Serum Neurofilament Light Concentration Research Articles

Serum GFAP, NfL, and tau concentrations are associated with worse neurobehavioral functioning following mild, moderate, and severe TBI: a cross-sectional multiple-cohort study.

The purpose of this study was to examine whether blood-based biomarkers associate with neurobehavioral functioning at three time points following traumatic brain injury (TBI). Participants were 328 United States service members and veterans (SMVs) prospectively enrolled in the Defense and Veterans Brain Injury Center-Traumatic Brain Injury Center of Excellence (DVBIC-TBICoE) 15-Year Longitudinal TBI Study, recruited into three groups: uncomplicated mild TBI (MTBI, n = 155); complicated mild, moderate, severe TBI combined (STBI, n = 97); non-injured controls (NIC, n = 76). Participants were further divided into three cohorts based on time since injury (≤12 months, 3-5 years, and 8-10 years). Participants completed the Minnesota Multiphasic Personality Inventory-2-Restructured Format (MMPI-2-RF) and underwent blood draw to measure serum concentrations of glial fibrillary acidic protein (GFAP), neurofilament light (NfL), and tau. A total of 11 MMPI-2-RF scales were examined (e.g., depression, anxiety, anger, somatic, cognitive symptoms). Stepwise hierarchical regression models were conducted within each group. Significant associations were found between biomarkers and MMPI-2-RF scales (all p < 0.05; R2Δ > 0.10). GFAP was inversely related to (a) neurological complaints in the MTBI group at ≤12 months, (b) demoralization, anger proneness in the STBI group at ≤12 months, and (c) head pain complaints in the STBI group at 8-10 years. NfL was (a) related to low positive emotions in the NIC group; and inversely related to (b) demoralization, somatic complaints, neurological complaints, cognitive complaints in the MTBI group at ≤12 months, (c) demoralization in the STBI group at ≤12 months, and (d) demoralization, head pain complaints, stress/worry in the STBI group at 3-5 years. In the STBI group, there were meaningful findings (R2Δ > 0.10) for tau, NFL, and GFAP that did not reach statistical significance. Results indicate worse scores on some MMPI-2-RF scales (e.g., depression, stress/worry, neurological and head pain complaints) were associated with lower concentrations of serum GFAP, NfL, and tau in the sub-acute and chronic phase of the recovery trajectory up to 5 years post-injury, with a reverse trend observed at 8-10 years. Longitudinal studies are needed to help elucidate any patterns of association between blood-based biomarkers and neurobehavioral outcome over the recovery trajectory following TBI.

Triangulating brain alterations in anorexia nervosa: a multimodal investigation of magnetic resonance spectroscopy, morphometry and blood-based biomarkers

The acute state of anorexia nervosa (AN) is associated with widespread reductions in cortical gray matter (GM) thickness and white matter (WM) volume, suspected changes in myelin content and elevated levels of the neuronal damage marker neurofilament light (NF-L), but the underlying mechanisms remain largely unclear. To gain a deeper understanding of brain changes in AN, we applied a multimodal approach combining advanced neuroimaging methods with analysis of blood-derived biomarkers. In addition to standard measures of cortical GM thickness and WM volume, we analyzed tissue-specific profiles of brain metabolites using multivoxel proton magnetic resonance spectroscopy, T1 relaxation time as a proxy of myelin content leveraging advanced quantitative MRI methods and serum NF-L concentrations in a sample of 30 female, predominately adolescent patients with AN and 30 age-matched female healthy control participants. In patients with AN, we found a reduction in GM cortical thickness and GM total N-acetyl aspartate. The latter predicted higher NF-L levels, which were elevated in AN. Furthermore, GM total choline was elevated. In WM, there were no group differences in either imaging markers, choline levels or N-acetyl aspartate levels. The current study provides evidence for neuronal damage processes as well as for increased membrane lipid catabolism and turnover in GM in acute AN but no evidence for WM pathology. Our results illustrate the potential of multimodal research including tissue-specific proton magnetic resonance spectroscopy analyses to shed light on brain changes in psychiatric and neurological conditions, which may ultimately lead to better treatments.

Serum neurofilament light concentrations are associated with cortical thinning in anorexia nervosa.

