Role of plasma phosphorylated neurofilament heavy chain (pNfH) in amyotrophic lateral sclerosis.
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ABSTRACT:
SUBMITTER: Zecca C
PROVIDER: S-EPMC9258711 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:As potential treatments for C9ORF72-associated amyotrophic lateral sclerosis (c9ALS) approach clinical trials, the identification of prognostic biomarkers for c9ALS becomes a priority. We show that levels of phosphorylated neurofilament heavy chain (pNFH) in cerebrospinal fluid (CSF) predict disease status and survival in c9ALS patients, and are largely stable over time. Moreover, c9ALS patients exhibit higher pNFH levels, more rapid disease progression, and shorter survival after disease onset than ALS patients without C9ORF72 expansions. These data support the use of CSF pNFH as a prognostic biomarker for clinical trials, which will increase the likelihood of successfully developing a treatment for c9ALS. Ann Neurol 2017;82:139-146.
| S-EPMC5676468 | biostudies-literature
Project description:To investigate the role of longitudinal plasma neurofilament heavy chain protein (NfH) levels as an indicator of clinical progression and survival in amyotrophic lateral sclerosis (ALS).A cross-sectional study involving 136 clinically heterogeneous patients with ALS and 104 healthy and neurological controls was extended to include a prospective analysis of 74 of these ALS cases, with samplings at approximately 3-month intervals in a follow-up period of up to 3 years. We analysed the correlation between longitudinal NfH-phosphoform levels and disease progression. Temporal patterns of NfH changes were evaluated using multilevel linear regression.Baseline plasma NfH levels were higher than controls only in patients with ALS with short disease duration to baseline sampling. Compared with controls, fast-progressing patients with ALS, particularly those with a short diagnostic latency and disease duration, had higher plasma NfH levels at an early stage and lower levels closer to end-stage disease. Lower NfH levels between visits were associated with rapid functional deterioration. We also detected antibodies against NfH, NfH aggregates and NfH cleavage products.Disease progression in ALS involves defined trajectories of plasma NfH levels, reflecting speed of neurological decline and survival. Intervisit plasma NfH changes are also indicative of disease progression. This study confirms that longitudinal measurements of NfH plasma levels are more informative than cross-sectional studies, where the time of sampling may represent a bias in the interpretation of the results. Autoantibodies against NfH aggregates and NfH cleavage products may explain the variable expression of plasma NfH with disease progression.NIHRID6160.
| S-EPMC4413806 | biostudies-other
Project description:ObjectiveTo test blood and CSF neurofilament light chain (NfL) levels in relation to disease progression and survival in amyotrophic lateral sclerosis (ALS).MethodsUsing an electrochemiluminescence immunoassay, NfL levels were measured in samples from 2 cohorts of patients with sporadic ALS and healthy controls, recruited in London (ALS/control, plasma: n = 103/42) and Oxford (ALS/control, serum: n = 64/36; paired CSF: n = 38/20). NfL levels in patients were measured at regular intervals for up to 3 years. Change in ALS Functional Rating Scale-Revised score was used to assess disease progression. Survival was evaluated using Cox regression and Kaplan-Meier analysis.ResultsCSF, serum, and plasma NfL discriminated patients with ALS from healthy controls with high sensitivity (97%, 89%, 90%, respectively) and specificity (95%, 75%, 71%, respectively). CSF NfL was highly correlated with serum levels (r = 0.78, p < 0.0001). Blood NfL levels were approximately 4 times as high in patients with ALS compared with controls in both cohorts, and maintained a relatively constant expression during follow-up. Blood NfL levels at recruitment were strong, independent predictors of survival. The highest tertile of blood NfL at baseline had a mortality hazard ratio of 3.91 (95% confidence interval 1.98-7.94, p < 0.001).ConclusionBlood-derived NfL level is an easily accessible biomarker with prognostic value in ALS. The individually relatively stable levels longitudinally offer potential for NfL as a pharmacodynamic biomarker in future therapeutic trials.Classification of evidenceThis report provides Class III evidence that the NfL electrochemiluminescence immunoassay accurately distinguishes patients with sporadic ALS from healthy controls.
