Light Chain Concentrations Research Articles

Glial fibrillary acidic protein in cerebrospinal fluid of patients with spinal muscular atrophy.

ObjectiveActivated astroglia is involved in the pathophysiology of neurodegenerative diseases and has also been described in animal models of spinal muscular atrophy (SMA). Given the urgent need of biomarkers for treatment monitoring of new RNA‐modifying and gene replacement therapies in SMA, we examined glial fibrillary acidic protein concentrations in cerebrospinal fluid (cGFAP) as a marker of astrogliosis in SMA.Methods58 adult patients and 21 children with genetically confirmed 5q‐associated SMA from four German motor neuron disease specialist care centers and 30 age‐ and sex‐matched controls were prospectively included in this study. cGFAP was measured and correlated to motor performance and disease severity. Additionally, we compared cGFAP with neurofilament light chain concentrations in cerebrospinal fluid (cNfL).ResultscGFAP concentrations did not differ from controls but showed higher levels in more severely affected patients after adjustment for patients' age. Normalized cNfL values were associated with disease severity. Within 14 months of nusinersen treatment, cGFAP concentrations did not change, while cNfL decreased significantly.InterpretationcGFAP is not an outstanding biomarker in SMA, but might support the hypothesis that glial activation is involved in SMA pathology. Unlike previously suggested, cNfL may be a promising biomarker also in adult patients with SMA, which should be subject to further investigations.

The prognostic significance of early blood neurofilament light chain concentration and magnetic resonance imaging variables in relapse-onset multiple sclerosis.

BackgroundImproved prognostication remains vital in multiple sclerosis to inform personalized treatment approaches. Blood neurofilament light (bNfL) is a promising prognostic biomarker, but to what extent it provides additional information, independent of established MRI metrics, is yet to be established.MethodsWe obtained all available bNfL data for 133 patients from a longitudinal observational cohort study. Patients were dichotomized into good or poor outcome groups based upon clinical and cognitive assessments performed 15 years after a clinically isolated syndrome. We performed longitudinal modeling of early NfL and MRI variables to examine differences between outcome groups.ResultsThe bNfL dataset was incomplete, with one to three (mean 1.5) samples available per participant. Within 3 months of onset, bNfL was similar between groups. The bNfL concentration subsequently decreased in those with a good outcome, and remained persistently elevated in those with a poor outcome. By year 5, NfL in the poor outcome group was approximately double that of those with a good outcome (14.58 [10.40–18.77] vs. 7.71 [6.39–9.04] pg/ml, respectively). Differences were reduced after adjustment for longitudinal changes in T2LV, but trends persisted for a greater rate of increase in NfL in those with a poor outcome, independent of T2LV.ConclusionsThis analysis requires replication in cohorts with more complete bNfL datasets, but suggests that persistently elevated blood NfL may be more common in patients with a poor long‐term outcome. Persistent elevation of blood NfL may provide additional prognostic information not wholly accounted for by standard monitoring techniques.

Neurofilament light levels predict clinical progression and death in multiple system atrophy.

