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

Neurology ◽  
2020 ◽  
Vol 95 (1) ◽  
pp. e59-e69 ◽  
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.

scholarly journals Validation of Serum Neurofilaments as Prognostic & Potential Pharmacodynamic Biomarkers for ALS

2019 ◽  
Author(s):  
Michael Benatar ◽  
Lanyu Zhang ◽  
Lily Wang ◽  
Volkan Granit ◽  
Jeffrey Statland ◽  
...  
Keyword(s):  
Sample Size ◽  
Limit Of Detection ◽  
Muscular Atrophy ◽  
Serum Samples ◽  
Baseline Serum ◽  
Research Organizations ◽  
Coefficients Of Variation ◽  
Blinded Manner ◽  
Pharmacodynamic Biomarkers ◽  
Lateral Sclerosis

AbstractObjectiveIdentify preferred neurofilament assays, and clinically validate serum NfL and pNfH as prognostic and potential pharmacodynamic biomarkers relevant to ALS therapy development.MethodsProspective, multi-center, longitudinal observational study of patients with ALS (n=229), primary lateral sclerosis (PLS, n=20) and progressive muscular atrophy (PMA, n=11). Biological specimens were collected, processed and stored according to strict standard operating procedures (SOPs) 1. Neurofilament assays were performed in a blinded manner by independent contract research organizations (CROs).ResultsFor serum NfL and pNfH measured using the Simoa assay, missing data (i.e. both technical replicates below the lower limit of detection (LLD) was 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 (CVs) for pNfH in serum and CSF were ∼4-5% and ∼2-3% respectively in all assays. Baseline NfL concentration, but not pNfH, predicted the future 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, have potential utility as pharmacodynamic biomarkers of treatment effect.

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

2021 ◽  
pp. 1-9
Author(s):  
Kelly A. Rich ◽  
Ashley Fox ◽  
Mehmet Yalvac ◽  
Sarah Heintzman ◽  
Marco Tellez ◽  
...  
Keyword(s):  
Muscular Atrophy ◽  
Pearson Correlation ◽  
Correlation Coefficients ◽  
Serum Samples ◽  
Neurofilament Light Chain ◽  
Cross Sectional ◽  
Neurofilament Light ◽  
Total Strength ◽  
Baseline Serum ◽  
Age Related

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.

scholarly journals Assessment of Bulbar Function in Adult Patients with 5q-SMA Type 2 and 3 under Treatment with Nusinersen

2021 ◽  
Vol 11 (9) ◽  
pp. 1244
Author(s):  
Svenja Brakemeier ◽  
Benjamin Stolte ◽  
Andreas Thimm ◽  
Kathrin Kizina ◽  
Andreas Totzeck ◽  
...  
Keyword(s):  
Antisense Oligonucleotide ◽  
Treatment Initiation ◽  
Rating Scale ◽  
Muscular Atrophy ◽  
Therapeutic Effects ◽  
Measurement Instruments ◽  
Sydney Swallow Questionnaire ◽  
Bulbar Dysfunction ◽  
Lateral Sclerosis

The antisense oligonucleotide nusinersen has been shown to improve trunk and limb motor function in patients with spinal muscular atrophy (SMA). Bulbar dysfunction, which is regularly present in SMA, is not captured by standard motor scores, and validated measurement instruments to assess it have not yet been established. Data on whether and how bulbar function changes under gene-based therapies in adult SMA patients are also unavailable. Here, we present data on the course of bulbar dysfunction assessed prospectively before nusinersen treatment initiation and 6 and 14 months later in 23 adult SMA patients using the Sydney Swallow Questionnaire (SSQ) and the bulbar subscore of the Amyotrophic Lateral Sclerosis Functional Rating Scale Revised (ALSFRS-R). While no improvement in bulbar scores was observed under treatment with nusinersen, the absence of a decline still implies a therapeutic effect of nusinersen on bulbar dysfunction. The results of this study aim to contribute to a standardized assessment of bulbar function in adult SMA patients, which may show therapeutic effects of gene-based therapies that are not evident from standard motor scores.

scholarly journals Neurofilament light and heterogeneity of disease progression in amyotrophic lateral sclerosis: development and validation of a prediction model to improve interventional trials

2021 ◽  
Vol 10 (1) ◽  
Author(s):  
Simon Witzel ◽  
Felix Frauhammer ◽  
Petra Steinacker ◽  
David Devos ◽  
Pierre-François Pradat ◽  
...  
Keyword(s):  
Amyotrophic Lateral Sclerosis ◽  
Observational Study ◽  
Prediction Model ◽  
Disease Progression ◽  
Statistical Power ◽  
Rating Scale ◽  
Disease Onset ◽  
Neurofilament Light ◽  
The Impact ◽  
Lateral Sclerosis