| S-EPMC4456658 | biostudies-literature
Project description: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.
| S-EPMC8569186 | biostudies-literature
Project description:BackgroundSpinal muscular atrophy (SMA) and amyotrophic lateral sclerosis (ALS) were two major motor neuron diseases with similar symptoms and poor outcomes. This study aimed to identify potential biomarkers in disease monitoring and differential diagnosis of adult SMA patients with sporadic ALS patients.MethodsThis was a pilot study with ten adult SMA patients and ten ALS patients consecutively enrolled during hospitalization. Serum and cerebrospinal fluid (CSF) samples were collected for assessment of neurofilament light (NFL) and phosphorylated neurofilament heavy chain (pNFH). Serum creatine kinase (CK) and creatinine (Cr) were also compared between groups. The receiver operating characteristic (ROC) curves were used to identify differentiated values among ALS and SMA patients.ResultsSerum Cr, CSF NFL, and CSF pNFH levels of ALS patients were significantly higher than those of the adult SMA patients (p < .01). Serum CK and Cr were strongly correlated with baseline ALSFRS-R scores in SMA patients (p < .001). The ROC curves revealed an area under the curve (AUC) of 0.94 in serum Cr with a cut-off value of 44.5 μmol/L (Sensitivity 90%, Specificity 90%). AUC from the ROC curve of CSF NFL and CSF pNFH were 1.0 and 0.84, with cut-off values of 1275 pg/mL and 0.395 ng/mL, respectively (Sensitivity and Specificity of 100% and 100% in CSF NFL; Sensitivity and Specificity of 90% and 80% in CSF pNFH).ConclusionCSF NFL and pNFH might be useful biomarkers for differential diagnosis of adult SMA and ALS.
| S-EPMC10175988 | biostudies-literature
Project description:A biomarker specific for the diagnosis of amyotrophic lateral sclerosis must be sensitive across a spectrum of clinical heterogeneity. Neurofilament light chain levels in amyotrophic lateral sclerosis correlate with the rate of disability progression. Previous attempts to establish a diagnostic role for neurofilament light chain have been limited to comparison with healthy individuals or controls with alternative diagnoses unlikely to be confused with amyotrophic lateral sclerosis in real-world clinical practice. In a tertiary amyotrophic lateral sclerosis referral clinic, at first visit, serum was taken for neurofilament light chain measurement after prospectively recording the clinical diagnosis as 'amyotrophic lateral sclerosis', 'primary lateral sclerosis', 'alternative' or 'currently uncertain'. Of 133 referrals, 93 patients were diagnosed with amyotrophic lateral sclerosis (median neurofilament light chain 218.1 pg/ml, interquartile range 130.7-311.9), three primary lateral sclerosis (65.6, 51.5-106.9) and 19 alternative diagnoses (45.2, 13.5-71.9) at first visit. Of 18 initially uncertain diagnoses, eight were subsequently diagnosed with amyotrophic lateral sclerosis (98.5, 45.3-300.1). Neurofilament light chain ≥110.9 pg/ml had a positive predictive value of 0.92 for amyotrophic lateral sclerosis; <110.9 pg/ml had a negative predictive value of 0.48. In a specialized clinic, neurofilament light chain is largely confirmatory to clinical judgement in diagnosing amyotrophic lateral sclerosis and has limited ability to exclude alternative diagnoses. The current, important, value of neurofilament light chain is its potential to stratify patients with amyotrophic lateral sclerosis by disease activity and as a biomarker in therapeutic trials.
