Longitudinal assessment of brain injury biomarker neurofilament light in female football players during a competitive season of football heading

ObjectiveWe aimed to (1) assess and compare baseline plasma and CSF neurofilament light (NfL) for cross-sectional and longitudinal associations with neuroimaging or cognition and (2) determine whether change in plasma NfL corresponded with change in these outcomes.MethodsSeventy-nine participants without dementia, median age 76 years, had plasma and CSF NfL, neuropsychological testing, and neuroimaging (MRI, amyloid PET, FDG-PET) at the same study visit, and a repeat visit (15 or 30 months later) with both plasma NfL and neuroimaging. Plasma NfL was measured on the Simoa-HD1 Platform and CSF NfL with an in-house ELISA. Linear mixed effects models were used to examine the associations between baseline plasma or CSF NfL and cognitive and neuroimaging outcomes adjusting for age, sex, and education. The relationship between change in plasma NfL and change in the outcomes was assessed using linear regression.ResultsThere were no cross-sectional associations between CSF or plasma NfL and any neuroimaging or cognitive measure. Longitudinally, higher baseline plasma NfL was associated with worsening in all neuroimaging measures, except amyloid PET, and global cognition. Higher baseline CSF NfL was associated with worsening in cortical thickness and diffusion MRI. The beta estimates for CSF NfL were similar to those for plasma NfL. Change in plasma NfL was associated with change in global cognition, attention, and amyloid PET.ConclusionElevated baseline plasma NfL is a prognostic marker of cognitive decline and neuroimaging measures of neurodegeneration, and has similar effect sizes to baseline CSF NfL. Change in plasma NfL also tracked with short-term cognitive change.

Interaction of obstructive sleep apnea severity and amyloid burden on novel plasma biomarkers of tau and neurofilament light protein in community‐dwelling cognitively normal older‐adults

Background Huntington’s disease (HD) is a progressive neurodegenerative disorder where there is a pressing need for sensitive biomarkers. Aims We assessed mutant huntingtin (mHTT) and neurofilament light (NfL) in parallel. Methods CSF mHTT, CSF NfL and plasma NfL were measured using immunoassays in 80 participants (20 healthy controls, 20 premanifest HD and 40 manifest HD) underwent clinical assessments, and standardized CSF and blood collections. Analysis included multiple linear regression models, Pearson’s correlations, receiver operating characteristics curves and samples sizes calculations. An event-based model was used to assess the temporal sequence of HD-related biomarker alterations. Results CSF mHTT, CSF NfL and plasma NfL were significantly higher as disease progressed and associated with all clinical measures. Both CSF and plasma NfL were associated with brain volume measures, but CSF mHTT was not. CSF mHTT, CSF NfL and plasma NfL were closely correlated, and highly stable within individuals. CSF mHTT had perfect accuracy for distinguishing between controls and HD mutation carriers, and both CSF and plasma NfL had excellent accuracy for distinguishing between premanifest and manifest HD. Sample size calculations suggest low participant numbers needed to incorporate these measures into clinical trials. The biofluid biomarkers emerged as the earliest detectable alterations in HD, followed by brain volume, motor and cognitive measures. Conclusion In this cross-sectional study we provide evidence to support mHTT and NfL as having favourable properties as biofluid biomarkers for HD. Our data suggests that these key biofluid biomarkers are some of the earliest detectable changes in HD.

