Neurofilament Light Chain Research Articles

Serum growth differentiation factor-15, glial fibrillary acidic protein, and neurofilament light chain: Their link and role in Creutzfeldt-Jakob disease

BackgroundCreutzfeldt-Jakob disease (CJD) is a rapidly progressive neurodegenerative disorder characterized by neuronal damage. Emerging biomarkers, such as serum neurofilament light chain (sNfL), glial fibrillary acidic protein (sGFAP), and growth differentiation factor-15 (sGDF-15), are currently being studied for their potential use in this disease. ObjectivesThis study analyzes the levels of sNfL, sGFAP, and sGDF-15, as well as their relationships, in patients with CJD compared to healthy controls (HC). MethodsA total of 19 CJD patients and 81 age- and sex-matched HCs were enrolled. Serum levels of sNfL and sGFAP were measured using ultrasensitive immunoassays, while sGDF-15 levels were assessed via ELISA. Statistical analyses included correlation analysis and analysis of covariance (ANCOVA) models. ResultsCJD patients showed significantly higher serum levels of sNfL and sGFAP compared to HCs (p 〈0,001). sNfL levels were positively correlated with both sGFAP (Rho = 0,70; p < 0,001) and sGDF-15 (Rho = 0,60; p = 0,004). Interestingly, sGFAP levels were higher in female CJD patients compared to males (p = 0,001), while no significant difference in sNfL levels was observed between sexes. ConclusionsIn conclusion, this study explores the potential of sNfL, sGDF-15, and sGFAP as biomarkers in CJD patients. The higher levels of sNfL and sGFAP in CJD patients compared to healthy controls, along with the observed sex differences in sGFAP, highlight the need for further research into the interaction between astroglia and neurons in CJD, with a focus on sex as a key variable.

Population-Based Evidence for the Use of Serum Neurofilaments as Individual Diagnostic and Prognostic Biomarkers in Amyotrophic Lateral Sclerosis.

Neurofilament light chains (NfL) and phosphorylated neurofilament heavy chains (pNfH), established as diagnostic and prognostic biomarkers in hospital-based amyotrophic lateral sclerosis (ALS) cohorts, are now surrogate markers in clinical trials. This study extends their evaluation to a population level, with the aim of advancing their full establishment and assessing the transferability of biomarker findings from controlled cohorts to real-world ALS populations. We measured serum NfL and pNfH levels in all ALS patients (n = 790) and general population controls (n = 570) with available baseline samples participating in the epidemiological ALS Registry Swabia, providing platform-specific (ELLA™) reference data and Z-scores for controls, as well as reference data, disease-specific Z-scores and longitudinal data in ALS. We evaluated the diagnostic and prognostic utility of neurofilaments and quantified the impact of ALS-related factors and non-ALS confounders. Neurofilaments showed high diagnostic and prognostic utility at the population level, with NfL superior to pNfH. The novel concept of a population-based ALS Z-score significantly improved the prognostic utility compared to absolute raw values. Both biomarkers increased more strongly with age in controls than in ALS, and age adjustment improved diagnostic accuracy. Our data show that disease progression rates, ALS phenotype, body mass index (BMI), and renal function need to be considered when interpreting neurofilament levels; longitudinal neurofilament levels were generally stable in individual patients, especially when adjusted for age and baseline levels. Population-based assessment enhances the utility of particularly serum NfL as a diagnostic and prognostic biomarker in ALS and improves the translation of findings from controlled cohorts to real-world populations. ANN NEUROL 2024;96:1040-1057.

Reduced Serum Brain-Derived Neurotrophic Factor in Infants Affected by Severe Bronchiolitis.

Bronchiolitis is an acute viral infection of the lower respiratory tract, typical of infants in their first year of life and causing hypoxia in the most serious cases. Bronchiolitis recognizes various demographic risk factors that are associated with greater clinical severity; however, no laboratory factors are yet able to correlate with the clinical severity. Neurotrophins as Brain-Derived Neurotrophic Factor (BDNF) are mediators of neuronal plasticity. BDNF is constitutively expressed in smooth muscle cells and epithelium of the lower respiratory tract, and as it is released during inflammatory conditions, serum levels may have a relevant role in the prognosis of infants with bronchiolitis. In the present pilot study, we aimed to disclose the presence of serum BDNF in infants hospitalized with bronchiolitis at discharge as a disease severity indicator. Serum BDNF, measured at hospital discharge, was significantly lower in severe bronchiolitis (expressed as O2-supplemented infants). Furthermore, no changes were disclosed for the Tropomyosin receptor kinase B, the main BDNF receptor and neurofilament light chain, a biomarker of neuronal degeneration. Low serum BDNF in infants with severe bronchiolitis could be associated with a higher utilization by lung cells or with an altered production by lung cells. Therefore, further research is required to study if a decreased production or increased consumption of this biomarker is at the base of the above-mentioned findings.

