Neurofilaments can differentiate ALS subgroups and ALS from common diagnostic mimics.
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ABSTRACT:
SUBMITTER: Behzadi A
PROVIDER: S-EPMC8585882 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:Objective. To evaluate serum and cerebrospinal fluid (CSF) levels of phosphorylated neurofilament heavy (pNfH), and to compare these to levels of neurofilament light (NfL), as biomarkers of pre-symptomatic ALS. Design. The study population includes 34 controls, 79 individuals at-risk for ALS, 22 ALS patients, and 14 phenoconverters. At-risk individuals are enrolled through Pre-Symptomatic Familial ALS (Pre-fALS), a longitudinal natural history and biomarker study of individuals who are carriers of any ALS-associated gene mutation, but who demonstrate no clinical evidence of disease at the time of enrollment. pNfH and NfL in serum and CSF were quantified using established enzyme-linked immunosorbent assays. Results. There is a longitudinal increase in serum pNfH in advance of the emergence of clinically manifest ALS. A similar pattern is observed for NfL, but with the absolute levels also frequently exceeding a normative threshold. Although CSF data are more sparse, similar patterns are observed for both neurofilaments, with absolute levels exceeding a normative threshold prior to phenoconversion. In serum, these changes are observed in the 6-12 months prior to disease among SOD1 A4V mutation carriers, and as far back as 2 and 3.5 years, respectively, in individuals with a FUS c.521del6 mutation and a C9ORF72 hexanucleotide repeat expansion. Conclusions. Serum and CSF pNfH increase prior to phenoconversion. In CSF, the temporal course of these changes is similar to NfL. In serum, however, pNfH is less sensitive to pre-symptomatic disease than NfL. The duration of pre-symptomatic disease, as defined by changes in neurofilaments, may vary depending on underlying genotype.
| S-EPMC6768722 | biostudies-literature
Project description:ObjectiveTo appraise the utility as biomarkers of blood antibodies and immune complexes to neurofilaments and dipeptide repeat proteins, the products of translation of the most common genetic mutation in amyotrophic lateral sclerosis (ALS).MethodsAntibodies and immune complexes against neurofilament light, medium, heavy chains as well as poly-(GP)-(GR) dipeptide repeats were measured in blood samples from the ALS Biomarkers (n = 107) and the phenotype-genotype biomarker (n = 129) studies and in 140 healthy controls. Target analyte levels were studied longitudinally in 37 ALS cases. Participants were stratified according to the rate of disease progression estimated before and after baseline and C9orf72 genetic status. Survival and longitudinal analyses were undertaken with reference to matched neurofilament protein expression.ResultsCompared to healthy controls, total neurofilament proteins and antibodies, neurofilament light immune complexes (p < 0.0001), and neurofilament heavy antibodies (p = 0.0061) were significantly elevated in ALS, patients with faster progressing disease (p < 0.0001) and in ALS cases with a C9orf72 mutation (p < 0.0003). Blood neurofilament light protein discriminated better ALS from healthy controls (AUC: 0.92; p < 0.0001) and faster from slower progressing ALS (AUC: 0.86; p < 0.0001) compared to heavy-chain antibodies and light-chain immune complexes (AUC: 0.79; p < 0.0001 and AUC: 0.74; p < 0.0001). Lower neurofilament heavy antibodies were associated with longer survival (Log-rank Chi-square: 7.39; p = 0.0065). Increasing levels of antibodies and immune complexes between time points were observed in faster progressing ALS.ConclusionsWe report a distinctive humoral response characterized by raising antibodies against neurofilaments and dipeptide repeats in faster progressing and C9orf72 genetic mutation carriers ALS patients. We confirm the significance of plasma neurofilament proteins in the clinical stratification of ALS.