Disease-modifying treatments are currently being trialled in multiple system atrophy. Approaches based solely on clinical measures are challenged by heterogeneity of phenotype and pathogenic complexity. Neurofilament light chain protein has been explored as a reliable biomarker in several neurodegenerative disorders but data on multiple system atrophy have been limited. Therefore, neurofilament light chain is not yet routinely used as an outcome measure in multiple system atrophy. We aimed to comprehensively investigate the role and dynamics of neurofilament light chain in multiple system atrophy combined with cross-sectional and longitudinal clinical and imaging scales and for subject trial selection. In this cohort study, we recruited cross-sectional and longitudinal cases in a multicentre European set-up. Plasma and CSF neurofilament light chain concentrations were measured at baseline from 212 multiple system atrophy cases, annually for a mean period of 2 years in 44 multiple system atrophy patients in conjunction with clinical, neuropsychological and MRI brain assessments. Baseline neurofilament light chain characteristics were compared between groups. Cox regression was used to assess survival; receiver operating characteristic analysis to assess the ability of neurofilament light chain to distinguish between multiple system atrophy patients and healthy controls. Multivariate linear mixed-effects models were used to analyse longitudinal neurofilament light chain changes and correlated with clinical and imaging parameters. Polynomial models were used to determine the differential trajectories of neurofilament light chain in multiple system atrophy. We estimated sample sizes for trials aiming to decrease neurofilament light chain levels. We show that in multiple system atrophy, baseline plasma neurofilament light chain levels were better predictors of clinical progression, survival and degree of brain atrophy than the neurofilament light chain rate of change. Comparative analysis of multiple system atrophy progression over the course of disease, using plasma neurofilament light chain and clinical rating scales, indicated that neurofilament light chain levels rise as the motor symptoms progress, followed by deceleration in advanced stages. Sample size prediction suggested that significantly lower trial participant numbers would be needed to demonstrate treatment effects when incorporating plasma neurofilament light chain values into multiple system atrophy clinical trials in comparison to clinical measures alone. In conclusion, neurofilament light chain correlates with clinical disease severity, progression and prognosis in multiple system atrophy. Combined with clinical and imaging analysis, neurofilament light chain can inform patient stratification and serve as a reliable biomarker of treatment response in future multiple system atrophy trials of putative disease-modifying agents.

Association of plasma neurofilament light chain with disease activity in chronic inflammatory demyelinating polyradiculoneuropathy.

This study was undertaken to explore associations between plasma neurofilament light chain (pNfL) concentration (pg/ml) and disease activity in patients with chronic inflammatory demyelinating polyradiculoneuropathy (CIDP) and examine the usefulness of pNfL concentrations in determining disease remission. We examined pNfL concentrations in treatment-naïve CIDP patients (n= 10) before and after intravenous immunoglobulin (IVIg) induction treatment, in pNfL concentrations in patients on maintenance IVIg treatment who had stable (n= 15) versus unstable disease (n= 9), and in clinically stable IVIg-treated patients (n= 10) in whom we suspended IVIg to determine disease activity and ongoing need for maintenance IVIg. pNfL concentrations in an age-matched healthy control group were measured for comparison. Among treatment-naïve patients, pNfL concentration was higher in patients before IVIg treatment than healthy controls and subsequently reduced to be comparable to control group values after IVIg induction. Among CIDP patients on IVIg treatment, pNfL concentration was significantly higher in unstable patients than stable patients. A pNFL concentration > 16.6pg/ml distinguished unstable treated CIDP from stable treated CIDP (sensitivity=86.7%, specificity=66.7%, area under receiver operating characteristic curve=0.73). Among the treatment withdrawal group, there was a statistically significant correlation between pNfL concentration at time of IVIg withdrawal and the likelihood of relapse (r= 0.72, p< 0.05), suggesting an association of higher pNfL concentration with active disease. pNfL concentrations may be a sensitive, clinically useful biomarker in assessing subclinical disease activity.

No increase of serum neurofilament light in relapsing-remitting multiple sclerosis patients switching from standard to extended-interval dosing of natalizumab

Background: Accumulating evidence supports the efficacy of administering natalizumab (NZ) with extended-interval dosing (EID) in patients with relapsing-remitting multiple sclerosis (RRMS). Objectives: We switched NZ dosing from 4-week to 6-week intervals in patients with RRMS, and investigated the effect on serum neurofilament light chain (sNfL) concentrations. Methods: We included two cohorts of patients with RRMS treated with NZ: one received the standard-interval dosing (4 weeks) at baseline, and were switched to 6-week intervals (EID4–6, N = 45). The other cohort received EID (5- or 6-week intervals) both at baseline and during follow-up (EID5/6, N = 25). Serum samples were collected in the EID4–6 cohort at every NZ infusion, for 12 months. The primary outcome was the change in sNfL concentrations after switching to EID. Results: The baseline mean sNfL concentration in the EID4–6 cohort was 10.5 ng/L (standard deviation (SD) = 6.1), and it remained unchanged at 12 months. Moreover, individual sNfL concentrations did not change significantly after extending the NZ dosing intervals. In addition, the EID4–6 and EID5/6 cohorts had similar baseline sNfL concentrations. Conclusion: We concluded that extending the NZ dosing interval did not increase axonal damage, as determined with sNfL, in patients with RRMS.

