The Role of Osteopontin in Amyotrophic Lateral Sclerosis: A Systematic Review

Context: Osteopontin (OPN) is a matrix phosphoprotein expressed by a variety of tissues and cells, including the immune system and the nervous system. Previous studies have shown that OPN may have a role in neurodegenerative diseases, including multiple sclerosis, Parkinson’s disease, and Alzheimer’s disease. Objectives: The present study aimed to systematically review studies investigating the role of OPN in amyotrophic lateral sclerosis (ALS) patients or the disease animal model. Evidence Acquisition: We searched the Cochrane Library, PubMed, Web of Science, and Scopus to find relevant articles published up to January 20, 2019. Both human and animal model studies of ALS were considered. Results: A total of nine articles (four human studies and five animal model studies) were included. Two of the human studies reported that the CSF levels of OPN were higher among ALS patients compared to controls. The other two human studies found that OPN levels in cortical neurons did not differ significantly between ALS cases and the non-neurological control group. One of the studies found that the expression level of OPN in astrocytes was similar between ALS patients and the control group, but the level of microglial OPN significantly increased in ALS cases. Four of the animal model studies reported that the expression of OPN mRNA in spinal cord microglia significantly increased during the disease progression. The remaining animal model study found that OPN was selectively expressed by fast fatigue-resistant and slow motor neurons (MNs), which are resistant to ALS, and that the OPN expression was low among fast-fatigable MNs. Conclusions: Prompt microglial activation is a hallmark pathology of ALS, and OPN is among the most widely expressed proteins by these activated glial cells. Therefore, OPN might have a role in ALS pathogenesis. The existing evidence is not sufficient to justify whether OPN has a neurotoxic or neuroprotective role in ALS. We encourage researchers to investigate the role of OPN in ALS pathogenesis more extensively.

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Cortical and Striatal Electroencephalograms and Apomorphine Effects in the FUS Mouse Model of Amyotrophic Lateral Sclerosis

Journal of Alzheimer s Disease ◽

10.3233/jad-201472 ◽

2021 ◽

pp. 1-15

Author(s):

Vasily Vorobyov ◽

Alexander Deev ◽

Frank Sengpiel ◽

Vladimir Nebogatikov ◽

Aleksey A. Ustyugov

Keyword(s):

Amyotrophic Lateral Sclerosis ◽

Motor Neurons ◽

Cortical Neurons ◽

Primary Motor Cortex ◽

Beta Activity ◽

Systemic Injection ◽

Eeg Spectra ◽

Electroencephalogram Eeg ◽

Lateral Sclerosis

Background: Amyotrophic lateral sclerosis (ALS) is characterized by degeneration of motor neurons resulting in muscle atrophy. In contrast to the lower motor neurons, the role of upper (cortical) neurons in ALS is yet unclear. Maturation of locomotor networks is supported by dopaminergic (DA) projections from substantia nigra to the spinal cord and striatum. Objective: To examine the contribution of DA mediation in the striatum-cortex networks in ALS progression. Methods: We studied electroencephalogram (EEG) from striatal putamen (Pt) and primary motor cortex (M1) in ΔFUS(1–359)-transgenic (Tg) mice, a model of ALS. EEG from M1 and Pt were recorded in freely moving young (2-month-old) and older (5-month-old) Tg and non-transgenic (nTg) mice. EEG spectra were analyzed for 30 min before and for 60 min after systemic injection of a DA mimetic, apomorphine (APO), and saline. Results: In young Tg versus nTg mice, baseline EEG spectra in M1 were comparable, whereas in Pt, beta activity in Tg mice was enhanced. In older Tg versus nTg mice, beta dominated in EEG from both M1 and Pt, whereas theta and delta 2 activities were reduced. In younger Tg versus nTg mice, APO increased theta and decreased beta 2 predominantly in M1. In older mice, APO effects in these frequency bands were inversed and accompanied by enhanced delta 2 and attenuated alpha in Tg versus nTg mice. Conclusion: We suggest that revealed EEG modifications in ΔFUS(1–359)-transgenic mice are associated with early alterations in the striatum-cortex interrelations and DA transmission followed by adaptive intracerebral transformations.

