Serum Neurofilament Light Protein Research Articles

Serum NfL and GFAP as biomarkers of progressive neurodegeneration in TBI.

We examined spatial patterns of brain atrophy after mild, moderate, and severe traumatic brain injury (TBI), the relationship between progression of brain atrophy with initial traumatic axonal injury (TAI), cognitive outcome, and with serum biomarkers of brain injury. A total of 143 patients with TBI and 43 controls were studied cross-sectionally and longitudinally up to 5 years with multiple assessments, which included brain magnetic resonance imaging, cognitive testing, and serum biomarkers. TBI patients showed progressive volume loss regardless of injury severity over several years, andTAI was independently associated with accelerated brain atrophy. Cognitive performance improved over time. Higher baseline serum neurofilament light (NfL) and glial fibrillary acidic protein (GFAP) were associated with greater rate of brain atrophy over 5 years. Spatial patterns of atrophy differ by injury severity and TAI is associated with the progression of brain atrophy. Serum NfL and GFAP show promise as non-invasive prognostic biomarkers of progressive neurodegeneration in TBI. In this longitudinal study of patient with mild, moderate, and severe traumatic brain injury (TBI) who were assessed with paired magnetic resonance imaging (MRI), blood biomarkers, and cognitive assessments, we found that brain atrophy after TBI is progressive and continues for many years even after a mild head trauma without signs of brain injury on conventional MRI. We found that spatial pattern of brain atrophy differs between mild, moderate, and severe TBI, where in patients with mild TBI , atrophy is mainly seen in the gray matter, while in those with moderate to severe brain injury atrophy is predominantly seen in the subcortical gray matter and whiter matter. Cognitive performance improves over time after a TBI. Serum measures of neurofilament light or glial fibrillary acidic protein are associated with progression of brain atrophy after TBI.

Association of serum glial fibrillary acidic protein with progression independent of relapse activity in multiple sclerosis

ObjectiveInsidious disability worsening is a common feature in relapsing–remitting multiple sclerosis (RRMS). Many patients experience progression independent of relapse activity (PIRA) despite being treated with high efficacy disease-modifying therapies. We prospectively investigated associations of body-fluid and imaging biomarkers with PIRA.MethodsPatients with early RRMS (n = 104) were prospectively included and followed up for 60 months. All patients were newly diagnosed and previously untreated. PIRA was defined using a composite score including the expanded disability status scale, 9-hole peg test, timed 25 foot walk test, and the symbol digit modalities test. Eleven body fluid and imaging biomarkers were determined at baseline and levels of serum neurofilament light (sNfL) and glial fibrillary acidic protein (sGFAP) were also measured annually thereafter. Association of baseline biomarkers with PIRA was investigated in multivariable logistic regression models adjusting for clinical and demographic confounding factors. Longitudinal serum biomarker dynamics were investigated in mixed effects models.ResultsOnly sGFAP was significantly higher in PIRA at baseline (median [IQR] 73.9 [60.9–110.1] vs. 60.3 [45.2–79.9], p = 0.01). A cut-off of sGFAP > 65 pg/mL resulted in a sensitivity of 68% and specificity of 61%, to detect patients at higher risk of PIRA. In a multivariable logistic regression, sGFAP > 65 pg/mL was associated with higher odds of developing PIRA (odds ratio 4.3, 95% CI 1.44–12.86, p = 0.009). Repeated measures of sGFAP levels showed that patients with PIRA during follow-up had higher levels of sGFAP along the whole follow-up compared to stable patients (p < 0.001).ConclusionDetermination of sGFAP at baseline and follow-up may be useful in capturing disability accrual independent of relapse activity in early RRMS.

Racial discrimination during middle age predicts higher serum phosphorylated tau and neurofilament light chain levels a decade later: A study of aging black Americans.