Identifying genetic targets in clinical subtypes of Parkinson’s disease for optimizing pharmacological treatment strategies

Abstract The heterogeneity of Parkinson’s disease (PD) has been recognized in clinical, with patients categorized into distinct subsets based on motor phenotype, such as tremor-dominant PD (TD), postural instability and gait difficulty-dominant PD (PIGD) and mixed PD (Mix). Despite this categorization, the underlying mechanisms of this heterogeneity remain poorly understood, and there is no personalized effective treatment for each PD subtype. To address this, a rat model for PD subtypes was established by unilateral stereotaxic injection of 6-OHDA, followed by cluster analysis of behavioral data. The serum neurofilament light chain (NfL) and uric acid (UA) levels as well as alterations in brain autonomic activity in rats were consistent with clinical patients, and metabolomics results showed that more than 70% of the metabolites in the serum of different subtypes of PD rats and clinical patients appeared to be consistently altered. Further transcriptomic analysis by RNA-seq has elucidated that the development of PD subtypes is associated with altered gene expression in neurotransmitter, neuronal damage in the central or peripheral nervous system, and lipid metabolism. In addition, based on the subtype-specific differentially expressed genes, 25 potential drug candidates were identified. Notably, the Alox15 inhibitor baicalein showed a greater efficacy on Mix rats, highlighting the possibility of selecting targeted treatments for well-defined individuals.

Phenotypic and oncological insights in ANNA1 autoimmunity: Age stratification and biomarker analysis

AbstractObjectiveTo describe the phenotypes, oncological associations, biomarker profiles, and outcomes across different age groups in patients with ANNA1 (anti‐Hu) autoimmunity.MethodsA retrospective review of patients with ANNA1‐IgG in serum/CSF between January 1, 2001, and December 31,2019 was performed. Patients were classified into three groups based on the age of symptom onset. Phage immunoprecipitation sequencing (PhIP‐Seq) and neurofilament light chain (NfL) measurements were done in patient sera/CSF with archived samples.ResultsOf 122 patients, 81 (66%), 20 (16%), and 21 (17%) patients belonged to older adults, young adults, and pediatric groups, respectively. Lung cancer and neuromuscular presentations were more common in older adults (p &lt; 0.001), while limbic encephalitis and neuroblastoma were more common in pediatric patients (p &lt; 0.005). Most young adults (75%) did not have cancer identified. Proportions of patients with a favorable response to immunotherapy were 20%, 30%, and 52% among older adults, young adults, and pediatric groups, respectively. PhIP‐Seq demonstrated significant enrichment for ELAVL4 peptides especially for amino acids 240–289, in the majority of samples evaluated (36/67, 54%). ZIC and SOX2 peptides were significantly enriched in those with central nervous system presentations. Serum NfL levels were elevated in patients with cancer and those with poor long‐term outcomes.InterpretationYoung adults with ANNA1 autoimmunity phenotypically resembled older adults but rarely had an underlying cancer. Pediatric patients frequently presented with limbic encephalitis and neuroblastoma and often responded favorably to immunotherapy. Distinct antigenic signatures may underlie differences in clinical presentations. Serum NfL levels may be a biomarker of poor long‐term outcomes in ANNA1 autoimmunity.

Comparative neurofilament light chain trajectories in CSF and plasma in autosomal dominant Alzheimer’s disease

AbstractDisease-modifying therapies for Alzheimer’s disease (AD) are likely to be most beneficial when initiated in the presymptomatic phase. To track the benefit of such interventions, fluid biomarkers are of great importance, with neurofilament light chain protein (NfL) showing promise for monitoring neurodegeneration and predicting cognitive outcomes. Here, we update and complement previous findings from the Dominantly Inherited Alzheimer Network Observational Study by using matched cross-sectional and longitudinal cerebrospinal fluid (CSF) and plasma samples from 567 individuals, allowing timely comparative analyses of CSF and blood trajectories across the entire disease spectrum. CSF and plasma trajectories were similar at presymptomatic stages, discriminating mutation carriers from non-carrier controls 10-20 years before the estimated onset of clinical symptoms, depending on the statistical model used. However, after symptom onset the rate of change in CSF NfL continued to increase steadily, whereas the rate of change in plasma NfL leveled off. Both plasma and CSF NfL changes were associated with grey-matter atrophy, but not with Aβ-PET changes, supporting a temporal decoupling of Aβ deposition and neurodegeneration. These observations support NfL in both CSF and blood as an early marker of neurodegeneration but suggest that NfL measured in the CSF may be better suited for monitoring clinical trial outcomes in symptomatic AD patients.

