Neurofilament light chain in serum of cancer patients with acute neurological complications.

Aim: Neurofilament light chain (NfL) is a nonspecific sensitive biomarker of axonal damage.Methods: This case series identified cancer patients with neurological complications who had serum NfL measurements and paired these results to outcomes.Results: NfL serum levels were available in 15 patients with hematological malignancies or solid tumors. The neurological complications studied were immune effector cell-associated neurotoxicity syndrome, immune checkpoint inhibitor-related encephalopathy, anoxic brain injury, Guillain-Barre syndrome, hemophagocytic lymphohistiocytosis, transverse myelitis, paraneoplastic syndrome, central nervous system demyelinating disorder and chronic lymphocytic inflammation with pontine perivascular enhancement responsive to steroids. All patients but one with serum NfL >900 pg/ml died during hospitalization.Conclusion: Serum NfL levels consistently corresponded to death, disease severity or recovery in this series.

[Box: see text].

[Possibilities of magnetic resonance morphometry and laboratory biomarkers in studying the progression of multiple sclerosis]. / Vozmozhnosti magnitno-rezonansnoi morfometrii i laboratornykh biomarkerov v izuchenii progressirovaniya rasseyannogo skleroza.

OBJECTIVE: To show that magnetic resonance morphometry and laboratory biomarkers are promising methods for early detection of progressive forms of multiple sclerosis (MS). MATERIAL AND METHODS: Eighty-one patients with MS were examined, magnetic resonance morphometry was performed in all of them, 60 patients were analyzed for neurofilament light chains (sNFL), phosphorylated neurofilament heavy chains (spNFH) and glial fibrillary protein (sGFAP) in serum by enzyme-linked immunosorbent assay. RESULTS: Brain volumes were negatively correlated with disease duration, EDSS score, 25-foot walk test score and 9-ring test and positively correlated with the Symbol-Numeric Test and the Montreal Cognitive Assessment. Patients with progressive types of MS (PMS) had smaller volumes of brain gray matter, cerebellar white matter, occipital lobes, caudate nucleus, hippocampus, pallidum, thalamus, and contiguous nucleus. A CSF volume greater than 15.06% could suggest progression (CI 54.79-91%) with a sensitivity of 77.78% and specificity of 70.18%. When patients were on DMT, they had larger thalamic volumes (median 1.09% [1.6; 1.16] vs 1.04% [0.95; 1.14]; p=0.02) and smaller CSF volumes (13.86±2.87% vs. 15.55±3.49%; p=0.03). The levels of sNFL and spNFH were not increased in PMS and during exacerbations, and the low obtained values of sNFL suggest poor sensitivity of the method. There were trends (p=0.374) towards higher sGFAP in patients with PRS (median 3.2 ng/mL [1.85; 4.6] compared to remitting MS (2.05 ng/mL [1.29; 4.52]). CONCLUSION: The results demonstrate the differences in brain volumes in patients with different types of MS and emphasize the importance of long-term follow-up to better assess disease progression.

J-shaped relationship of serum neurofilament light chain with urinary albumin excretion in US adults: NHANES 2013-2014.

INTRODUCTION: This study focuses on investigating the relationship between serum neurofilament light chain (sNfL) and urinary albumin-to-creatinine ratio (uACR) among American adults aged 25-75. METHODS: An analysis was conducted on information gathered from 1741 individuals aged between 25 and 75 who participated in the National Health and Nutrition Examination Survey (NHANES) during the years 2013-2014. Generalized linear models were utilized, and restricted cubic spline (RCS) analysis was conducted to assess a non-linear relationship. RESULTS: Upon adjusting for multiple variables, a non-linear inverse J-shaped relationship was observed between sNfL and uACR. Compared with individuals in quartile 1 (Q1) of sNfL (2.8-8.3), those with quartile 4 (Q4) (≥19.1) had an adjusted ß for uACR of 51.57. CONCLUSIONS: The study found a J-shaped curve linking sNfL and uACR in American adults, with a turning point around log(sNfL) 2.928 pg/mL.

