King's college progression rate at first clinical evaluation: A new measure of disease progression in amyotrophic lateral sclerosis

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.

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

Journal of Neurology Neurosurgery & Psychiatry ◽

10.1136/jnnp-2017-316605 ◽

2017 ◽

Vol 89 (4) ◽

pp. 367-373 ◽

Cited By ~ 37

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.

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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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Cerebral degeneration in amyotrophic lateral sclerosis

Neurology Clinical Practice ◽

10.1212/cpj.0000000000000674 ◽

2019 ◽

Vol 9 (5) ◽

pp. 400-407 ◽

Cited By ~ 4

Author(s):

Ojas Srivastava ◽

Chris Hanstock ◽

Sneha Chenji ◽

Dennell Mah ◽

Dean Eurich ◽

...

Keyword(s):

Amyotrophic Lateral Sclerosis ◽

Prefrontal Cortex ◽

Motor Cortex ◽

Disease Progression ◽

Progression Rate ◽

Healthy Controls ◽

Potential Biomarker ◽

Disease Progression Rate ◽

Lateral Sclerosis ◽

Cerebral Degeneration

BackgroundWe investigated cerebral degeneration and neurochemistry in patients with amyotrophic lateral sclerosis (ALS) using magnetic resonance spectroscopy (MRS).MethodsWe prospectively studied 65 patients and 43 age-matched healthy controls. Participants were recruited from 4 centers as part of a study in the Canadian ALS Neuroimaging Consortium. All participants underwent single-voxel proton MRS using a protocol standardized across all sites. Metabolites reflecting neuronal integrity (total N-acetyl aspartyl moieties [tNAA]) and gliosis (myo-inositol [Ino]), as well as creatine (Cr) and choline (Cho), were quantified in the midline motor cortex and midline prefrontal cortex. Comparisons were made between patients with ALS and healthy controls. Metabolites were correlated with clinical measures of upper motor neuron dysfunction, disease progression rate, and cognitive performance.ResultsIn the motor cortex, tNAA/Cr, tNAA/Cho, and tNAA/Ino ratios were reduced in the ALS group compared with controls. Group differences in tNAA/Cr and tNAA/Cho in the prefrontal cortex displayed reduced ratios in ALS patients; however, these were not statistically significant. Reduced motor cortex ratios were associated with slower foot tapping rate, whereas only motor tNAA/Ino was associated with finger tapping rate. Disease progression rate was associated with motor tNAA/Cho. Verbal fluency, semantic fluency, and digit span forwards and backwards were associated with prefrontal tNAA/Cr.ConclusionsThis study demonstrates that cerebral degeneration in ALS is more pronounced in the motor than prefrontal cortex, that multicenter MRS studies are feasible, and that motor tNAA/Ino shows promise as a potential biomarker.

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Side of Limb-Onset Predicts Laterality of Gray Matter Loss in Amyotrophic Lateral Sclerosis

BioMed Research International ◽

10.1155/2014/473250 ◽

2014 ◽

Vol 2014 ◽

pp. 1-11 ◽

Cited By ~ 7

Author(s):

Qiuli Zhang ◽

Cuiping Mao ◽

Jiaoting Jin ◽

Chen Niu ◽

Lijun Bai ◽

...

Keyword(s):

Amyotrophic Lateral Sclerosis ◽

Disease Progression ◽

Gray Matter ◽

Brain Atrophy ◽

Disease Onset ◽

Progression Rate ◽

Imaging Evaluation ◽

Als Patients ◽

Lateral Sclerosis ◽

Limb Onset

Conflicting findings have been reported regarding the lateralized brain abnormality in patients with amyotrophic lateral sclerosis (ALS). In this study, we aimed to investigate the probable lateralization of gray matter (GM) atrophy in ALS patients. We focused on the relationship between the asymmetry in decreased GM volume and the side of disease onset in patients with limb-onset. Structural imaging evaluation of normalized atrophy (SIENAX) and voxel-based morphometry (VBM) were used to assess differences in global and local brain regions in patients with heterogeneous body onset and subgroups with different side of limb-onset. We found global brain atrophy and GM losses in the frontal and parietal areas in each patient group as well as left predominant GM losses in the total cohort. The intriguing findings in subgroup analyses demonstrated that the motor cortex in the contralateral hemisphere of the initially involved limb was most affected. We also found that regional brain atrophy was related to disease progression rate. Our observations suggested that side of limb-onset can predict laterality of GM loss in ALS patients and disease progression correlates with the extent of cortical abnormality.

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Relationship between Dietary Fiber Intake and the Prognosis of Amyotrophic Lateral Sclerosis

10.20944/preprints202010.0466.v1 ◽

2020 ◽

Author(s):

Haelim Yu ◽

Seung Hyun Kim ◽

Min-Young Noh ◽

Sang-Gon Lee ◽

Yongsoon Park

Keyword(s):