Gut Mycobiome in Patients With Chronic Kidney Disease Was Altered and Associated With Immunological Profiles.

ObjectivesMounting evidence suggests that bacterial dysbiosis and immunity disorder are associated with patients with chronic kidney disease (CKD), but the mycobiome is beginning to gain recognition as a fundamental part of our microbiome. We aim to characterize the profile of the mycobiome in the gut of CKD patients and its correlation to serum immunological profiles.Methods and materialsNinety-two CKD patients and sex–age–body mass index (BMI)–matched healthy controls (HCs) were recruited. Fresh samples were collected using sterile containers. ITS transcribed spacer ribosomal RNA gene sequencing was performed on the samples. An immunoturbidimetric test was used to assess the serum levels of immunological features.ResultsThe CKD cohort displayed a different microbial community from that in the HC cohort according to principal coordinate analysis (PCoA). (P=0.001). The comparison of the two cohorts showed that the CKD cohort had significantly higher gut microbial richness and diversity (P<0.05). The CKD cohort had lower abundances of Candida, Bjerkandera, Rhodotorula, and Ganoderma compared to the HC cohort, while it had higher Saccharomyces (P<0.05). However, the microbial community alteration was inconsistent with the severity of kidney damage in patients, as only patients in CKD stage 1~3 had differed microbial community concerning for HCs based on PCoA (P<0.05). The serum concentration of the kappa light chain in CKD patients was positively associated with Saccharomyces, whereas the it was negatively associated with Ganoderma (P<0.05).ConclusionsNot only was gut mycobiome dysbiosis observed in CKD patients, but the dysbiosis was also associated with the immunological disorder. These findings suggest that therapeutic strategies targeting gut mycobiome might be effective.

Serum neurofilament light chain concentration predicts disease worsening in multiple sclerosis

Background: Serum neurofilament light (sNfL) chain is a promising biomarker reflecting neuro-axonal injury in multiple sclerosis (MS). However, the ability of sNfL to predict outcomes in real-world MS cohorts requires further validation. Objective: The aim of the study is to investigate the associations of sNfL concentration, magnetic resonance imaging (MRI) and retinal optical coherence tomography (OCT) markers with disease worsening in a longitudinal European multicentre MS cohort. Methods: MS patients (n = 309) were prospectively enrolled at four centres and re-examined after 2 years (n = 226). NfL concentration was measured by single molecule array assay in serum. The patients’ phenotypes were thoroughly characterized with clinical examination, retinal OCT and MRI brain scans. The primary outcome was disease worsening at median 2-year follow-up. Results: Patients with high sNfL concentrations (⩾8 pg/mL) at baseline had increased risk of disease worsening at median 2-year follow-up (odds ratio (95% confidence interval) = 2.8 (1.5–5.3), p = 0.001). We found no significant associations of MRI or OCT measures at baseline with risk of disease worsening. Conclusion: Serum NfL concentration was the only factor associated with disease worsening, indicating that sNfL is a useful biomarker in MS that might be relevant in a clinical setting.

Factors associated with mortality in early stages of parkinsonism

Prognosis of patients with parkinsonism varies greatly between the various parkinsonian syndromes. However, it is often difficult to distinguish the different forms, particularly in early stages. We examined predictors of mortality and functional outcome in patients with recent-onset parkinsonism with an initially uncertain diagnosis (n = 156). Patients were recruited between 2003 and 2006, comprehensively investigated, and followed prospectively (up to 15 years, mean 7 years). A final clinical diagnosis was established after follow-up. Independent predictors of mortality were investigated with multivariable Cox regression and combined into a simple prediction model. Model performance to predict 5- and 10-year mortality and functional outcome after 3 years was evaluated and externally validated in a second cohort of 62 patients with parkinsonism with an initially uncertain diagnosis. Ninety-one patients died (58%). Orthostatic hypotension, impaired cognition, abnormal tandem gait, and elevated neurofilament light chain concentration in serum or CSF were associated with mortality. A simple model that combined these factors showed excellent performance for prediction of functional outcome after 3 years and mortality after 5 and 10 years (c-statistic ~0.90 for all models). Model performance was confirmed after external validation: prediction of functional outcome after 3 years (c-statistic 0.89, 95% CI 0.80–0.98) and mortality after 5 years (c-statistic 0.91, 95% CI 0.84–0.99) were comparable to the results in the discovery cohort. These findings help clinicians to estimate a patient’s prognosis, irrespective of the specific diagnosis.

