Phosphorylated Neurofilament Heavy Subunit Research Articles

The dynamic of changes of pNFH levels in the CSF compared with the motor scales’ scores during three years of nusinersen treatment in children with spinal muscular atrophy types 2 and 3

Abstract: Neurofilaments are crucial in neuronal cytoskeleton formation, influencing axonal growth and impulse modulation. This study focuses on understanding the dynamics of the phos-phorylated neurofilament heavy subunit (pNFH) in pediatric spinal muscular atrophy (SMA) pa-tients undergoing Nusinersen treatment. The presence of five neurofilament types, particularly pNFH, is explored as a potential biomarker. SMA, an autosomal recessive disease impacting motor neurons, is characterized by disease severity linked to the number of SMN2 gene copies. Approved drugs, including Nusinersen, have demonstrated efficacy in enhancing motor activity. Methods: A retrospective analysis was conducted on 18 pediatric SMA patients treated with Nusinersen from October 2018 to July 2023. Cerebrospinal fluid (CSF) samples were utilized to assess pNFH levels. Motor scales were employed to evaluate performance, focusing on patients with varying SMN2 gene copies. Results: Following the initiation of Nusinersen treatment, a substantial decrease in pNFH levels was observed in CSF samples. Motor scales indicated improved performance, partic-ularly in patients with more SMN2 copies. However, the correlation between pNFH levels and motor improvement was not strongly evident, suggesting a limited role as a prognostic indicator within this timeframe. Conclusion: Nusinersen effectively reduced pNFH levels in pediatric SMA patients, showcasing promising outcomes in motor function. However, the predictive value of pNFH remains inconclusive, emphasizing the need for further research. Study limitations, including the rarity of SMA, the absence of a control group, and the disease's dynamic nature over time, should be considered when interpreting these findings.

A pediatric quantitative systems pharmacology model of neurofilament trafficking in spinal muscular atrophy treated with the antisense oligonucleotide nusinersen.

Phosphorylated neurofilament heavy subunit (pNfH) has been recently identified as a promising biomarker of disease onset and treatment efficacy in spinal muscular atrophy (SMA). This study introduces a quantitative systems pharmacology model representing the SMA pediatric scenario in the age range of 0-20 years with and without treatment with the antisense oligonucleotide nusinersen. Physiological changes typical of the pediatric age and the contribution of SMA and its treatment to the peripheral pNfH levels were included in the model by extending the equations of a previously developed mathematical model describing the neurofilament trafficking in healthy adults. All model parameters were estimated by fitting data from clinical trials that enrolled SMA patients treated with nusinersen. The data from the control group of the study was employed to build an in silico population of untreated subjects, and the parameters related to the treatment were estimated by fitting individual pNfH time series of SMA patients followed during the treatment. The final model reproduces well the pNfH levels in the presence of SMA in both the treated and untreated conditions. The results were validated by comparing model predictions with the data obtained from an additional cohort of SMA patients. The reported good predictive model performance makes it a valuable tool for investigating pNfH as a biomarker of disease progression and treatment response in SMA and for the in silico evaluation of novel treatment protocols.

Elevation of serum plasminogen activator inhibitor-1 predicts postoperative delirium independent of neural damage: a sequential analysis

Older adult surgical patients are susceptible to developing delirium. Early intervention can be initiated if a potential biomarker associated with delirium can be identified during the acute phase of surgery. Therefore, we investigated the changes in the levels of serum inflammatory mediators responsible for delirium. Serum biomarkers were measured preoperatively to postoperative day 3 in 96 patients who underwent esophageal cancer surgery and compared between patients who did and did not develop delirium. Serum concentrations of the brain-derived phosphorylated neurofilament heavy subunit remained at higher levels throughout the entire perioperative period in patients with delirium (n = 15) than in those without delirium (n = 81). The interaction between delirium and non-delirium was significant for plasminogen activator inhibitor-1 (including age as a covariate, F = 13.360, p < 0.0001, η2p = 0.134, observed power 1.000) during the perioperative periods. Plasminogen activator inhibitor-1 level discriminated between patients with and without clinically diagnosed delirium with significantly high accuracy (area under curve, 0.864; sensitivity, 1.00: negative predictive value, 1.000; p = 0.002). Rapid increases in the levels of serum plasminogen activator inhibitor-1 may enable clinicians to identify patients at risk of developing postoperative delirium and initiate early prevention and intervention.