Abstract Background Interventional trials in amyotrophic lateral sclerosis (ALS) suffer from the heterogeneity of the disease as it considerably reduces statistical power. We asked if blood neurofilament light chains (NfL) could be used to anticipate disease progression and increase trial power. Methods In 125 patients with ALS from three independent prospective studies—one observational study and two interventional trials—we developed and externally validated a multivariate linear model for predicting disease progression, measured by the monthly decrease of the ALS Functional Rating Scale Revised (ALSFRS-R) score. We trained the prediction model in the observational study and tested the predictive value of the following parameters assessed at diagnosis: NfL levels, sex, age, site of onset, body mass index, disease duration, ALSFRS-R score, and monthly ALSFRS-R score decrease since disease onset. We then applied the resulting model in the other two study cohorts to assess the actual utility for interventional trials. We analyzed the impact on trial power in mixed-effects models and compared the performance of the NfL model with two currently used predictive approaches, which anticipate disease progression using the ALSFRS-R decrease during a three-month observational period (lead-in) or since disease onset (ΔFRS). Results Among the parameters provided, the NfL levels (P < 0.001) and the interaction with site of onset (P < 0.01) contributed significantly to the prediction, forming a robust NfL prediction model (R = 0.67). Model application in the trial cohorts confirmed its applicability and revealed superiority over lead-in and ΔFRS-based approaches. The NfL model improved statistical power by 61% and 22% (95% confidence intervals: 54%–66%, 7%–29%). Conclusion The use of the NfL-based prediction model to compensate for clinical heterogeneity in ALS could significantly increase the trial power. NCT00868166, registered March 23, 2009; NCT02306590, registered December 2, 2014.

scholarly journals Monitoring disease progression with plasma creatinine in amyotrophic lateral sclerosis clinical trials

2017 ◽  
Vol 89 (2) ◽  
pp. 156-161 ◽  
Author(s):  
Ruben P A van Eijk ◽  
Marinus J C Eijkemans ◽  
Toby A Ferguson ◽  
Stavros Nikolakopoulos ◽  
Jan H Veldink ◽  
...  
Keyword(s):  
Clinical Trial ◽  
Clinical Trials ◽  
Amyotrophic Lateral Sclerosis ◽  
Muscle Strength ◽  
Sample Size ◽  
Disease Progression ◽  
Rating Scale ◽  
Plasma Creatinine ◽  
Rate Of Decline ◽  
Lateral Sclerosis

ObjectivesPlasma creatinine is a predictor of survival in amyotrophic lateral sclerosis (ALS). It remains, however, to be established whether it can monitor disease progression and serve as surrogate endpoint in clinical trials.MethodsWe used clinical trial data from three cohorts of clinical trial participants in the LITRA, EMPOWER and PROACT studies. Longitudinal associations between functional decline, muscle strength and survival with plasma creatinine were assessed. Results were translated to trial design in terms of sample size and power.ResultsA total of 13 564 measurements were obtained for 1241 patients. The variability between patients in rate of decline was lower in plasma creatinine than in ALS functional rating scale–Revised (ALSFRS-R; p<0.001). The average rate of decline was faster in the ALSFRS-R, with less between-patient variability at baseline (p<0.001). Plasma creatinine had strong longitudinal correlations with the ALSFRS-R (0.43 (0.39–0.46), p<0.001), muscle strength (0.55 (0.51–0.58), p<0.001) and overall mortality (HR 0.88 (0.86–0.91, p<0.001)). Using plasma creatinine as outcome could reduce the sample size in trials by 21.5% at 18 months. For trials up to 10 months, the ALSFRS-R required a lower sample size.ConclusionsPlasma creatinine is an inexpensive and easily accessible biomarker that exhibits less variability between patients with ALS over time and is predictive for the patient’s functional status, muscle strength and mortality risk. Plasma creatinine may, therefore, increase the power to detect treatment effects and could be incorporated in future ALS clinical trials as potential surrogate outcome.

scholarly journals Nusinersen in adult patients with 5q spinal muscular atrophy: a multicenter observational cohorts study

2021 ◽  
Author(s):  
Juan F Vazquez Costa ◽  
Monica Povedano ◽  
Andres E Nascimento-Osorio ◽  
Antonio Moreno Escribano ◽  
Solange Kapetanovic Garcia ◽  
...  
Keyword(s):  
Spinal Muscular Atrophy ◽  
Vital Capacity ◽  
Rating Scale ◽  
Muscular Atrophy ◽  
Response To Treatment ◽  
Benefit Ratio ◽  
Safety And Efficacy ◽  
Global Impression Of Change ◽  
Lateral Sclerosis