Anorexia nervosa (AN) is characterized by severe emaciation and drastic reductions of brain mass, but the underlying mechanisms remain unclear. The present study investigated the putative association between the serum-based protein markers of brain damage neurofilament light (NF-L), tau protein, and glial fibrillary acidic protein (GFAP) and cortical thinning in acute AN. Blood samples and magnetic resonance imaging scans were obtained from 52 predominantly adolescent, female patients with AN before and after partial weight restoration (increase in body mass index >14%). The effect of marker levels before weight gain and change in marker levels on cortical thickness (CT) was modeled at each vertex of the cortical surface using linear mixed-effect models. To test whether the observed effects were specific to AN, follow-up analyses exploring a potential general association of marker levels with CT were conducted in a female healthy control (HC) sample (n = 147). In AN, higher baseline levels of NF-L, an established marker of axonal damage, were associated with lower CT in several regions, with the most prominent clusters located in bilateral temporal lobes. Tau protein and GFAP were not associated with CT. In HC, no associations between damage marker levels and CT were detected. A speculative interpretation would be that cortical thinning in acute AN might be at least partially a result of axonal damage processes. Further studies should thus test the potential of serum NF-L to become a reliable, low-cost and minimally invasive marker of structural brain alterations in AN.

Neurofilament light (NfL) as biomarker in serum and CSF in status epilepticus

ObjectiveWe explored the potential of neurofilament light chain (NfL) in serum and cerebrospinal fluid as a biomarker for neurodestruction in status epilepticus.MethodsIn a retrospective analysis, we measured NfL in serum and cerebrospinal fluid samples of patients with status epilepticus using a highly sensitive single-molecule array technique (Simoa). Status epilepticus was diagnosed according to ILAE criteria. Additionally, we employed an alternative classification with more emphasis on the course of status epilepticus. We used data from three large control groups to compare NfL in status epilepticus versus neurologically healthy controls.ResultsWe included 28 patients (mean age: 69.4 years, SD: 15 years) with a median status duration of 44 h (IQR: 80 h). Twenty-one patients (75%) suffered from convulsive status epilepticus and seven (25%) from non-convulsive status epilepticus. Six patients died (21%). Cerebrospinal fluid and serum NfL concentrations showed a high correlation (r = 0.73, p < 0.001, Pearson). The main determinant of NfL concentration was the status duration. NfL concentrations did not differ between convulsive status epilepticus and convulsive status epilepticus classified according to the ILAE or to the alternative classification without and with adjusting for status duration and time between status onset and sampling. We found no association of NfL concentration with death, treatment refractoriness, or prognostic scores.ConclusionThe results suggest that neurodestruction in status epilepticus measured by NfL is mainly determined by status duration, not status type nor therapy refractoriness. Therefore, our results suggest that regarding neurodestruction convulsive and non-convulsive status epilepticus are both neurological emergencies of comparable urgency.

Serum Neurofilament Light in Neurosyphilis: A Pilot Study.

Background Lumbar puncture is recommended for individuals with syphilis who have neurological symptoms; however, symptoms have poor sensitivity for predicting symptomatic neurosyphilis. Neurofilament light chain (NfL) is a marker for neuroaxonal injury; cerebrospinal fluid concentrations are higher in symptomatic neurosyphilis than in uncomplicated syphilis or asymptomatic neurosyphilis. Methods Serum NfL was quantified in 20 individuals with uncomplicated syphilis, 10 with asymptomatic neurosyphilis and 10 with symptomatic neurosyphilis using an ultrasensitive single-molecule array assay; it was repeated a median of 12.5 months after neurosyphilis therapy. Serum NfL concentration was age-adjusted using a published formula. Results Age-adjusted serum NfL concentration was significantly higher in symptomatic neurosyphilis compared with each of the other 2 groups. It was above the highest value in uncomplicated syphilis in 1 of 10 participants with asymptomatic neurosyphilis and 3 of 10 with symptomatic neurosyphilis. Serum NfL concentration increased in 1 participant with asymptomatic neurosyphilis with possible treatment failure. Conclusions If confirmed in a larger study, serum NfL may be a useful adjunct for identifying central nervous system infection by Treponema pallidum.

Life course, genetic, and neuropathological associations with brain age in the 1946 British Birth Cohort: a population-based study