Physical function is associated with cognitive status, brain amyloid-beta deposition, and blood biomarkers in Chinese Han population.

BACKGROUND: The physical function of elderly individuals reflects whether they have had a history of regular physical activity over the long term. Such indicators have been found to have a certain connection with cognitive function these years. However, there is limited research that associates it with mechanisms such as cerebral Aß deposition. We aim to investigate this relationship and unveil the underlying mechanisms. METHOD: Physical function and cognition data of 4189 participants were obtained from the Chinese preclinical Alzheimer's disease study. Participants were divided into six groups according to disease severity. Among them, 1048 participants underwent the positron emission tomography-computed tomography (PET-CT) and plasma biomarker test. Grip strength and gait were combined into a score indicating physical function. Multiple linear regression models and logistic regression models were mainly used to conduct the analysis. RESULTS: There was a significant positive correlation between physical function and cognitive function (R = 0.48, p < 0.001), independent of sex, age, apolipoprotein E-ε4 genotype, and disease stages (p < 0.001). Physical function was effective in distinguishing individuals with cognitive impairment from those without (AUC = 0.835). Physical function was negatively associated with brain Aß deposition (p = 0.008) and brain Aß had an intermediary effect (p < 0.01) on the association between physical function and cognition in women. This association was mainly evident in the lateral parietal, lateral temporal, posterior cingulate, frontal, occipital, and precuneus regions. Physical function was negatively associated with plasma neurofilament light-chain (Nfl) level (p < 0.001). CONCLUSIONS: Physical function is strongly associated with cognitive function in the Chinese elderly, and brain Aß deposition partly mediates the linkage in women. Plasma Nfl can be used as a potential target for exercise intervention in cognitive function. Improving physical function will contribute to the alleviation of cognition decline.

Blood biomarkers for neuroaxonal injury and astrocytic activation in chemotherapy-induced peripheral neuropathy.

BACKGROUND AND PURPOSE: Chemotherapy-induced peripheral neuropathy (CIPN) is a troublesome side effect in patients exposed to taxanes in the treatment of cancer and may affect quality of life dramatically. Here we assessed whether serum levels of neurofilament light (NfL) and tau (two neuroaxonal injury biomarkers) and glial fibrillary acidic protein (GFAP, a biomarker for astrocytic activation) correlate with the development of CIPN in the adjuvant setting of early breast cancer. MATERIALS AND METHODS: Using ultrasensitive single molecule array technology, serum levels of NfL, GFAP, and tau were measured before and every 3 weeks in 10 women receiving adjuvant EC (epirubicin 90 mg/m² and cyclophosphamide 600 mg/m²) every 3 weeks × 3, followed by weekly paclitaxel 80 mg/m² × 9-12 weeks after surgery due to early breast cancer. CIPN was graded according to the NCI Common Terminology Criteria for Adverse Events (CTCAE v5.0) and the questionnaire EORTC QLQ CIPN-20. RESULTS: Serum levels of GFAP increased successively during cycles of EC. NfL increased instead in response to the treatment of paclitaxel. NfL and GFAP continued to rise throughout exposure of cumulatively higher doses of paclitaxel and were reduced 3 months after the end of chemotherapy. Serums levels of tau were marginally affected by exposure to chemotherapy. Women with worse symptoms of CIPN had higher concentrations of NfL than women with mild symptoms of CIPN. INTERPRETATION: NfL and GFAP are promising biomarkers to identify women at risk of developing CIPN. Larger prospective studies are now needed.

Differential neuropsychiatric associations of plasma biomarkers in older adults with major depression and subjective cognitive decline.

