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Plasma neurofilament heavy chain levels and disease progression in amyotrophic lateral sclerosis: insights from a longitudinal study.

ABSTRACT: 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.

SUBMITTER: Lu CH

PROVIDER: S-EPMC4413806 | biostudies-other | 2015 May

REPOSITORIES: biostudies-other

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Plasma neurofilament heavy chain levels and disease progression in amyotrophic lateral sclerosis: insights from a longitudinal study.

Lu Ching-Hua CH Petzold Axel A Topping Jo J Allen Kezia K Macdonald-Wallis Corrie C Clarke Jan J Pearce Neil N Kuhle Jens J Giovannoni Gavin G Fratta Pietro P Fratta Pietro P Sidle Katie K Fish Mark M Orrell Richard R Howard Robin R Greensmith Linda L Malaspina Andrea A

Journal of neurology, neurosurgery, and psychiatry 20140709 5

<h4>Objective</h4>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).<h4>Methods</h4>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 y ...[more]

PMID: 25009280

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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.

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.

Project description: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.

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Plasma neurofilament heavy chain levels and disease progression in amyotrophic lateral sclerosis: insights from a longitudinal study.

Publications

Plasma neurofilament heavy chain levels and disease progression in amyotrophic lateral sclerosis: insights from a longitudinal study.

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