Recent evidence suggests that exposure to the stress of racism may increase the risk of dementia for Black Americans. The present study used 17 years of data from a sample of 255 Black Americans to investigate the extent to which exposure to racial discrimination predicts subsequent changes in serum Alzheimer's Disease Research Center (ADRC) biomarkers: serum phosphorylated tau181(p-tau181), neurofilament light (NfL), and glial fibrillary acidic protein (GFAP). We hypothesized that racial discrimination assessed during middle age would predict increases in these serum biomarkers as the participants aged into their 60s. Our findings indicate that exposure to various forms of racial discrimination during a person's 40s and early 50s predicts an 11-year increase in both serum p-tau181 and NfL. Racial discrimination was not associated with subsequent levels of GFAP. These findings suggest that racial discrimination in midlife may contribute to increased AD pathology and neurodegeneration later in life. A 17-year longitudinal study of Black Americans. Assessments of change in serum p-tau181, neurofilament light, and glial fibrillary acidic protein. Exposure to racial discrimination during middle age predicted increases in p-tau181 and neurofilament light. Education was positively related to both p-tau181 and exposure to racial discrimination.

Association between the blood pressure variability and cognitive decline in Parkinson's disease.

High visit-to-visit blood pressure variability (BPV) was found to be associated with cognitive decline in the elderly. This study aimed to investigate the impact of visit-to-visit BPV on cognition in patients with early-stage Parkinson's disease (PD). This is a retrospective analysis of a prospective cohort. A total of 297 patients with early-stage PD (103 mild cognitive impairments [PD-MCI] and 194 normal cognitions [PD-NC] at baseline) were included from the Parkinson's Progression Markers Initiative study. Variation independent of mean (VIM) of the first year was used as the indicator of BPV. The Montreal Cognitive Assessment (MoCA) was used to assess global cognition. Patients were divided into PD-MCI and PD-NC according to the MoCA score at baseline. Longitudinal cerebrospinal fluid (Aβ-42, Aβ, α-synuclein, neurofilament light protein, tau phosphorylated at the threonine 181 position, total tau, glial fibrillary acidic protein) and serum (neurofilament light protein) biomarkers were assessed. The Bayesian linear growth model was used to evaluate the relationship between baseline BPV and the rate of change in cognition and biomarkers. Higher systolic VIM of the first year was related to a greater rate of decline in MoCA score in the following years in PD-MCI (β=-.15 [95% CI -.29, -.01]). No association was found between BPV and biomarkers. Higher systolic VIM predicted a steeper decline in cognitive tests in PD-MCI independently from the mean value of blood pressure, orthostatic hypotension, and supine hypertension.

Pediatric reference intervals for serum neurofilament light and glial fibrillary acidic protein using the Canadian Laboratory Initiative on Pediatric Reference Intervals (CALIPER) cohort.

Blood biomarkers have the potential to transform diagnosis and prognosis for multiple neurological indications. Establishing normative data is a critical benchmark in the analytical validation process. Normative data are important in children as little is known about how brain development may impact potential biomarkers. The objective of this study is to generate pediatric reference intervals (RIs) for serum neurofilament light (NfL), an axonal marker, and glial fibrillary acidic protein (GFAP), an astrocytic marker. Serum from healthy children and adolescents aged 1 to <19 years were obtained from the Canadian Laboratory Initiative on Pediatric Reference Intervals (CALIPER) cohort. Serum NfL (n=300) and GFAP (n=316) were quantified using Simoa technology, and discrete RI (2.5th and 97.5th percentiles) and continuous RI (5th and 95th percentiles) were generated. While there was no association with sex, there was a statistically significant (p<0.0001) negative association between age and serum NfL (Rho-0.400) and GFAP (Rho-0.749). Two statistically significant age partitions were generated for NfL: age 1 to <10 years (lower, upper limit; 3.13, 20.6 pg/mL) and 10 to <19 years (1.82, 7.44 pg/mL). For GFAP, three statistically significant age partitions were generated: age 1 to <3.5 years (80.4, 601 pg/mL); 3.5 to <11 years (50.7, 224 pg/mL); and 11 to <19 years (26.2, 119 pg/mL). Taken together with the literature on adults, NfL and GFAP display U-shaped curves with high levels in infants, decreasing levels during childhood, a plateau during adolescence and early adulthood and increasing levels in seniors. These normative data are expected to inform future pediatric studies on the importance of age on neurological blood biomarkers.

Serum total tau, neurofilament light, and glial fibrillary acidic protein are associated with mortality in a population study.

