scholarly journals Diagnostic and Prognostic Role of Blood and Cerebrospinal Fluid and Blood Neurofilaments in Amyotrophic Lateral Sclerosis: A Review of the Literature

2019 ◽  
Vol 20 (17) ◽  
pp. 4152 ◽  
Author(s):  
Delia Gagliardi ◽  
Megi Meneri ◽  
Domenica Saccomanno ◽  
Nereo Bresolin ◽  
Giacomo Pietro Comi ◽  
...  
Keyword(s):  
Amyotrophic Lateral Sclerosis ◽  
Cerebrospinal Fluid ◽  
Disease Progression ◽  
Neurodegenerative Disorder ◽  
Diagnostic Delay ◽  
Cytoskeletal Proteins ◽  
Pharmacological Intervention ◽  
Prognostic Role ◽  
Lateral Sclerosis

Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disorder affecting upper and lower motor neurons (MNs) that still lacks an efficacious therapy. The failure of recent therapeutic trials in ALS, other than depending on the poor knowledge of pathogenic mechanisms responsible for MNs loss, is largely due to diagnostic delay and the lack of reliable biomarkers for diagnosis, prognosis and response to pharmacologic intervention. Neurofilaments (Nfs) are neuron-specific cytoskeletal proteins, whose levels increased in biological fluids proportionally to the degree of axonal damage, both in normal and in pathologic conditions, representing potential biomarkers in various neurological disorders, such as motor neuron disorder (MND). Growing evidence has shown that phosphorylated neurofilaments heavy chain (p-NfH) and neurofilaments light chain (NfL) are increased in blood and cerebrospinal fluid (CSF) of ALS patients compared to healthy and neurological controls and are found to correlate with disease progression. In this review, we reported the most relevant studies investigating the diagnostic and prognostic role of Nfs in ALS. Given their reliability and reproducibility, we consider Nfs as promising and useful biomarkers in diagnosis of MND, early patient identification for inclusion in clinical trials, prediction of disease progression, and response to pharmacological intervention, and we suggest the validation of their measurement in clinical activity.

scholarly journals Minimizing the Diagnostic Delay in Amyotrophic Lateral Sclerosis: The Role of Nonneurologist Practitioners

2020 ◽  
Vol 2020 ◽  
pp. 1-8
Author(s):  
Martin Matharan ◽  
Stéphane Mathis ◽  
Sarah Bonabaud ◽  
Louis Carla ◽  
Antoine Soulages ◽  
...  
Keyword(s):  
Amyotrophic Lateral Sclerosis ◽  
Neurodegenerative Disorder ◽  
Diagnostic Delay ◽  
Total Duration ◽  
Clinical Signs ◽  
Medical Doctor ◽  
Total Delay ◽  
Als Patients ◽  
Lateral Sclerosis

Introduction. Amyotrophic lateral sclerosis (ALS), usually fatal in a few years, is a neurodegenerative disorder where the diagnostic delay, although variable according to the studies, remains too long. The main objective of this study was to determine the average time to diagnose ALS and the role of each physician, general practitioner (GP), or specialist (neurologist or not) involved in the management of these patients. The secondary objective was to propose some simple schemes to quickly identify an ALS suspicion with the aim to reduce this delay. Patients and Methods. This retrospective study evaluated the diagnostic delay (and other intermediate delays) of 90 ALS patients registered in the ALS Center of Bordeaux (France) in 2013. The main clinical signs encountered (and their order of appearance) were studied. Results. The average diagnostic delay was 17 months, with a median diagnostic delay of 12 months. The average diagnostic delay was 2.7 months between the first symptoms and the first complaint to GP, followed by an additional 6.5 month delay before the patient’s first visit to a neurologist. This period could be shortened, especially if GP performed additional tests quickly (p=0.01), as the time spent consulting various specialists often extends this crucial step. Overall, diagnostic delay accounted for 40% of the total duration of the disease progression. Conclusion. In relation to total survival time, the diagnostic delay of ALS appears to be proportionately very long, sometimes longer than that observed in previous studies (because it also included the total delay to diagnostic or treatment initiation). The rapid execution of useful additional tests by the first medical doctor, often GP (with the help of a neurologist), considerably reduces the diagnostic delay. The central role of GP seems to be crucial in the management of patients with ALS. The main objective is, of course, to initiate appropriate treatment and care as soon as possible. Finally, based on our results, we also provide a short practical diagram to help nonneurologist practitioners to quickly discuss the diagnosis of ALS in case of some specific symptoms (“red flags”).

Inflammatory markers in cerebrospinal fluid: independent prognostic biomarkers in amyotrophic lateral sclerosis?