Older adults with major depressive disorder (MDD) or early cognitive decline during the subjective cognitive decline (SCD) stage may exhibit neuropsychiatric symptoms such as anxiety, depression, and subtle cognitive impairment. The clinicopathological features and biological mechanisms of MDD differ from those of SCD among older adults; these conditions thus require different treatment strategies. This study enrolled 82 participants above 50 years old with normal cognitive levels from the communities to examine biomarker-behavior correlations between MDD (n = 23) and SCD (n = 23) relative to a normal control (NC) group (n = 36). Multidomain assessments were performed for all participants, including immunomagnetic reduction tests to detect plasma beta-amyloid (Aß), total tau (Tau), phosphorylated tau-181 (p-Tau181), neurofilament light chain, and glial fibrillary acidic protein (GFAP). This study observed that depressive symptoms in MDD were associated with amyloid pathology (plasma Aß40 vs. HADS-D: R = 0.45, p = 0.031; Aß42/Aß40 vs. HADS-D: R = -0.47, p = 0.024), which was not observed in the NC (group difference p < 0.05). Moreover, cognitive decline in MDD was distinguished by a mixed neurodegenerative process involving amyloid (plasma Aß42 vs. facial memory test: R = 0.48, p = 0.025), tau (Tau/Aß42 vs. digit symbol substitution test (DSST): R = -0.53, p = 0.01), and astrocytic injury (plasma GFAP vs. Montreal cognitive assessment score: R = -0.44, p = 0.038; plasma GFAP vs. DSST: R = -0.52, p = 0.014), findings that did not apply to the NC (group difference p < 0.05). Moreover, this study revealed different biomarker-behavior correlations between individuals with SCD and the NC. Compared with the NC, cognitive decline in the SCD group might be unrelated to amyloid pathology and instead might be early manifestations of tau pathology. This study underscores the difference in clinicopathological features between MDD and SCD among older adults, which differ from those of the NC. These findings enhance our understanding of the mechanisms underlying MDD and SCD in older individuals.

Inflammatory Markers Predict Blood Neurofilament Light Chain Levels in Acute COVID-19 Patients.

Acute coronavirus disease 2019 (COVID-19) is paralleled by a rise in the peripheral levels of neurofilament light chain (NfL), suggesting early nervous system damage. In a cohort of 103 COVID-19 patients, we studied the relationship between the NfL and peripheral inflammatory markers. We found that the NfL levels are significantly predicted by a panel of circulating cytokines/chemokines, including CRP, IL-4, IL-8, IL-9, Eotaxin, and MIP-1ß, which are highly up-regulated during COVID-19 and are associated with clinical outcomes. Our findings show that peripheral cytokines influence the plasma levels of the NfL, suggesting a potential role of the NfL as a marker of neuronal damage associated with COVID-19 inflammation.

Longitudinal Changes of Clinical, Imaging, and Fluid Biomarkers in Preataxic and Early Ataxic Spinocerebellar Ataxia Type 2 and 7 Carriers.

BACKGROUND AND OBJECTIVES: Brain MRI abnormalities and increases in neurofilament light chain (NfL) have mostly been observed in cross-sectional studies before ataxia onset in polyglutamine spinocerebellar ataxias. Our study aimed to identify longitudinal changes in biological, clinical, and/or imaging biomarkers in spinocerebellar ataxia (SCA) 2 and SCA7 carriers over 1 year. METHODS: We studied SCA2 and SCA7 carriers and controls (expansion-negative relatives) at the Paris Brain Institute. Inclusion criteria included Scale for the Assessment and Rating of Ataxia (SARA) scores between 0 and 15. Assessments at baseline, 6 months, and 12 months comprised neurologic, quality of life, orofacial motor, neuropsychological, and ophthalmologic examinations, along with gait and oculomotor recordings, brain MRI, CSF, and blood sampling. The primary outcome was the longitudinal change in these assessments over 1 year. RESULTS: We included 15 SCA2 carriers, 15 SCA7 carriers, and 10 controls between May 2020 and April 2021. At baseline, the ages were similar (41 [37, 46] for SCA2, 38 [28.5, 39.8] for SCA7, and 39.5 [31, 54.5] for controls, p = 0.78), as well the sex (p = 0.61); SARA scores were low but different (4 [1.25, 6.5] in SCA2, 2 [0, 11.5] in SCA7, and 0 in controls, p < 0.01). Pons and medulla volumes were smaller in SCAs (p < 0.05) and cerebellum volume only in SCA2 (p = 0.01). Plasma NfL levels were higher in SCA participants (SCA2: 14.2 pg/mL [11.52, 15.89], SCA7: 15.53 [13.27, 23.23]) than in controls (4.88 [3.56, 6.17], p < 0.001). After 1-year follow-up, in SCA2, there was significant pons (-144 ± 60 mm3) and cerebellum (-1,508 ± 580 mm3) volume loss and a worsening of gait assessment; in SCA7, SARA score significantly increased (+1.3 ± 0.4) and outer retinal nuclear layer thickness decreased (-15.4 ± 1.6 µm); for both SCA groups, the orofacial motor assessment significantly worsened. For preataxic and early ataxic carriers, the strongest longitudinal deterioration on outcome measures was orofacial motility in SCA2 and retinal thickness in SCA7. DISCUSSION: Despite the limitation of the small sample size, we detected annual changes in preataxic and early ataxic SCA individuals across brain MRI imaging, clinical scores, gait parameters, and retinal thickness. These parameters could serve as potential end points for future therapeutic trials in the preataxic phase. TRIAL REGISTRATION INFORMATION: ClinicalTrials.gov NCT04288128.