Preoperative detection of serum phosphorylated neurofilament heavy chain subunit predicts postoperative delirium: a prospective observational study

Background &amp; Aims. Elderly surgical patients are susceptible to development of postoperative delirium. Interventions for postoperative delirium have little effect on its progression, indicating the importance of early detection and prevention. This study investigated preoperative biomarkers to predict postoperative delirium.Methods. Delirium-related serum biomarkers were measured before the start of surgery in patients who underwent esophageal cancer surgery and were compared between patients who did and did not develop postoperative delirium.Results. Fifteen of 96 patients (15.6%) developed postoperative delirium. Brain-derived phosphorylated neurofilament heavy subunit was preoperatively detected in 80% of patients with postoperative delirium. The preoperative interleukin-6 (IL-6) concentration was significantly higher whereas the concentrations of plasminogen activator inhibitor-1 (PAI-1) was significantly lower in patients with postoperative delirium. Detection of phosphorylated neurofilament heavy subunit was associated with postoperative delirium independent of age (adjusted odds ratio, 5.86; 95% confidence interval, 1.60-29.03; p = 0.0064). The sensitivity and specificity of postoperative delirium detection was increased when age was combined with detection of phosphorylated neurofilament heavy subunit.Conclusions. Preoperative evaluation of phosphorylated neurofilament heavy subunit can predict postoperative delirium independent of age. Early detection of serum phosphorylated neurofilament heavy subunit before surgery may enable clinicians to identify patients at risk for postoperative delirium and start early intervention.

Serum levels of apolipoprotein A-I and E are associated with postoperative delirium: A post hoc analysis.

Postoperative delirium is a common complication for elderly patients. Detection of phosphorylated neurofilament heavy subunit in the serum reflects axonal damage with postoperative delirium. Although it has been implicated that serum apolipoprotein levels might be associated with senile cognitive disorder, its role in the development of delirium has not been fully investigated. This study examined the association of apolipoproteins with delirium after surgery.This was a post hoc analysis of 117 patients who participated in a prospective observational study of delirium in patients undergoing cancer surgery. Patients were clinically assessed for delirium within the first 5 days of surgery. Serum levels of apolipoprotein A-I, B, and E were measured on postoperative day 3.Forty-one patients (35%) were clinically diagnosed with postoperative delirium. Serum levels of apolipoprotein A-I and B were increased in patients with delirium whereas those of apolipoprotein E were decreased. These changes in apolipoprotein A-I and E levels were associated with the presence of phosphorylated neurofilament heavy subunit in the serum, and were significantly associated with delirium (A-I: adjusted odds ratio [aOR], 6.238; 95% confidence interval [CI], 2.766–20.68; P < .0001; E: aOR, 0.253; 95% CI, 0.066–0.810; P = .0193). A combination of apolipoprotein A-I and E offers significant discrimination between delirium and nondelirium with high accuracy (area under the curve, 0.8899).Serum apolipoprotein A-I and E levels were associated with delirium and the presence of phosphorylated neurofilament heavy subunit in serum. Therefore, apolipoproteins might be useful biomarkers of postoperative delirium.

Serum Phosphorylated Neurofilament Heavy Subunit Levels and its Association with the Risk for Catastrophic Injury in Thoroughbred Racehorses

Neurofilaments are structural proteins that are concentrated in the body and axons of neurons. Damage to the neurons or axons as a result of trauma or infectious diseases leads to the release of neurofilaments into blood and cerebrospinal fluid (CSF). This case-control study was carried out to compare serum levels of phosphorylated neurofilament heavy chain (pNF-H) between clinically healthy Thoroughbred (TB) horses and TB horses that suffered catastrophic musculoskeletal injuries (cMSI), and to investigate the correlation between putative risk factors and serum concentrations of pNF-H in injured horses. Blood samples were collected from clinically healthy horses and from horses that suffered cMSI. The concentration of pNF-H in serum samples was determined using the Phosphorylated Neurofilament H Sandwich enzyme-linked immunosorbent assay kit. A total of 343 horses were enrolled in the study (148 cases and 195 controls). The median serum concentration of pNF-H for controls was 0.0 ng/ml and for cases was 0.07 ng/ml. No significant difference was observed between the 2 groups in racing. The number of lifetime starts was correlated with serum pNF-H concentration in case horses. The serum concentration of pNF-H was higher in case horses that experienced cMSI while training than while racing. The number of lifetime starts is a proxy measure for several risk factors related to cumulative exercise load during the career of racehorses. Measurement of serum concentrations of pNF-H in TB racehorses does not support the hypothesis that subclinical neurologic injury or conditions are associated with catastrophic injury of TB racehorses.