Elevated Cerebrospinal Fluid Ubiquitin Carboxyl-Terminal Hydrolase Isozyme L1 in Asymptomatic C9orf72 Hexanucleotide Repeat Expansion Carriers.

To identify biochemical changes in individuals at higher risk of developing amyotrophic lateral sclerosis (ALS) or frontotemporal dementia (FTD) via C9orf72 hexanucleotide repeat expansion (HRE) heterozygosity. Cross-sectional observational study of 48 asymptomatic C9orf72 HRE carriers, 39 asymptomatic non-carrier controls, 19 people with sporadic ALS, 10 with C9orf72 ALS, 14 with sporadic FTD, and 10 with C9orf72 FTD. Relative abundance of 30 pre-defined cerebrospinal fluid biomarkers of ALS and FTD were compared in asymptomatic C9orf72 HRE carriers and age-matched non-carrier controls. Differential abundance of these proteins was quantified using data independent acquisition mass spectrometry or electro chemiluminescent assay for neurofilament light chain. Unbiased analysis of the entire cerebrospinal fluid proteome was then carried out. Ubiquitin carboxyl-hydrolase isozyme L1 levels were higher in asymptomatic C9orf72 HRE carriers compared with age-matched non-carriers (log2fold change 0.20, FDR-adjusted p-value = 0.034), whereas neurofilament light chain levels did not significantly differ. Ubiquitin carboxyl-hydrolase isozyme L1 levels remained elevated after matching of groups by neurofilament levels (p = 0.011), and after adjusting for age, sex, and neurofilament levels. A significant difference was also observed when restricting analysis to younger participants (<37) matched by neurofilament level (p = 0.007). Elevated cerebrospinal fluid ubiquitin carboxyl-hydrolase isozyme L1 levels in C9orf72 HRE carriers can occur in the absence of increased neurofilament levels, potentially reflecting either compensatory or pathogenic mechanisms preceding rapid neuronal loss. This brings forward the window on changes associated with the C9orf72 HRE carrier state, with potential to inform understanding of penetrance and approaches to prevention. ANN NEUROL 2024.

Neurofilament light chain: a biomarker at the crossroads of clarity and confusion for gene-directed therapies.

Neurofilament light chain (NfL) is a promising biomarker for neurodegenerative diseases, measurable in both CSF and blood upon neuroaxonal damage. While CSF analysis was traditionally used, blood-based assays now offer a less invasive alternative. NfL levels correlate with disease severity and progression in conditions like Alzheimer's disease, amyotrophic lateral sclerosis, multiple sclerosis and Huntington's disease. Clinical trials demonstrate its utility as a pharmacodynamic biomarker in MS and ALS. The FDA's approval of Tofersen for SOD1-ALS based on NfL reduction underscores its growing acceptance as surrogate marker. However, challenges remain in standardizing assays, interpreting clinical correlations, low specificity and understanding the dynamics between CSF and blood NfL levels. Addressing these issues is crucial for maximizing NfL's potential in neurodegenerative disease management.

Investigating the efficacy of ergothioneine to delay cognitive decline in mild cognitively impaired subjects: A pilot study.

Dementia, particularly Alzheimer's disease, is a major healthcare challenge in ageing societies. This study aimed to investigate the efficacy and safety of a dietary compound, ergothioneine, in delaying cognitive decline in older individuals. Nineteen subjects aged 60 or above with mild cognitive impairment were recruited for this double-blinded, randomized, and placebo-controlled study (ClinicalTrials.gov identifier: NCT03641404, registration date: 19/08/2018). Subjects received either ergothioneine (25 mg per capsule) or a placebo, taken 3 times a week for one year. The whole blood profile, markers of renal and liver functions, neurocognitive performance, plasma levels of ergothioneine and its metabolites, and plasma biomarkers related to neurodegeneration were measured across the study. Ergothioneine intake did not alter clinical safety markers (blood counts, kidney and liver function) throughout the study, further validating its safety for human consumption. Subjects receiving ergothioneine demonstrated improved performance in assessment of learning ability and stabilized plasma levels of neurofilament light chain, compared with the placebo group, which saw no improvement in cognitive assessments and a significant increase in neurofilament light chain levels. Prolonged intake of ergothioneine showed no toxicity in elderly people. Enhanced Rey Auditory Verbal Learning Test performance and stabilized neurofilament light chain levels suggest improvements in memory and learning abilities and a deceleration of neuronal damage, respectively. Our results add to existing data that ergothioneine is safe for extended consumption and may hold the potential to delay cognitive decline in elderly adults.

Identifying amyotrophic lateral sclerosis using diffusion tensor imaging, and correlation with neurofilament markers.