Serum Beta-Secretase 1 Activity Is a Potential Marker for the Differential Diagnosis between Alzheimer's Disease and Frontotemporal Dementia: A Pilot Study.

Alzheimer's disease (AD) and frontotemporal dementia (FTD) are the two major neurodegenerative diseases causing dementia. Due to similar clinical phenotypes, differential diagnosis is challenging without specific biomarkers. Beta-site Amyloid Precursor Protein cleaving enzyme 1 (BACE1) is a ß-secretase pivotal in AD pathogenesis. In AD and mild cognitive impairment subjects, BACE1 activity is increased in brain/cerebrospinal fluid, and plasma levels appear to reflect those in the brain. In this study, we aim to evaluate serum BACE1 activity in FTD, since, to date, there is no evidence about its role. The serum of 30 FTD patients and 30 controls was analyzed to evaluate (i) BACE1 activity, using a fluorescent assay, and (ii) Glial Fibrillary Acid Protein (GFAP) and Neurofilament Light chain (NfL) levels, using a Simoa kit. As expected, a significant increase in GFAP and NfL levels was observed in FTD patients compared to controls. Serum BACE1 activity was not altered in FTD patients. A significant increase in serum BACE1 activity was shown in AD vs. FTD and controls. Our results support the hypothesis that serum BACE1 activity is a potential biomarker for the differential diagnosis between AD and FTD.

Elevated plasma neurofilament light was associated with multi-modal neuroimaging features in Alzheimer's disease signature regions and predicted future tau deposition.

BACKGROUND: Neurofilament Light (NfL) is a biomarker for early neurodegeneration in Alzheimer's disease (AD). This study aims to examine the association between plasma NfL and multi-modal neuroimaging features across the AD spectrum and whether NfL predicts future tau deposition. METHODS: The present study recruited 517 participants comprising Aß negative cognitively normal (CN-) participants (n = 135), Aß positive cognitively normal (CN +) participants (n = 64), individuals with amnestic mild cognitive impairment (aMCI) (n = 212), and those diagnosed with AD dementia (n = 106). All the participants underwent multi-modal neuroimaging examinations. Cross-sectional and longitudinal associations between plasma NfL and multi-modal neuro-imaging features were evaluated using partial correlation analysis and linear mixed effects models. We also used linear regression analysis to investigate the association of baseline plasma NfL with future PET tau load. Mediation analysis was used to explore whether the effect of NfL on cognition was mediated by these imaging biomarkers. RESULTS: The results showed that baseline NfL levels and the rate of change were associated with Aß deposition, brain atrophy, brain connectome, glucose metabolism, and brain perfusion in AD signature regions (P<0.05). In both Aß positive CN and MCI participants, baseline NfL showed a significant predictive value of elevating tau burden in the left medial orbitofrontal cortex and para-hippocampus (ß = 0.336, P = 0.032; ß = 0.313, P = 0.047). Lastly, the multi-modal neuroimaging features mediated the association between plasma NfL and cognitive performance. CONCLUSIONS: The study supports the association between plasma NfL and multi-modal neuroimaging features in AD-vulnerable regions and its predictive value for future tau deposition.