Serum and cerebrospinal fluid phosphorylated neurofilament heavy subunit as a marker of neuroaxonal damage in tick-borne encephalitis.

Extensive axonal and neuronal loss is the main cause of severe manifestations and poor outcomes in tick-borne encephalitis (TBE). Phosphorylated neurofilament heavy subunit (pNF-H) is an essential component of axons, and its detection in cerebrospinal fluid (CSF) or serum can indicate the degree of neuroaxonal damage. We examined the use of pNF-H as a biomarker of neuroaxonal injury in TBE. In 89 patients with acute TBE, we measured CSF levels of pNF-H and 3 other markers of brain injury (glial fibrillary acidic protein, S100B and ubiquitin C-terminal hydrolase L1) and compared the results to those for patients with meningitis of other aetiology and controls. Serum pNF-H levels were measured in 80 patients and compared with findings for 90 healthy blood donors. TBE patients had significantly (P<0.001) higher CSF pNF-H levels than controls as early as hospital admission. Serum pNF-H concentrations were significantly higher in samples from TBE patients collected at hospital discharge (P<0.0001) than in controls. TBE patients with the highest peak values of serum pNF-H, exceeding 10 000 pg ml-1, had a very severe disease course, with coma or tetraplegia. Patients requiring intensive care had significantly higher serum pNF-H levels than other TBE patients (P<0.01). Elevated serum pNF-H values were also observed in patients with incomplete recovery (P<0.05). Peak serum pNF-H levels correlated positively with the duration of hospitalization (P=0.005). Measurement of pNF-H levels in TBE patients might be useful for assessing disease severity and determining prognosis.

Levels of Serum Phosphorylated Neurofilament Heavy Subunit in Clinically Healthy Standardbred Horses

Neurofilaments heavy chain proteins (pNF-H) have been identified as useful serum biomarkers for humans and animals with neurologic conditions, some of which can lead to poor performance, and athletic injuries. However, there are no published reports that describe a reference range for serum pNF-H levels in healthy racehorses. This cross-sectional study was carried out to determine the serum concentration of pNF-H in 1,349 samples collected from 1,291 clinically healthy standardbred (SB) racehorses. Data on age, time of sampling (pre-race or post-race), and finishing position during a race were collected. The concentration of pNF-H in serum samples was determined using an enzyme-linked immunosorbent assay (ELISA). The appropriate statistical techniques were used to determine the median serum concentration of pNF-H in these horses, if the serum concentration of pNF-H changed with age, if there were changes in the serum concentration of pNF-H during a race, and if there was an association between serum concentration of pNF-H, and the finishing position for the horse. The median serum concentration of pNF-H in this group of clinically healthy SB horses was 0.0 ng/mL. The concentration of pNF-H in serum was not associated with the age of the horses in this study as was determined by regression analysis. There was no significant change in the serum concentration of pNF-H before and after a race in paired samples. There was no association of serum concentration of pNF-H and the finishing position of the horses after the race. The data from this study supports use of <0.412 ng/mL as a reference interval for measurement of serum levels of pNF-H in SB racehorses as 95% of the collected samples fell into the range 0.0–0.412 ng/mL.

Elevated neuron-specific enolase level is associated with postoperative delirium and detection of phosphorylated neurofilament heavy subunit: A prospective observational study