Total tau (t-tau), neurofilament light (NfL), and glial fibrillary acidic protein (GFAP) are neuronal cytoskeletal biomarkers that may indicate greater risk of poor outcomes in age-related conditions, including mortality. Health disparities experienced by some racial minority subgroups may influence biomarker expression and effects on longevity. We aimed to examine (a) associations of serum t-tau, NfL, and GFAP with overall and cardiovascular mortality and (b) differences in associations by racial background. Data came from 1327 older participants from the Chicago Health and Aging Project (CHAP), a longitudinal population-based study. Cox proportional hazards regression models were used to examine associations between concentrations of serum t-tau, NfL, and GFAP biomarker(s) and mortality (overall/cardiovascular mortality based on age at death). Interaction terms were used to examine differences between African-American and European-American participants. Models were adjusted for age, sex, education, the APOE-ε4 allele, body mass index, chronic health conditions, and cognitive and physical functioning. Models showed that fivefold higher concentrations of t-tau (HR = 1.46, 95% CI: 1.27, 1.68), NfL (HR = 2.13, 95% CI: 1.76, 2.58), and GFAP (HR = 1.43, 95% CI: 1.08, 1.90) were separately associated with increased risk of overall mortality, with higher risk in African Americans in t-tau or NfL. In models with all biomarkers, NfL (HR = 2.17, 95% CI: 1.65, 2.85) was associated with risk of overall mortality, with racial differences in t-tau. Higher concentrations of t-tau (HR = 1.32, 95% CI: 1.02, 1.70), NfL (HR = 1.95, 95% CI: 1.40, 2.72), and GFAP (HR = 1.87, 95% CI: 1.18, 2.98) were separately associated with risk of cardiovascular mortality, with racial differences in t-tau, NfL, or GFAP. In combined models, NfL (HR = 1.73, 95% CI: 1.08, 2.78) was associated with cardiovascular mortality. Serum t-tau, NfL, and GFAP may be early indicators for mortality outcomes among older adults, with racial differences among associations.

Accuracy of serum neurofilament light to identify contrast-enhancing lesions in multiple sclerosis

Background: Contrast-enhancing magnetic resonance imaging (MRI) lesions (CELs) indicate acute multiple sclerosis inflammation. Serum biomarkers, neurofilament light (sNfL), and glial fibrillary acidic protein (sGFAP) may increase in the presence of CELs, and indicate a need to perform MRI. Objective: We assessed the accuracy of biomarkers to detect CELs. Methods: Patients with two gadolinium-enhanced MRIs and serum biomarkers tested within 3 months were included (N = 557, 66% female). Optimal cut-points from Bland–Altman analysis for spot biomarker level and Youden’s index for delta-change from remission were evaluated. Results: A total of 116 patients (21%) had CELs. A spot sNfL measurement >23.0 pg/mL corresponded to 7.0 times higher odds of CEL presence (95% CI: 3.8, 12.8), with 25.9% sensitivity, 95.2% specificity, operating characteristic curve (AUC) 0.61; while sNfL delta-change >30.8% from remission corresponded to 5.0 times higher odds (95% CI: 3.2, 7.8), 52.6% sensitivity, 81.9% specificity, AUC 0.67. sGFAP had poor CEL detection. In patients > 50 years, neither cut-point remained significant. sNfL delta-change outperformed spot levels at identifying asymptomatic CELs (AUC 0.67 vs 0.59) and in patients without treatment escalation between samples (AUC 0.67 vs 0.57). Conclusion: Spot sNfL >23.0 pg/mL or a 30.8% increase from remission provides modest prediction of CELs in patients <50 years; however, low sNfL does not obviate the need for MRI.

Serum and CSF brain damage markers NFL and GFAP correlate with tick-borne encephalitis disease severity - a multicenter study on Lithuanian and Swedish patients.

