Neurofilament Levels in CSF and Serum in an Adult SMA Cohort Treated with Nusinersen

Objective: To retrospectively evaluate the utility of serum and cerebrospinal fluid (CSF) levels of neurofilament light chain (NfL) and phosphorylated neurofilament heavy chain (pNfH) as biomarkers for spinal muscular atrophy (SMA) progression and response to nusinersen treatment. Methods: NfL and pNfH levels were quantified using single molecular array (SIMOA) in CSF of 33 adult SMA patients (SMN copy number 3–5) before and in response to nusinersen treatment. In 11 of the patients, blood serum samples were also collected. CSF NfL and pNfH from patients were compared to CSF Nfs from age-matched controls without neurological disease (n = 6). For patients, pearson correlation coefficients (r) were calculated to investigate associations between Nf levels and other functional outcome measures. Results: Nf levels were similar between SMA and control adults and showed no change in response to nusinersen treatment in CSF or serum. Cross-sectional analyses showed an increase in CSF NfL and pNfH with age in patients (NfL p = 0.0013; pNfH p = 0.0035) and an increase in CSF NfL in controls (p = 0.002). In non-ambulatory patients, baseline serum pNfH showed a negative correlation with multiple strength and functional assessment metrics including Revised Upper Limb Module (r = –0.822, p = 0.04), upper extremity strength (r = –0.828, p = 0.042), lower extremity strength (r = –0.860, p = 0.028), and total strength (r = –0.870, p = 0.024). Conclusions: Nf levels did not change in response to nusinersen in adults with SMA and were not different from controls. In patients and controls, we detected an age-related increase in baseline CSF NfL and pNfH levels. Though some associations were identified, our results suggest Nf levels are not preditive or prognostic biomarkers in this population.

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Validation of Serum Neurofilament Light Chain as a Biomarker of Parkinson’s Disease Progression

10.1101/762237 ◽

2019 ◽

Cited By ~ 2

Author(s):

Brit Mollenhauer ◽

Mohammed Dakna ◽

Tzu-Ying Liu ◽

Douglas Galasko ◽

Tatiana Foroud ◽

...

Keyword(s):

Parkinson’S Disease ◽

Parkinson's Disease ◽

Light Chain ◽

Validation Cohort ◽

Serum Samples ◽

Neurofilament Light Chain ◽

Cross Sectional ◽

Neurofilament Light ◽

Baseline Serum ◽

Disease Stratification

AbstractObjectiveTo assess neurofilament light chain (NfL), as a biomarker for Parkinson’s disease (PD).MethodsWe quantified NfL in (1) longitudinal CSF samples from PD, other cognate/neurodegenerative disorders (OND), and healthy controls (HC); (2) a cross-sectional cohort with paired CSF and serum samples from participants with PD, OND, and HC, and (3) a large longitudinal validation cohort with serum samples from PD, OND, HC, prodromal conditions, and mutation carriers.ResultsIn the longitudinal discovery cohort (1) NfL in CSF was highest in OND and higher in PD vs. HC across all visits (p<0.05) but did not change longitudinally. In the cross-sectional cohort (2) paired CSF and serum NfL samples were highly correlated (Spearman’s rank ; p<10^-6). In the large validation cohort (3) mean baseline serum NfL was higher in PD (13±7.2pg/ml) vs. HC (12±6.7pg/ml; p=0.0336) and was highest in OND (18±7pg/ml; p=0.0351). Serum NfL increased longitudinally in PD vs. HC (p<0.01). Longitudinal motor scores were positively longitudinally associated with NfL, whereas some cognitive scores showed a negative longitudinal association with NfL.ConclusionsNfL levels in serum samples are increased in PD vs. HC, increase significantly over time, and correlate with clinical measures of PD severity. Although the specificity of NfL in PD is low and more specific biomarkers are needed, serum NfL is the first blood-based biomarker candidate that could support disease stratification (PD vs. OND), track clinical progression, and possibly assess responsiveness to neuroprotective treatments. NfL as a biomarker of response to neuroprotective interventions remains to be determined.Funding sources for studyPPMI is sponsored by the Michael J. Fox Foundation for Parkinson’s Research (MJFF) and is co-funded by MJFF, Abbvie, Avid Radiopharmaceuticals, Biogen Idec, Bristol-Myers Squibb, Covance, Eli Lilly & Co., F. Hoffman-La Roche, Ltd., GE Healthcare, Genentech, GlaxoSmithKline, Lundbeck, Merck, MesoScale, Piramal, Pfizer and UCB. The funders had no role in the design and conduct of the study, in the collection, management, analysis, and interpretation of the data, in the preparation, review, or approval of the manuscript or in the decision to submit the manuscript for publication.Financial Disclosure/Conflict of Interest concerning the research related to the manuscriptBrit Mollenhauer, Douglas Galasko, Tatiana Foroud, Lana M. Chahine, Christopher S. Coffey, Andrew B. Singleton, Tanya Simuni, Daniel Weintraub, John Seibyl, Arthur W. Toga, and Caroline M. Tanner received funding from The Michael J. Fox Foundation for Parkinson’s Research.Mohammed Dakna, Tzu-Ying Liu, Henrik Zetterberg, Sebastian Schade, Roland G. Gera, Wenting Wang, Feng Gao, Niels Kruse, Mark Frasier, Jesse M. Cedarbaum, Samantha J. Hutten, Claudia Trenkwalder, and Danielle Graham report no disclosures.