Delirium is the most common central nervous system complication after surgery. Detection of phosphorylated neurofilament heavy subunit in the serum reflects axonal damage within the central cervous system and is associated with the severity of postoperative delirium. Neuron-specific enolase and S100 calcium-binding protein β have been identified as possible serum biomarkers of postoperative delirium. This study examined the association of the levels of these markers with incidence of postoperative delirium and detection of phosphorylated neurofilament heavy subunit. This study represents a post hoc analysis of 117 patients who participated in a prospective observational study of postoperative delirium in patients undergoing cancer surgery. Patients were clinically assessed for development of postoperative delirium within the first five days of surgery. Serum levels of phosphorylated neurofilament heavy subunit, neuron-specific enolase, and S100 calcium-binding protein β levels were measured on postoperative day 3. Forty-one patients (35%) were clinically diagnosed with postoperative delirium. Neuron-specific enolase level (P < 0.0001) and the proportion of patients positive for phosphorylated neurofilament heavy subunit (P < 0.0001) were significantly higher in the group of patients with postoperative delirium. Neuron-specific enolase level discriminated between patients with and without clinically diagnosed postoperative delirium with significantly high accuracy (area under the curve [AUC], 0.87; 95% confidence interval [CI], 0.79-0.95; P < 0.0001). Neuron-specific enolase level was associated with incidence of postoperative delirium independently of age (adjusted odds ratio, 8.291; 95% Cl, 3.506-33.286; P < 0.0001). The AUC for the serum neuron-specific enolase level in detecting phosphorylated neurofilament heavy subunit was significant (AUC, 0.78; 95% CI, 0.66-0.90; P < 0.0001). Elevated serum neuron-specific enolase was associated with postoperative delirium independent of age as well as detection of phosphorylated neurofilament heavy subunit in serum. Serum neuron-specific enolase and phosphorylated neurofilament heavy subunit might be useful as biomarkers of postoperative delirium. University Medical Information Network (UMIN) trial ID: UMIN000010329; https://clinicaltrials.gov/.

CSF Neurofilament-H Levels as a Potential Prognostic Marker in Patients of Guillain- Barré Syndrome- A Cohort Study

Introduction: The prognosis of Guillain-Barré Syndrome (GBS) at an early stage with explicit biomarkers is critical to distinguish patients with possibility of poor recovery. Cerebrospinal Fluid (CSF) serves as an impending source for biomarkers that portrays the exact biochemical changes. Aim: To find out if there is any prognostic value of high CSF phosphorylated Neurofilament Heavy subunit (pNf-H) levels, measured during first two weeks of onset of GBS, as assessed by the level of disability at six months after the onset of GBS. Materials and Methods: The cohort study was conducted in the Department of Neurology and Department of Immunology and Molecular Medicine, at the Sher-I-Kashmir Institute of Medical Sciences, Soura, Srinagar, Jammu and Kashmir, India, over a period of two years from August 2015 to August 2017. Sixty two patients who satisfied the required diagnostic standards for GBS (study group) and 35 patients with tension-type headache (control group) were selected for the study. After clinical and electrophysiological assessment, CSF samples were collected. A commercially available sandwich enzyme immunoassay kit, manufactured by BioVendor-Laboratorní medicína (Czech Republic), was used for measuring human pNf-H quantitatively. Results: Mean CSF pNf-H level in patients with good outcome was 325.3 pg/mL whereas, in patients with poor outcome it was 3655.2 pg/mL. CSF pNf-H levels were found to be suggestively higher in GBS patients with poor outcome as compared to those with good outcome. Only eight patients in good outcome group had pathologically high CSF Nf-H levels whereas 10 patients in poor outcome group had CSF Nf-H levels ≤730 pg/mL. The odds ratio was 17.1 (95% Confidence Interval (CI) 3.83-76.29). Thus, high CSF Nf-H levels on admission predicted poor outcome in GBS (p-value &lt;0.001). Moderate degree of positive correlation was found between CSF Nf-H levels and outcome (F score) at six months (R=0.684; p-value &lt;0.001). Conclusion: It can be determined that higher values of CSF pNf-H in GBS (acute stage), could serve as a predictive marker indicative of poor prognosis.

Serial changes in serum phosphorylated neurofilament and value for prediction of clinical outcome after traumatic brain injury.

Background: Phosphorylated neurofilament heavy subunit (pNF-H) is a constituent protein of the nerve axon, which leaks into the peripheral blood in various central nervous disorders. This study examined the time course of pNF-H value up to 1 month after injury and investigated the correlation with clinical outcome.Methods: Serum pNF-H concentration was measured on admission, and at 24 h, 72 h, 1 week, 2 weeks, and 1 month after injury in 20 patients, 15 males and 5 females aged 35–68 years (mean 52 years), with traumatic brain injury (TBI) transported to our hospital between April 2016 and March 2017. The clinical outcome at discharge was evaluated by Glasgow Outcome Scale.Results: The pNF-H value showed no increase in patients without brain parenchymal injury, but pNF-H value increased depending on the severity of brain damage. pNF-H value peaked at 2 weeks after injury. Two patients with peak value exceeding 10,000 unit had very severe injury and died during hospitalization. Peak pNF-H value was 3210 ± 1073 unit in 12 patients with good outcome and 9884 ± 2353 unit in 8 patients with poor outcome (P = 0.0119).Conclusion: Serum pNF-H level tended to increase and peak at 2 weeks after injury, and the peak pNF-H value was correlated with clinical outcome after TBI. The temporal profile of blood pNF-H seems to be useful to predict the clinical outcome after TBI.