A neuroimaging-based biomarker termed the brain age is thought to reflect variability in the brain's ageing process and predict longevity. Using Insight 46, a unique narrow-age birth cohort, we aimed to examine potential drivers and correlates of brain age. Participants, born in a single week in 1946 in mainland Britain, have had 24 prospective waves of data collection to date, including MRI and amyloid PET imaging at approximately 70 years old. Using MRI data from a previously defined selection of this cohort, we derived brain-predicted age from an established machine-learning model (trained on 2001 healthy adults aged 18-90 years); subtracting this from chronological age (at time of assessment) gave the brain-predicted age difference (brain-PAD). We tested associations with data from early life, midlife, and late life, as well as rates of MRI-derived brain atrophy. Between May 28, 2015, and Jan 10, 2018, 502 individuals were assessed as part of Insight 46. We included 456 participants (225 female), with a mean chronological age of 70·7 years (SD 0·7; range 69·2 to 71·9). The mean brain-predicted age was 67·9 years (8·2, 46·3 to 94·3). Female sex was associated with a 5·4-year (95% CI 4·1 to 6·8) younger brain-PAD than male sex. An increase in brain-PAD was associated with increased cardiovascular risk at age 36 years (β=2·3 [95% CI 1·5 to 3·0]) and 69 years (β=2·6 [1·9 to 3·3]); increased cerebrovascular disease burden (1·9 [1·3 to 2·6]); lower cognitive performance (-1·3 [-2·4 to -0·2]); and increased serum neurofilament light concentration (1·2 [0·6 to 1·9]). Higher brain-PAD was associated with future hippocampal atrophy over the subsequent 2 years (0·003 mL/year [0·000 to 0·006] per 5-year increment in brain-PAD). Early-life factors did not relate to brain-PAD. Combining 12 metrics in a hierarchical partitioning model explained 33% of the variance in brain-PAD. Brain-PAD was associated with cardiovascular risk, and imaging and biochemical markers of neurodegeneration. These findings support brain-PAD as an integrative summary metric of brain health, reflecting multiple contributions to pathological brain ageing, and which might have prognostic utility. Alzheimer's Research UK, Medical Research Council Dementia Platforms UK, Selfridges Group Foundation, Wolfson Foundation, Wellcome Trust, Brain Research UK, Alzheimer's Association.

Association of Neurofilament Light With the Development and Severity of Parkinson Disease.

Blood biomarkers may allow earlier identification of Parkinson disease (PD), parkinsonism, and poor PD-related outcomes, such as physical functioning. Neurofilament light (NfL), a neuronal cytoplasmic protein, is a biomarker of neurodegeneration measurable in biofluids. Our objective was to examine the association of serum NfL at baseline with clinically diagnosed PD, parkinsonian signs, and physical functioning change over 16 years in a population-based sample of older adults. Data came from 1,327 older participants from the Chicago Health and Aging Project, a longitudinal population-based study. Clinical evaluations included assessing parkinsonian signs in 4 domains-bradykinesia, parkinsonian gait, rigidity, and tremors-using a structured version of the Unified Parkinson's Disease Rating Scale. Board-certified neurologists diagnosed PD. Physical functioning was assessed using chair stands, tandem walk, and timed walk. An ultrasensitive immunoassay was used to measure the concentration of NfL in blood. Of the 1,254 participants examined for clinical PD, 77 (6.1%) developed clinical PD and parkinsonian signs were on average 9.5 (range 0-66.0). After adjusting for demographic characteristics, APOE ε4 allele, and global cognition, a 2-fold higher concentration of serum NfL was associated with incident clinical PD (odds ratio [OR] 2.54, 95% CI 1.70, 3.81) and global parkinsonian signs (OR 2.44, 95% CI 1.94, 2.94). This association was significant >5 years before diagnosis. Compared with participants with levels below 18.5 pg/mL of serum NfL at baseline, participants with levels between 18.5 and 25.4 pg/mL, between 25.4 and 37.3 pg/mL, and above 37.3 pg/mL had a higher OR of clinical PD at all time intervals from the time of diagnosis to >5 years before diagnosis. A higher concentration of serum NfL was associated with a faster rate of physical functioning decline. In participants with 2-fold higher concentrations of serum NfL, the annual rate of decline in physical functioning increased by 0.15 units (95% CI 0.21, 0.08). Serum NfL was associated with incident clinical PD, parkinsonian signs, and physical functioning decline in a population-based sample. Our findings suggest that NfL may serve as a potential biomarker for neurodegeneration, including PD outcomes. This study provides Class II evidence that serum NfL levels are associated with incident PD, parkinsonian signs, and physical functioning decline.