Objective To assess safety and efficacy of nusinersen in adult 5q spinal muscular atrophy (SMA) patients. Methods Patients older than 15 years and followed at least for 6 months with one motor scale (Hammersmith Functional Motor Scale Expanded, HFMSE; Revised Upper Limb module, RULM) in five referral centers were included. Clinical and patients global impression of change (CGI-C and PGI-C) were recorded in treated patients at the last visit. Functional scales (Egen Klassification, EK2; Revised Amyotrophic Lateral Sclerosis Functional Rating Scale, ALSFRS-R) and the percent-predicted forced vital capacity were collected when available. Results Seventy-nine SMA patients (39 treated with nusinersen) were included. Compared with untreated patients, treated patients showed a significant improvement of 2 points (±0.46) in RULM (p<0.001) after six months. After a mean follow-up of 16 months, nusinersen treatment was associated with a significant improvement in HFMSE (OR=1.15, p=0.006), 6MWT (OR=1.07, p<0.001), and EK2 (OR=0.81, p=0.001). Compared with untreated patients, more treated patients experienced clinically meaningful improvements in all scales, but these differences were statistically significant only for RULM (p=0.033), ALSFRS-R (p=0.005), and EK2 (p<0.001). According to the CGI-C and PGI-C, 64.1% and 61.5% of treated patients improved with treatment. Being non-sitter was associated with less response to treatment, while longer time of treatment was associated with better response. Most treated patients (77%) presented at least one adverse event, mostly mild. Conclusions Nusinersen treatment associates to some improvements in adult SMA patients. Most severely affected patients with complex spines are probably those with the most unfavorable risk-benefit ratio.  

scholarly journals Serum neurofilament light chain in behavioral variant frontotemporal dementia

Neurology ◽  
2018 ◽  
Vol 91 (15) ◽  
pp. e1390-e1401 ◽  
Author(s):  
Petra Steinacker ◽  
Sarah Anderl-Straub ◽  
Janine Diehl-Schmid ◽  
Elisa Semler ◽  
Ingo Uttner ◽  
...  
Keyword(s):  
Frontotemporal Dementia ◽  
Light Chain ◽  
Brain Atrophy ◽  
Rating Scale ◽  
Neurofilament Light Chain ◽  
Behavioral Variant Frontotemporal Dementia ◽  
Neurofilament Light ◽  
Baseline Serum ◽  
Functional Scores

ObjectiveTo determine the association of serum neurofilament light chain (NfL) with functional deterioration and brain atrophy during follow-up of patients with behavioral variant frontotemporal dementia (bvFTD).MethodsBlood NfL levels from 74 patients with bvFTD, 26 with Alzheimer disease (AD), 17 with mild cognitive impairment (MCI), and 15 healthy controls (Con) at baseline and follow-up were determined and analyzed for the diagnostic potential in relation to functional assessment (Clinical Dementia Rating Scale Sum of Boxes [CDR-SOB], frontotemporal lobar degeneration–related CDR-SOB, Mini-Mental State Examination [MMSE]) and brain volumetry.ResultsAt baseline, serum NfL level correlated with CSF NfL (bvFTDr= 0.706,p< 0.0001; AD/MCIr= 0.666,p= 0.0003). Highest serum levels were observed in bvFTD (p<0 0.0001 vs Con and MCI,p= 0.0078 vs AD, respectively). Discrimination of bvFTD from Con/MCI/AD was possible with 91%/74%/74% sensitivity and 79%/74%/58% specificity. At follow-up, serum NfL increased in bvFTD and AD (p= 0.0039 andp= 0.0006, respectively). At baseline and follow-up, NfL correlated with functional scores of patients with bvFTD (e.g., CDR-SOB [baseline]r= 0.4157,p= 0.0006; [follow-up]r= 0.5629,p< 0.0001) and with atrophy in the gray and white matter of many brain regions including frontal and subcortical areas (e.g., frontal lobe:r= −0.5857,p< 0.0001; 95% confidence interval −0.7415 to −0.3701). For patients with AD/MCI, NfL correlated with the functional performance as well (e.g., CDR-SOB [baseline]r= 0.6624,p< 0.0001; [follow-up]r= 0.5659,p= 0.0003) but not with regional brain volumes.ConclusionsAs serum NfL correlates with functional impairment and brain atrophy in bvFTD at different disease stages, we propose it as marker of disease severity, paving the way for its future use as outcome measure for clinical trials.Classification of evidenceThis study provides Class III evidence that for patients with cognitive problems, serum NfL concentration discriminates bvFTD from other forms of dementia.