Use of Cognitive Testing, Questionnaires, and Plasma Biomarkers to Quantify Cognitive Impairment in an Aging Pet Dog Population.

Aging dogs may suffer from canine cognitive dysfunction syndrome (CCDS), a condition in which cognitive decline is associated with amyloid pathology and cortical atrophy. Presumptive diagnosis is made through physical examination, exclusion of systemic/metabolic conditions, and completion of screening questionnaires by owners. This study aimed to determine whether cognitive function could be quantified in aging pet dogs, and to correlate cognitive testing with validated questionnaires and plasma neurofilament light chain (pNfL) concentration. Thirty-nine dogs from fifteen breeds were recruited (9.3 to 15.3 years). Owners completed the Canine Dementia Scale (CADES) and Canine Cognitive Dysfunction Rating scale (CCDR). Executive control and social cues were tested, and pNfL was measured with single molecule array assay. Comparisons were made between cognitive testing scores, CADES, CCDR scores, and pNfL. CADES scoring classified five dogs as severe CCDS, six as moderate, ten as mild, and eighteen as normal. CCDR identified seven dogs at risk of CCDS and thirty-two as normal. Cognitive testing was possible in the majority of dogs, although severely affected dogs were unable to learn tasks. CADES score correlated with sustained attention duration (r = -0.47, p = 0.002), inhibitory control (r = -0.51, p = 0.002), detour (r = -0.43, p = 0.001), and pNfL (r = 0.41, p = 0.025). Concentration of pNfL correlated with inhibitory control (r = -0.7, p≤0.001). The CCDR scale correlated with performance on inhibitory control (r = -0.46, p = 0.005). Our findings suggest that a multi-dimensional approach using a combination of questionnaires, specific cognitive tests, and pNfL concentration can be used to quantify cognitive decline in aging pet dogs.

Paving the Way Toward Meaningful Trials in Ataxias: An Ataxia Global Initiative Perspective.

Paving the Way Toward Meaningful Trials in Ataxias: An Ataxia Global Initiative Perspective.

An Update on Laboratory-Based Diagnostic Biomarkers for Multiple Sclerosis and Beyond.

Multiple sclerosis (MS) is an immune-mediated central nervous system (CNS) inflammatory demyelinating disease in which analysis of clinical presentation, imaging studies, and laboratory tests aid in diagnosis. This review discusses laboratory tests ordered to rule out and rule in MS, such as the traditional measurement of cerebrospinal fluid (CSF) IgG index and oligoclonal bands. Biomarkers discovered in the past 2 decades, such as aquaporin-4 (AQP4) antibodies and myelin oligodendrocyte glycoprotein (MOG) antibodies, have been incorporated into clinical practice in the diagnosis of disorders referred to as MS mimics. The importance of test selection, assay methodology, optimal sample for testing, and diagnostic utility of these biomarkers is reviewed. Other laboratory testing that can aid in the differentiation between MS and these biomarker-defined CNS demyelinating diseases is described. There is a focus on emerging biomarkers such as the use of kappa immunoglobulin free light chain concentration in CSF and kappa CSF index measurement as an alternative to oligoclonal bands which has a potential for an improvement in laboratory workflows. Finally, the role of biomarkers of disease activity and prognosis are discussed, including neurofilament light chain, glial fibrillary acidic protein, and myelin basic protein. Future perspectives with improved laboratory testing tools and discovery of additional biomarkers are provided. Laboratory testing for demyelinating disorders using CSF and serum are routine practices that can benefit from an update, as novel biomarker-defined entities have reduced the potential for MS misdiagnosis, and CSF/serum biomarkers reinstated in the diagnostic criteria of MS.