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Significance of Serological Markers in Neurological Function and Progression Rate of Amyotrophic Lateral Sclerosis

10.21203/rs.3.rs-667353/v1 ◽

2021 ◽

Author(s):

Xiaowen Chen ◽

Junrong Li ◽

Yingying Lv ◽

Wei Zhang ◽

xiujian Xu ◽

...

Keyword(s):

Amyotrophic Lateral Sclerosis ◽

Creatine Kinase ◽

Uric Acid ◽

Total Cholesterol ◽

Cystatin C ◽

Control Group ◽

Progression Rate ◽

Cholesterol Levels ◽

Als Patients ◽

Lateral Sclerosis

Abstract Objective The present study was to investigate the significance of creatinine, uric acid, creatine kinase, total cholesterol, triglyceride, HCY (Homocysteine), and cystatin C in neurological function and progression rate of amyotrophic lateral sclerosis. Methods According to the diagnostic criteria of EI-Escorial (2000), 103 patients with ALS were enrolled. All patients were given corresponding serological tests at the initial diagnosis. The Revised ALS Functional Rating Scale (ALSFRS-R) and Disease Progression Rate (DPR) were evaluated. The detected indexes in blood tests included creatinine, uric acid, creatine kinase, total cholesterol, triglycerides, homocysteine, and cystatin C. All data were input into the computer, and the data analysis was performed by SPSS22.0 statistical software.Results 1. There were significant differences in creatinine, uric acid, creatine kinase, total cholesterol, HCY and cystatin C between the two groups (P<0.05). The levels of uric acid and creatinine of ALS group were lower than those of the control group, and the levels of creatine kinase, total cholesterol, triglyceride, HCY and cystatin C were higher than that in the control group. 2. The results from correlation analysis demonstrated that there was a significant correlation between ALSFRS-R and creatinine (P<0.01), the correlation coefficient was 0.567 (positive correlation); There was also a significant correlation between DPR and creatinine (P<0.01), and the correlation coefficient was -0.808 (negative correlation). The correlations of DPR with triglyceride and total cholesterol were significantly negative correlated (P<0.05), with -0.201 and -0.210 of correlation coefficients, respectively. The remaining indexes did not show any correlation with ALSFRS-R and DPR. Conclusions 1. Uric acid and creatinine of ALS patients were lower than that in healthy people. Creatine kinase, triglyceride, total cholesterol, HCY, and cystatin C in ALS patients were higher than those in health controls. There were significant metabolic abnormalities in ALS patients. 2. Creatinine level is an independent risk factor affecting ALSFRS-R. The creatinine and total cholesterol levels are also the independent risk factors affecting DPR. Creatinine and total cholesterol levels could be used as reliable indicators to evaluate the ALSFRS-R and DPR of ALS patients.

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Role of Blood Neurofilaments in the Prognosis of Amyotrophic Lateral Sclerosis: A Meta-Analysis

Frontiers in Neurology ◽

10.3389/fneur.2021.712245 ◽

2021 ◽

Vol 12 ◽

Author(s):

Yan-ni Zhou ◽

You-hong Chen ◽

Si-qi Dong ◽

Wen-bo Yang ◽

Ting Qian ◽

...