Our aim was to examine the correlation between biomarkers of neuronal and glial cell damage and severity of disease in patients with tick-borne encephalitis. One hundred and fifteen patients with tick-borne encephalitis diagnosed in Lithuania and Sweden were prospectively included, and CSF and serum samples obtained shortly after hospitalization. Using pre-defined criteria, cases were classified as mild, moderate, or severe TBE. Additionally, the presence of spinal nerve paralysis (myelitis) and/or cranial nerve affection were noted. Concentrations of brain cell biomarkers glial fibrillary acidic protein (GFAP), YKL40, S-100B, neurogranin, neurofilament light (NFL), and tau were analyzed in CSF, and in addition, NFL, GFAP and S-100B levels were measured in serum. The Jonckheere Terpstra test was used for group comparisons of continuous variables and Spearman's partial correlation test to adjust for age. CSF and serum concentrations of GFAP and NFL correlated with disease severity, independent of age, and with presence of nerve paralysis. The markers neurogranin, YKL40, tau and S-100B in CSF and S-100B in serum were detected, but their concentrations did not correlate with disease severity. Neuronal cell damage and astroglial cell activation with increased NFL and GFAP in CSF and serum were associated with a more severe disease, independent of age. Increased GFAP and NFL concentrations in CSF and NFL in serum were also indicative of spinal and/or cranial nerve damage. NFL and GFAP are promising prognostic biomarkers in TBE, and future studies should focus on determining the association between these biomarkers and long-term sequelae.

Serum total tau, neurofilament light, and glial fibrillary acidic protein are associated with overall and cardiovascular mortality in a biracial longitudinal population‐based cohort

AbstractBackgroundSerum cytoskeletal biomarkers may indicate greater risk of poor outcomes in age‐related conditions, including mortality. Total tau (t‐tau), neurofilament light (Nf‐L) and glial fibrillary acidic protein (GFAP) are neuronal cytoskeletal biomarkers that are measurable in biofluids. Our objective is to examine separate and combined associations of serum t‐tau, Nf‐L, and GFAP with overall and cardiovascular mortality in a biracial population‐based sample.MethodData came from 1,327 older participants who were either of Black or White racial background from the Chicago Health and Aging Project (CHAP), a longitudinal population‐based study of chronic conditions of aging. An ultrasensitive immunoassay was used to measure the concentration of t‐tau, Nf‐L, and GFAP in blood serum. Mortality based on age at death included overall mortality and cardiovascular mortality. A series of Cox proportional hazard regression models were used to examine associations between biomarker(s) and outcomes (overall and cardiovascular mortality), adjusting for age, gender, education, the APOE‐e4 allele, global cognitive function, and physical functioning.ResultIn univariate models, 5‐fold higher concentrations of serum t‐tau (HR = 1.46, 95% CI: 1.28, 1.68), Nf‐L (HR = 2.14, 95% CI: 1.79, 2.57), and GFAP (HR = 1.39, 95% CI: 1.07, 1.81) were separately associated with increased risk of overall mortality, with higher risk in participants of Black race versus White in models with t‐tau or Nf‐L. In combined models with all three biomarkers, t‐tau (HR = 1.38, 95% CI: 1.09, 1.75) and Nf‐L (HR = 3.05, 95% CI: 2.35, 3.95) were associated with risk of overall mortality, with racial differences in t‐tau only. In univariate models, higher concentrations of t‐tau (HR = 1.32, 95% CI: 1.03, 1.68), Nf‐L (HR = 2.11, 95% CI: 1.56, 2.88), and GFAP (HR = 1.74, 95% CI: 1.13, 2.69) were separately associated with risk of cardiovascular mortality, with racial differences in t‐tau or Nf‐L. In combined models, only Nf‐L was associated with cardiovascular mortality (HR = 2.84, 95% CI: 1.84, 4.38).ConclusionSerum t‐tau, Nf‐L, and GFAP were associated with increased risk of overall and cardiovascular mortality, with racial differences among associations, in a biracial population‐based sample. Our findings suggest that serum t‐tau, Nf‐L, and GFAP may serve as a potential biomarker for overall and cardiovascular mortality among older adults.

Application Value of Serum Neurofilament Light Protein for Disease Staging in Huntington's Disease.