A set of core cerebrospinal fluid (CSF) biomarkers for Alzheimer’s disease (AD) includes total tau (T-tau), phosphorylated tau (P-tau) and β-amyloid 42 (Aβ42). These biomarkers reflect some of the key aspects of AD pathophysiology, including neuronal degeneration, tau phosphorylation with tangle formation, and Aβ aggregation with deposition of the peptide into plaques. The core AD CSF biomarkers have been validated clinically in numerous studies, and found to have a very high diagnostic performance to identify AD, both in the dementia and in the mild cognitive impairment stages of the disease. CSF Aβ42 has also been found to show very high concordance with amyloid PET to identify brain amyloid deposition. The synaptic protein neurogranin is a novel candidate CSF biomarker for AD and prodromal AD. High CSF neurogranin predicts future cognitive decline and seems to be more specific for AD than, for example, T-tau. Importantly, technical developments have given ultrasensitive measurement techniques that allow measurement of brain-specific proteins such as tau and neurofilament light (NFL) in blood samples. Both plasma tau and NFL are increased in AD, and a recent study showed that plasma NFL has a diagnostic performance comparable to the core AD CSF biomarkers, and predicted future cognitive decline. Future large longitudinal clinical studies are warranted to determine the potential for plasma tau and NFL to serve as first-in-line screening tools for neurodegeneration in primary care.

Comparison of the prognostic value of cerebrospinal fluid and plasma neurofilament light in predicting longitudinal decline in white matter integrity among older adults

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.

PurposeTo describe the injury prevalence, injury pattern, and potential baseline risk factors for injuries in male and female adolescent and adult amateur football players.MethodsThis prospective study followed adolescent and adult amateur football players over one season March–October 2020. The study was completed by 462 players (130 men, age 20.0 ± 5.7, 14–46 years) who answered a baseline survey and a weekly web survey during the season. A total of 1456 weekly surveys were registered from males and 5041 from females. Injuries were recorded with the Oslo Sports Trauma Research Center Overuse Injury Questionnaire (OSTRC-O2). Potential baseline risk factors (age, performance of strength/conditioning training, participation in other sports, perceived importance of sporting success, self-rated training and match load, perceived balance between training/match load and recovery, previous/present injury at start of season, and injury beliefs) and their association with injury were analysed with Poisson regressions within each sex.ResultsMales reported 95 injuries (262 injury weeks, weekly prevalence 18.0% (95% CI 16.1–20.1)) and females 350 injuries (1206 injury weeks, weekly prevalence 23.9% (95% CI 22.8–25.1)). Gradual-onset injuries accounted for 57% of the injuries in males and 66% in females. For males, substantial injuries were most common in the hip/groin (weekly prevalence 3.8%), ankle (2.1%), posterior thigh (2.0%), and knee (2.0%); and for females, in the knee (4.3%), ankle (2.5%), and lower leg/Achilles tendon (2.0%). Significant risk factors for injury were higher age (rate ratio males 1.05 per year increase (95% CI 1.02–1.08), females 1.03 (95% CI 1.01–1.05)), and present injury at baseline (males 1.92 (95% CI 1.27–2.89), females 1.58 (95% CI 1.19–2.09)).ConclusionAt any given week, almost one in five male and one in four female amateur football players reported new or ongoing injuries. Hip/groin injuries were more frequent in males, while female players had a higher prevalence of knee injuries. Older players and those with an existing injury at the start of the season were more prone to new injury during the season. Rehabilitation of pre-season injury and complaints are key to reduce the injury burden in amateur football.Level of evidenceLevel II.Trial registration number NCT04272047, Clinical trials

The aim of this study is to evaluate longitudinal change in plasma neurofilament light (NF-L) and tau levels in relationship to clinical and radiological measures in professional fighters. Participants (active and retired professional fighters and control group) underwent annual blood sampling, 3-Tesla magnetic resonance imaging (MRI) brain imaging, computerized cognitive testing, and assessment of exposure to traumatic brain injury. Plasma tau and NF-L concentrations were measured using Simoa assays. Multiple linear regression models were used to compare the difference across groups in regard to baseline measurements, whereas mixed linear models was used for the longitudinal data with multiple measurements for each participant. Plasma samples were available on 471 participants. Baseline NF-L measures differed across groups (F3,393 = 6.99; p = 0.0001), with the active boxers having the highest levels. Higher NF-L levels at baseline were correlated with lower baseline MRI regional volumes and lower cognitive scores. The number of sparring rounds completed by the active fighters was correlated with NF-L (95% confidence interval, 0.0116-0.4053; p = 0.0381), but not tau, levels. Among 126 subjects having multiple yearly samples, there was a significant difference in average yearly percentage change in tau across groups (F3,83 = 3.87; p = 0.0121). We conclude that plasma NF-L and tau behave differently in a group of active and retired fighters; NF-L better reflects acute exposure whereas the role of plasma tau levels in signifying chronic change in brain structure over time requires further study.