Keyword(s):

Amyotrophic Lateral Sclerosis ◽

Meta Analysis ◽

Progression Rate ◽

Neurofilament Light Chain ◽

Neurofilament Light ◽

Risk Of Death ◽

Disease Progression Rate ◽

Als Patients ◽

Lateral Sclerosis

Background: Neurofilaments in cerebrospinal fluid (CSF) and in blood are considered promising biomarkers of amyotrophic lateral sclerosis (ALS) because their levels can be significantly increased in patients with ALS. However, the roles of neurofilaments, especially blood neurofilaments, in the prognosis of ALS are inconsistent. We performed a meta-analysis to explore the prognostic roles of blood neurofilaments in ALS patients.Methods: We searched all relevant studies on the relationship between blood neurofilament levels and the prognosis of ALS patients in PubMed, Embase, Scopus, and Web of Science before February 2, 2021. The quality of the included articles was assessed using the Quality in Prognosis Studies (QUIPS) scale, and R (version 4.02) was used for statistical analysis.Results: Fourteen articles were selected, covering 1,619 ALS patients. The results showed that higher blood neurofilament light chain (NfL) levels in ALS patients were associated with a higher risk of death [medium vs. low NfL level: HR = 2.43, 95% CI (1.34–4.39), p < 0.01; high vs. low NfL level: HR = 4.51, 95% CI (2.45–8.32), p < 0.01]. There was a positive correlation between blood phosphorylated neurofilament heavy chain (pNfH) levels and risk of death in ALS patients [HR = 1.87, 95% CI (1.35–2.59), p < 0.01]. The levels of NfL and pNfH in blood positively correlated with disease progression rate (DPR) of ALS patients [NfL: summary r = 0.53, 95% CI (0.45–0.60), p < 0.01; pNfH: summary r = 0.51, 95% CI (0.24–0.71), p < 0.01].Conclusion: The blood neurofilament levels can predict the prognosis of ALS patients; specifically, higher levels of blood neurofilaments are associated with a greater risk of death.

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Eye Movement Abnormalities in Amyotrophic Lateral Sclerosis

10.21203/rs.3.rs-1114560/v1 ◽

2021 ◽

Author(s):

Xintong Guo ◽

Xiaoxuan Liu ◽

Shan Ye ◽

Xiangyi Liu ◽

Xu Yang ◽

...

Keyword(s):

Amyotrophic Lateral Sclerosis ◽

Eye Movement ◽

Smooth Pursuit ◽

Oculomotor System ◽

Control Group ◽

Clinical Markers ◽

Square Wave ◽

Movement Parameters ◽

Als Patients ◽

Lateral Sclerosis

Abstract Background and Purpose It is generally believed that eye movements are completely spared in amyotrophic lateral sclerosis (ALS). Although a series of eye movement abnormalities has been recognized in recent years, the findings are highly controversial, and the corresponding pattern has not yet been established. Furthermore, bulbar disabilities should be considered in relation to eye movement abnormalities. The present study aimed to determine whether eye movement abnormalities are present in ALS and, if so, to investigate their characteristics and their association with bulbar disability in ALS patients. Methods Patients with clinically definite, probable or laboratory-supported probable ALS (n=60) and a control group composed of their caregivers (n=30) underwent clinical assessments and standardized evaluations of the oculomotor system using videonystagmography. The gaze test, reflexive saccade test and smooth pursuit test were administered to all subjects. Results Eye movement abnormalities such as square-wave jerks, abnormal cogwheeling during smooth pursuit, and saccade hypometria were observed in ALS patients. Square-wave jerks (p<0.001) and abnormal cogwheeling during smooth pursuit (p=0.001) were more frequently observed in ALS patients than in the control subjects. In subgroup analyses, square-wave jerks (p=0.004) and abnormal cogwheeling during smooth pursuit (p=0.031) were found to be more common in ALS patients with bulbar involvement (n=44) than in those without bulbar involvement (n=16). There were no significant differences in the investigated eye movement parameters between bulbar-onset (n=12) and spinal-onset patients (n=48). Conclusion ALS patients showed a range of eye movement abnormalities, affecting mainly the ocular fixation and smooth pursuit systems. These abnormalities were observed more common in the ALS patients with bulbar involvement. Our pioneering study indicates that the region of involvement could better indicate the pathophysiological essence of the abnormalities than the type of onset pattern in ALS. Eye movement abnormalities may be potential clinical markers for objectively evaluating upper brainstem or supratentorial cerebral lesion neurodegeneration in ALS.