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Correlation between lens thickness and lens density in patients with mild to moderate cataracts

British Journal of Ophthalmology ◽

10.1136/bjophthalmol-2019-314171 ◽

2020 ◽

Vol 104 (10) ◽

pp. 1350-1357

Author(s):

Maria A Henriquez ◽

Josefina A Mejías ◽

Mirel Rincon ◽

Luis Izquierdo ◽

Perry S Binder

Keyword(s):

Pearson Correlation ◽

Anterior Segment ◽

Anterior Chamber Depth ◽

Correlation Coefficients ◽

Clinical Parameter ◽

Cross Sectional Study ◽

Cross Sectional ◽

Lens Thickness ◽

Age Related ◽

Lens Density

PurposeTo determine the relationships between lens thickness (LT), lens density and anterior segment parameters in patients with mild to moderate cataracts.SettingOftalmosalud Instituto de Ojos, Lima, Perú.DesignProspective, single-centre, cross-sectional study.Methods169 eyes with age-related mild to moderate cataracts had lens density assessed using the Lens Opacification Classification System III, the built-in Pentacam HR Nucleus Staging software and ImageJ software. LT and axial length (AL) were measured with the IOLMaster 700, and angle parameters were measured using anterior segment optical coherence tomography. Pearson correlation coefficients and Kruskal-Wallis tests were used for statistical analyses.ResultsNuclear colour score was the only clinical parameter with a weak significant correlation with LT (r=0.24, p=0.003) after accounting for age, AL, gender and anterior chamber depth (ACD). The maximum value of average lens density and the mean nuclear density were significantly correlated with LT (r=0.24, p=0.003 and −0.17, p=0.03, respectively) after controlling for the same factors. Central LT greater than 4.48 mm was present in 54.5% of the eyes with a nuclear opalescence grade 1.ConclusionsLT is independent of lens density in mild to moderate cataracts after accounting for age, AL, ACD and gender contrary to previous studies.

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Validation of serum neurofilaments as prognostic and potential pharmacodynamic biomarkers for ALS

Neurology ◽

10.1212/wnl.0000000000009559 ◽

2020 ◽

Vol 95 (1) ◽

pp. e59-e69 ◽

Cited By ~ 8

Author(s):

Michael Benatar ◽

Lanyu Zhang ◽

Lily Wang ◽

Volkan Granit ◽

Jeffrey Statland ◽

...

Keyword(s):

Sample Size ◽

Rating Scale ◽

Limit Of Detection ◽

Muscular Atrophy ◽

Serum Samples ◽

Neurofilament Light ◽

Baseline Serum ◽

Coefficients Of Variation ◽

Pharmacodynamic Biomarkers ◽

Lateral Sclerosis

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.

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Leader-Member Exchange (LMX) Impact on Work-Home Interference in a South African Commuter Transport Engineering Company

African Journal of Employee Relations (Formerly South African Journal of Labour Relations) ◽

10.25159/2520-3223/4553 ◽

2019 ◽

Vol 43 ◽

Author(s):

Jan Christoff Visagie ◽

Michael M. Jones ◽

Herman L. Linde

Keyword(s):

South African ◽

Structural Equation ◽

Pearson Correlation ◽

Correlation Coefficients ◽

Leader Member Exchange ◽

Negative Consequences ◽

Dyadic Relationship ◽

Cross Sectional ◽

Engineering Company ◽

Member Exchange

The South African workplace is confronted with many leadership challenges, specifically those relating to the employment relationship between subordinates and their supervisors. A high-quality relationship is essential, considering the work-family spillovers employees experience. Limited research has been conducted on the potential positive and negative consequences of the leader-member exchange (LMX) dyadic relationship. In this study, we used a cross-sectional research design, and drew an employee sample (N = 120) from a commuter transport engineering company. A five-point Likert scale was employed and statistical analyses were carried out using the SAS statistical program. We calculated Pearson correlation coefficients and used structural equation modelling to test the proposed conceptual model to indicate possible correlations between the different variables. The main finding of the study was that the nature of the LMX relationship quality in the relevant company appeared to be high and positively related to work-home enrichment but negatively related to work-home conflict and role overload. The article concludes by making a number of suggestions to respond to challenges.

