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

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.

scholarly journals Plasma and CSF Neurofilament Light Chain in Amyotrophic Lateral Sclerosis: A Cross-Sectional and Longitudinal Study

2021 ◽  
Vol 13 ◽  
Author(s):  
Veria Vacchiano ◽  
Andrea Mastrangelo ◽  
Corrado Zenesini ◽  
Marco Masullo ◽  
Corinne Quadalti ◽  
...  
Keyword(s):  
Amyotrophic Lateral Sclerosis ◽  
Light Chain ◽  
Progression Rate ◽  
Disease Course ◽  
Neurofilament Light Chain ◽  
Neurofilament Light ◽  
Body Regions ◽  
Slow Progressors ◽  
Als Patients ◽  
Lateral Sclerosis

Background: Neurofilament light chain (NfL) is a validated biofluid marker of neuroaxonal damage with great potential for monitoring patients with neurodegenerative diseases. We aimed to further validate the clinical utility of plasma (p) vs. CSF (c) NfL for distinguishing patients with Amyotrophic Lateral Sclerosis (ALS) from ALS mimics. We also assessed the association of biomarker values with clinical variables and survival and established the longitudinal changes of pNfL during the disease course.Methods: We studied 231 prospectively enrolled patients with suspected ALS who underwent a standardized protocol including neurological examination, electromyography, brain MRI, and lumbar puncture. Patients who received an alternative clinical diagnosis were considered ALS mimics. We classified the patients based on the disease progression rate (DPR) into fast (DPR > 1), intermediate (DPR 0.5–1), and slow progressors (DPR < 0.5). All patients were screened for the most frequent ALS-associated genes. Plasma and CSF samples were retrospectively analyzed; NfL concentrations were measured with the SIMOA platform using a commercial kit.Results: ALS patients (n = 171) showed significantly higher pNfL (p < 0.0001) and cNfL (p < 0.0001) values compared to ALS mimics (n = 60). Both cNfL and pNfL demonstrated a good diagnostic value in discriminating the two groups, although cNfL performed slightly better (cNfL: AUC 0.924 ± 0.022, sensitivity 86.8%, specificity 92.4; pNfL: AUC 0.873 ± 0.036, sensitivity 84.7%, specificity 83.3%). Fast progressors showed higher cNfL and pNfL as compared to intermediate (p = 0.026 and p = 0.001) and slow progressors (both p < 0.001). Accordingly, ALS patients with higher baseline cNfL and pNfL levels had a shorter survival (highest tertile of cNfL vs. lowest tertile, HR 4.58, p = 0.005; highest tertile of pNfL vs. lowest tertile, HR 2.59, p = 0.015). Moreover, there were positive associations between cNfL and pNfL levels and the number of body regions displaying UMN signs (rho = 0.325, p < 0.0001; rho = 0.308, p = 0.001). Finally, longitudinal analyses in 57 patients showed stable levels of pNfL during the disease course.Conclusion: Both cNfL and pNfL have excellent diagnostic and prognostic performance for symptomatic patients with ALS. The stable longitudinal trajectory of pNfL supports its use as a marker of drug effect in clinical trials.

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

2017 ◽  
Vol 2017 ◽  
pp. 1-16 ◽  
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.

scholarly journals Circulating miR-181 is a prognostic biomarker for amyotrophic lateral sclerosis

2021 ◽  
Author(s):  
Eran Hornstein ◽  
Iddo Magen ◽  
Anna Coenen-Stass ◽  
Nancy Yacovzada ◽  
Julian Grosskreutz ◽  
...  
Keyword(s):  
Clinical Trials ◽  
Amyotrophic Lateral Sclerosis ◽  
Neurofilament Light Chain ◽  
Protein Biomarker ◽  
Neurofilament Light ◽  
Risk Of Death ◽  
Novel Mirna ◽  
Independent Replication ◽  
Clinical Phenotyping ◽  
Lateral Sclerosis