Light Chain Restriction in Proximal Tubules-Implications for Light Chain Proximal Tubulopathy.

Monoclonal gammopathy (MG) causes various nephropathies, which may suffice for cytoreductive therapy even in the absence of diagnostic criteria for multiple myeloma or B-cell non-Hodgkin lymphoma. The aim of this study was to better understand the significance of light chain (LC) restriction or crystals (LC-R/C) in proximal tubules in the spectrum of LC-induced nephropathies. A consecutive cohort of 320 renal specimens with a history of B-cell dyscrasia was characterized. Special attention was paid to immunohistochemical LC restriction in proximal tubules, tubular crystals or constipation, and ultrastructural findings. Complementary cell culture experiments were performed to assess the role of LC concentrations in generating LC restriction. Light chain restriction or crystals in proximal tubules was found in a quarter of analyzed cases (81/316) and was associated with another LC-induced disease in 70.4% (57/81), especially LC cast-nephropathy (cast-NP) and interstitial myeloma infiltration. LC restriction without significant signs of acute tubular injury was observed in 11.1% (9/81). LC-R/C was not associated with inferior renal function compared to the remainder of cases, when cases with accompanying cast-NP were excluded. Besides crystals, cloudy lysosomes were significantly associated with LC-R/C on an ultrastructural level. In summary, LC-R/C is frequent and strongly associated with cast-NP, possibly indicating that a high load of clonal LC is responsible for this phenomenon, supported by the observation that LC restriction can artificially be generated in cell culture. This and the lack of significant tubular injury in a subgroup imply that in part LC-R/C is a tubular trafficking phenomenon rather than an independent disease process.

Examination of Neurofilament Light Chain Serum Concentrations, Physical Activity, and Cognitive Decline in Older Adults

Little is known about the association of serum neurofilament light chain (NfL) concentrations and physical activity with the rate of cognitive decline in older adults. To examine the association of physical activity and NfL concentrations with cognitive decline in older adults over time. This cohort study used data from the Chicago Health and Aging Project (CHAP), a population-based cohort study that recruited participants through door-to-door census in 4 Chicago-area communities and collected data between 1993 and 2012 in cycles of 3 years. Participants in CHAP who had 2 or more cognitive function assessments and at least 1 blood sample collected for NfL measurement were selected for inclusion in the current study. Data were analyzed from January to December 2021. Self-reported physical activity (minutes per week) and serum NfL concentration (pg/mL). Associations of baseline physical activity and NfL concentrations with changes in global cognitive function over time as evaluated using the East Boston Memory Test for episodic memory, the Symbol Digit Modalities Test for perceptual speed, and the Mini-Mental State Examination. Mixed-effects regression analyses were conducted to examine associations at baseline and longitudinally. The study sample included 1158 participants (695 [60%] African American; 728 [63%] female), with a mean (SD) age of 77.4 (6.0) years and a mean educational level of 12.6 (3.5) years. Among participants with high NfL concentrations (>25 pg/mL), those who engaged in medium physical activity (<150 minutes per week) had a 12% slower rate of global cognitive decline (SD units, or β, -0.065; 95% CI, -0.099 to -0.032) and participants who engaged in high physical activity (≥150 minutes per week) had a 36% slower rate of decline (β, -0.048; 95% CI, -0.080 to -0.016) than did participants with low physical activity (no reported participation) (β, -0.075; 95% CI, -0.108 to -0.041). For participants with low NfL concentrations (≤25 pg/mL), those who took part in medium physical activity had 43% slower global cognitive decline (β, -0.025; 95% CI, -0.043 to -0.007) and individuals who participated in high physical activity had 30% slower decline (β, -0.031; 95% CI, -0.048 to -0.014) than did those who participated in low physical activity (β, -0.046; 95% CI, -0.066 to -0.025). The findings suggest that physical activity is associated with diminished cognitive decline among older adults with increased serum NfL concentrations. The results support the potential use of blood biomarkers in measuring the benefits of health behaviors, such as physical activity, and early intervention for older adults at risk for cognitive decline.