P 90 Clinical feasibility of novel ultra-sensitive multiplex NfL, Tau, UCHL-1 and GFAP assay for evaluation of neuro-axonal and glial damage in serum samples of patients with multiple sclerosis using reduced cost protocol

Introduction: Multiple sclerosis (MS) is an inflammatory disease of CNS with neuro-axonal injury as the key morphological correlate for long-term disability. Novel ultra-sensitive single molecule array (SiMoA) based detection of neurofilament light (NfL) and other neuroglial proteins is being considered as a promising tool for evaluation of disease activity 1 . However, clinical applicability is hampered by 1) considerable per-sample-costs, 2) scarcity of inter-laboratory comparisons and 3) absence of accepted cut-off values with good sensitivity and specificity. In this small single-center study, we aimed to a) show feasibility and clinical validity of an adapted reduced-cost protocol and to b) test sensitivity and specificity of an available 4-plex assay for NfL, Tau, UCHL-1 and GFAP in patients vs. controls and active vs. stable disease from a real-world data set of patients with MS and age matched healthy controls. Patients & Methods: We prospectively recruited serum samples from 114 adult patients with relapsing remitting MS (RRMS) including 42 with radiological/clinical active and 72 patients with stable disease as well as 70 healthy controls. Serum samples were measured with Neurology 4-Plex assay on fully automated HD-X-Analyzer (Quanterix) using standard and reduced cost protocols (measuring the serum samples in duplicates and singlicates). We determined precision, inter- and intra-assay variation, inter-laboratory comparisons, ROC-analysis, specificity and sensitivity using standard and modified protocols. Results: Using our reduced-cost approach, we confirmed inter- and intra-assay as well as inter-laboratory comparison coefficients of variations across relevant concentration levels of <10% for NfL. We reproduced higher mean serum NfL concentrations in patients with active RRMS (12.1pg/ml [95%CI 10.1-21.6]) compared to stable RRMS (7.1 pg/ml [95%CI 6.3-8.6], p<0,0001) and healthy controls (9.2 pg/ml [95%CI 8.2-10.3] p<0,0001) and significantly reduced per-sample-costs while applying our adapted approach. Serum tau (p<0.0001) but not GFAP and UCH-L1 concentrations were higher in RRMS versus controls. ROC-analysis (AUC=76.9±0,05) using a cut-off with maximal sensitivity showed a sensitivity of 70% and a specificity of 76% for active RRMS versus stable disease. The combinations of biomarkers showed no additional benefit over serum NfL concentration alone for prediction of disease activity. Conclusion: Using fully-automated analysis pipelines, reduced cost protocols are feasible and precise and could facilitate clinical application of serum neuronal biomarkers. While NfL discriminates fairly well between RRMS and healthy controls, sensitivity and specificity for active disease is lacking. Further prospective studies should evaluate the use of serial NfL measurements to determine clinical validity in detecting active RRMS.

Differences and similarities between familial and sporadic frontotemporal dementia: An Italian single-center cohort study.

IntroductionThe possibility to generalize our understandings on treatments and assessments to both familial frontotemporal dementia (f‐FTD) and sporadic FTD (s‐FTD) is a fundamental perspective for the near future, considering the constant advancement in potential disease‐modifying therapies that target particular genetic forms of FTD. We aimed to investigate differences in clinical features, cerebrospinal fluid (CSF), and blood‐based biomarkers between f‐FTD and s‐FTD.MethodsIn this longitudinal cohort study, we evaluated a consecutive sample of symptomatic FTD patients, classified as f‐FTD and s‐FTD according to Goldman scores (GS). All patients underwent clinical, behavioral, and neuropsychiatric symptom assessment, CSF biomarkers and serum neurofilament light (NfL) analysis, and brain atrophy evaluation with magnetic resonance imaging.ResultsOf 570 patients with FTD, 123 were classified as f‐FTD, and 447 as s‐FTD. In the f‐FTD group, 95 had a pathogenic FTD mutation while 28 were classified as GS = 1 or 2; of the s‐FTD group, 133 were classified as GS = 3 and 314 with GS = 4. f‐FTD and s‐FTD cases showed comparable demographic features, except for younger age at disease onset, age at diagnosis, and higher years of education in the f‐FTD group (all P < .05). f‐FTD showed worse behavioral disturbances as measured with Frontal Behavioral Inventory (FBI) negative behaviors (14.0 ± 7.6 vs. 11.6 ± 7.4, P = .002), and positive behaviors (20.0 ± 11.0 vs. 17.4 ± 11.8, P = .031). Serum NfL concentrations were higher in patients with f‐FTD (70.9 ± 37.9 pg/mL) compared to s‐FTD patients (37.3 ± 24.2 pg/mL, P < .001), and f‐FTD showed greater brain atrophy in the frontal and temporal regions and basal ganglia. Patients with f‐FTD had significantly shorter survival than those with s‐FTD (P = .004).Discussionf‐FTD and s‐FTD are very similar clinical entities, but with different biological mechanisms, and different rates of progression. The parallel characterization of both f‐FTD and s‐FTD will improve our understanding of the disease, and aid in designing future clinical trials for both genetic and sporadic forms of FTD.Highlights Do clinical features and biomarkers differ between patients with familial frontotemporal dementia (f‐FTD) and sporadic FTD (s‐FTD)?In this cohort study of 570 patients with FTD, f‐FTD and s‐FTD share similar demographic features, but with younger age at disease onset and diagnosis in the f‐FTD group.f‐FTD showed higher serum neurofilament light concentrations, greater brain damage, and shorter survival, compared to s‐FTD.f‐FTD and s‐FTD are very similar clinical entities, but with different cognitive reserve mechanisms and different rates of progression.