Elevation of Cerebrospinal Fluid Light and Heavy Neurofilament Levels in Symptomatic Neurosyphilis.

Although clinical manifestations of symptomatic and asymptomatic neurosyphilis are different, few laboratory tests could reflect the difference. A total of 92 non-HIV-infected patients with syphilis were enrolled in this study, including 23 with symptomatic neurosyphilis, 51 with asymptomatic neurosyphilis, and 18 with latent syphilis, which were excluded neurosyphilis because they were found to have no symptom and normal cerebrospinal fluid (CSF) tests and served as the control group. The concentrations of neurofilament light subunit (NF-L) and phosphorylated neurofilament heavy subunit (pNF-H) in the CSF were measured and compared among these groups, as well as before and after treatment in the symptomatic and asymptomatic groups. The median concentrations of NF-L in the symptomatic neurosyphilis, asymptomatic neurosyphilis, and control groups were 5806, 218, and 266 pg/mL, respectively (P < 0.001), and the median concentrations of pNF-H were 986, 43, and 49 pg/mL, respectively (P < 0.001). A subgroup of 15 symptomatic neurosyphilis and 10 asymptomatic neurosyphilis patients were followed up and underwent CSF examination 6 months after the antineurosyphilis treatment. The median concentration of NF-L in the symptomatic neurosyphilis group decreased from baseline 6420 to 2914 pg/mL after the treatment (P = 0.03), and the median concentration of pNF-H in the symptomatic neurosyphilis group decreased from baseline 1399 to 246 pg/mL after the treatment (P = 0.03). Neurofilament light subunit and pNF-H were significantly elevated in the symptomatic neurosyphilis patients, not in asymptomatic neurosyphilis, which was an implication of the different pathogeneses in neurosyphilis.

Dysfunction of the blood-brain barrier in postoperative delirium patients, referring to the axonal damage biomarker phosphorylated neurofilament heavy subunit.

BackgroundDelirium is the most common postoperative complication of the central nervous system (CNS) that can trigger long-term cognitive impairment. Its underlying mechanism is not fully understood, but the dysfunction of the blood-brain barrier (BBB) has been implicated. The serum levels of the axonal damage biomarker, phosphorylated neurofilament heavy subunit (pNF-H) increase in moderate to severe delirium patients, indicating that postoperative delirium can induce irreversible CNS damage. Here, we investigated the relationship among postoperative delirium, CNS damage and BBB dysfunction, using pNF-H as reference.MethodsBlood samples were collected from 117 patients within 3 postoperative days. These patients were clinically diagnosed with postoperative delirium using the Confusion Assessment Method for the Intensive Care Unit. We measured intercellular adhesion molecule-1, platelet and endothelial cell adhesion molecule-1, vascular cell adhesion molecule-1, E-selectin, and P-selectin as biomarkers for BBB disruption, pro-inflammatory cytokines (tumor necrosis factor-alpha, interleukin-1 beta, interleukin-6), and pNF-H. We conducted logistic regression analysis including all participants to identify independent biomarkers contributing to serum pNF-H detection. Next, by multiple regression analysis with a stepwise method we sought to determine which biomarkers influence serum pNF-H levels, in pNF-H positive patients.ResultsOf the 117 subjects, 41 were clinically diagnosed with postoperative delirium, and 30 were positive for serum pNF-H. Sensitivity and specificity of serum pNF-H detection in the patients with postoperative delirium were 56% and 90%, respectively. P-selectin was the only independent variable to associate with pNF-H detection (P < 0.0001) in all 117 patients. In pNF-H positive patients, only PECAM-1 was associated with serum pNF-H levels (P = 0.02).ConclusionsSerum pNF-H could be an objective delirium biomarker, superior to conventional tools in clinical settings. In reference to pNF-H, P-selectin may be involved in the development of delirium-related CNS damage and PECAM-1 may contribute to the progression of delirium- related CNS damage.