Serum neurofilament light chain, markers of systemic inflammation and clinically relevant depressive symptoms in US adults.

BACKGROUND: Neurofilament light chain (NFL), a biomarker of neuroaxonal damage, has been linked to inflammation and depressive disorders, albeit with inconsistent results. We aimed to evaluate the association between serum NFL concentration and clinically relevant depressive symptoms in the general population and to examine the potential involvement of systemic inflammation in this association. METHODS: The data of 1881 adults aged 20-75 years were extracted from the National Health and Nutrition Examination Survey (NHANES) 2013-2014 cycle. Serum NFL levels were quantified using a highly sensitive immunoassay. Further, markers of systemic inflammation, including systemic immune inflammation index (SII), system inflammation response index (SIRI), and white blood cell (WBC) counts were calculated based on whole blood cell counts. Clinically relevant depressive symptoms were evaluated using the 9-item Patient Health Questionnaire (PHQ-9) with a cut-off score of 10. RESULTS: After adjusting for potential confounders, we found that each one-unit increase in ln-transformed serum NFL concentration was significantly associated with a 1.37-fold increase in the risk of clinically relevant depressive symptoms (95 % confidence interval [CI]: 1.06, 1.77; p = 0.017). Serum NFL level was significantly related to increased SII (regression coefficient [ß] = 0.04, 95%CI: 0.01, 0.08; p = 0.027), SIRI (ß = 0.09, 95%CI: 0.05, 0.14; p < 0.001), and WBC (ß = 0.05, 95%CI: 0.03, 0.07; p < 0.001), respectively. These significant associations were observed only in elderly participants. LIMITATIONS: The cross-sectional study design is limited in causal inference. CONCLUSIONS: Our findings indicate that serum NFL levels are related to an increased risk of clinically relevant depressive symptoms and higher levels of markers of systemic inflammation.

Prevalence of elevated sNFL in a real-world setting: Results on 908 patients with different multiple sclerosis types and treatment conditions.

BACKGROUND: In the field of research for new validated surrogate biomarkers of treatment efficacy, disease activity and progression in Multiple Sclerosis (MS), serum neurofilament light-chain (sNFL) are actually the best candidate for MS patient monitoring. However, before they can be implemented in clinical practice, their usefulness as additional red flag routine measure must be demonstrated. To tackle the problem, this real-life cross-sectional study at the Regional Referring Center for Multiple Sclerosis (CRESM) aims to characterize sNFL levels and prevalence of elevated sNFL, according to our age-dependent cut-off values, in a large group of patients with different types of MS and treatment conditions. METHODS: 908 serum samples from as many MS patients being admitted at CRESM for diagnostic definition and/or during routinary treatment monitoring were consecutively collected between January 2019 and January 2020. sNFL levels were measured by single molecule array (Simoa™) technology on SR-X instrument using NF-light assays (Quanterix); results were interpreted using previously published cut-off values. RESULTS: Primary and Secondary Progressive MS (PPMS, SPMS) forms demonstrate higher levels and prevalence of elevated sNFL (PPMS= 32 %, SPMS= 21 %) compared to the Relapse and Remitting one (RRMS = 12 %). Besides, naïve samples of RRMS and PPMS subtypes showed higher prevalence of elevated sNFL (RRMS naïve= 31 %, PPMS naïve=67 %) compared to samples from patients treated for more than 12 months (RRMS treat>12m= 9 %, PPMS treat>12m= 19 %); treated SPMS patients demonstrated higher sNFL levels and a prevalence (22 %) of elevated sNFL compared to RRMS treated patients. Focusing on RRMS, no statistical difference was found between groups of patients treated for whatever time (up to or more than 60 months) and with either DMT type (high or low-efficacy DMT). Finally, RRMS patients treated with all DMTs for more than 12 months, with the exception of teriflunomide and alemtuzumab showed a prevalence of elevated sNFL in the range of 5-10 %. CONCLUSION: in a real-world setting comprising about 1000 MS patients, sNFL quantification was elevated in 5-to-67 % of patients, in different MS forms and treatment conditions. Elevated levels of sNFL must be considered a red-flag suggesting the need of a further clinical monitoring in any circumstance, as it can be indicative of new inflammation, ongoing degeneration or co-morbidities. This study supports the introduction of sNFL quantification in everyday patient management.