Serum Neurofilament Light concentrations are not associated with renal function in secondary progressive multiple sclerosis

Neurofilament Light (NFL) is a promising biomarker of neuroaxonal injury. Its utility may be improved by expression relative to age-matched controls and by adjusting for other covariates, such as body mass index. It has recently been suggested that renal function may modulate the rate of clearance of NFL from circulation, which if confirmed would make renal function an important additional covariate to take into account when interpreting NFL data in research or clinical settings. Here we explore the relationship between renal function and NFL in a cohort of patients with secondary progressive multiple sclerosis (SPMS). We examined data from patients with SPMS who took part in the MS-STAT randomised controlled trial. We use multivariable linear regression to explore the relationship between serum NFL and renal function, and additionally to examine whether including renal function as a covariate improves the ability of NFL to predict the subsequent rate of whole brain atrophy. Data on renal function and serum NFL was available for 122 patients. Mean eGFR 88 ml/min/1.73 m 2 (range 38.2–121.9). We found no evidence to support a relationship between renal function and serum NFL in this cohort. Furthermore, the inclusion of eGFR as a covariate in models assessing the relationship between NFL and the rate of whole brain atrophy had no significant effect upon the relationships observed. We find no evidence for a relationship between renal function and NFL in a cohort of patients with secondary progressive multiple sclerosis. We hypothesise that the previously observed relationships between NFL and renal function related to associations between renal function and subclinical neuropathology, rather than due to modulating clearance of NFL from the circulation, but further research would be required to confirm such mechanisms.

Serum Neurofilament Light: a Potential Diagnostic and Prognostic Biomarker in Obstetric Posterior Reversible Encephalopathy Syndrome.

Obstetric posterior reversible encephalopathy syndrome (PRES), caused by preeclampsia (PE) or eclampsia, is a clinical imaging syndrome and a critical maternal complication, with vasogenic edema in white matter as a typical imaging characteristic. Serum neurofilament light (NFL) is a marker of neuroaxonal injury. Therefore, we performed this study to explore the diagnostic and prognostic role of NFL in obstetric PRES. We used stored serum samples and clinical data obtained from 2148 PE or eclampsia patients from the Guangzhou Medical Centre for Critical Pregnant Women from January 2015 to January 2020. The serum NFL concentration was measured by Simoa assay. Patients without complete data and MRI examinations were excluded. All patients were grouped into the PRES and non-PRES groups based on the PRES diagnostic criteria. In total, 222 patients met the inclusion criteria and were grouped into the PRES (n = 123) and non-PRES (n = 99) groups. The NFL level was significantly higher in the PRES group than in the non-PRES group (p < 0.0001). The discriminatory accuracy of diagnostic panels (headaches + NFL, NFL) in receiver operating characteristic curve analysis (area under the curve) was 0.9338 and 0.7664. Importantly, the NFL level was significantly correlated with edema severity (Spearman's correlation, p < 0.0001), and a poorer pregnancy outcome was observed in the PRES group. In conclusion, an increased NFL level can add predictive value for diagnosing obstetric PRES, and its level is associated with both clinical severity and pregnancy outcome, suggesting that NFL could serve as a diagnostic and prognostic biomarker for obstetric PRES.

Complex Autoantibody Responses Occur following Moderate to Severe Traumatic Brain Injury

Abstract Most of the variation in outcome following severe traumatic brain injury (TBI) remains unexplained by currently recognized prognostic factors. Neuroinflammation may account for some of this difference. We hypothesized that TBI generated variable autoantibody responses between individuals that would contribute to outcome. We developed a custom protein microarray to detect autoantibodies to both CNS and systemic Ags in serum from the acute-phase (the first 7 d), late (6–12 mo), and long-term (6–13 y) intervals after TBI in human patients. We identified two distinct patterns of immune response to TBI. The first was a broad response to the majority of Ags tested, predominantly IgM mediated in the acute phase, then IgG dominant at late and long-term time points. The second was responses to specific Ags, most frequently myelin-associated glycopeptide (MAG), which persisted for several months post-TBI but then subsequently resolved. Exploratory analyses suggested that patients with a greater acute IgM response experienced worse outcomes than predicted from current known risk factors, suggesting a direct or indirect role in worsening outcome. Furthermore, late persistence of anti-MAG IgM autoantibodies correlated with raised serum neurofilament light concentrations at these time points, suggesting an association with ongoing neurodegeneration over the first year postinjury. Our results show that autoantibody production occurs in some individuals following TBI, can persist for many years, and is associated with worse patient outcome. The complexity of responses means that conventional approaches based on measuring responses to single antigenic targets may be misleading.