2019 ◽  
pp. jnnp-2018-319586 ◽  
Author(s):  
Benjamin Gille ◽  
Maxim De Schaepdryver ◽  
Lieselot Dedeene ◽  
Janne Goossens ◽  
Kristl G Claeys ◽  
...  
Keyword(s):  
Amyotrophic Lateral Sclerosis ◽  
Cerebrospinal Fluid ◽  
Disease Progression ◽  
Inflammatory Markers ◽  
Cox Regression ◽  
Characteristic Curve ◽  
Progression Rate ◽  
Cox Regression Analysis ◽  
Lateral Sclerosis ◽  
Discriminatory Performance

ObjectiveInflammation is a key pathological hallmark in amyotrophic lateral sclerosis (ALS), which seems to be linked to the disease progression. It is not clear what the added diagnostic and prognostic value are of inflammatory markers in the cerebrospinal fluid (CSF) of patients with ALS.MethodsChitotriosidase-1 (CHIT1), chitinase-3-like protein 1 (YKL-40) and monocyte chemoattractant protein-1 (MCP-1) were measured in CSF and serum of patients with ALS (n=105), disease controls (n=102) and patients with a disease mimicking ALS (n=16). The discriminatory performance was evaluated by means of a receiver operating characteristic curve analysis. CSF and serum levels were correlated with several clinical parameters. A multivariate Cox regression analysis, including eight other established prognostic markers, was used to evaluate survival in ALS.ResultsIn CSF, CHIT1, YKL-40 and MCP-1 showed a weak discriminatory performance between ALS and ALS mimics (area under the curve: 0.79, p<0.0001; 0.72, p=0.001; 0.75, p=0.001, respectively). CHIT1 and YKL-40 correlated with the disease progression rate (ρ=0.28, p=0.009; ρ=0.34, p=0.002, respectively). CHIT1 levels were elevated in patients with a higher number of regions displaying motor neuron degeneration (one vs three regions: 4248 vs 13 518 pg/mL, p = 0.0075). In CSF, YKL-40 and MCP-1 were independently associated with survival (HR: 29.7, p=0.0003; 6.14, p=0.001, respectively).ConclusionsOur findings show that inflammation in patients with ALS reflects the disease progression as an independent predictor of survival. Our data encourage the use of inflammatory markers in patient stratification and as surrogate markers of therapy response in clinical trials.

Comparison of elevated phosphorylated neurofilament heavy chains in serum and cerebrospinal fluid of patients with amyotrophic lateral sclerosis

2017 ◽  
Vol 89 (4) ◽  
pp. 367-373 ◽  
Author(s):  
Maxim De Schaepdryver ◽  
Andreas Jeromin ◽  
Benjamin Gille ◽  
Kristl G Claeys ◽  
Victor Herbst ◽  
...  
Keyword(s):  
Amyotrophic Lateral Sclerosis ◽  
Cerebrospinal Fluid ◽  
Motor Neuron ◽  
Disease Progression ◽  
Roc Curves ◽  
Symptom Duration ◽  
Progression Rate ◽  
Alternative Source ◽  
Disease Progression Rate ◽  
Lateral Sclerosis

ObjectivePhosphorylated neurofilament heavy chain (pNfH) levels are elevated in cerebrospinal fluid (CSF) of patients with amyotrophic lateral sclerosis (ALS). Instead of CSF, we explored blood as an alternative source to measure pNfH in patients with ALS.MethodsIn this single centre retrospective study, 85 patients with ALS, 215 disease controls (DC) and 31 ALS mimics were included. Individual serum pNfH concentrations were correlated with concentrations in CSF and with several clinical parameters. The performance characteristics of pNfH in CSF and serum of patients with ALS and controls were calculated and compared using receiver operating characteristic (ROC) curves.ResultsCSF and serum pNfH concentrations in patients with ALS correlated well (r=0.652, p<0.0001) and were significantly increased compared with DC (p<0.0001) and ALS mimics (p<0.0001). CSF pNfH outperformed serum pNfH in discriminating patients with ALS from DC and ALS mimics (difference between area under the ROC curves: p=0.0001 and p=0.0005; respectively). Serum pNfH correlated inversely with symptom duration (r=−0.315, p=0.0033). CSF and serum pNfH were lower when the disease progression rate was slower (r=0.279, p<0.01 and r=0.289, p<0.01; respectively). Unlike CSF, serum pNfH did not correlate with the burden of clinical and electromyographic motor neuron dysfunction.ConclusionsCSF and serum pNfH concentrations are elevated in patients with ALS and correlate with the disease progression rate. Moreover, CSF pNfH correlates with the burden of motor neuron dysfunction. Our findings encourage further pursuit of CSF and serum pNfH concentrations in the diagnostic pathway of patients suspected to have ALS.