A Novel Brain Injury Biomarker Correlates with Cyanosis in Infants with Congenital Heart Disease.

Cyanotic heart lesions are a complex subset of congenital heart disease (CHD) in which patients are desaturated until surgical repair or palliation. We hypothesized that a direct relationship would exist between degree of desaturation and presence of systemic inflammation and brain injury in unrepaired patients less than 1year of age. The pre-operative desaturation with augmented systemic inflammation would predict a more complex post-operative course. Fifty patients with CHD were enrolled in this study and classified as cyanotic (O2 ≤ 90%) or acyanotic (O2 > 90%) based on SpO2. Serum inflammatory mediators measured included interleukins (IL)-6, IL-8, IL-12p70, IL-10, IL-1β, tumor necrosis factor (TNF)-α, interferon (INF)-γ; macrophage inhibitory factor (MIF) and a novel brain biomarker, phosphorylated neurofilament heavy subunit (pNF-H). Twenty-two cyanotic and 28 acyanotic subjects were enrolled with SpO2 of 78 ± 18% and 98 ± 2% (p < 0.001), respectively, and mean age of 72days (range 2-303) and 102days (range 1-274), respectively. Cyanotic vs acyanotic subjects had elevated serum IL-6 (6.6 ± 7.6 vs 2.9 ± 2.9pg/ml, p = 0.019) and pNF-H (222 ± 637 vs 57 ± 121pg/ml, p = 0.046), and both biomarkers correlated with degree of desaturation (Spearman rank-order correlation ρ = - 0.30, p = 0.037 and ρ = - 0.29 p = 0.049, respectively). Post-operative inotrope scores at 24h and duration of mechanical ventilation correlated inversely with pre-operative oxygen saturation (ρ = - 0.380, p = 0.014 and ρ = - 0.362, p = 0.020, respectively). The degree of pre-operative desaturation correlated with a more complicated post-operative course supporting the need for advanced peri-operative therapy in this population.

Quantitative pupillometry and neuron-specific enolase independently predict return of spontaneous circulation following cardiogenic out-of-hospital cardiac arrest: a prospective pilot study

This study aimed to identify neurological and pathophysiological factors that predicted return of spontaneous circulation (ROSC) among patients with out-of-hospital cardiac arrest (OHCA). This prospective 1-year observational study evaluated patients with cardiogenic OHCA who were admitted to a tertiary medical center, Nippon Medical School Hospital. Physiological and neurological examinations were performed at admission for quantitative infrared pupillometry (measured with NPi-200, NeurOptics, CA, USA), arterial blood gas, and blood chemistry. Simultaneous blood samples were also collected to determine levels of neuron-specific enolase (NSE), S-100b, phosphorylated neurofilament heavy subunit, and interleukin-6. In-hospital standard advanced cardiac life support was performed for 30 minutes.The ROSC (n = 26) and non-ROSC (n = 26) groups were compared, which a revealed significantly higher pupillary light reflex ratio, which was defined as the percent change between maximum pupil diameter before light stimuli and minimum pupil diameter after light stimuli, in the ROSC group (median: 1.3% [interquartile range (IQR): 0.0–2.0%] vs. non-ROSC: (median: 0%), (Cut-off: 0.63%). Furthermore, NSE provided the great sensitivity and specificity for predicting ROSC, with an area under the receiver operating characteristic curve of 0.86, which was created by plotting sensitivity and 1-specificity. Multivariable logistic regression analyses revealed that the independent predictors of ROSC were maximum pupillary diameter (odds ratio: 0.25, 95% confidence interval: 0.07–0.94, P = 0.04) and NSE at admission (odds ratio: 0.96, 95% confidence interval: 0.93–0.99, P = 0.04). Pupillary diameter was also significantly correlated with NSE concentrations (r = 0.31, P = 0.027). Conclusively, the strongest predictors of ROSC among patients with OHCA were accurate pupillary diameter and a neuronal biomarker, NSE. Quantitative pupillometry may help guide the decision to terminate resuscitation in emergency departments using a neuropathological rationale. Further large-scale studies are needed.