Serum Neurofilament Dynamics Predicts Cognitive Progression in de novo Parkinson's Disease.

Neurofilament light (NfL) can reflect the extent of neuron/axon damage, thus providing an opportunity to examine the severity and progression of the diseases with such damage. Whether serum NfL can be used as an indicator to monitor the cognitive progress of de novo Parkinson's disease (PD) remains unclear. In this research, 144 healthy controls and 301 de novo PD patients from Parkinson's Progression Markers Initiative (PPMI) were recruited. Linear mixed effects models were used to examine the associations of baseline/longitudinal serum NfL with cognitive decline. Cox regression was used to detect cognitive progression in PD participants. We found PD patients had higher serum NfL than controls at baseline (p = 0.031), and NfL increase was faster in PD group (p < 0.001). Both baseline serum NfL and its rate of change predicted measurable cognitive decline in early PD (MoCA, β= -0.014, p < 0.001; β= -0.002, p < 0.001, respectively). Additionally, we observed that NfL levels were also able to predict progression in different diagnostic groups and Amyloid- PD and Amyloid+PD groups. After an average follow-up of 6.37±1.84 years, the baseline NfL of the third tertile of high concentrations was associated with a future high risk of PD dementia (adjusted HR 6.33, 95% CI 2.62-15.29, p < 0.001). In conclusion, our results indicated that the serum NfL concentration could function as an easily accessible biomarker to monitor the severity and progression of cognitive decline in PD.

Serum Neurofilament Light as a Biomarker of Traumatic Brain Injury in the Presence of Concomitant Peripheral Injury.

Introduction:Serum neurofilament light (NfL) is an emerging biomarker of traumatic brain injury (TBI). However, the effect of peripheral injuries such as long bone fracture and skeletal muscle injury on serum NfL levels is unknown. Therefore, the aim of this study was to determine whether serum NfL levels can be used as a biomarker of TBI in the presence of concomitant peripheral injuries.Methods:Rats were randomly assigned to one of four injury groups: polytrauma (muscle crush + fracture + TBI; n = 11); peripheral injuries (muscle crush + fracture + sham-TBI; n = 12); TBI-only (sham-muscle crush + sham-fracture + TBI; n = 13); and triple-sham (n = 7). At 2-days post-injury, serum levels of NfL were quantified using a Simoa HD-X Analyzer.Results:Compared to triple-sham rats, serum NfL concentrations were higher in rats with peripheral injuries-only, TBI-only, and polytrauma. When compared to peripheral injury-only rats, serum NfL levels were higher in TBI-only and polytrauma rats. No differences were found between TBI-only and polytrauma rats.Conclusion:Serum NfL levels did not differ between TBI-only and polytrauma rats, indicating that significant peripheral injuries did not affect the sensitivity and specificity of serum NfL as a biomarker of moderate TBI. However, the finding of elevated serum NfL levels in rats with peripheral injuries in the absence of a TBI suggests that the presence of such injuries may limit the utility of NfL as a biomarker of less severe TBI (eg, concussion).

Serum neurofilament light and whole brain volume associate with machine‐learning derived brain‐predicted age in the British 1946 birth cohort