Neurofilament light protein (NfL) has been proven to be a sensitive biomarker for Huntington's disease (HD). However, these studies did not include HD patients at advanced stages or with larger CAG repeats (>50), leading to a knowledge gap of the characteristics of NfL. Serum NfL (sNfL) levels were quantified using an ultrasensitive immunoassay. Participants were assessed by clinical scales and 7.0 T magnetic resonance imaging. Longitudinal samples and clinical data were obtained. Baseline samples were available from 110 controls, 90 premanifest HD (pre-HD) and 137 HD individuals. We found levels of sNfL significantly increased in HD compared to pre-HD and controls (both P < 0.0001). The increase rates of sNfL were differed by CAG repeat lengths. However, there was no difference in sNfL levels in manifest HD from early to late stages. In addition, sNfL levels were associated with cognitive measures in pre-HD and manifest HD group, respectively. The increased levels of sNfL were also closely related to microstructural changes in white matter. In the longitudinal analysis, baseline sNfL did not correlate with subsequent clinical function decline. Random forest analysis revealed that sNfL had good power for predicting disease onset. Although sNfL levels are independent of disease stages in manifest HD, it is still an optimal indicator for predicting disease onset and has potential use as a surrogate biomarker of treatment effect in clinical trials. © 2023 International Parkinson and Movement Disorder Society.

Utility of Serum Neurofilament Light Protein as a Biomarker in Traumatic Brain Injury

Utility of Serum Neurofilament Light Protein as a Biomarker in Traumatic Brain Injury

Association of CSF and Serum Neurofilament Light and Glial Fibrillary Acidic Protein, Injury Severity, and Outcome in Spinal Cord Injury.

Traumatic spinal cord injury (SCI) is highly heterogeneous, and tools to better delineate pathophysiology and recovery are needed. Our objective was to profile the response of 2 biomarkers, neurofilament light (NF-L) and glial fibrillary acidic protein (GFAP), in the serum and CSF of patients with acute SCI to evaluate their ability to objectively characterize injury severity and predict neurologic recovery. Blood and CSF samples were obtained from prospectively enrolled patients with acute SCI through days 1-4 postinjury, and the concentration of NF-L and GFAP was quantified using Simoa technology. Neurologic assessments defined the ASIA Impairment Scale (AIS) grade and motor score (MS) at presentation and 6 months postinjury. One hundred eighteen patients with acute SCI (78 AIS A, 20 AIS B, and 20 AIS C) were enrolled, with 113 (96%) completing 6-month follow-up. NF-L and GFAP levels were strongly associated between paired serum and CSF specimens, were both increased with injury severity, and distinguished among baseline AIS grades. Serum NF-L and GFAP were significantly (p = 0.02 to <0.0001) higher in AIS A patients who did not improve at 6 months, predicting AIS grade conversion with a sensitivity and specificity (95% CI) of 76% (61, 87) and 77% (55, 92) using NF-L and 72% (57, 84) and 77% (55, 92) using GFAP at 72 hours, respectively. Independent of clinical baseline assessment, a serum NF-L threshold of 170 pg/mL at 72 hours predicted those patients who would be classified as motor complete (AIS A/B) compared with motor incomplete (AIS C/D) at 6 months with a sensitivity of 87% (76, 94) and specificity of 84% (69, 94); a serum GFAP threshold of 13,180 pg/mL at 72 hours yielded a sensitivity of 90% (80, 96) and specificity of 84% (69, 94). The potential for NF-L and GFAP to classify injury severity and predict outcome after acute SCI will be useful for patient stratification and prognostication in clinical trials and inform communication of prognosis. This study provides Class I evidence that higher serum NF-L and GFAP are associated with worse neurological outcome after acute SCI. Registered on ClinicalTrials.gov: NCT00135278 (March 2006) and NCT01279811 (January 2012).

Canadian Spine Society

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Angiotensin‐(1‐7)/Mas receptor agonist: a disease modifying therapeutic for VCID protects cognitive function and inhibits serum neurofilament light protein

