scholarly journals Cerebrospinal Fluid Neurofilament Light Chain (NfL) Predicts Disease Aggressiveness in Amyotrophic Lateral Sclerosis: An Application of the D50 Disease Progression Model

2021 ◽  
Vol 15 ◽  
Author(s):  
Marie Dreger ◽  
Robert Steinbach ◽  
Nayana Gaur ◽  
Klara Metzner ◽  
Beatrice Stubendorff ◽  
...  
Keyword(s):  
Disease Progression ◽  
Analysis Of Covariance ◽  
Disease Course ◽  
Neurofilament Light Chain ◽  
Neurofilament Light ◽  
Progression Model ◽  
Therapeutic Trials ◽  
Disease Progression Model ◽  
Individual Disease ◽  
Lateral Sclerosis

Amyotrophic lateral sclerosis (ALS) is a relentlessly progressive neurodegenerative disorder. As previous therapeutic trials in ALS have been severely hampered by patients’ heterogeneity, the identification of biomarkers that reliably reflect disease progression represents a priority in ALS research. Here, we used the D50 disease progression model to investigate correlations between cerebrospinal fluid (CSF) neurofilament light chain (NfL) levels and disease aggressiveness. The D50 model quantifies individual disease trajectories for each ALS patient. The value D50 provides a unified measure of a patient’s overall disease aggressiveness (defined as time taken in months to lose 50% of functionality). The relative D50 (rD50) reflects the individual disease covered and can be calculated for any time point in the disease course. We analyzed clinical data from a well-defined cohort of 156 patients with ALS. The concentration of NfL in CSF samples was measured at two different laboratories using the same procedure. Based on patients’ individual D50 values, we defined subgroups with high (<20), intermediate (20–40), or low (>40) disease aggressiveness. NfL levels were compared between these subgroups via analysis of covariance, using an array of confounding factors: age, gender, clinical phenotype, frontotemporal dementia, rD50-derived disease phase, and analyzing laboratory. We found highly significant differences in NfL concentrations between all three D50 subgroups (p < 0.001), representing an increase of NfL levels with increasing disease aggressiveness. The conducted analysis of covariance showed that this correlation was independent of gender, disease phenotype, and phase; however, age, analyzing laboratory, and dementia significantly influenced NfL concentration. We could show that CSF NfL is independent of patients’ disease covered at the time of sampling. The present study provides strong evidence for the potential of NfL to reflect disease aggressiveness in ALS and in addition proofed to remain at stable levels throughout the disease course. Implementation of CSF NfL as a potential read-out for future therapeutic trials in ALS is currently constrained by its demonstrated susceptibility to (pre-)analytical variations. Here we show that the D50 model enables the discovery of correlations between clinical characteristics and CSF analytes and can be recommended for future studies evaluating potential biomarkers.

scholarly journals Applying the D50 disease progression model to gray and white matter pathology in amyotrophic lateral sclerosis

2020 ◽  
Vol 25 ◽  
pp. 102094 ◽  
Author(s):  
Robert Steinbach ◽  
Meerim Batyrbekova ◽  
Nayana Gaur ◽  
Annika Voss ◽  
Beatrice Stubendorff ◽  
...  
Keyword(s):  
Amyotrophic Lateral Sclerosis ◽  
White Matter ◽  
Disease Progression ◽  
Progression Model ◽  
Disease Progression Model ◽  
White Matter Pathology ◽  
Lateral Sclerosis

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 Plasma NfL levels and longitudinal change rates in C9orf72 and GRN-associated diseases: from tailored references to clinical applications

2021 ◽  
pp. jnnp-2021-326914
Author(s):  
Dario Saracino ◽  
Karim Dorgham ◽  
Agnès Camuzat ◽  
Daisy Rinaldi ◽  
Armelle Rametti-Lacroux ◽  
...  
Keyword(s):  
Single Molecule ◽  
Light Chain ◽  
Rate Of Change ◽  
Longitudinal Change ◽  
Youden Index ◽  
Clinical Genetic ◽  
Neurofilament Light Chain ◽  
Neurofilament Light ◽  
Link Type ◽  
Therapeutic Trials