The limited role of serum neurofilament light chain in predicting pain severity of patients with diabetic polyneuropathy.

Pain is one of many complaints expressed by patients with diabetic polyneuropathy. However, no objective measure for pain severity has been available. Neurofilament light chains have been widely used for assessing axonal damage in the neuronal system. Hence, we sought to investigate whether neurofilament light chains can serve as a marker reflecting pain severity in diabetic polyneuropathy. We enrolled the patients with diabetic polyneuropathy. Serum concentrations of neurofilament light chain were then measured using a single-molecule array. Pain severity was evaluated using painDETECT and the Brief Pain Inventory. Moreover, laboratory results including, serum creatinine, HbA1c, and glomerular filtration rate. A correlation test was used to analyze each variable. A total of 42 patients were enrolled. Neurofilament light chain levels were unable to reflect current neuropathic pain severity. However, high levels of neurofilament light chain were a significant predictor of poor diabetes control (r = 0.41; p = 0.02) and kidney damage (r = 0.45; p = 0.01). Serum levels of neurofilament light chain could not reflect current pain severity but was strongly associated with kidney dysfunction and poor diabetes control. Other biomarkers that could predict pain severity need to be uncovered.

Serum Biomarker Signatures of Choroid Plexus Volume Changes in Multiple Sclerosis.

Increased choroid plexus (CP) volume has been recently implicated as a potential predictor of worse multiple sclerosis (MS) outcomes. The biomarker signature of CP changes in MS are currently unknown. To determine the blood-based biomarker characteristics of the cross-sectional and longitudinal MRI-based CP changes in a heterogeneous group of people with MS (pwMS), a total of 202 pwMS (148 pwRRMS and 54 pwPMS) underwent MRI examination at baseline and at a 5-year follow-up. The CP was automatically segmented and subsequently refined manually in order to obtain a normalized CP volume. Serum samples were collected at both timepoints, and the concentration of 21 protein measures relevant to MS pathophysiology were determined using the Olink™ platform. Age-, sex-, and BMI-adjusted linear regression models explored the cross-sectional and longitudinal relationships between MRI CP outcomes and blood-based biomarkers. At baseline, there were no significant proteomic predictors of CP volume, while at follow-up, greater CP volume was significantly associated with higher neurofilament light chain levels, NfL (standardized ß = 0.373, p = 0.001), and lower osteopontin levels (standardized ß = -0.23, p = 0.02). Higher baseline GFAP and lower FLRT2 levels were associated with future 5-year CP % volume expansion (standardized ß = 0.277, p = 0.004 and standardized ß = -0.226, p = 0.014, respectively). The CP volume in pwMS is associated with inflammatory blood-based biomarkers of neuronal injury (neurofilament light chain; NfL) and glial activation such as GFAP, osteopontin, and FLRT2. The expansion of the CP may play a central role in chronic and compartmentalized inflammation and may be driven by glial changes.

The Inflammasome Adaptor Protein ASC in Plasma as a Biomarker of Early Cognitive Changes.

Dementia is a group of symptoms including memory loss, language difficulties, and other types of cognitive and functional impairments that affects 57 million people worldwide, with the incidence expected to double by 2040. Therefore, there is an unmet need to develop reliable biomarkers to diagnose early brain impairments so that emerging interventions can be applied before brain degeneration. Here, we performed biomarker analyses for apoptosis-associated speck-like protein containing a caspase recruitment domain (ASC), neurofilament light chain (NfL), glial fibrillary acidic protein (GFAP), and amyloid-ß 42/40 (Aß42/40) ratio in the plasma of older adults. Participants had blood drawn at baseline and underwent two annual clinical and cognitive evaluations. The groups tested either cognitively normal on both evaluations (NN), cognitively normal year 1 but cognitively impaired year 2 (NI), or cognitively impaired on both evaluations (II). ASC was elevated in the plasma of the NI group compared to the NN and II groups. Additionally, Aß42 was increased in the plasma in the NI and II groups compared to the NN group. Importantly, the area under the curve (AUC) for ASC in participants older than 70 years old in NN vs. NI groups was 0.81, indicating that ASC is a promising plasma biomarker for early detection of cognitive decline.