AbstractBackgroundVascular contributions to cognitive impairment and dementia (VCID) and Alzheimer’s disease related dementias (ADRD) are associated with increases in systemic and brain inflammatory cytokines, increased reactive oxygen species (ROS) and decreased brain blood flow. We have completed preclinical development of novel synthetic glycopeptide derivatives of Angiotensin‐(1‐7) (Ang‐1‐7) MasR agonists that have outstanding brain penetration, improved half‐life, reverse cognitive impairment and decreases plasma neurofilament light protein (NfL) in our preclinical model of VCID. Ang‐(1‐7)/MasR mechanisms of action include inhibition of 1) microglia activation, 2) brain cytokines activation and, 3) vascular endothelial ROS production. The purpose of this pilot study was to 1) determine if plasma NfL is increased in coronary artery bypass graft (CABG) surgery patients at‐risk for VCID and 2) determine if treatment with an Ang‐(1‐7)/MasR agonist protects cognitive function post‐surgy and modifies NfL.MethodSubjects were randomly assigned to receive either 200 micrograms/kg/day s.c. (n = 3) or saline‐placebo (n = 2). Injections were begun 2 hours prior to surgery and then daily for 21 days. Cognitive function was measured prior to surgery and at 21‐ and 90‐days post‐surgery. Serum NfL was measured via Quanterix Simoa assay. Statistical analysis was performed using GraphPad and significance tested using Welch’s ANOVA, Dunnett’s post. Memory function was measured using a composite score comprised of memory, executive functioning, language, and processing speed.ResultPlasma levels of NfL prior to surgery were significantly increased by 176% in CABG patients (n = 5) as compared to age‐matched healthy controls (n = 8, p = .003). Treatment with Ang‐(1‐7) for 21‐days via subcutaneous injections protected memory function as measured by both the Face‐Name and Cured Name Retrieval associative memory tests at both 21‐ and 90‐days post ‐surgery and significantly attenuated CABG induced increases in NfL as compared to placebo‐saline treatment (p = .004).ConclusionThese preliminary data suggest that NfL may serve as a biomarker of VCID in CABG surgery patients and for MasR target engagement for VCID‐modifying treatments with Ang‐(1‐7) analogs. We have begun studies to develop NfL as a biomarker for Ang‐(1‐7)/MasR target activation and for patient stratification for treatment of VCID (Supported by NIH U01HL131014, U01AG066623).

How to define ‘N’ in the ATN classification in subjective cognitive decline: The SCIENCe project

AbstractBackgroundDifferent biomarkers have been suggested to measure neurodegeneration (N) in the ATN classification. We aimed to compare N biomarkers measured with different modalities and assess their association with clinical progression.MethodWe included 401 individuals with subjective cognitive decline (SCD, 61±9y, 42%F, MMSE28±2, follow‐up 3±3y). We used the following biomarkers for N: CSF t‐tau, medial temporal atrophy (MTA) visual rating on MRI, hippocampal volume (HV), serum neurofilament light (NfL) and serum glial fibrillary acidic protein (GFAP). We first compared biomarkers (Pearson correlation) and assessed the association between N biomarkers and progression to mild cognitive impairment or dementia (Cox proportional hazards analysis). We additionally investigated whether the addition of N biomarkers improved a Cox model with CSF abeta and p‐tau as predictors (likelihood ratio test). Last, we compared associations between N biomarkers and MMSE score over time (linear mixed models). Models were corrected for age and sex, and additionally for intracranial volume when HV was used as predictor. P‐tau, t‐tau, NfL and GFAP were log‐transformed, abeta and HV were inverted, and all biomarkers were z‐transformed.ResultN biomarkers were weakly to moderately correlated (range r ‐0.20 – 0.58, Figure 1). Of these, NfL and GFAP, both serum markers, correlated most strongly (r 0.58). T‐tau was strongly correlated with p‐tau, although these biomarkers supposedly represent separate biomarker groups (r 0.89). T‐tau, HV, NfL and GFAP individually predicted clinical progression (range hazard ratios 1.4 – 2.1). Models including abeta and p‐tau improved when HV, NfL or GFAP were added as predictors (t‐tau not entered due to collinearity with p‐tau, Table 1). Last, t‐tau, HV and GFAP were individually associated with MMSE slope (range betas −0.17 – −0.15).ConclusionIn a sample of cognitively normal individuals, correlations between different N biomarkers were low, indicating they do not reflect the same underlying pathology. T‐tau was strongly associated with p‐tau, thereby disqualifying as measure for N. HV, NfL and GFAP predicted clinical progression. Our results do not allow to choose one most suitable biomarker for N, but illustrate room for improved prediction beyond abeta and p‐tau.

Serum Neurofilament Light is elevated in COVID-19 Positive Adults in the ICU and is associated with Co-Morbid Cardiovascular Disease, Neurological Complications, and Acuity of Illness.