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The patellofemoral morphology and the normal predicted value of tibial tuberosity-trochlear groove distance in the Chinese population

BMC Musculoskeletal Disorders ◽

10.1186/s12891-021-04454-8 ◽

2021 ◽

Vol 22 (1) ◽

Author(s):

Zhe Li ◽

Guanzhi Liu ◽

Run Tian ◽

Ning Kong ◽

Yue Li ◽

...

Keyword(s):

Individual Differences ◽

Chinese Population ◽

Pearson Correlation ◽

Three Dimensional ◽

Correlation Coefficients ◽

Tibial Tuberosity ◽

Trochlear Groove ◽

Lasso Regression ◽

Cross Sectional ◽

Anterior Posterior

Abstract Background Our objective was to obtain normal patellofemoral measurements to analyse sex and individual differences. In addition, the absolute values and indices of tibial tuberosity-trochlear groove (TT-TG) distances are still controversial in clinical application. A better method to enable precise prediction is still needed. Methods Seventy-eight knees of 78 participants without knee pathologies were included in this cross-sectional study. A CT scan was conducted for all participants and three-dimensional knee models were constructed using Mimics and SolidWorks software. We measured and analysed 19 parameters including the TT-TG distance and dimensions and shapes of the patella, femur, tibia, and trochlea. LASSO regression was used to predict the normal TT-TG distances. Results The dimensional parameters, TT-TG distance, and femoral aspect ratio of the men were significantly larger than those of women (all p values < 0.05). However, after controlling for the bias from age, height, and weight, there were no significant differences in TT-TG distances and anterior-posterior dimensions between the sexes (all p values > 0.05). The Pearson correlation coefficients between the anterior femoral offset and other indexes were consistently below 0.3, indicating no relationship or a weak relationship. Similar results were observed for the sulcus angle and the Wiberg index. Using LASSO regression, we obtained four parameters to predict the TT-TG distance (R2 = 0.5612, p < 0.01) to achieve the optimal accuracy and convenience. Conclusions Normative data of patellofemoral morphology were provided for the Chinese population. The anterior-posterior dimensions of the women were thicker than those of men for the same medial-lateral dimensions. More attention should be paid to not only sex differences but also individual differences, especially the anterior condyle and trochlea. In addition, this study provided a new method to predict TT-TG distances accurately.

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A Quantitative Comparison of Multispectral Refraction Topography and Autorefractometer in Young Adults

Frontiers in Medicine ◽

10.3389/fmed.2021.715640 ◽

2021 ◽

Vol 8 ◽

Author(s):

Yunru Liao ◽

Zhenlan Yang ◽

Zijing Li ◽

Rui Zeng ◽

Jing Wang ◽

...

Keyword(s):

Correlation Coefficient ◽

Pearson Correlation ◽

Intraclass Correlation ◽

Correlation Coefficients ◽

Cross Sectional Study ◽

Cross Sectional ◽

High Agreement ◽

Intraclass Correlation Coefficients ◽

Repeatability And Reproducibility ◽

The Mean

Purpose: Purpose of this study is to evaluate the measuring consistency of central refraction between multispectral refraction topography (MRT) and autorefractometry.Methods: This was a descriptive cross-sectional study including subjects in Sun Yat-sen Memorial Hospital from September 1, 2020, to December 31, 2020, ages 20 to 35 years with a best corrected visual acuity of 20/20 or better. All patients underwent cycloplegia, and the refractive status was estimated with autorefractometer, experienced optometrist and MRT. We analyzed the central refraction of the autorefractometer and MRT. The repeatability and reproducibility of values measured using both devices were evaluated using intraclass correlation coefficients (ICCs).Results: A total of 145 subjects ages 20 to 35 (290 eyes) were enrolled. The mean central refraction of the autorefractometer was −4.69 ± 2.64 diopters (D) (range −9.50 to +4.75 D), while the mean central refraction of MRT was −4.49 ± 2.61 diopters (D) (range −8.79 to +5.02 D). Pearson correlation analysis revealed a high correlation between the two devices. The intraclass correlation coefficient (ICC) also showed high agreement. The intrarater and interrater ICC values of central refraction were more than 0.90 in both devices and conditions. At the same time, the mean central refraction of experienced optometrist was −4.74 ± 2.66 diopters (D) (range −9.50 to +4.75D). The intra-class correlation coefficient of central refraction measured by MRT and subjective refraction was 0.939.Conclusions: Results revealed that autorefractometry, experienced optometrist and MRT show high agreement in measuring central refraction. MRT could provide a potential objective method to assess peripheral refraction.