| S-EPMC8419401 | biostudies-literature
Project description:ObjectiveTo identify preferred neurofilament assays and clinically validate serum neurofilament light (NfL) and phosphorylated neurofilament heavy (pNfH) as prognostic and potential pharmacodynamic biomarkers relevant to amyotrophic lateral sclerosis (ALS) therapy development.MethodsIn this prospective, multicenter, longitudinal observational study of patients with ALS (n = 229), primary lateral sclerosis (n = 20), and progressive muscular atrophy (n = 11), biological specimens were collected, processed, and stored according to strict standard operating procedures (SOPs). Neurofilament assays were performed in a blinded manner by independent contract research organizations.ResultsFor serum NfL and pNfH measured using the Simoa assay, there were no missing data (i.e., technical replicates below the lower limit of detection were not encountered). For the Iron Horse and Euroimmun pNfH assays, such missingness was encountered in ∼4% and ∼10% of serum samples, respectively. Mean coefficients of variation for NfL in serum and CSF were both ∼3%. Mean coefficients of variation for pNfH in serum and CSF were ∼4%-5% and ∼2%-3%, respectively, in all assays. Baseline serum NfL concentration, but not pNfH, predicted the future Revised ALS Functional Rating Scale (ALSFRS-R) slope and survival. Incorporation of baseline serum NfL into mixed effects models of ALSFRS-R slopes yields an estimated sample size saving of ∼8%. Depending on the method used to estimate effect size, use of serum NfL (and perhaps pNfH) as pharmacodynamic biomarkers, instead of the ALSFRS-R slope, yields significantly larger sample size savings.ConclusionsSerum NfL may be considered a clinically validated prognostic biomarker for ALS. Serum NfL (and perhaps pNfH), quantified using the Simoa assay, has potential utility as a pharmacodynamic biomarker of treatment effect.
| S-EPMC7371380 | biostudies-literature
Project description:Motor neuron diseases (MNDs) are etiologically and biologically heterogeneous diseases. The pathobiology of motor neuron degeneration is still largely unknown, and no effective therapy is available. Heterogeneity and lack of specific disease biomarkers have been appointed as leading reasons for past clinical trial failure, and biomarker discovery is pivotal in today's MND research agenda.In the last decade, neurofilaments (NFs) have emerged as promising biomarkers for the clinical assessment of neurodegeneration. NFs are scaffolding proteins with predominant structural functions contributing to the axonal cytoskeleton of myelinated axons. NFs are released in CSF and peripheral blood as a consequence of axonal degeneration, irrespective of the primary causal event. Due to the current availability of highly-sensitive automated technologies capable of precisely quantify proteins in biofluids in the femtomolar range, it is now possible to reliably measure NFs not only in CSF but also in blood.In this review, we will discuss how NFs are impacting research and clinical management in ALS and other MNDs. Besides contributing to the diagnosis at early stages by differentiating between MNDs with different clinical evolution and severity, NFs may provide a useful tool for the early enrolment of patients in clinical trials. Due to their stability across the disease, NFs convey prognostic information and, on a larger scale, help to stratify patients in homogenous groups. Shortcomings of NFs assessment in biofluids will also be discussed according to the available literature in the attempt to predict the most appropriate use of the biomarker in the MND clinic.
| S-EPMC7559190 | biostudies-literature
Project description:Objective: Neurofilaments in CSF are promising biomarkers which might help in the diagnosis of motor neuron disease (MND). We aim to assess the diagnostic value of neurofilaments in CSF for MND. Methods: Pubmed, Emabase, and Web of Science were searched for relevant studies systematically. Articles in English that evaluated the utility of neurofilaments in CSF in the diagnosis of MND were included. Data were extracted by two independent investigators. Diagnostic indexes for neurofilament light chain (NFL) and phosphorylated neurofilament heavy chain (pNFH) were calculated separately. Stata 12.0 software with a bivariate mixed-effects model was used to summarize the diagnostic indexes from eligible studies. Results: Five studies on NFL and eight studies on pNFH met inclusion criteria. For NFL, the pooled sensitivity and specificity were 81% (95% confidence interval [CI], 72-88%) and 85% (95% CI, 76-91%), respectively; the positive likelihood ratio (PLR) and negative likelihood ratio (NLR) were 5.5 (95% CI, 3.1-9.8) and 0.22 (95% CI, 0.14-0.35), respectively; the summary diagnostic odds ratio (DOR) was 25 (95% CI, 9-70), and the area under summary receiver operator characteristic curve (AUC) was 0.90 (95% CI, 0.87-0.92). For pNFH, the pooled sensitivity, specificity, PLR and NLR were 85% (95% CI, 80-88%), 85% (95% CI, 77-90%), 5.5 (95% CI, 3.6-8.4), and 0.18 (95% CI, 0.13-0.25), respectively; the DOR was 30 (95% CI, 16-58), and the AUC was 0.91 (95% CI, 0.88-0.93). Conclusion: Neurofilaments in CSF have a high value in the diagnosis of MND, though the optimal cutoff value remains to be further investigated.