| S-EPMC10244039 | biostudies-literature
Project description:ObjectiveTo assess the performance of serum neurofilament light chain (sNfL) in clinical phenotypes of amyotrophic lateral sclerosis (ALS).MethodsIn 2949 ALS patients at 16 ALS centers in Germany and Austria, clinical characteristics and sNfL were assessed. Phenotypes were differentiated for two anatomical determinants: (1) upper and/or lower motor involvement (typical, typMN; upper/lower motor neuron predominant, UMNp/LMNp; primary lateral sclerosis, PLS) and (2) region of onset and propagation of motor neuron dysfunction (bulbar, limb, flail-arm, flail-leg, thoracic onset). Phenotypes were correlated to sNfL, progression, and survival.ResultsMean sNfL was - compared to typMN (75.7 pg/mL, n = 1791) - significantly lower in LMNp (45.1 pg/mL, n = 413), UMNp (58.7 pg/mL n = 206), and PLS (37.6 pg/mL, n = 84). Also, sNfL significantly differed in the bulbar (92.7 pg/mL, n = 669), limb (64.1 pg/mL, n = 1305), flail-arm (46.4 pg/mL, n = 283), flail-leg (53.6 pg/mL, n = 141), and thoracic (74.5 pg/mL, n = 96) phenotypes. Binary logistic regression analysis showed highest contribution to sNfL elevation for faster progression (odds ratio [OR] 3.24) and for the bulbar onset phenotype (OR 1.94). In contrast, PLS (OR 0.20), LMNp (OR 0.45), and thoracic onset (OR 0.43) showed reduced contributions to sNfL. Longitudinal sNfL (median 12 months, n = 2862) showed minor monthly changes (<0.2%) across all phenotypes. Correlation of sNfL with survival was confirmed (p < 0.001).ConclusionsThis study underscored the correlation of ALS phenotypes - differentiated for motor neuron involvement and region of onset/propagation - with sNfL, progression, and survival. These phenotypes demonstrated a significant effect on sNfL and should be recognized as independent confounders of sNfL analyses in ALS trials and clinical practice.
| S-EPMC11295170 | biostudies-literature
Project description:The routine clinical integration of individualized objective markers of disease activity in those diagnosed with the neurodegenerative disorder amyotrophic lateral sclerosis is a key requirement for therapeutic development. A large, multicentre, clinic-based, longitudinal cohort was used to systematically appraise the leading candidate biofluid biomarkers in the stratification and potential therapeutic assessment of those with amyotrophic lateral sclerosis. Incident patients diagnosed with amyotrophic lateral sclerosis (n = 258), other neurological diseases (n = 80) and healthy control participants (n = 101), were recruited and followed at intervals of 3-6 months for up to 30 months. Cerebrospinal fluid neurofilament light chain and chitotriosidase 1 and blood neurofilament light chain, creatine kinase, ferritin, complement C3 and C4 and C-reactive protein were measured. Blood neurofilament light chain, creatine kinase, serum ferritin, C3 and cerebrospinal fluid neurofilament light chain and chitotriosidase 1 were all significantly elevated in amyotrophic lateral sclerosis patients. First-visit plasma neurofilament light chain level was additionally strongly associated with survival (hazard ratio for one standard deviation increase in log10 plasma neurofilament light chain 2.99, 95% confidence interval 1.65-5.41, P = 0.016) and rate of disability progression, independent of other prognostic factors. A small increase in level was noted within the first 12 months after reported symptom onset (slope 0.031 log10 units per month, 95% confidence interval 0.012-0.049, P = 0.006). Modelling the inclusion of plasma neurofilament light chain as a therapeutic trial outcome measure demonstrated that a significant reduction in sample size and earlier detection of disease-slowing is possible, compared with using the revised Amyotrophic Lateral Sclerosis Functional Rating Scale. This study provides strong evidence that blood neurofilament light chain levels outperform conventional measures of disease activity at the group level. The application of blood neurofilament light chain has the potential to radically reduce the duration and cost of therapeutic trials. It might also offer a first step towards the goal of more personalized objective disease activity monitoring for those living with amyotrophic lateral sclerosis.