AbstractBackgroundAge is the biggest risk factor for dementia, yet human brains do not age uniformly. The British 1946 birth cohort, the world’s longest continuously running birth cohort, provides a unique opportunity to assess these variations in biological ageing. So‐called ‘brain age’ is a biomarker of brain ageing, derived from machine‐learning analysis trained on a large sample of healthy brains (N=2001). Brain age has previously been related to cognitive ageing, physiological ageing and mortality risk (DOI: 10.1038/mp.2017.62), supporting the validity of this approach for assessing biological ageing.Method502 participants in the Insight 46 study, all born during one week in 1946, completed baseline cognitive and neuroimaging assessments at age 69‐71. 468 underwent combined 18florbetapir PET‐MRI scans, from which amyloid status (positive/negative), whole brain volume (WBV), total intracranial volume (TIV) and hippocampal volumes (HV) were derived. The T1‐weighted sequence was passed through the Brain‐age algorithm (https://github.com/james‐cole/brainageR), deriving brain predicted‐age (BPA) and brain‐predicted age difference (brain‐PAD; BPA minus chronological age). Serum neurofilament light (NFL) concentration was measured via Simoa immunoassay. A Preclinical Alzheimer’s Cognitive Composite Score (PACC) was calculated as a mean of z‐scores of the Mini‐mental state exam (MMSE), logical memory delayed recall, digit symbol substitution score and the Face‐Name test. Life course metrics (childhood cognitive scores, education level and Framingham Risk scores) were obtained from previous cohort assessments. Multivariate regression models were used to investigate whether life course metrics predict BPA, as well as whether NFL levels, brain volumes, or cognitive scores correlated with BPA, adjusting for chronological age.ResultThere was a significant difference between the 229 females assessed (mean BPA 65.2 years) compared with the 239 males assessed (mean BPA 70.7). BPA was independently associated with serum NFL concentration (p = 0.071) and inversely with whole brain volume (p &lt; 0.001). Life course factors did not predict brain age.ConclusionThe results showed a significant association of BPA, a cross‐sectional imaging metric, with a biochemical marker of neuronal damage (NFL) and sex. BPA has utility as an imaging metric that can integrate multiple modalities contributing to biological age, with potential as a predictive biomarker of cognitive decline.

Serum neurofilament light concentration does not increase following exposure to low velocity football heading

ABSTRACT Objectives: To investigate if heading frequency and impact biomechanics in a single session influence the concentration of serum neurofilament light (NF-L), a sensitive biomarker for axonal damage, up to 7 days after heading incident at ball velocities reflecting basic training drills. Methods: Forty-four males were randomized into either control (n = 8), 10 header (n = 12), 20 header (n = 12) or 40 header (n = 12) groups. Linear and angular head accelerations were quantified during heading. Venous blood samples were taken at baseline, 6 h, 24 h and 7 days after heading. Serum NF-L was quantified using Quanterix NF-L assay kit on the Simoa HD-1 Platform. Results: Serum NF-L did not alter over time (p = 0.44) and was not influenced by number of headers [p = 0.47; mean (95% CI) concentrations at baseline 6.00 pg · ml− 1 (5.00–7.00 pg · ml− 1); 6 h post 6.50 pg · ml−1 (5.70–7.29 pg · ml−1); 24 h post 6.07 pg · ml−1 (5.14–7.01 pg · ml− 1); and 7 days post 6.46 pg · ml−1 (5.45–7.46 pg · ml−1)]. There was no relationship between percentage change in NF-L and summed session linear and angular head accelerations. Conclusion: In adult men, heading frequency or impact biomechanics did not affect NF-L response during a single session of headers at ball velocities reflective of basic training tasks.

Serum neurofilament level increases after ascent to 4559m but is not related to acute mountain sickness.

Background and purposeAt high altitude the brain is exposed to hypoxic stress, which may result in neurological conditions, with acute mountain sickness (AMS) being the most common. We aimed to test the hypothesis that rapid ascent to high altitude alters neuro‐axonal integrity, which can be detected by increased concentration of serum neurofilament light (sNfL) in the blood and may even be exaggerated in people with AMS.MethodsSerum neurofilament light was measured using a single‐molecule array (Simoa, Quanterix, Lexington, MA, USA) assay at low altitude (423 m) in 47 healthy study participants and 44 h after rapid and active ascent to high altitude (4559 m). Peripheral oxygen saturation (SpO2) and partial pressures of oxygen (pO2) were obtained at low and high altitude. The Acute Mountain Sickness‐Cerebral (AMS‐C) scoring system was used to assess AMS incidence and AMS severity.ResultsThere was an increase in sNfL from its baseline value compared with its value at high altitude (6.34 ± 1.96 vs. 7.19 ± 3.14 pg/ml; p = 0.014), but sNfL level did not correlate with SpO2 (r = −0.19; p = 0.066) or pO2 (r = −0.19; p = 0.068). The incidence of AMS at high altitude was 62%. Neither at low altitude (p = 0.706) nor at high altitude (p = 0.985) was there a difference in sNfL between participants with and without AMS as measured 3 days after rapid ascent and 44 h of high‐altitude exposure. Altitude sNfL did not correlate with AMS‐C, either overall or with single‐item scores such as headache severity.ConclusionsRapid ascent of healthy people to high altitude provokes an increase in sNfL 44 h after arrival at 4559 m, which is not related to the magnitude of hypoxemia or AMS incidence and severity, suggesting that neuro‐axonal injury does not directly contribute to AMS.