ObjectiveTo explore the potential of neurofilament light (NfL) and glial fibrillary acidic protein (GFAP) as biomarkers of spinal cord degeneration in adrenoleukodystrophy, as objective treatment‐outcome parameters are needed.MethodsPlasma NfL and GFAP levels were measured in 45 male and 47 female ALD patients and compared to a reference cohort of 73 healthy controls. For male patients, cerebrospinal fluid (CSF) samples (n = 33) and 1‐year (n = 39) and 2‐year (n = 18) follow‐up data were also collected. Severity of myelopathy was assessed with clinical parameters: Expanded Disability Status Scale (EDSS), Severity Scoring system for Progressive Myelopathy (SSPROM), and timed up‐and‐go.ResultsNfL and GFAP levels were higher in male (P < 0.001, effect size (partial ƞ2) NfL = 0.49, GFAP = 0.13) and female (P < 0.001, effect size NfL = 0.19, GFAP = 0.23) patients compared to controls; levels were higher in both symptomatic and asymptomatic patients. In male patients, NfL levels were associated with all three clinical parameters of severity of myelopathy (EDSS, SSPROM, and timed up‐and go), while GFAP in male and NfL and GFAP in female patients were not. Changes in clinical parameters during follow‐up did not correlate with (changes in) NfL or GFAP levels. Plasma and CSF NfL were strongly correlated (r = 0.60, P < 0.001), but plasma and CSF GFAP were not (r = 0.005, P = 0.98).InterpretationOur study illustrates the potential of plasma NfL as biomarker of spinal cord degeneration in adrenoleukodystrophy, which was superior to plasma GFAP in our cohort.

Cerebrospinal fluid neurofilament light and plasma neurofilament light concentrations are elevated in patients with mild cognitive impairment and Alzheimer's disease. We investigated the clinical relevance of increased neurofilament light concentrations in mild cognitive impairment and Alzheimer's disease patients. In this study, 244 subjects were divided into cognitively normal control (n = 67), stable mild cognitive impairment (n = 52), progressive mild cognitive impairment (n = 68), and Alzheimer's disease (n = 57). Linear regression examined the relationships between neurofilament light levels in cerebrospinal fluid or plasma and the diagnostic group. The relationships between neurofilament light and other biomarkers were assessed by Spearman correlation. Linear mixed-effects models were used to test cerebrospinal fluid and plasma neurofilament light as predictors of Alzheimer's disease characteristics, including cognition, cortical glucose metabolism, and brain structure. Cerebrospinal fluid and plasma neurofilament light levels were significantly elevated in Alzheimer's disease. Still, the correlations between neurofilament light and other cerebrospinal fluid biomarkers within the diagnostic groups were often not statistically significant. In addition, the diagnostic accuracy of cerebrospinal fluid and plasma neurofilament light for progressive mild cognitive impairment and Alzheimer's disease was almost the same as that of cerebrospinal fluid total tau (T-tau). It is phosphorylated tau (P-tau) and high cerebrospinal fluid. Neurofilament light predicted conversion from mild cognitive impairment to Alzheimer's disease. A high neurofilament light is related to poor cognition, low cerebral metabolism, hippocampal atrophy, and ventricular enlargement caused by Alzheimer's disease. Our work further identifies cerebrospinal fluid neurofilament light and plasma neurofilament light as biomarkers of axonal degeneration in patients with mild cognitive impairment and Alzheimer's disease.