| S-EPMC8870425 | biostudies-literature
Project description:ImportanceA clearer definition of the role of neurofilament light chain (NFL) as a biomarker in amyotrophic lateral sclerosis (ALS) is needed.ObjectivesTo assess the ability of NFL to serve as a diagnostic biomarker in ALS and the prognostic value of cerebrospinal fluid NFL in patients with ALS.Design, setting, and participantsIn this single-center, retrospective, longitudinal study, disease progression was assessed by the ALS Functional Rating Score-Revised and the ALS Milano-Torino Staging system at baseline and 6, 12, 24, and 36 months. Cerebrospinal fluid samples were obtained from 176 patients admitted to the Department of Neurosciences of the University of Padua, Padova, Italy, from January 1, 2010, through February 29, 2016. Patients with ALS underwent ambulatory follow-up at the same department.Main outcomes and measuresLevels of NFL.ResultsThe study included 94 patients with ALS (64 men [36.4%] and 30 women [17.0%]; median age, 62.5 years), 20 patients with frontotemporal dementia (FTD) (8 men [4.5%] and 12 women [6.8%]; median age, 65 years), 18 patients with motor neuropathies (14 men [8.0%] and 4 women [2.3%]; median age, 63 years), and 44 controls (24 men [13.6%] and 20 women [11.4%]; median age, 54 years). Log-transformed NFL (log[NFL]) concentrations were higher in the ALS and FTD groups compared with the motor neuropathies and control groups (hazard ratio [HR], 2.45; 95% CI, 1.66-3.61; P < .001). Patients with typical ALS (HR, 1.0 [reference]), progressive bulbar palsy (HR, 1.48; 95% CI, 0.58-3.75; P = .41), and upper motor neuron dominant ALS (HR, 0.12; 95% CI, 0.02-0.61; P = .01) had higher levels of NFL than did those with flail arm or leg syndrome (HR, 0.28; 95% CI, 0.08-0.10; P = .049) and progressive muscular atrophy (HR, 0.17; 95% CI, 0.22-1.36; P = .10). There was an inverse correlation between log[NFL] concentration and overall survival (HR, 2.45; 95% CI, 1.66-3.61; P < .001). There was no evidence of different log[NFL] concentrations and survival in genetic ALS.Conclusions and relevanceThis study confirms the role of NFL as a biomarker in ALS. Elevation in NFL levels in patients with upper motor neuron involvement and FTD might reflect the corticospinal tract degeneration. Low NFL levels in patients with lower motor neuron signs might be a prognostic indicator of milder phenotypes of disease.
| S-EPMC5822207 | biostudies-literature
Project description:An increasingly varied clinical spectrum of cases with amyotrophic lateral sclerosis (ALS) has been identified, and objective criteria for clinical trial eligibility are necessary.To develop a cerebrospinal fluid (CSF) biomarker sensitive and specific for the diagnosis of ALS.A case-control study including 51 individuals with ALS and 23 individuals with a disorder associated with a 4-repeat tauopathy was conducted at an academic medical center.The CSF level of tau phosphorylated at threonine 181 (ptau) and ratio of ptau to total tau (ttau).Using a cross-validation prediction procedure, we found significantly reduced CSF levels of ptau and the ptau:ttau ratio in ALS relative to 4-repeat tauopathy and to controls. In the validation cohort, the receiver operating characteristic area under the curve for the ptau:ttau ratio was 0.916, and the comparison of ALS with 4-repeat tauopathy showed 92.0% sensitivity?and 91.7% specificity. Correct classification based on a low CSF ptau:ttau ratio was confirmed in 18 of 21 cases (86%) with autopsy-proved or genetically determined disease. In patients with available measures, ptau:ttau in ALS correlated with clinical measures of disease severity, such as the Mini-Mental State Examination (n?=?51) and ALS Functional Rating Scale-Revised (n?=?42), and regression analyses related the ptau:ttau ratio to magnetic resonance imaging (n?=?10) evidence of disease in the corticospinal tract and white matter projections involving the prefrontal cortex.The CSF ptau:ttau ratio may be a candidate biomarker to provide objective support for the diagnosis of ALS.
| S-EPMC3989393 | biostudies-literature