ObjectiveNeurofilament light chain (NfL) is a promising biomarker in genetic frontotemporal dementia (FTD) and amyotrophic lateral sclerosis (ALS). We evaluated plasma neurofilament light chain (pNfL) levels in controls, and their longitudinal trajectories in C9orf72 and GRN cohorts from presymptomatic to clinical stages.MethodsWe analysed pNfL using Single Molecule Array (SiMoA) in 668 samples (352 baseline and 316 follow-up) of C9orf72 and GRN patients, presymptomatic carriers (PS) and controls aged between 21 and 83. They were longitudinally evaluated over a period of >2 years, during which four PS became prodromal/symptomatic. Associations between pNfL and clinical–genetic variables, and longitudinal NfL changes, were investigated using generalised and linear mixed-effects models. Optimal cut-offs were determined using the Youden Index.ResultspNfL levels increased with age in controls, from ~5 to~18 pg/mL (p<0.0001), progressing over time (mean annualised rate of change (ARC): +3.9%/year, p<0.0001). Patients displayed higher levels and greater longitudinal progression (ARC: +26.7%, p<0.0001), with gene-specific trajectories. GRN patients had higher levels than C9orf72 (86.21 vs 39.49 pg/mL, p=0.014), and greater progression rates (ARC:+29.3% vs +24.7%; p=0.016). In C9orf72 patients, levels were associated with the phenotype (ALS: 71.76 pg/mL, FTD: 37.16, psychiatric: 15.3; p=0.003) and remarkably lower in slowly progressive patients (24.11, ARC: +2.5%; p=0.05). Mean ARC was +3.2% in PS and +7.3% in prodromal carriers. We proposed gene-specific cut-offs differentiating patients from controls by decades.ConclusionsThis study highlights the importance of gene-specific and age-specific references for clinical and therapeutic trials in genetic FTD/ALS. It supports the usefulness of repeating pNfL measurements and considering ARC as a prognostic marker of disease progression.Trial registration numbersNCT02590276 and NCT04014673.

scholarly journals PK/PD Modeling of the PDE7 Inhibitor—GRMS-55 in a Mouse Model of Autoimmune Hepatitis

Pharmaceutics ◽  
2021 ◽  
Vol 13 (5) ◽  
pp. 597
Author(s):  
Artur Świerczek ◽  
Hanna Plutecka ◽  
Marietta Ślusarczyk ◽  
Grażyna Chłoń-Rzepa ◽  
Elżbieta Wyska
Keyword(s):  
Mouse Model ◽  
Autoimmune Hepatitis ◽  
Disease Progression ◽  
Hepatoprotective Activity ◽  
Mechanisms Of Action ◽  
Progression Model ◽  
Adrenoceptor Agonist ◽  
Tnf Α ◽  
Disease Progression Model ◽  
Time Courses

This study aimed to assess the efficacy and explore the mechanisms of action of a potent phosphodiesterase (PDE)7A and a moderate PDE4B inhibitor GRMS-55 in a mouse model of autoimmune hepatitis (AIH). The concentrations of GRMS-55 and relevant biomarkers were measured in the serum of BALB/c mice with concanavalin A (ConA)-induced hepatitis administered with GRMS-55 at two dose levels. A semi-mechanistic PK/PD/disease progression model describing the time courses of measured biomarkers was developed. The emetogenicity as a potential side effect of the studied compound was evaluated in the α2-adrenoceptor agonist-induced anesthesia model. The results indicate that liver damage observed in mice challenged with ConA was mainly mediated by TNF-α and IFN-γ. GRMS-55 decreased the levels of pro-inflammatory mediators and the transaminase activities in the serum of mice with AIH. The anti-inflammatory properties of GRMS-55, resulting mainly from PDE7A inhibition, led to a high hepatoprotective activity in mice with AIH, which was mediated by an inhibition of pro-inflammatory signaling. GRMS-55 did not induce the emetic-like behavior. The developed PK/PD/disease progression model may be used in future studies to assess the potency and explore the mechanisms of action of new investigational compounds for the treatment of AIH.

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