Recent studies show that levels of the brain injury biomarkers glial fibrillary acidic protein (GFAP) and neurofilament light (NfL) are elevated postoperatively in infants undergoing surgery for craniosynostosis. The aim of this study was to investigate the relationship between intraoperative hypotension and blood loss on biomarker levels. This retrospective study included all consecutive patients undergoing surgery for metopic synostosis at our institution from January 2019 to September 2020 who were included in a previous trial. We extracted data from the medical record on intraoperative blood pressure, heart rate, and intraoperative blood loss. Pre- and postoperative GFAP and NfL levels were measured in stored blood samples. Hypotension was defined as the area under the curve (AUC) of mean arterial blood pressure (MAP) at 4 threshold levels (35, 40, 45, and 50mmHg, respectively). This AUC and intraoperative blood loss were used to identify correlations with postoperative changes in baseline GFAP and NfL levels. A total of 20 patients [age: 190±65d (mean±SD); and weight: 8.0±1.0kg] undergoing an open cranial vault procedure for metopic synostosis repair were included. Intraoperative blood loss was 27±11mL/kg, and we did not identify significant association between plasma NfL or GFAP level and any MAP threshold (NfL AUC40 rs=0.08, AUC45 rs=0.15, AUC50 rs=0.30. GFAP AUC40 rs=-0.17, AUC45 rs=0.01, AUC50 rs=-0.06) or blood loss parameter [NfL rs=0.26, GFAP rs=-0.15]. We did not identify a relationship between MAP, blood loss, and markers of brain injury. Our findings suggest that other factors (eg, mechanical manipulation) may explain the observed elevations in brain injury biomarkers after craniosynostosis surgery. This study is limited by its sample size and further investigation is needed.

Perioperative ischaemic brain injury and plasma neurofilament light: a secondary analysis of two prospective cohort studies

Sex differences in blood biomarkers and cognitive performance in individuals with autosomal dominant Alzheimer's disease.

ObjectivesTo explore the relationships between physical fitness and i) technical skills and ii) time-loss from Australian football injury in female players across the talent and participation pathways.MethodsThis study uses a subset of data from two cross-sectional and one prospective cohort studies. A total of 223 female Australian football players across five competition levels (elite/non-elite senior, high-level junior, and non-elite junior (14–17 years)/(10–13 years)) were included in this study. Comprehensive physical fitness assessments and modified Australian football kicking and handballing tests were conducted in the 2018/19 pre-seasons. During the respective competitive in-season, time-loss injuries were recorded by team personnel. Stepwise multiple linear regressions were performed to determine the relationship between physical fitness and kicking and handballing scores. Cox proportional regressions were conducted to identify physical fitness factors associated with injury.ResultsIncreased running vertical jump height, greater hip abduction strength, and faster timed 6 m hop speed demonstrated a relationship with kicking accuracy when adjusted for years of Australian football playing experience (adjusted R2 = 0.522, p < 0.001). Faster agility time and increased lean mass were associated with better handballing accuracy (adjusted R2 = 0.221, p < 0.001). Multivariate Cox regression revealed an increased risk for sustaining a time-loss injury in less agile players (adjusted HR 2.41, 95% CI 1.23, 4.73, p = 0.010). However, this relationship no longer remained when adjusted for age and years of Australian football experience (adjusted HR 1.68, 95% CI 0.81, 3.50, p = 0.166).ConclusionsPhysical fitness may be a significant factor contributing to development of Australian football technical skills in female players. However, its role is unclear in protecting against injury risk in this athlete population. Further research is needed to explore the multifactorial and complex phenomenon of talent development and injury risk reduction in female Australian football players.

Background: Despite the growing popularity of women’s football and the increasing number of female players, there has been little research on injuries sustained by female football players. Purpose: Analysis of...