In critically ill COVID-19 patients, the risk of long-term neurological consequences is just beginning to be appreciated. While recent studies have identified that there is an increase in structural injury to the nervous system in critically ill COVID-19 patients, there is little known about the relationship of COVID-19 neurological damage to the systemic inflammatory diseases also observed in COVID-19 patients. The purpose of this pilot observational study was to examine the relationships between serum neurofilament light protein (NfL, a measure of neuronal injury) and co-morbid cardiovascular disease (CVD) and neurological complications in COVID-19 positive patients admitted to the intensive care unit (ICU). In this observational study of one-hundred patients who were admitted to the ICU in Tucson, Arizona between April and August 2020, 89 were positive for COVID-19 (COVID-pos) and 11 was COVID-negative (COVID-neg). A healthy control group (n=8) was examined for comparison. The primary outcomes and measures were subject demographics, serum NfL, presence and extent of CVD, diabetes, sequential organ failure assessment score (SOFA), presence of neurological complications, and blood chemistry panel data. COVID-pos patients in the ICU had significantly higher mean levels of Nfl (229.6 ± 163 pg/ml) compared to COVID-neg ICU patients (19.3 ± 5.6 pg/ml), Welch’s t-test, p =.01 and healthy controls (12.3 ± 3.1 pg/ml), Welch’s t-test p =.005. Levels of Nfl in COVID-pos ICU patients were significantly higher in patients with concomitant CVD and diabetes (n=35, log Nfl 1.6±.09), and correlated with higher SOFA scores (r=.5, p =.001). These findings suggest that in severe COVID-19 disease, the central neuronal and axonal damage in these patients may be driven, in part, by the level of systemic cardiovascular disease and peripheral inflammation. Understanding the contributions of systemic inflammatory disease to central neurological degeneration in these COVID-19 survivors will be important to the design of interventional therapies to prevent long-term neurological and cognitive dysfunction.

Serum neurofilament light protein correlates with unfavorable clinical outcomes in hospitalized patients with COVID-19.

Brain imaging studies of patients with COVID-19 show evidence of macro- and microhemorrhagic lesions, multifocal white matter hyperintensities, and lesions consistent with posterior reversible leukoencephalopathy. Imaging studies, however, are subject to selection bias, and prospective studies are challenging to scale. Here, we evaluated whether serum neurofilament light chain (NFL), a neuroaxonal injury marker, could predict the extent of neuronal damage in a cohort of 142 hospitalized patients with COVID-19. NFL was elevated in the serum of patients with COVID-19 compared to healthy controls, including those without overt neurological manifestations. Higher NFL serum concentrations were associated with worse clinical outcomes. In 100 hospitalized patients with COVID-19 treated with remdesivir, a trend toward lower NFL serum concentrations was observed. These data suggest that patients with COVID-19 may experience neuroaxonal injury and may be at risk for long-term neurological sequelae. Neuroaxonal injury should be considered as an outcome in acute pharmacotherapeutic trials for COVID-19.

Serum Neurofilament Light and GFAP Are Associated With Disease Severity in Inflammatory Disorders With Aquaporin-4 or Myelin Oligodendrocyte Glycoprotein Antibodies.