Evaluation of Plasma Neurofilament Light Chain Levels as a Biomarker of Neuronal Injury in the Active and Chronic Phases of Autoimmune Neurologic Disorders.

ObjectiveTo evaluate plasma neurofilament light (NfL) levels in autoimmune neurologic disorders (AINDs) and autoimmune encephalitis (AE).BackgroundEach particular neural autoantibody syndrome has a different clinical phenotype, making one unifying clinical outcome measure difficult to assess. While this is a heterogeneous group of disorders, the final common pathway is likely CNS damage and inflammation. Defining a biomarker of CNS injury that is easily obtainable through a blood sample and reflects a positive treatment response would be highly advantageous in future therapeutic trials. Measurement of blood concentration of neurofilament light (NfL) chain, however, may provide a biomarker of central nervous system (CNS) injury in AE and other AINDs. Here we provide an initial evaluation of plasma NfL levels in AE as well as other AINDs during active and chronic phases of disease and demonstrate its potential utility as a minimally-invasive biomarker for AE and AINDs.Design/MethodsPatients were retrospectively identified who were enrolled in the biorepository at the Rocky Mountain MS Center at the University of Colorado, or were prospectively enrolled after initial presentation. Patients had a well-defined AIND and were followed between 2014 and 2021. NfL was tested using the Single Molecule Array (SIMOA) technology. Patients with headaches but without other significant neurologic disease were included as controls.ResultsTwenty-six plasma and 14 CSF samples of patients with AINDs, and 20 plasma control samples stored in the biorepository were evaluated. A positive correlation was found between plasma and CSF NfL levels for patients with an AIND (R2 = 0.83, p < 0.001). Elevated plasma levels of NfL were seen in patients with active AE compared to controls [geometric mean (GM) 51.4 vs. 6.4 pg/ml, p = 0.002]. Patients with chronic symptoms (>6 months since new or worsening symptoms) of AE or cerebellar ataxia (CA) showed a trend toward lower plasma NfL levels (GM 15.1 pg/ml) compared to active AE or CA. Six patients with longitudinal, prospective sampling available demonstrated a trend in decreased plasma NfL levels over time.ConclusionsOur findings support the use of plasma NfL as a potential minimally-invasive biomarker of CNS injury.

Serum Neurofilament Light Chain as a Biomarker of Brain Injury in Wilson's Disease: Clinical and Neuroradiological Correlations.

Clinical scales and neuroimaging are used to monitor nervous system injury in Wilson's disease, while data on serum markers are scarce. To investigate whether serum concentrations of neurofilament light chain (sNfL) correlate with brain injury in Wilson's disease patients. In 61 treatment-naïve patients, the Unified Wilson's Disease Rating Scale and a validated semiquantitative brain magnetic resonance imaging scale were compared with concentrations of sNfL. Concentrations of sNfL were significantly higher in patients with neurological disease compared with patients presenting with other forms (39.7 ± 73.4pg/mL vs. 13.3 ± 9.2pg/mL; P < 0.01). Moreover, the sNfL concentration positively correlated with neurological severity scores and with acute and chronic brain damage based on the neuroimaging scale. Neurofilament light chain concentrations may be used as a marker of brain injury in Wilson's disease, in addition to the clinical and neuroimaging disease severity scales. © 2022 International Parkinson and Movement Disorder Society.