| S-EPMC5126108 | biostudies-literature
Project description:To determine the frequency of amyotrophic lateral sclerosis (ALS) plateaus and reversals in the Pooled Resource Open-Access ALS Clinical Trials (PRO-ACT) database.We analyzed Amyotrophic Lateral Sclerosis Functional Rating Scale (ALSFRS) and ALSFRS-revised (ALSFRS-R) data from PRO-ACT participants. The frequencies of participants experiencing plateaus (periods where scores did not change) were calculated over 6-, 12-, and 18-month epochs. The percentage of participants ever experiencing reversals (periods where scores improved) of different lengths were also calculated and plotted.Over 6 months, 25% of 3,132 participants did not decline. Over 12 months, 16% of 2,105 participants did not decline. Over 18 months, 7% of 1,218 participants did not decline. Small ALS reversals were also common, especially over shorter follow-up intervals; 14% of 1,343 participants had a 180-day interval where their ALSFRS-R slope was greater than zero. Fewer than 1% of participants ever experienced improvements of 4 or more ALSFRS-R points lasting at least 12 months.ALS plateaus and small reversals are common, especially over brief intervals. In light of these data, stable disease, especially for a short period of time, should not be interpreted as an ALS treatment effect. Large sustained ALS reversals, on the other hand, are rare, potentially important, and warrant further study.
| S-EPMC4793781 | biostudies-other
Project description:The behavioral variant of frontotemporal dementia (bvFTD) is a clinical syndrome resulting from various causes of neuronal demises associated with frontotemporal lobar degeneration. Symptoms include behavioral and personality changes, social cognitive impairment, and executive function deficits. There is a significant clinical overlap between this syndrome and various primary psychiatric disorders (PPD). Structural and functional neuroimaging are considered helpful to support the diagnosis of bvFTD, but their sensitivity and specificity remain imperfect. There is growing evidence concerning the potential of neurofilaments as biomarkers reflecting axonal and neuronal lesions. Ultrasensitive analytic platforms have recently enabled neurofilament light chains' (NfL) detection not only from cerebrospinal fluid but also from peripheral blood samples in FTD patients. In this short review, we present recent advances and perspectives for the use of NfL assessments as biomarkers of neuroaxonal damage to differentiate bvFTD from primary psychiatric disorders.
| S-EPMC8146697 | biostudies-literature
Project description:Rearrangements of the transcription factors FOS and FOSB have recently been identified as the genetic driver event underlying osteoid osteoma and osteoblastoma. Nuclear overexpression of FOS and FOSB have since then emerged as a reliable surrogate marker despite limitations in specificity and sensitivity. Indeed, osteosarcoma can infrequently show nuclear FOS expression and a small fraction of osteoblastomas seem to arise independent of FOS/FOSB rearrangements. Acid decalcification and tissue preservation are additional factors that can negatively influence immunohistochemical testing and make diagnostic decision-making challenging in individual cases. Particularly aggressive appearing osteoblastomas, also referred to as epithelioid osteoblastomas, and osteoblastoma-like osteosarcoma can be difficult to distinguish, underlining the need for additional markers to support the diagnosis. Methylation and copy number profiling, a technique well established for the classification of brain tumors, might fill this gap. Here, we set out to comprehensively characterize a series of 77 osteoblastomas by immunohistochemistry, fluorescence in-situ hybridization as well as copy number and methylation profiling and compared our findings to histologic mimics. Our results show that osteoblastomas are uniformly characterized by flat copy number profiles that can add certainty in reaching the correct diagnosis. The methylation cluster formed by osteoblastomas, however, so far lacks specificity and can be misleading in individual cases.