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Death Receptors in the Selective Degeneration of Motoneurons in Amyotrophic Lateral Sclerosis

Journal of Neurodegenerative Diseases ◽

10.1155/2013/746845 ◽

2013 ◽

Vol 2013 ◽

pp. 1-11 ◽

Cited By ~ 5

Author(s):

Julianne Aebischer ◽

Nathalie Bernard-Marissal ◽

Brigitte Pettmann ◽

Cédric Raoul

Keyword(s):

Amyotrophic Lateral Sclerosis ◽

Immune Cells ◽

Microglial Activation ◽

Death Receptors ◽

Strong Body ◽

Als Patients ◽

Brain And Spinal Cord ◽

The Brain ◽

Lateral Sclerosis

While studies on death receptors have long been restricted to immune cells, the last decade has provided a strong body of evidence for their implication in neuronal death and hence neurodegenerative disorders such as amyotrophic lateral sclerosis (ALS). ALS is a fatal paralytic disorder that primarily affects motoneurons in the brain and spinal cord. A neuroinflammatory process, associated with astrocyte and microglial activation as well as infiltration of immune cells, accompanies motoneuron degeneration and supports the contribution of non-cell-autonomous mechanisms in the disease. Hallmarks of Fas, TNFR, LT-βR, and p75NTR signaling have been observed in both animal models and ALS patients. This review summarizes to date knowledge of the role of death receptors in ALS and the link existing between the selective loss of motoneurons and neuroinflammation. It further suggests how this recent evidence could be included in an ultimate multiapproach to treat patients.

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Amyotrophic Lateral Sclerosis, a Multisystem Pathology: Insights into the Role of TNFα

Mediators of Inflammation ◽

10.1155/2017/2985051 ◽

2017 ◽

Vol 2017 ◽

pp. 1-16 ◽

Cited By ~ 19

Author(s):

Massimo Tortarolo ◽

Daniele Lo Coco ◽

Pietro Veglianese ◽

Antonio Vallarola ◽

Maria Teresa Giordana ◽

...

Keyword(s):

Amyotrophic Lateral Sclerosis ◽

Immune System ◽

Disease Progression ◽

Protective Role ◽

Progression Rate ◽

Neuron Death ◽

Multisystem Disease ◽

Als Patients ◽

Lateral Sclerosis

Amyotrophic lateral sclerosis (ALS) is considered a multifactorial, multisystem disease in which inflammation and the immune system play important roles in development and progression. The pleiotropic cytokine TNFαis one of the major players governing the inflammation in the central nervous system and peripheral districts such as the neuromuscular and immune system. Changes in TNFαlevels are reported in blood, cerebrospinal fluid, and nerve tissues of ALS patients and animal models. However, whether they play a detrimental or protective role on the disease progression is still not clear. Our group and others have recently reported opposite involvements of TNFR1 and TNFR2 in motor neuron death. TNFR2 mediates TNFαtoxic effects on these neurons presumably through the activation of MAP kinase-related pathways. On the other hand, TNFR2 regulates the function and proliferation of regulatory T cells (Treg) whose expression is inversely correlated with the disease progression rate in ALS patients. In addition, TNFαis considered a procachectic factor with a direct catabolic effect on skeletal muscles, causing wasting. We review and discuss the role of TNFαin ALS in the light of its multisystem nature.

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Rare CYLD Variants in Chinese Patients With Amyotrophic Lateral Sclerosis

Frontiers in Genetics ◽

10.3389/fgene.2021.740052 ◽

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.

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Evaluation of Peripheral Immune Activation in Amyotrophic Lateral Sclerosis

Frontiers in Neurology ◽

10.3389/fneur.2021.628710 ◽

2021 ◽

Vol 12 ◽

Author(s):

Mengli Wang ◽

Zhen Liu ◽

Juan Du ◽

Yanchun Yuan ◽

Bin Jiao ◽

...