Neurofilament light chain concentration in an aging population

BackgroundNeurofilament light chain (NF-L) concentration is recognized to be modified in neurological diseases and traumatic brain injuries, but studies in the normal aging population are lacking. It is, therefore, urgent to identify influencing factors of NF-L concentration in the aging population.MethodWe assessed NF-L concentration in sera of a large cohort of 409 community-dwelling adults aged over 65 years. We studied the association between NF-L and various physiological factors but also with self-reported comorbidities or life-style habits.ResultsWe showed that NF-L concentration in serum was tightly associated with cystatin C concentration (r = 0.501, p < 0.0001) and consequently, to the estimated glomerular filtration rate (eGFR) (r = − 0.492; p < 0.0001). Additionally, NF-L concentration was dependent on age and body mass index (BMI) but not sex. Among the self-reported comorbidities, subjects who reported neurological disorders, cardiovascular diseases or history of fracture had higher NF-L concentration in univariate analysis, whereas it was only the case for subjects who reported neurological disorders in the multivariate analysis. NF-L concentration was also increased when Mini-Mental State Examination (MMSE) was decreased (≤ 25 points) but not when geriatric depression score (GDS) was increased (> 5 points) in both univariate and multivariate analysis. Finally, we are providing reference ranges by age categories for subjects with or without altered renal function.ConclusionNF-L concentration in the aging population is not driven by the increasing number of comorbidities or depression. Yet, NF-L blood concentration is dependent on kidney function and NF-L interpretation in patients suffering from renal failure should be taken with caution.

Association of Serum Neurofilament Light Chain Concentration and MRI Findings in Older Adults: The Cardiovascular Health Study.

Neurofilament light chain (NfL) in blood is a sensitive but nonspecific marker of brain injury. This study sought to evaluate associations between NfL concentration and MRI findings of vascular brain injury in older adults. A longitudinal cohort study included 2 cranial MRI scans performed about 5 years apart and assessed for white matter hyperintensities (WMH) and infarcts. About 1 year before their second MRI, 1,362 participants (median age 77 years, 61.4% women) without a history of TIA or stroke had measurement of 4 biomarkers: NfL, total tau, glial fibrillary acidic protein (GFAP), and ubiquitin carboxyl-terminal hydrolase L1. Most (n = 1,279) also had the first MRI scan, and some (n = 633) had quantitative measurements of hippocampal and WMH. In primary analyses, we assessed associations of NfL with a 10-point white matter grade (WMG) and prevalent infarcts on second MRI and with worsening WMG and incident infarct comparing the 2 scans. A p value <0.0125 (0.05/4) was considered significant for these analyses. We also assessed associations with hippocampal and WMH volume. In fully adjusted models, log2(NfL) concentration was associated with WMG (β = 0.27; p = 2.3 × 10-4) and worsening WMG (relative risk [RR] 1.24; p = 0.0022), but less strongly with prevalent brain infarcts (RR 1.18; p = 0.013) and not with incident brain infarcts (RR 1.18; p = 0.18). Associations were also present with WMH volume (β = 2,242.9, p = 0.0036). For the other 3 biomarkers, the associations for log2 (GFAP) concentration with WMG and worsening WMG were significant. Among older adults without a history of stroke, higher serum NfL concentration was associated with covert MRI findings of vascular brain injury, especially the burden of WMH and its worsening. Whether these results offer opportunities for the use of NfL as a noninvasive biomarker of WMH or to control vascular risk factors remains to be determined.

Serological markers exploration and real-world effectiveness and safety of teriflunomide in south Chinese patients with multiple sclerosis

BackgroundSince September 2012, when teriflunomide was approved as a disease-modifying treatment for relapsing multiple sclerosis, real-world observational studies on teriflunomide in Chinese patients are limited. MethodsWe collected demographic characteristics and peripheral blood samples at different time points. Clinical symptoms, magnetic resonance imaging data, and concentrations of neurofilament light chains and multiple cytokines at different time points were compared to assess the efficacy. Moreover, the safety was assessed by blood routine, liver and kidney function, and a questionnaire to report adverse reactions. ResultsTeriflunomide significantly reduced serum levels of neurofilament light chains and several inflammatory cytokines. After accepting teriflunomide treatment, many clinical symptoms improved, scores of the expanded disability status scale decreased from 2.0 to 1.75, and annualized relapse rates decreased from 1.45 to 0.31. 29 (80.56%) and 15 (78.95%) patients achieved the no evidence of disease activity-3 status after 6 months and 12 months treatment, respectively. Teriflunomide was associated with mild or moderate discomfort, and discontinuation rates due to adverse events were low. ConclusionSerum neurofilament light chain protein is sensitive to teriflunomide treatment, suggesting that it has the potential to be used as an indicator to assess the efficacy of teriflunomide. Teriflunomide can significantly reduce the concentrations of inflammatory cytokines, indicating that teriflunomide may regulate neuroinflammation through the inhibitory effect on a variety of immune cells and their cytokines. Teriflunomide can improve clinical symptoms and disease severity in MS patients in southern China, and patients have good compliance.