Amyotrophic Lateral Sclerosis ◽

Survival Time ◽

Disease Progression ◽

Dietary Fiber ◽

Progression Rate ◽

Fiber Intake ◽

Dietary Fiber Intake ◽

Disease Progression Rate ◽

Lateral Sclerosis ◽

Vegetable Fiber

The gut microbiota has been suggested as an important factor in the pathogenic mechanisms of amyotrophic lateral sclerosis (ALS). This study aimed to investigate whether the intake of different kinds of dietary fiber was related to the disease progression rate (∆FS) and survival time. In total, 272 sporadic ALS patients diagnosed according to the revised EI Escorial criteria were recruited from March 2011 and were followed-up until the occurrence of events or the end of September 2020. The events included percutaneous endoscopic gastrostomy, tracheostomy, and death. Dietary fiber intake was calculated based on a 24-hour dietary recall and classified according to five major fiber-rich foods: vegetables, fruits, grains, legumes, and nuts/seeds. Among the total participants, the group with ∆FS values lower than the mean ∆FS (0.75) was noted in the highest tertiles of total and vegetable fiber intake. Participants with the highest tertile of vegetable fiber intake showed longer survival in the Kaplan–Meier analysis (p = 0.033). Notably, vegetable fiber intake was negatively correlated with pro-inflammatory cytokine (interleukin [IL]-1β, IL-6, and monocyte chemoattractant protein-1) levels in the cerebrospinal fluid. This study showed that vegetable fiber intake could influence the disease progression rate and survival time. Further clinical trials are needed to confirm whether dietary fiber supplementation improves the prognosis of ALS.

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

10.1101/2021.10.05.21264570 ◽

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.

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Neurofilament Subunit L Levels in the Cerebrospinal Fluid and Serum of Patients with Amyotrophic Lateral Sclerosis

Neurodegenerative Diseases ◽

10.1159/000488681 ◽

2018 ◽

Vol 18 (2-3) ◽

pp. 165-172 ◽

Cited By ~ 5

Author(s):

Zhong-Ying Gong ◽

Gao-Peng Lv ◽

Li-Na Gao ◽

Yi Lu ◽

Jie Guo ◽

...

Keyword(s):

Amyotrophic Lateral Sclerosis ◽

Cerebrospinal Fluid ◽

Disease Progression ◽

Rating Scale ◽

Enzyme Linked Immunosorbent Assay ◽

Progression Rate ◽

Serum Samples ◽

High Level ◽

Als Patients ◽

Lateral Sclerosis

Background: There are no reliable biomarkers that could evaluate the disease burden in amyotrophic lateral sclerosis (ALS). Objectives: The aim of our study is to evaluate the changes in cerebrospinal fluid (CSF) and serum neurofilament subunit L (NF-L) in patients with ALS and to analyze the correlations between the levels of NF-L and clinical parameters. Method: CSF and serum samples were obtained from 80 ALS patients and 40 controls. The levels of NF-L in CSF and serum were assessed, and disease progression parameters including duration, revised ALS Functional Rating Scale (ALSFRS-r) score, disease progression rate (DPR), upper motor neuron (UMN) score, and survival were analyzed by registered neurologists. All samples were measured using a commercial enzyme-linked immunosorbent assay. Statistical analyses were performed using Prism software. Results: Compared to the controls, the ALS patients displayed significantly increased levels of NF-L; these values were negatively correlated with the ALSFRS-r score and positively correlated with the decrease in ALSFRS-r score, DPR, and UMN score. There was no correlation between levels of NF-L and duration. In addition, the cumulative survival rate in ALS patients with a low level of NF-L was higher than in patients with a high level of NF-L. Conclusions: NF-L levels increased in CSF and serum of patients with ALS. NF-L may thus be a neurodegenerative biomarker for predicting ALS severity and progression, and the survival of patients with this disease.

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Therapeutic Nanocatalysis to Slow Disease Progression of Amyotrophic Lateral Sclerosis (ALS)

Case Medical Research ◽

10.31525/ct1-nct04098406 ◽

2019 ◽

Author(s):

Keyword(s):

Amyotrophic Lateral Sclerosis ◽

Disease Progression ◽

Slow Disease Progression ◽

Lateral Sclerosis

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Clinical Determinants of Disease Progression in Amyotrophic Lateral Sclerosis—A Retrospective Cohort Study

Journal of Clinical Medicine ◽

10.3390/jcm10081623 ◽

2021 ◽

Vol 10 (8) ◽

pp. 1623

Author(s):

Maria Viktoria Requardt ◽

Dennis Görlich ◽

Torsten Grehl ◽

Matthias Boentert

Keyword(s):

Amyotrophic Lateral Sclerosis ◽

Motor Neuron ◽

Disease Progression ◽

Rating Scale ◽

Rapid Decline ◽

Chronic Obstructive ◽

Obstructive Pulmonary Disease ◽

Hazard Ratios ◽

Sum Score ◽

Lateral Sclerosis

Background: Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease that is ultimately fatal but characterized by substantial phenotypic heterogeneity, which is known to impact long-term course and survival. This study investigated clinical determinants of disease progression and outcome in a large cohort of patients with ALS. Methods: Retrospective analysis included comprehensive data from 625 patients who attended a tertiary ALS centre at least twice. Patients were stratified according to five distinct clinical phenotypes: classical ALS; bulbar ALS; ALS with frontotemporal dementia (ALS-FTD); upper motor neuron predominant (UMNP); and lower motor neuron predominant (LMNP). Results: This study confirmed higher age at symptom onset, shorter latency to diagnosis and more rapid decline in the revised ALS Functional Rating Scale sum score as predictors of poor prognosis. Hazard ratios for shorter survival were higher in patients with ALS-FTD versus classical ALS, and in patients with versus without chronic obstructive pulmonary disease (COPD). Mean survival was longest in the UMNP phenotype group. Conclusions: This study confirmed established predictors of shorter survival in ALS and showed that concomitant COPD in particular relates to poor outcome.

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