Establishing Normal Serum Values of Neurofilament Light Chains and Glial Fibrillary Acidic Protein Considering the Effects of Age and Other Demographic Factors in Healthy Adults.

Multiple studies have shown the importance of blood-based biomarkers indicating axonal damage (serum neurofilament light chains [sNfL]) or astroglia activation (serum glial fibrillary acidic protein [sGFAP]) for monitoring different neurological diseases. However, normal values of these variables remain to be clearly defined, partly due to the influence of different demographic factors. We investigated demographic differences in a cohort of healthy volunteers. A cross-sectional study was conducted including 116 healthy controls with ages between 18 and 69 years (67.5% females; n = 79). sNfL and sGFAP concentrations were measured using single-molecule arrays. Age and body mass index affected sNfL values, and age was found to be the most important factor. The normal values changed with age, and we established normal values for individuals younger than 45 years as <10 pg/mL and for controls older than 45 years as <15 pg/mL. We established normal values at <10 pg/mL for individuals younger than 45 years and <15 pg/mL for older individuals. Alternatively, a Z-score of 1.5 was relevant for all controls. sGFAP was only affected by age. Differences in normal values were evident by 55 years. The highest normality limit for sGFAP was 140 pg/mL for controls under 55 years and 280 for older controls. We defined normal levels for sNfL and sGFAP and their corresponding age-associated changes. These data may contribute to the application of such variables in clinical practice.

Clinical utility of the Lumipulse™ immunoassay for plasma neurofilament light chain in multiple sclerosis.

OBJECTIVE: Blood neurofilament light chain (NfL) is robustly associated with disease worsening in multiple sclerosis (MS), though potentially affected by concomitant factors also determining neuro-axonal loss. We investigated the association between plasma NfL (pNfL) measured with Lumipulse™ immunoassay and demographic and clinical variables in MS. METHODS: This cross-sectional study included 685 people with MS (age 49.7 ± 12.4 years; sex 65.55% females). On the same day, we collected plasma samples, along with demographics, comorbidities, and clinical variables (MS disease duration, expanded disability status scale (EDSS), Symbol Digit Modalities Test (SDMT), descriptor of disease progression, current disease modifying treatment (DMT), number of previous DMTs, evidence of disease activity in the past year (i.e. relapse or MRI new lesions), EDSS progression). pNfL was evaluated using Lumipulse™ fully automated chemiluminescent enzyme immunoassay. RESULTS: On multivariable linear regression model, higher pNfL was associated with higher EDSS (Coeff = 1.73; 95%CI 0.78, 2.68; p < 0.01), recent disease activity (Coeff = 15.70; 95%CI = 5.35, 26.06; p < 0.01), and presence of cardiovascular comorbidity (Coeff = 3.84; 95%CI 0.48, 7.20; p = 0.025). Lower pNfL was found in patients on DMT treatment (Coeff = -10.23; 95%CI -18.42, -2.04; p = 0.015), when compared with no DMT (reference). For 77.81% of our population there was correspondence between pNfL levels and two previously-validated cutoffs. CONCLUSIONS: pNfL measured using Lumipulse™ confirms known associations with MS activity, disability and treatments, and related confounding (e.g., cardiovascular comorbidity), thus granting further utilization in research and clinical practice.

Plasma neurofilament light protein is differentially associated with age in individuals with treatment-resistant schizophrenia and bipolar affective disorder compared to controls.