Keyword(s):

Amyotrophic Lateral Sclerosis ◽

Neurodegenerative Diseases ◽

Late Onset ◽

Meta Analysis ◽

Age At Onset ◽

Serum Levels ◽

Als Patients ◽

Immune Dysfunctions ◽

Lateral Sclerosis

Accumulating evidence has revealed that immunity plays an important role in amyotrophic lateral sclerosis (ALS) progression. However, the results regarding the serum levels of immunoglobulin and complement are inconsistent in patients with ALS. Although immune dysfunctions have also been reported in patients with other neurodegenerative diseases, few studies have explored whether immune dysfunction in ALS is similar to that in other neurodegenerative diseases. Therefore, we performed this study to address these gaps. In the present study, serum levels of immunoglobulin and complement were measured in 245 patients with ALS, 65 patients with multiple system atrophy (MSA), 60 patients with Parkinson's disease (PD), and 82 healthy controls (HCs). Multiple comparisons revealed that no significant differences existed between patients with ALS and other neurodegenerative diseases in immunoglobulin and complement levels. Meta-analysis based on data from our cohort and eight published articles was performed to evaluate the serum immunoglobulin and complement between patients with ALS and HCs. The pooled results showed that patients with ALS had higher C4 levels than HCs. In addition, we found that the IgG levels were lower in early-onset ALS patients than in late-onset ALS patients and HCs, and the correlations between age at onset of ALS and IgG or IgA levels were significant positive. In conclusion, our data supplement existing literature on understanding the role of peripheral immunity in ALS.

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VGF Protein and Its C-Terminal Derived Peptides in Amyotrophic Lateral Sclerosis: Human and Animal Model Studies

PLoS ONE ◽

10.1371/journal.pone.0164689 ◽

2016 ◽

Vol 11 (10) ◽

pp. e0164689 ◽

Cited By ~ 9

Author(s):

Carla Brancia ◽

Barbara Noli ◽

Marina Boido ◽

Andrea Boi ◽

Roberta Puddu ◽

...

Keyword(s):

Animal Model ◽

Amyotrophic Lateral Sclerosis ◽

Model Studies ◽

Lateral Sclerosis

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Rapid Voice Tremor, or “Flutter,” in Amyotrophic Lateral Sclerosis

Annals of Otology Rhinology & Laryngology ◽

10.1177/000348949210100612 ◽

1992 ◽

Vol 101 (6) ◽

pp. 511-518 ◽

Cited By ~ 37

Author(s):

Arnold E. Aronson ◽

William S. Winholtz ◽

Lorraine Olson Ramig ◽

Sandra R. Silber

Keyword(s):

Amyotrophic Lateral Sclerosis ◽

Matched Control ◽

Normal Subjects ◽

Control Group ◽

Fast Fourier Transform Analysis ◽

Frequency Components ◽

Low Levels ◽

Frequency Modulations ◽

Als Patients ◽

Lateral Sclerosis

In an attempt to clarify the origin and frequency characteristics of a rapid voice tremor, or “flutter,” in patients with amyotrophic lateral sclerosis (ALS), eight patients (four men and four women; ages 42 to 70 years) who had ALS and rapid voice tremor and an age-and sex-matched control group of eight subjects were asked to sustain the vowel /a/ and their voices were recorded for later analysis. Each segment of phonation was demodulated into amplitude and frequency components. From each subject's 8-second amplitude and frequency signals, a fast Fourier transform analysis was done on a 1-second segment previously identified perceptually as having the most apparent tremor or flutter. The results showed that patients with ALS had multiple combinations of levels and frequencies for amplitude and frequency modulations in comparison with control subjects, who had consistently low levels of modulations. In an attempt to quantify the tremor or flutter in ALS, amplitude and frequency modulations were not clearly or predominantly represented at one point along the spectrum. Nevertheless, these frequency and amplitude modulations are more prominent in patients with ALS than in normal subjects. The origins of these aberrant frequency and amplitude modulations in ALS patients remain obscure, although speculation is that they are of peripheral rather than central nervous system origin.

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