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

2019 ◽  
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.

scholarly journals Correlation Between Maximal Tongue Pressure and Swallowing Function in Spinal and Bulbar Muscular Atrophy

2021 ◽  
Vol 12 ◽  
Author(s):  
Dae-Won Gwak ◽  
Seung-Hwan Jung ◽  
Yu-Sun Min ◽  
Jin-Sung Park ◽  
Hee-Jin Cho ◽  
...  
Keyword(s):  
Rating Scale ◽  
Muscular Atrophy ◽  
Correlation Coefficients ◽  
Tongue Pressure ◽  
Swallowing Function ◽  
Progressive Muscle Weakness ◽  
Potential Biomarker ◽  
Functional States ◽  
Common Manifestation ◽  
Lateral Sclerosis

Background: Spinal and bulbar muscular atrophy (SBMA) is an X-lined motor neuron disease characterized by progressive muscle weakness, bulbar palsy, and dysphagia. Dysphagia is associated with tongue weakness, which is a common manifestation of SBMA. This study aimed to investigate the correlations between tongue pressure and dysphagia in patients with SBMA.Materials and Methods: Thirty-nine genetically confirmed SBMA patients underwent a videofluoroscopic swallowing study (VFSS) and tongue pressure assessment. Then, we analyzed the maximal tongue pressure (MTP), oral transit time, penetration-aspiration scale (PAS), videofluoroscopic dysphagia scale (VDS), amyotrophic lateral sclerosis functional rating scale-revised (ALSFRS-R), and 6-min walk test (6MWT). Pearson and Spearman correlation coefficients were calculated to analyze the association of the MTP with clinical, swallowing, and functional parameters.Results: In the correlation analysis, MTP was negatively correlated with disease duration (r = −0.396, p = 0.013) and VDS (r = −0.426, p = 0.007), and positively correlated with ALSFRS-R (r = 0.483, p = 0.002) and 6MWT (r = 0.396, p = 0.013). The bulbar (r = 0.367, p = 0.022) and gross motor (r = 0.486, p = 0.002) domains of the ALSFRS-R were correlated with MTP.Conclusion: Tongue pressure assessment can be used as a safe and easy tool to assess swallowing function in SBMA patients. Moreover, MTP reflects functional states, including activities of daily living and gait performance, showing it to be a potential biomarker for physical performance in SBMA.

scholarly journals Neurochemical markers in CSF of adolescent and adult SMA patients undergoing nusinersen treatment

2019 ◽  
Vol 12 ◽  
pp. 175628641984605 ◽  
Author(s):  
Claudia D. Wurster ◽  
René Günther ◽  
Petra Steinacker ◽  
Jens Dreyhaupt ◽  
Kurt Wollinsky ◽  
...  
Keyword(s):  
Rating Scale ◽  
Muscular Atrophy ◽  
Control Group ◽  
Limited Information ◽  
Csf Flow ◽  
Neurofilament Light Chain ◽  
Neurofilament Light ◽  
Significant Difference ◽  
And Control

Background: There is limited information on neurochemical markers being used to support and monitor the affection of motoneurons in patients with spinal muscular atrophy (SMA). The objective of this study was to examine neurochemical markers in cerebrospinal fluid (CSF) under treatment with the antisense-oligonucleotide (ASO), nusinersen. Methods: We measured markers of axonal degeneration [neurofilament light chain (NfL) and phosphorylated neurofilament heavy chain (pNfH)] along with basic CSF parameters in 25 adolescent and adult SMA type 2 and 3 patients at baseline and after four intrathecal injections of nusinersen. Neurochemical markers were compared with controls. In addition, neurochemical markers in SMA patients were related to the Hammersmith Functional Rating Scale Expanded (HFMSE). Results: No significant difference in neurofilament (Nf) values was observed between SMA and control group, neither at baseline nor after four injections of nusinersen. NfL, protein and quotients of albumin (Qalb) increased slightly in SMA patients after the fourth injection. The slight increase of NfL could be related to the development of mild CSF flow change. No relations were observed between changes in Nf and HFMSE. Conclusion: We assume that Nf levels in CSF in these patients may result from slow disease progression in this stage of disease, pre-existing loss of motoneurons due to long disease duration besides affection of the LMN only. Therefore, we conclude that Nf levels in CSF do not seem useful as diagnostic and monitoring markers in adolescent and adult SMA type 2 and 3 patients.

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