Abstract Amyotrophic lateral sclerosis (ALS) is a relentless neurodegenerative syndrome of the human motor neuron system, for which no effective treatment exists. Variability in the rate of disease progression limits the efficacy of ALS clinical trials, suggesting that developing of better biomarkers for prognosis will facilitate therapeutic progress. Here, we applied unbiased next-generation sequencing to investigate the potential of plasma cell-free microRNAs as biomarkers of ALS prognosis, in 252 patients with detailed clinical-phenotyping. First, we identified miRNAs, whose plasma levels remain stable over the course of disease in a longitudinal cohort of 22 patients. Next, we demonstrated that high levels of miR-181, a miRNA enriched in neurons of the brain and spinal cord, predicts a >2 fold risk of death in discovery cohort (126 patients) and an independent replication cohort (additional 122 patients). miR-181 performance is comparable with the established neurofilament light chain (NfL) biomarker and when combined together, miR-181+NfL establish a novel RNA-protein biomarker pair with superior prediction capacity of ALS prognosis. Therefore, plasma miR-181 predicts ALS disease course, and a novel miRNA-protein biomarker approach, based on miR-181+NfL, boosts precision of patient stratification and may greatly enhance the power of clinical trials.

scholarly journals Evaluation of Peripheral Immune Activation in Amyotrophic Lateral Sclerosis

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.

scholarly journals Correlation between leukocyte phenotypes and prognosis of amyotrophic lateral sclerosis: a longitudinal cohort study

2021 ◽  
Author(s):  
Can Cui ◽  
Caroline Ingre ◽  
Li Yin ◽  
Xia Li ◽  
John Andersson ◽  
...  
Keyword(s):  
T Cells ◽  
Amyotrophic Lateral Sclerosis ◽  
Nk Cells ◽  
Functional Status ◽  
Disease Progression ◽  
Lymphocyte Subpopulations ◽  
Progression Rate ◽  
Risk Of Death ◽  
Disease Progression Rate ◽  
Lateral Sclerosis

Background: Immune response changes have been reported in amyotrophic lateral sclerosis (ALS), but their clinical relevance remains undetermined. Therefore, we aim to evaluate the relationships between blood leukocyte subpopulations and prognosis of ALS.<br />Methods: A longitudinal cohort of 288 ALS patients with up to 5 years of follow-up during 2015-2020 were recruited at the only tertiary referral center for ALS in Stockholm, Sweden. Routine differential leukocyte counts, and determination of lymphocyte subpopulations including an extended T cell panel with flow cytometry, collected at diagnosis and at regular intervals thereafter. The primary outcome was risk of death (alternatively use of invasive ventilation) after diagnosis of ALS. The secondary outcomes included repeatedly measured functional status - through Amyotrophic Lateral Sclerosis Functional Rating Scale-revised (ALSFRS-R) score and disease progression rate. Cox model was used to evaluate the associations between leukocytes and risk of death. Generalized estimating equation model (GEE) was used to assess the correlation between leukocytes and ALSFRS-R score<br />and disease progression rate.<br />Results: The counts of leukocytes, neutrophils and monocytes increased gradually over time since diagnosis and were negatively correlated with ALSFRS-R score, but not associated with risk of death or disease progression rate. Focusing on lymphocyte subpopulations, increasing counts of natural killer (NK) cells (HR=0.61, 95% CI= [0.42-0.88] per SD increase) and proportions of Th2-diffrentiated CD4+ central memory (CM) T cells (HR=0.64, 95% CI= [0.48-0.85] per SD increase) were correlated with a lower risk of death. Increasing proportions of CD4+ effector memory cells re-expressing CD45RA (EMRA) T cells (HR=1.39, 95% CI= [1.01-1.92] per SD increase) and CD8+ T cells (HR=1.38, 95% CI= [1.03-1.86] per SD increase) were associated with a higher risk of death. None of the lymphocyte subpopulations was correlated with ALSFRS-R score or disease progression rate.<br />Conclusion: Our findings suggest a dual role of immune responses in ALS prognosis, where neutrophils and monocytes primarily reflect functional status whereas NK cells and different T lymphocyte populations act as prognostic markers for survival.