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Association of intrathecal pleocytosis and IgG synthesis with axonal damage in early MS

Neurology Neuroimmunology & Neuroinflammation ◽

10.1212/nxi.0000000000000679 ◽

2020 ◽

Vol 7 (3) ◽

pp. e679 ◽

Cited By ~ 2

Author(s):

Sinah Engel ◽

Falk Steffen ◽

Timo Uphaus ◽

Peter Scholz-Kreisel ◽

Frauke Zipp ◽

...

Keyword(s):

Single Molecule ◽

Leukocyte Count ◽

Cross Sectional Study ◽

Axonal Damage ◽

Oligoclonal Bands ◽

Neurofilament Light Chain ◽

Cross Sectional ◽

Neurofilament Light ◽

Igg Synthesis ◽

Healthy Donors

ObjectiveTo investigate the association of serum neurofilament light chain (sNfL) levels with CSF parameters in clinically isolated syndrome (CIS) and early relapsing-remitting MS (RRMS), taking into account radiologic and clinical parameters of disease activity.MethodsSimultaneously collected serum and CSF samples of 112 untreated patients newly diagnosed with CIS or RRMS were included in this cross-sectional study. CSF parameters were obtained as part of routine diagnostic tests. sNfL levels of patients and of 62 healthy donors were measured by highly sensitive single molecule array (SiMoA) immunoassay.ResultsPatients with RRMS (n = 91, median 10.13 pg/mL, interquartile range [IQR] 6.67–17.77 pg/mL) had higher sNfL levels than healthy donors (n = 62, median 5.25 pg/mL, IQR 4.05–6.81 pg/mL, p < 0.001) and patients with CIS (n = 21, median 5.69 pg/mL, IQR 4.73–9.07 pg/mL, p < 0.001). Patients positive for oligoclonal bands (OCBs) (n = 101, median 9.19 pg/mL, IQR 6.34–16.38 pg/mL) had higher sNfL levels than OCB-negative patients (n = 11, median 5.93 pg/mL, IQR 2.93–8.56 pg/mL, p = 0.001). sNfL levels correlated with CSF immunoglobulin G (IgG) levels (r = 0.317, p = 0.002), IgG ratio (QIgG) (r = 0.344, p < 0.001), and CSF leukocyte count (r = 0.288, p = 0.002). In linear regression modeling, the CSF leukocyte count combined with the number of contrast-enhancing lesions in MRI predicted sNfL levels best.ConclusionsIn active MS, sNfL levels correlate with intrathecal pleocytosis and IgG synthesis, indicating that axonal damage is associated with both acute and chronic CNS-intrinsic inflammation.

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Serum GFAP and neurofilament light as biomarkers of disease activity and disability in NMOSD

Neurology ◽

10.1212/wnl.0000000000008160 ◽

2019 ◽

Vol 93 (13) ◽

pp. e1299-e1311 ◽

Cited By ~ 21

Author(s):

Mitsuru Watanabe ◽

Yuri Nakamura ◽

Zuzanna Michalak ◽

Noriko Isobe ◽

Christian Barro ◽

...

Keyword(s):

Disease Activity ◽

Single Molecule ◽

Multivariate Analyses ◽

Serum Levels ◽

Strongly Correlated ◽

Serum Samples ◽

Neurofilament Light Chain ◽

Neurofilament Light ◽

Disability Status ◽

Spectrum Disorders

ObjectiveTo test the hypothesis that serum levels of glial fibrillary acidic protein (GFAP) and neurofilament light chain (NfL), which are an intermediate astrocyte and neuron filaments, respectively, are clinically useful biomarkers of disease activity and disability in neuromyelitis optica spectrum disorders (NMOSD).MethodsLevels of GFAP and NfL in serum (sGFAP and sNfL, respectively) and in CSF samples were measured in healthy controls (HCs) (n = 49; 49 serum samples), patients with NMOSD (n = 33; 42 CSF and 102 serum samples), and patients with multiple sclerosis (MS) (n = 49; 53 CSF and 91 serum samples) by ultrasensitive single-molecule array assays. Association of sGFAP and sNfL levels with clinical parameters was determined.ResultsFor both GFAP and NfL, CSF and serum levels were strongly correlated. Both were higher in the serum of patients with NMOSD than in HCs (both p < 0.001). Moreover, sGFAP was higher in NMOSD than in MS (median 207.7 vs 121.1 pg/mL, p < 0.001). In NMOSD, sGFAP concentration increased after recent relapse (540.9 vs 152.9 pg/mL, p < 0.001). Multivariate analyses indicated that sGFAP and sNfL were associated with Expanded Disability Status Scale score in NMOSD (p = 0.026 and p < 0.001, respectively). Higher sGFAP/sNfL quotient at relapse differentiated NMOSD from MS with a sensitivity of 73.0% and a specificity of 75.8%.ConclusionssGFAP and sNfL are likely to be good biomarkers of disease activity and disability, and the sGFAP/sNfL quotient at relapse is a potential diagnostic marker for NMOSD.

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