Abstract P6-12-26: The axonal damage marker, serum phosphorylated neurofilament heavy subunit, as a potential marker of chemotherapy-induced neuropathy

Abstract Background: Chemotherapy-induced neurologic disorders such as peripheral neuropathy and cognitive disturbance are clinically significant problems for cancer survivors, but their objective assessment methods have not been established. We previously reported in a cross-sectional study that the serum phosphorylated neurofilament heavy subunit (pNF-H), a biomarker of axonal damage, was increased in breast cancer patients treated with chemotherapy. The aim of this study is to temporally assess the neurological adverse events and evaluate the association of serum pNF-H level with cognitive functions and neuropathy following sequential chemotherapy. Methods: Thirty-five breast cancer patients who received neoadjuvant or adjuvant chemotherapy were enrolled prospectively. They underwent brain MRI and cognitive function tests including Controlled Oral Word Association (COWA), Trail Making Test (TMT), and Hopkins Verbal Learning Test-Revised (HVLT-R) before chemotherapy (baseline), one month after completing sequential chemotherapy (post-phase) and more than six months after completing chemotherapy (late-phase). Serum pNF-H levels and questionnaires reporting peripheral neuropathy were measured at the three phases, and every 3 weeks during chemotherapy. Brain MRI volumetry was calculated by the automatic analysis software, BAAD® (Brain Anatomical Analysis using Dartel). The correlations among cognitive functions, brain volume, peripheral neuropathy and serum pNF-H levels were statistically analyzed. Results: Patients' median age was 48 years (range 24-71). A decrease of more than 10% in cognitive function test (COWA) scores was seen in 10 cases (31%) at post-phase. A brain volume loss of more than 10% was seen in 5 cases (15%) at post-phase. The correlation between brain volume change and cognitive disturbance was not significant (p=0.45) and both changes were improved at late-phase. A peripheral neuropathy grade above CTCAE grade 2 was seen in 19 cases (54%). The neuropathy was significantly more severe in anthracycline followed by taxane regimen than taxane followed by anthracycline during chemotherapy (p=0.016), although this difference was not seen at the late-phase (p=0.08). An elevated serum pNF-H level at baseline was seen in only one case, and this case demonstrated the cognitive disturbance, brain volume loss, and peripheral neuropathy following chemotherapy. During chemotherapy, pNF-H was elevated in 24 patients (69%), with especially higher levels noted during the taxane regimen compared to the anthracycline regimen (p=0.019). In the cases treated with anthracycline followed by taxane, the taxane-phase elevation was especially significant (p=0.014). The maximum pNF-H level during taxane therapy was significantly correlated with peripheral neuropathy grade (p=0.002). At late-phase, the significant reduction of pNF-H level was seen in all cases. Conclusions: Change of cognitive function, brain volume and peripheral neuropathy was observed following chemotherapy in breast cancer patients. This study suggests that the serum axonal damage marker, pNF-H, may reflect chemotherapy-induced neuropathy. Citation Format: Kida K, Sumitani M, Ogata T, Kotake R, Natori A, Hashimoto J, Shimokawa T, Yamauchi H, Yamauchi T. The axonal damage marker, serum phosphorylated neurofilament heavy subunit, as a potential marker of chemotherapy-induced neuropathy [abstract]. In: Proceedings of the 2017 San Antonio Breast Cancer Symposium; 2017 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2018;78(4 Suppl):Abstract nr P6-12-26.

Direct evidence of central nervous system axonal damage in patients with postoperative delirium: A preliminary study of pNF-H as a promising serum biomarker

IntroductionApproximately 50–80% patients experience postoperative delirium, an acute cognitive dysfunction associated with prolonged hospitalization, increased mortality, excess healthcare costs, and persistent cognitive impairment. Elucidation of the mechanism of delirium and associated diagnostic and therapeutic measures are urgently required. Here we investigated the role of phosphorylated neurofilament heavy subunit (pNF-H), a major structural protein in axons, as a predictive maker of postoperative delirium. Material and methodsTwenty-three patients who underwent surgery for abdominal cancer were screened for postoperative delirium, and they were assessed for its severity using the memorial delirium assessment scale (MDAS) at and 48h after delirium onset. Serum pNF-H levels were also measured at both time points. The patients were divided into two groups according to the presence or absence of pNF-H. Clinical variables were compared between groups using the Mann–Whitney U test, and the relationship between pNF-H levels and delirium severity was analyzed using the exponential curve fitting. ResultsFifteen of the 23 (65.2%) patients tested positive for pNF-H, and these patients exhibited significantly higher MDAS scores compared with the pNF-H-negative patients only at the onset of delirium. Although the MDAS score significantly improved over time in the positive group, pNF-H positivity persisted. There was a correlation between the maximum pNF-H level and maximum MDAS score (R2=0.31, p=0.013). ConclusionsMore severe postoperative delirium was directly related to higher serum pNF-H levels, suggesting the potential application of pNF-H as a quantitative biomarker of neural damage in postoperative delirium.