A longitudinal and cross-sectional study of plasma neurofilament light chain concentration in Charcot-Marie-Tooth disease.

Advances in genetic technology and small molecule drug development have paved the way for clinical trials in Charcot-Marie-Tooth disease (CMT); however, the current FDA-approved clinical trial outcome measures are insensitive to detect a meaningful clinical response. There is, therefore, a need to identify sensitive outcome measures or clinically relevant biomarkers. The aim of this study was to further evaluate plasma neurofilament light chain (NFL) as a disease biomarker in CMT. Plasma NFL was measured using SIMOA technology in both a cross-sectional study of a US cohort of CMT patients and longitudinally over 6 years in a UK CMT cohort. In addition, plasma NFL was measured longitudinally in two mouse models of CMT2D. Plasma concentrations of NFL were increased in a US cohort of patients with CMT1B, CMT1X and CMT2A but not CMT2E compared with controls. In a separate UK cohort, over a 6-year interval, there was no significant change in plasma NFL concentration in CMT1A or HSN1, but a small but significant reduction in patients with CMT1X. Plasma NFL was increased in wild type compared to GARSC201R mice. There was no significant difference in plasma NFL in GARSP278KY compared to wild type mice. In patients with CMT1A, the small difference in cross-sectional NFL concentration vs healthy controls and the lack of change over time suggests that plasma NFL may lack sufficient sensitivity to detect a clinically meaningful treatment response in adulthood.

Neurochemical signs of astrocytic and neuronal injury in acute COVID‐19 normalizes during long‐term follow‐up

BackgroundNeurologic manifestations are well‐recognized features of coronavirus disease 2019 (COVID‐19). However, the longitudinal association of biomarkers reflecting CNS impact and neurological symptoms is not known. We wished to determine whether plasma biomarkers of CNS injury were associated with neurologic sequelae after COVID‐19.MethodPatients with confirmed acute COVID‐19 were studied prospectively. Neurological symptoms were recorded during the acute phase of the disease and at six months follow‐up, and blood samples were collected longitudinally. Healthy age‐matched individuals were included as controls. We analyzed plasma concentrations of neurofilament light‐chain (NfL), glial fibrillary acidic protein (GFAp), and growth differentiation factor 15 (GDF‐15).ResultWe recruited 100 patients with mild (n = 24), moderate (n = 28), and severe (n = 48) COVID‐19 who were followed for a median of (IQR) 225 (187–262) days. In the acute phase, patients with severe COVID‐19 had higher concentrations of NfL than all other groups (all p < 0.001) and higher GFAp than controls (p < 0.001). GFAp was also significantly increased in moderate disease (p < 0.05) compared with controls. NfL (r = 0.53, p < 0.001) and GFAp (r = 0.39, p < 0.001) correlated with GDF‐15 during the acute phase. After six months, NfL and GFAp concentrations had normalized, with no persisting group differences. Despite this, 50 patients reported persistent neurological symptoms, most commonly included fatigue (n = 40), “brain‐fog” (n = 29), and changes in cognition (n = 25). We found no relation between persistent neurological symptoms and CNS injury biomarkers in the acute phase.ConclusionThe normalization of CNS injury biomarkers in all individuals, regardless of previous disease severity or persisting neurological symptoms, indicate that post‐acute COVID‐19 neurological sequelae are not accompanied by ongoing CNS injury. Although injury biomarkers commonly increase in severe acute COVID‐19, further investigations into the causes of post‐infectious sequelae are needed.