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 Oxidative Stress in Amyotrophic Lateral Sclerosis: Pathophysiology and Opportunities for Pharmacological Intervention

2020 ◽  
Vol 2020 ◽  
pp. 1-29
Author(s):  
Teresa Cunha-Oliveira ◽  
Liliana Montezinho ◽  
Catarina Mendes ◽  
Omidreza Firuzi ◽  
Luciano Saso ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Amyotrophic Lateral Sclerosis ◽  
Motor Neurons ◽  
Therapeutic Benefit ◽  
Pharmacological Intervention ◽  
Antioxidant Compounds ◽  
Pathological Feature ◽  
Beneficial Effects ◽  
Lateral Sclerosis

Amyotrophic lateral sclerosis (ALS), also known as Lou Gehrig’s disease or Charcot disease, is a fatal neurodegenerative disease that affects motor neurons (MNs) and leads to death within 2–5 years of diagnosis, without any effective therapy available. Although the pathological mechanisms leading to ALS are still unknown, a wealth of evidence indicates that an excessive reactive oxygen species (ROS) production associated with an inefficient antioxidant defense represents an important pathological feature in ALS. Substantial evidence indicates that oxidative stress (OS) is implicated in the loss of MNs and in mitochondrial dysfunction, contributing decisively to neurodegeneration in ALS. Although the modulation of OS represents a promising approach to protect MNs from degeneration, the fact that several antioxidants with beneficial effects in animal models failed to show any therapeutic benefit in patients raises several questions that should be analyzed. Using specific queries for literature search on PubMed, we review here the role of OS-related mechanisms in ALS, including the involvement of altered mitochondrial function with repercussions in neurodegeneration. We also describe antioxidant compounds that have been mostly tested in preclinical and clinical trials of ALS, also describing their respective mechanisms of action. While the description of OS mechanism in the different mutations identified in ALS has as principal objective to clarify the contribution of OS in ALS, the description of positive and negative outcomes for each antioxidant is aimed at paving the way for novel opportunities for intervention. In conclusion, although antioxidant strategies represent a very promising approach to slow the progression of the disease, it is of utmost need to invest on the characterization of OS profiles representative of each subtype of patient, in order to develop personalized therapies, allowing to understand the characteristics of antioxidants that have beneficial effects on different subtypes of patients.

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.

Role of transition metals in the pathogenesis of amyotrophic lateral sclerosis

2008 ◽  
Vol 36 (6) ◽  
pp. 1322-1328 ◽  
Author(s):  
Willianne I.M. Vonk ◽  
Leo W.J. Klomp
Keyword(s):  
Spinal Cord ◽  
Amyotrophic Lateral Sclerosis ◽  
Superoxide Dismutase ◽  
Transition Metals ◽  
Motor Neurons ◽  
Neurodegenerative Disorder ◽  
Sod1 Gene ◽  
Brain And Spinal Cord ◽  
Lateral Sclerosis

ALS (amyotrophic lateral sclerosis) is a devastating progressive neurodegenerative disorder resulting in selective degeneration of motor neurons in brain and spinal cord and muscle atrophy. In approx. 2% of all cases, the disease is caused by a mutation in the Cu,Zn-superoxide dismutase (SOD1) gene. The transition metals zinc and copper regulate SOD1 protein stability and activity, and disbalance of the homoeostasis of these metals has therefore been implicated in the pathogenesis of ALS. Recent data strengthen the hypothesis that these transition metals are excellent potential targets to develop an effective therapy for ALS.

scholarly journals Prognostic Role of Serum Levels of Uric Acid in Amyotrophic Lateral Sclerosis

2015 ◽  
Vol 11 (4) ◽  
pp. 376 ◽  
Author(s):  
Seong-il Oh ◽  
Soojeong Baek ◽  
Jin-Seok Park ◽  
Liying Piao ◽  
Ki-Wook Oh ◽  
...  
Keyword(s):  
Amyotrophic Lateral Sclerosis ◽  
Uric Acid ◽  
Serum Levels ◽  
Prognostic Role ◽  
Lateral Sclerosis

Diagnostic and prognostic role of plasma phosphorylated neurofilament heavy chain (pNf-H) in amyotrophic lateral sclerosis

2021 ◽  
Vol 429 ◽  
pp. 119400
Author(s):  
Maria Teresa Dell'Abate ◽  
Chiara Zecca ◽  
Giuseppe Pasculli ◽  
Roberta Barone ◽  
Rosa Capozzo ◽  
...  
Keyword(s):  
Amyotrophic Lateral Sclerosis ◽  
Heavy Chain ◽  
Prognostic Role ◽  
Lateral Sclerosis
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