161 - Serum Phosphorylated Neurofilament Heavy Subunit (pNF-H) Levels in Patients with Cervical Compressive Myelopathy

161 - Serum Phosphorylated Neurofilament Heavy Subunit (pNF-H) Levels in Patients with Cervical Compressive Myelopathy

136P - Serum phosphorylated neurofilament heavy subunit as a predictive marker of chemotherapy-induced cognitive impairment: a preliminary result

Chemotherapy-induced cognitive impairments (CICI) have been recognized as a clinically significant problem for cancer survivors, but its assessment method has not been established yet. We previously reported in a cross-sectional study that the serum phosphorylated neurofilament heavy subunit (pNF-H), a biomarker of axonal damage, is increased in breast cancer patients treated with chemotherapy. The aim of this study is to evaluate the association of serum pNF-H level with cognitive functions and brain volume changes after sequential chemotherapy. Fifteen breast cancer patients who received neoadjuvant or adjuvant chemotherapy underwent cognitive functions tests [Controlled Oral Word Association (COWA), Trail Making Test (TMT), and Hopkins Verbal Learning Test-Revised (HVLT-R)], questionnaires reporting anxiety/depression, and brain MRI, at the baseline period (before chemotherapy) and at one month after finishing the course of chemotherapy (post-period). Serum pNF-H levels were measured at the baseline, every 3 weeks during chemotherapy and at the post-period (9 times in total). Brain MRI volumetry was determined by the BAAD® (Brain Anatomical Analysis using Dartel) software. The correlations between cognitive functions, brain volume, and pNF-H levels [cumulative pNF-H (cumulo-pNF-H), maximum pNF-H (max-pNF-H), pNF-H at 3 weeks after beginning chemotherapy (3wks-pNF-H)] were statistically analyzed. Patients' median age was 48 years (range 42-73). At baseline, only one patient demonstrated elevated pNF-H level, which was not associated with cognitive functions or brain volumetry. During the course of chemotherapy, pNF-H was elevated in 13 patients. Cumulo-pNF-H, max-pNF-H and 3wks-pNF-H were significantly correlated with cognitive dysfunction on TMT and COWA taken at the post-period. Furthermore, cumulo-pNF-H and max-pNF-H at the post-period were significantly correlated with brain atrophy index and white matter volume loss in some regions. This preliminary study suggests that serum pNF-H levels of breast cancer patients undergoing chemotherapy can predict CICI and brain atrophy.

The Serum Phosphorylated Neurofilament Heavy Subunit as a Predictive Marker for Outcome in Adult Patients after Traumatic Brain Injury.

The serum phosphorylated neurofilament heavy subunit (pNF-H) is a nervous system-specific protein that is released from damaged neural tissue after traumatic brain injury (TBI). The aim of this study was to elucidate the usefulness of serum pNF-H as a predictive marker for the outcome of patients after TBI. Patients with TBI (Glasgow Coma Scale score of 13 or less on admission) were included. Patients who were younger than age 18, dependent on others for daily activities before injury, pregnant, or who were not likely to survive for more than 24 h after injury were excluded. The outcome was assessed using the Glasgow Outcome Scale at 6 months after injury. Blood was collected from subjects (n = 32), and the serum pNF-H value was assessed at 24 and 72 h after TBI. The optimal cutoff value and usefulness of the serum pNF-H value for predicting the long-term outcome were investigated. We found that the serum pNF-H value at 24 h after injury was a good predictive marker of death at 6 months (p < 0.001) after injury. The optimal cutoff value was 240 pg/mL, and the area under the curve in the receiver operating characteristic analysis was 0.930. The serum pNF-H value at 72 h after injury was correlated with an unfavorable outcome (vegetative state or death) at 6 months (p < 0.01) with a cutoff value of 80 pg/mL. Collectively, the results of this study indicate that the serum pNF-H value is a useful predictive marker for patient outcome after TBI.