Neurofilament light chain in serum for the diagnosis of amyotrophic lateral sclerosis

2018 ◽  
Vol 90 (2) ◽  
pp. 157-164 ◽  
Author(s):  
Federico Verde ◽  
Petra Steinacker ◽  
Jochen H Weishaupt ◽  
Jan Kassubek ◽  
Patrick Oeckl ◽  
...  
Keyword(s):  
Amyotrophic Lateral Sclerosis ◽  
Neurodegenerative Diseases ◽  
Light Chain ◽  
Diffusion Tensor ◽  
Progression Rate ◽  
Neurofilament Light Chain ◽  
Neurofilament Light ◽  
Prospective Longitudinal Study ◽  
Prospective Longitudinal ◽  
Lateral Sclerosis

ObjectiveTo determine the diagnostic and prognostic performance of serum neurofilament light chain (NFL) in amyotrophic lateral sclerosis (ALS).MethodsThis single-centre, prospective, longitudinal study included the following patients: 124 patients with ALS; 50 patients without neurodegenerative diseases; 44 patients with conditions included in the differential diagnosis of ALS (disease controls); 65 patients with other neurodegenerative diseases (20 with frontotemporal dementia, 20 with Alzheimer’s disease, 19 with Parkinson’s disease, 6 with Creutzfeldt-Jakob disease (CJD)). Serum NFL levels were measured using the ultrasensitive single molecule array (Simoa) technology.ResultsSerum NFL levels were higher in ALS in comparison to all other categories except for CJD. A cut-off level of 62 pg/mL discriminated between ALS and all other conditions with 85.5% sensitivity (95% CI 78% to 91.2%) and 81.8% specificity (95% CI 74.9% to 87.4%). Among patients with ALS, serum NFL correlated positively with disease progression rate (rs=0.336, 95% CI 0.14 to 0.506, p=0.0008), and higher levels were associated with shorter survival (p=0.0054). Serum NFL did not differ among patients in different ALS pathological stages as evaluated by diffusion-tensor imaging, and in single patients NFL levels were stable over time.ConclusionsSerum NFL is increased in ALS in comparison to other conditions and can serve as diagnostic and prognostic biomarker. We established a cut-off level for the diagnosis of ALS.

scholarly journals Neurofilament Light Chain as Biomarker for Amyotrophic Lateral Sclerosis and Frontotemporal Dementia

2021 ◽  
Vol 15 ◽  
Author(s):  
Federico Verde ◽  
Markus Otto ◽  
Vincenzo Silani
Keyword(s):  
Amyotrophic Lateral Sclerosis ◽  
Frontotemporal Dementia ◽  
Light Chain ◽  
Ex Vivo ◽  
Specific Marker ◽  
Progression Rate ◽  
Prognostic Information ◽  
Neurofilament Light Chain ◽  
Neurofilament Light ◽  
Lateral Sclerosis

Amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) are two related currently incurable neurodegenerative diseases. ALS is characterized by degeneration of upper and lower motor neurons causing relentless paralysis of voluntary muscles, whereas in FTD, progressive atrophy of the frontal and temporal lobes of the brain results in deterioration of cognitive functions, language, personality, and behavior. In contrast to Alzheimer’s disease (AD), ALS and FTD still lack a specific neurochemical biomarker reflecting neuropathology ex vivo. However, in the past 10 years, considerable progress has been made in the characterization of neurofilament light chain (NFL) as cerebrospinal fluid (CSF) and blood biomarker for both diseases. NFL is a structural component of the axonal cytoskeleton and is released into the CSF as a consequence of axonal damage or degeneration, thus behaving in general as a relatively non-specific marker of neuroaxonal pathology. However, in ALS, the elevation of its CSF levels exceeds that observed in most other neurological diseases, making it useful for the discrimination from mimic conditions and potentially worthy of consideration for introduction into diagnostic criteria. Moreover, NFL correlates with disease progression rate and is negatively associated with survival, thus providing prognostic information. In FTD patients, CSF NFL is elevated compared with healthy individuals and, to a lesser extent, patients with other forms of dementia, but the latter difference is not sufficient to enable a satisfying diagnostic performance at individual patient level. However, also in FTD, CSF NFL correlates with several measures of disease severity. Due to technological progress, NFL can now be quantified also in peripheral blood, where it is present at much lower concentrations compared with CSF, thus allowing less invasive sampling, scalability, and longitudinal measurements. The latter has promoted innovative studies demonstrating longitudinal kinetics of NFL in presymptomatic individuals harboring gene mutations causing ALS and FTD. Especially in ALS, NFL levels are generally stable over time, which, together with their correlation with progression rate, makes NFL an ideal pharmacodynamic biomarker for therapeutic trials. In this review, we illustrate the significance of NFL as biomarker for ALS and FTD and discuss unsolved issues and potential for future developments.

Sign in / Sign up

Export Citation Format

Share Document