Accelerated brain ageing has been observed in multiple psychiatric disorders. This study examined whether relationships between age and plasma neurofilament light (NfL) protein differed in individuals with psychiatric disorders (major depressive disorder (n = 42), bipolar affective disorder (n = 121), treatment-resistant schizophrenia (TRS, n = 82)) compared to two healthy control (HC) groups (n = 1,926 and n = 59). Compared to two independent HC samples, individuals with TRS demonstrated a stronger positive relationship between age and NfL levels. Individuals with BPAD had a stronger negative relationship between age and NfL levels compared to the large normative HC cohort, but not locally-acquired HCs. These findings show that plasma NfL levels are differentially associated with age in individuals with TRS and BPAD compared to healthy individuals.

Clinical and patient-reported outcomes and neurofilament response during tofersen treatment in SOD1-related ALS-A multicenter observational study over 18 months.

INTRODUCTION/AIMS: In amyotrophic lateral sclerosis (ALS) caused by SOD1 mutations (SOD1-ALS), tofersen received accelerated approval in the United States and is available via expanded access programs (EAP) outside the United States. This multicenter study investigates clinical and patient-reported outcomes (PRO) and serum neurofilament light chain (sNfL) during tofersen treatment in an EAP in Germany. METHODS: Sixteen SOD1-ALS patients receiving tofersen for at least 6 months were analyzed. The ALS progression rate (ALS-PR), as measured by the monthly change of the ALS functional rating scale-revised (ALSFRS-R), slow vital capacity (SVC), and sNfL were investigated. PRO included the Measure Yourself Medical Outcome Profile (MYMOP2), Treatment Satisfaction Questionnaire for Medication (TSQM-9), and Net Promoter Score (NPS). RESULTS: Mean tofersen treatment was 11 months (6-18 months). ALS-PR showed a mean change of -0.2 (range 0 to -1.1) and relative reduction by 25%. Seven patients demonstrated increased ALSFRS-R. SVC was stable (mean 88%, range -15% to +28%). sNfL decreased in all patients except one heterozygous D91A-SOD1 mutation carrier (mean change of sNfL -58%, range -91 to +27%, p < .01). MYMOP2 indicated improved symptom severity (n = 10) or yet perception of partial response (n = 6). TSQM-9 showed high global treatment satisfaction (mean 83, SD 16) although the convenience of drug administration was modest (mean 50, SD 27). NPS revealed a very high recommendation rate for tofersen (NPS +80). DISCUSSION: Data from this EAP supported the clinical and sNfL response to tofersen in SOD1-ALS. PRO suggested a favorable patient perception of tofersen treatment in clinical practice.

High levels of plasma neurofilament light chain correlated with brainstem and peripheral nerve damage.

BACKGROUND AND OBJECTIVES: Blood neurofilament light chain (NfL) is a minimally invasive, but highly sensitive biomarker of neurological diseases. However, diseases and neurological damage associated with increased NfL remain unclear. Therefore, the present study investigated factors associated with increased plasma NfL levels in various neurological diseases, focal lesions and pathological processes. METHODS: This was a retrospective cohort study on 410 participants with various neurological diseases and 17 healthy and cognitively unimpaired controls (HCU). Plasma samples were analyzed to measure NfL using ECL immunoassay. The focal lesions were classified as the cerebrum, cerebellum, brainstem, meninges, spinal cord, peripheral nerves, neuromuscular junction, and muscles based on medical records. A multiple regression analysis and receiver operating characteristic curve (ROC) analysis were performed to investigate whether plasma NfL levels predict specific diseases and focal lesions. RESULTS: Plasma NfL levels discriminated between the HCU and all disease groups (area under the curve (AUC), 0.97), with a cut-off value of 63.4 pg/mL. A multiple regression analysis of focal lesions adjusted by pathogenic processes showed that brainstem and peripheral nerve involvement was associated with higher plasma NfL levels. A cut-off value of 53.8 pg/mL of NfL discriminated between the HCU and neurological disease group except for brainstem or peripheral disorders (AUC 0.962), while a cut-off value of 208.0 pg/mL distinguished this group from brainstem or peripheral nervous system disorders (AUC 0.716). DISCUSSION: These results demonstrate that plasma NfL has a potential to be a highly sensitive biomarker for neurological diseases and focal lesions.