| S-EPMC9424109 | biostudies-literature
Project description:Several studies have attempted to reduce diagnostic delay and identify biomarkers for drug development in amyotrophic lateral sclerosis (ALS). In this study, we aimed to evaluate the diagnostic accuracy for ALS of cerebrospinal fluid (CSF) neurofilament (Nf), Tau protein, and inflammatory factors such as interleukin (IL)-2, IL-6, IL-10, IL-15, and granulocyte-macrophage colony-stimulating factor (GMCSF) in Chinese patients. Our prospective study measured the concentration of phosphorylated Nf heavy chain (pNfH), Nf light chain (NfL), Tau, pTau, and inflammatory factors in the CSF of 85 patients. Detailed clinical data and laboratory, neuroimaging, and neurophysiological findings were recorded. The concentrations of pNfH and NfL were higher in the ALS group than in the control group. At the 1104 pg/mL pNfH cutoff, the specificity was 68.8%, the sensitivity 100%, and the area under the curve (AUC) 0.907. At the 1,139 pg/mL NfL cutoff, the specificity was 56.3%, the sensitivity 96.2%, and the AUC 0.775. There was no significant difference in the concentrations of Tau, pTau, IL-2, IL-6, IL-10, IL-15, and GMCSF between the ALS and control groups (p > 0.05). In the ALS group, the concentration of pNfH in the CSF was correlated with disease duration (r = -0.475, p < 0.001). This is the first prospective study to confirm the diagnostic value of Nf for ALS in Chinese patients.
| S-EPMC6121092 | biostudies-literature
Project description:BackgroundDistinguishing arboviral infections from bacterial causes of febrile illness is of great importance for clinical management. The Infection Manager System (IMS) is a novel diagnostic algorithm equipped on a Sysmex hematology analyzer that evaluates the host response using novel techniques that quantify cellular activation and cell membrane composition. The aim of this study was to train and validate the IMS to differentiate between arboviral and common bacterial infections in Southeast Asia and compare its performance against C-reactive protein (CRP) and procalcitonin (PCT).Methodology/principal findings600 adult Indonesian patients with acute febrile illness were enrolled in a prospective cohort study and analyzed using a structured diagnostic protocol. The IMS was first trained on the first 200 patients and subsequently validated using the complete cohort. A definite infectious etiology could be determined in 190 of 463 evaluable patients (41%), including 89 arboviral infections (81 dengue and 8 chikungunya), 94 bacterial infections (26 murine typhus, 16 salmonellosis, 6 leptospirosis and 46 cosmopolitan bacterial infections), 3 concomitant arboviral-bacterial infections, and 4 malaria infections. The IMS detected inflammation in all but two participants. The sensitivity, specificity, positive predictive value (PPV), and negative predictive value (NPV) of the IMS for arboviral infections were 69.7%, 97.9%, 96.9%, and 77.3%, respectively, and for bacterial infections 77.7%, 93.3%, 92.4%, and 79.8%. Inflammation remained unclassified in 19.1% and 22.5% of patients with a proven bacterial or arboviral infection. When cases of unclassified inflammation were grouped in the bacterial etiology group, the NPV for bacterial infection was 95.5%. IMS performed comparable to CRP and outperformed PCT in this cohort.Conclusions/significanceThe IMS is an automated, easy to use, novel diagnostic tool that allows rapid differentiation between common causes of febrile illness in Southeast Asia.
| S-EPMC6435198 | biostudies-literature