Objective: To evaluate the potential of serum neurofilament light (sNfL) and serum glial fibrillary acidic protein (sGFAP) as disease biomarkers in neuromyelitis optica spectrum disorder (NMOSD) with aquaporin-4 antibody (AQP4-ab) or myelin oligodendrocyte glycoprotein-antibody-associated disease (MOGAD).Methods: Patients with AQP4-ab-positive NMOSD (n = 51), MOGAD (n = 42), and relapsing-remitting multiple sclerosis (RRMS) (n = 31 for sNfL and n = 22 for sGFAP testing), as well as healthy controls (HCs) (n = 28), were enrolled prospectively. We assessed sNfL and sGFAP levels using ultrasensitive single-molecule array assays. Correlations of sNfL and sGFAP levels with clinical parameters were further examined in AQP4-ab-positive NMOSD and MOGAD patients.Results: sNfL levels were significantly higher in patients with AQP4-ab-positive NMOSD (median 17.6 pg/mL), MOGAD (27.2 pg/mL), and RRMS (24.5 pg/mL) than in HCs (7.4 pg/mL, all p < 0.001). sGFAP levels were remarkably increased in patients with AQP4-ab-positive NMOSD (274.1 pg/mL) and MOGAD (136.7 pg/mL) than in HCs (61.4 pg/mL, both p < 0.001). Besides, sGFAP levels were also significantly higher in patients with AQP4-ab-positive NMOSD compared to those in RRMS patients (66.5 pg/mL, p < 0.001). The sGFAP/sNfL ratio exhibited good discrimination among the three disease groups. sNfL levels increased during relapse in patients with MOGAD (p = 0.049) and RRMS (p < 0.001), while sGFAP levels increased during relapse in all three of the disease groups (all p < 0.05). Both sNfL and sGFAP concentrations correlated positively with Expanded Disability Status Scale scores in AQP4-ab-positive NMOSD (β = 1.88, p = 0.018 and β = 2.04, p = 0.032) and MOGAD patients (β = 1.98, p = 0.013 and β = 1.52, p = 0.008).Conclusion: sNfL and sGFAP levels are associated with disease severity in AQP4-ab-positive NMOSD and MOGAD patients, and the sGFAP/sNfL ratio may reflect distinct disease pathogenesis.

Biological Significance of Serum Biomarkers in Sports- Related Concussion Injury-A Systematic Review.

To evaluate all serum biomarkers in sports-related concussion injury (SRC) to determine diagnostic validity, changes with symptom severity, and return to play, as well as detect early changes in serum concentration. Studies were searched in various electronic databases (MEDLINE/PubMed, EMBASE, CINAHL, Scopus and Cochrane databases) from their commencement to May 2021. Studies were included if athletes aged 12 years and older were diagnosed with a concussion injury and evaluated using serum biomarkers. Studies including athletes with injuries other than concussion injuries were excluded. Articles with fewer than 20 concussed athletes were excluded. There were 1782 articles identified. After exclusion a total of 17 articles qualified for systematic review. S100 calcium binding protein ? (S-100?) and ubiquitin carboxyl-terminal hydrolase L1 (UCH-L1) showed promising results in distinguishing concussed athletes from contact sports and non-athlete controls. Most of the serum biomarkers increased within 6 hours of SRC. Serum neurofilament light protein (NFL) positively correlated with the severity of post-concussion symptoms. NFL, tau and Interleukins (IL-1 Ra and IL-6) have the potential to determine return to play. Serum biomarker measurement is an objective tool that aids in early diagnosis and predicts the severity and prognosis of injury.

Association of serum neurofilament light and disease severity in patients with spinocerebellar ataxia type 3.

To investigate serum neurofilament light protein (sNfL) levels in patients with spinocerebellar ataxia type 3 (SCA3) and to determine whether they are associated with disease severity. This cross-sectional study enrolled 185 healthy controls and 235 ATXN3 mutation carriers (17 asymptomatic stage, 20 preclinical stage, and 198 ataxic stage). We measured sNfL levels with the single molecule array (Simoa) platform. Clinical disease severity was assessed using the Scale of Assessment and Rating of Ataxia (SARA) and the Inventory of Nonataxia Signs (INAS). In a subgroup of 50 ataxic stage patients, we further evaluated the gray matter volume and the integrity of white matter fibers by MRI. sNfL concentrations were elevated in asymptomatic, preclinical, and ataxic ATXN3 mutation carriers compared to controls (12.18 [10.20-13.92], 21.84 [18.37-23.45], 36.06 [30.04-45.90], and 8.24 [5.92-10.84] pg/mL, median [interquartile range], respectively, p < 0.001). sNfL correlated with SARA (r = 0.406, 95% confidence interval [CI] 0.284-0.515, p < 0.0001) and INAS (r = 0.375, 95% CI 0.250-0.487, p < 0.0001), and remained significant after adjustment for age and CAG repeats. In addition, we observed negative correlations of the sNfL with gray matter volume in the left precentral gyrus and the left paracentral lobule as well as with the mean diffusivity in widespread white matter tracts. Our results demonstrate that sNfL levels are increased in SCA3 and are associated with clinical disease severity, which supports sNfL as a biomarker for disease severity in SCA3. This study provides Class II evidence that in patients with SCA3, sNfL elevations are associated with clinical disease severity.