Association of Serum Neurofilament Light Levels With Long-term Brain Atrophy in Patients With a First Multiple Sclerosis Episode

Data are needed on the potential long-term prognostic association of serum neurofilament light in multiple sclerosis (MS). To evaluate serum neurofilament light as a biomarker associated with long-term disease outcomes in clinically isolated syndrome. This post hoc cohort study used data from the Controlled High-Risk Avonex Multiple Sclerosis Prevention Study, a 36-month, multicenter, placebo-controlled interferon β-1a randomized clinical trial conducted from April 1996 to March 2000, and its long-term (5- and 10-year) extension study from February 2001 to March 2009. Participants included individuals with a symptomatic initial demyelinating event and brain magnetic resonance imaging (MRI) lesions suggestive of MS. Data were analyzed from April 2017 through 2019. The variable of interest was naturally occurring serum neurofilament light concentration. Gadolinium-enhancing (Gd+) lesion number, T2 lesion volume, and brain parenchymal fraction, a measure of brain atrophy were measured at baseline and 5 and 10 years. Multivariate regression models evaluated whether age, sex, and baseline covariates, including serum neurofilament light, brain parenchymal fraction, Expanded Disability Status Scale, Gd+ lesion count, and T2 lesion volume, were associated with brain parenchymal fraction changes over 5 and 10 years. Among 308 included participants (mean [SD] age, 33.2 [7.6] years; 234 [76.0%] women), baseline serum neurofilament light concentrations were associated with Gd+ lesions (Spearman r = 0.41; P < .001) and T2 lesion volume (Spearman r = 0.42; P < .001). Among covariates for brain parenchymal fraction change, serum neurofilament light concentration had the greatest correlation with change in brain parenchymal fraction at 5 years (Spearman r = -0.38; P < .001) and was the only variable associated with brain parenchymal fraction at 10 years (Spearman r = -0.45; P < .001). Participants in the highest vs lowest baseline serum neurofilament light tertiles showed brain parenchymal fraction reduction at 5 years (-1.83% [95% CI, -1.49% to -2.18%] vs -0.95% [95% CI, -0.78% to -1.12%]; P < .001) and 10 years (-3.54% [95% CI, -2.90% to -4.17%] vs -1.90% [95% CI, -1.43% to -2.37%]; P < .001). At 5 years, 6 of 45 participants (13.3%) in the highest neurofilament tertile and 2 of 52 participants (3.8%) in the lowest neurofilament tertile achieved an Expanded Disability Status Scale score of 3.5 or greater. This cohort study found that higher baseline serum neurofilament light levels were associated with increased brain atrophy over 5 and 10 years. These findings suggest that serum neurofilament light could be a biomarker associated with disease severity stratification in early MS and may help to guide intervention.

Serum neurofilament-light concentration and real-world outcome in MS

BackgroundPrognostication in multiple sclerosis (MS) remains challenging. Biomarkers capable of providing this information at diagnosis would be valuable in shaping therapeutic decisions. Measurement of neurofilament light (NfL) has shown promise in predicting clinical outcomes in established MS, but its ability to predict outcomes in real-world cohorts at diagnosis requires further validation. MethodsWe used linear regression to evaluate the relationship between serum NfL (sNfL), measured at the time of diagnosis with short-term (1-year) and medium-term (5-year) clinical outcomes in 164 people with MS from a real-world, population-based cohort. Cox proportional hazards regression was used to analyse the association between sNfL and subsequent hazard of relapse or sustained accumulation of disability (SAD). Analyses were adjusted for age and disease-modifying treatment (DMT). ResultssNfL concentration at diagnosis was modestly associated with baseline EDSS score (β = 0.272, 95% CI 0.051 to 0.494, p = 0.016). However, no significant associations were found between baseline sNfL and odds of relapse at 12-months, 5-year EDSS change, or the hazard of relapse or SAD over 5 years follow-up. Dichotomising baseline sNfL according to the median sNfL did not change these findings. ConclusionssNfL appears to be of limited clinical utility in predicting future irreversible neurological disability in a largely untreated real-world population, and remains insufficiently validated to shape treatment decisions at the time of diagnosis. Further studies may be needed for sNfL to be considered as a prognostic marker in the MS clinic. However the masking effect of DMTs on the natural disease trajectory will continue to pose challenges.

Diagnostic and prognostic value of serum NfL and p-Tau181 in frontotemporal lobar degeneration

ObjectiveTo assess the diagnostic and prognostic value of serum neurofilament light (NfL) and serum phospho-Tau181 (p-Tau181) in a large cohort of patients with frontotemporal lobar degeneration (FTLD).MethodsIn this retrospective study,...