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.

Plasma Total α-Synuclein and Neurofilament Light Chain: Clinical Validation for Discriminating Parkinson’s Disease from Normal Control

2020 ◽  
pp. 1-9
Author(s):  
Wei-Che Lin ◽  
Cheng-Hsien Lu ◽  
Pai-Yi Chiu ◽  
Shieh-Yueh Yang
Keyword(s):  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Clinical Diagnosis ◽  
Light Chain ◽  
Validation Cohort ◽  
Neurofilament Light Chain ◽  
Original Cohort ◽  
Neurofilament Light ◽  
Cutoff Value ◽  
Normal Controls

<b><i>Background:</i></b> A previously published paper (referred to as the original cohort) showed that using a cutoff value of 116.1 fg/mL for the plasma total α-synuclein concentrations could discriminate Parkinson’s disease (PD) patients from normal controls (NCs). In this study, another independent cohort (referred to as the validation cohort) was recruited to validate the agreement between the clinical diagnosis and the use of plasma total α-synuclein to identify PD patients. In addition to total α-synuclein, plasma neurofilament light chain (NfL) in the validation cohort was detected. <b><i>Methods:</i></b> Seventy PD patients and 33 NCs were enrolled in the validation cohort. A clinical diagnosis and the immunomagnetic reduction (IMR) assay for plasma total α-synuclein were performed for each participant. Thirty-three of 70 PD patients and 23 of 33 NCs were subjected to the plasma NfL assay via IMR. <b><i>Results:</i></b> The positive, negative, and overall percentages of agreement between the clinical diagnosis and plasma total α-synuclein diagnosis determined based on 116.1 fg/mL as the cutoff value were found to be 0.943, 0.818, and 0.903, respectively. The PD patients and NCs showed plasma NfL levels of 8.38 ± 4.19 pg/mL and 17.6 ± 7.95 pg/mL (<i>p</i> &#x3c; 0.001), respectively. The cutoff value of the plasma NfL level used to differentiate PD patients from NCs was 12.8 pg/mL, with sensitivity and specificity values of 0.788 and 0.870, respectively. <b><i>Conclusion:</i></b> The results demonstrate the usefulness of the plasma total α-synuclein concentration to discriminate PD patients from NCs and reveal the elevation of the plasma NfL level in PD patients.

Serum neurofilament light chain levels reflect cortical neurodegeneration in de novo Parkinson's disease

2020 ◽  
Vol 74 ◽  
pp. 43-49 ◽  
Author(s):  
Frederic Sampedro ◽  
Rocío Pérez-González ◽  
Saul Martínez-Horta ◽  
Juan Marín-Lahoz ◽  
Javier Pagonabarraga ◽  
...  
Keyword(s):  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Light Chain ◽  
De Novo ◽  
Neurofilament Light Chain ◽  
Neurofilament Light

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 Assessing Plasma Levels of α-Synuclein and Neurofilament Light Chain by Different Blood Preparation Methods

2021 ◽  
Vol 13 ◽  
Author(s):  
Kuo-Hsuan Chang ◽  
Kou-Chen Liu ◽  
Chao-Sung Lai ◽  
Shieh-Yueh Yang ◽  
Chiung-Mei Chen
Keyword(s):  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Light Chain ◽  
Plasma Levels ◽  
Room Temperature ◽  
Neurofilament Light Chain ◽  
Neurofilament Light ◽  
Preparation Methods ◽  
Different Types ◽  
Temperature Preparation

The potential biomarkers of Parkinson’s disease are α-synuclein and neurofilament light chain (NFL). However, inconsistent preanalytical preparation of plasma could lead to variations in levels of these biomarkers. Different types of potassium salts of EDTA and different centrifugation temperatures during plasma preparation may affect the results of α-synuclein and NFL measurements. In this study, we prepared plasma from eight patients with Parkinson’s disease (PD) and seven healthy controls (HCs) by using di- and tri-potassium (K2- and K3-) EDTA tubes and recruited a separated cohort with 42 PD patients and 40 HCs for plasma samples prepared from whole blood by centrifugation at room temperature and 4°C, respectively, in K2-EDTA tubes. The plasma levels of α-synuclein and NFL in K2- and K3-EDTA were similar. However, the levels of α-synuclein in the plasma prepared at 4°C (101.57 ± 43.43 fg/ml) were significantly lower compared with those at room temperature (181.23 ± 196.31 fg/ml, P &lt; 0.001). Room temperature preparation demonstrated elevated plasma levels of α-synuclein in PD patients (256.6 ± 50.2 fg/ml) compared with the HCs (102.1 ± 0.66 fg/ml, P &lt; 0.001), whereas this increase in PD was not present by preparation at 4°C. Both plasma preparations at room temperature and 4°C demonstrated consistent results of NFL, which are increased in PD patients compared with HCs. Our findings confirmed that K2- and K3-EDTA tubes were interchangeable for analyzing plasma levels of α-synuclein and NFL. Centrifugation at 4°C during plasma preparation generates considerable reduction and variation of α-synuclein level that might hinder the detection of α-synuclein level changes in PD.

