakob disease (CJD), Alzheimer’s disease (AD), Parkinson’s disease (PD) and healthy controls (Con). CHIT1 and neurofilament levels were determined in cerebrospinal fluid (CSF) and blood and analysed with regard to diagnostic sensitivity and specificity and prognostic performance. Additionally, postmortem tissue was analysed for CHIT1 expression.ResultsIn ALS, CHIT1 CSF levels were higher compared with Con (p<0.0001), DCo (p<0.05) and neurodegenerative diseases (AD p<0.05, PD p<0.01, FTLD p<0.0001) except CJD. CHIT1 concentrations were correlated with ALS disease progression and severity but not with the survival time, as did neurofilaments. Serum CHIT1 levels were not different in ALS compared with any other study group. In the spinal cord of patients with ALS, but not Con, AD or CJD cases, CHIT1 was expressed in the corticospinal tract and CHIT1 staining colocalised with markers of microglia (IBA1) and macrophages (CD68).ConclusionsCHIT1 concentrations in the CSF of patients with ALS may reflect the extent of microglia/macrophage activation in the white matter of the spinal cord. CHIT1 could be a potentially useful marker for differential diagnosis and prediction of disease progression in ALS and, therefore, seems suitable as a supplemental marker for patient stratification in therapeutic trials.

scholarly journals Genetics and Sex in the Pathogenesis of Amyotrophic Lateral Sclerosis (ALS): Is There a Link?

2020 ◽  
Vol 21 (10) ◽  
pp. 3647 ◽  
Author(s):  
Francesca Trojsi ◽  
Giulia D’Alvano ◽  
Simona Bonavita ◽  
Gioacchino Tedeschi
Keyword(s):  
Amyotrophic Lateral Sclerosis ◽  
Disease Risk ◽  
Genetic Mutation ◽  
Chromosome 9 ◽  
Patient Specific ◽  
Reading Frame ◽  
Hexanucleotide Repeat ◽  
Sporadic Als ◽  
Als Patients ◽  
Lateral Sclerosis

Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease with no known cure. Approximately 90% of ALS cases are sporadic, although multiple genetic risk factors have been recently revealed also in sporadic ALS (SALS). The pathological expansion of a hexanucleotide repeat in chromosome 9 open reading frame 72 (C9orf72) is the most common genetic mutation identified in familial ALS, detected also in 5–10% of SALS patients. C9orf72-related ALS phenotype appears to be dependent on several modifiers, including demographic factors. Sex has been reported as an independent factor influencing ALS development, with men found to be more susceptible than women. Exposure to both female and male sex hormones have been shown to influence disease risk or progression. Moreover, interplay between genetics and sex has been widely investigated in ALS preclinical models and in large populations of ALS patients carrying C9orf72 repeat expansion. In light of the current need for reclassifying ALS patients into pathologically homogenous subgroups potentially responsive to targeted personalized therapies, we aimed to review the recent literature on the role of genetics and sex as both independent and synergic factors, in the pathophysiology, clinical presentation, and prognosis of ALS. Sex-dependent outcomes may lead to optimizing clinical trials for developing patient-specific therapies for ALS.

scholarly journals Cerebrospinal Fluid TDP-43 in Frontotemporal Lobar Degeneration and Amyotrophic Lateral Sclerosis Patients with and without the C9ORF72 Hexanucleotide Expansion

2016 ◽  
Vol 6 (1) ◽  
pp. 142-149 ◽  
Author(s):  
Anna Junttila ◽  
Mari Kuvaja ◽  
Päivi Hartikainen ◽  
Maritta Siloaho ◽  
Seppo Helisalmi ◽  
...  
Keyword(s):  
Amyotrophic Lateral Sclerosis ◽  
Cerebrospinal Fluid ◽  
Frontotemporal Lobar Degeneration ◽  
Rapid Progression ◽  
Carrier Status ◽  
C9orf72 Expansion ◽  
Main Protein ◽  
Als Patients ◽  
T Tau ◽  
Lateral Sclerosis

Background: TDP-43 is the main protein component of ubiquitinated inclusions in a subgroup of frontotemporal lobar degeneration (FTLD) and amyotrophic lateral sclerosis (ALS) patients. The C9ORF72 hexanucleotide expansion is one of the main mutations associated with TDP-43 pathology in FTLD and ALS. Our aim was to analyze cerebrospinal fluid (CSF) TDP-43 levels and Alzheimer's disease biomarkers in FTLD and ALS patients and to test whether the C9ORF72 expansion carrier status affects these variables. Methods: The patient cohort consisted of 90 clinically well-characterized FTLD (n = 69) and ALS (n = 21) patients. There were 30 patients with the C9ORF72 expansion and 60 patients without the expansion. CSF TDP-43, Aβ1-42, t-tau, and phospho-tau levels were measured using commercial ELISA kits. Results: There was no difference in CSF TDP-43 levels between the C9ORF72 expansion carriers and the noncarriers. CSF TDP-43 levels were higher in ALS patients than in FTLD patients, and this finding was independent of the C9ORF72 expansion carrier status. Males had significantly higher TDP-43 levels than females (p = 0.008 in the total cohort). Conclusion: CSF TDP-43 does not seem to distinguish the C9ORF72 expansion carriers from noncarriers. However, higher CSF TDP-43 levels were detected in ALS than in FTLD, which might be an indicator of a more rapid progression of TDP-43 pathology in ALS.

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