scholarly journals Serum Neurofilament Light Chain as a Marker of Progression in Parkinson’s Disease: Long-Term Observation and Implications of Clinical Subtypes

2021 ◽  
pp. 1-14
Author(s):  
Emil Ygland Rödström ◽  
Niklas Mattsson-Carlgren ◽  
Shorena Janelidze ◽  
Oskar Hansson ◽  
Andreas Puschmann
Keyword(s):  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Disease Progression ◽  
Light Chain ◽  
Progression Rate ◽  
Neurofilament Light Chain ◽  
Neurofilament Light ◽  
Clinical Biomarkers ◽  
Combined Models

Background: Biochemical and clinical biomarkers correlate with progression rate and disease severity in Parkinson’s disease (PD) but are not sufficiently studied in late PD. Objective: To examine how serum neurofilament light chain (S-NfL) alone or combined with clinical classifications predicts PD outcome in later disease stages. Methods: Eighty-five patients with 7.9±5.1 years of PD duration were included in an observational cohort. Clinical scores were obtained at two separate examinations 8.2±2.0 years apart. S-NfL levels were determined with single molecule array (SiMoA). Five predefined disease progression milestones were assessed. After affirming combination potential of S-NfL and either of two clinical classifications, three combined models were constructed based on these factors and age at onset in different combinations. Results: S-NfL levels showed significant hazard ratios for four out of five disease progression milestones: walking-aid usage (HR 3.5; 95% CI 1.4–8.5), nursing home living (5.1; 2.1–12.5), motor end-stage (6.2; 2.1–17.8), and death (4.1; 1.7–9.7). Higher S-NfL levels were associated with lower ability in activities of daily living and poorer cognition at baseline and/or at follow-up. Combined models showed significantly improved area under receiver operating characteristic curves (0.77–0.91) compared to S-NfL levels alone (0.68–0.71) for predicting the five disease milestones. Conclusion: S-NfL levels stratified patients according to their likelihood to reach clinically relevant progression milestones during this long-term observational study. S-NfL alone reflected motor and social outcomes in later stages of PD. Combining S-NfL with clinical factors was possible and exploratory combined models improved prognostic accuracy.

scholarly journals Neurofilament light chain level in plasma extracellular vesicles and Parkinson’s disease

2020 ◽  
Vol 13 ◽  
pp. 175628642097591
Author(s):  
Chen-Chih Chung ◽  
Lung Chan ◽  
Jia-Hung Chen ◽  
Oluwaseun Adebayo Bamodu ◽  
Chien-Tai Hong
Keyword(s):  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Extracellular Vesicles ◽  
Light Chain ◽  
Rating Scale ◽  
Neuronal Damage ◽  
Control Group ◽  
Motor Symptoms ◽  
Neurofilament Light Chain ◽  
Neurofilament Light

Background: Neurofilament light chain (NfL) is essential for axonal maintenance and reflects neuronal damage. Extracellular vesicles (EVs), especially exosomes, secreted by cells into the blood, are emerging as novel biomedical research platforms of physiological and pathological processes. The present study investigated the possible association between plasma EV NfL and Parkinson’s disease (PD). Methods: One hundred and sixteen patients with mild to moderate PD and 46 non-PD, neurological controls were recruited, and their clinical motor symptoms and cognitive function were evaluated. Plasma EVs were isolated using an exoEasy kit, and immunomagnetic reduction assay was used to assess EV NfL level. Statistical analysis was performed using SPSS 25.0, and p < 0.05 was considered significant. Results: The isolated plasma EVs were validated according to size and the presence of specific surface markers. Compared with the neurological control group, the levels of plasma EV NfL in patients with PD were not significantly different (PD: 9.42 ± 3.89, control: 9.53 ± 3.62 pg/mL plasma, p = 0.71). On the other hand, plasma EV NfL in patients with PD trendwise correlated with the severity of akinetic rigidity ( p = 0.05). PD patients with optimal EV NfL (lowest quartile) had 6.66 ± 2.08 lower Unified Parkinson’s Disease Rating Scale-III score after adjustment for age, sex, and disease duration. Conclusion: Plasma EV NfL levels did not distinguish patients with PD from the neurological control group. The possible correlation between plasma EV NfL with the severity of motor symptoms within the PD patients, especially with akinetic rigidity, was noted. Further clinical validation of the blood EV NfL by a longitudinal follow-up study of PD patients is warranted.

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