To determine diagnostic value of diffusion tensor imaging (DTI) in amyotrophic lateral sclerosis (ALS) patients and investigate the association between DTI and neurofilaments (NFs), including serum and cerebrospinal fluid (CSF) levels of neurofilament light chain (NFL) and phosphorylated neurofilament heavy chain (pNFH). Forty-three clinically diagnosed ALS patients and 32 control subjects without neurological disorders underwent routine MRI (magnetic resonance imaging) and DTI scans. DTI parameters (mean diffusivity [MD] and fractional anisotropy [FA]) at axial levels of internal capsules and cerebral peduncles along the corticospinal tract (CST) were measured. The study compared the differences of DTI parameters between ALS patients and controls using the Mann-Whitney U test. Diagnostic efficacy of each DTI metric was evaluated using the receiver operating characteristic (ROC) curve. NFs (NFL and pNFH levels in serum and CSF) were measured by enzyme-linked immunosorbent assay. Correlation analyses were conducted between DTI parameters and NFs. Capsule-MD and Peduncle-MD in ALS patients were higher than those in controls; whereas Capsule-FA and Peduncle-FA in ALS patients were lower than those in controls (all, p < 0.05). The area under curve (AUC) was 0.730 for Capsule-FA, 0.828 for Capsule-MD, 0.890 for Peduncle-FA, and 0.896 for Peduncle-MD. Capsule-FA was negatively correlated with CSF-NFL (r = -0.813, p < 0.001), Serum-NFL (r = -0.493, p = 0.001), CSF-pNFH (r = -0.637, p < 0.001), and Serum-pNFH (r = -0.672, p < 0.001); Peduncle-FA negatively with CSF-NFL (r = -0.562, p < 0.001), CSF-pNFH (r = -0.506, p = 0.001), and Serum-pNFH (r = -0.488, p = 0.001); Peduncle-MD positively with CSF-NFL (r = 0.516, p < 0.001), CSF-pNFH (r = 0.494, p = 0.001). DTI had superior performance in identifying ALS patients and could serve as a reliable predictor. DTI parameters related to neurofilament markers, and Capsule-FA may become a robust surrogate biomarker indicating disease severity and progression rate for ALS patients.

Considering Biomarkers of Neurodegeneration in Alzheimer’s Disease: The Potential of Circulating Cell-Free DNA in Precision Neurology

Neurodegenerative diseases, such as Alzheimer’s disease (AD), are a growing public health crisis, exacerbated by an aging global population and the lack of effective early disease-modifying therapies. Early detection of neurodegenerative disorders is critical to delaying symptom onset and mitigating disease progression, but current diagnostic tools often rely on detecting pathology once clinical symptoms have emerged and significant neuronal damage has already occurred. While disease-specific biomarkers, such as amyloid-beta and tau in AD, offer precise insights, they are too limited in scope for broader neurodegeneration screening for these conditions. Conversely, general biomarkers like neurofilament light chain (NfL) provide valuable staging information but lack targeted insights. Circulating cell-free DNA (cfDNA), released during cell death, is emerging as a promising biomarker for early detection. Derived from dying cells, cfDNA can capture both general neurodegenerative signals and disease-specific insights, offering multi-layered genomic and epigenomic information. Though its clinical potential remains under investigation, advances in cfDNA detection sensitivity, standardized protocols, and reference ranges could establish cfDNA as a valuable tool for early screening. cfDNA methylation signatures, in particular, show great promise for identifying tissue-of-origin and disease-specific changes, offering a minimally invasive biomarker that could transform precision neurology. However, further research is required to address technological challenges and validate cfDNA’s utility in clinical settings. Here, we review recent work assessing cfDNA as a potential early biomarker in AD. With continued advances, cfDNA could play a pivotal role in shifting care from reactive to proactive, improving diagnostic timelines and patient outcomes.

Blood biomarkers in Down syndrome: Facilitating Alzheimer's disease detection and monitoring.

Blood-based biomarkers continue to be explored for disease detection, monitoring of progression, and therapeutic outcomes as the diagnostic determination of Alzheimer's Disease in Down Syndrome (DS-AD) remains challenging in clinical settings. This perspective highlights the current status of this effort. Overall, amyloid (A), tau (T), and neurodegeneration (AT[N]) blood-based biomarkers have been shown to increase with disease pathology for individuals with DS. Phosphorylated tau biomarkers (p-tau217, p-tau181) have been consistently shown to track disease progression for DS-AD and are likely good candidates for use in clinical settings. Biomarkers of inflammation (glial fibrillary acidic protein) also show promise; however, additional work is needed. Findings from stability work of blood-based biomarkers conducted among non-DS also supportthe potential longitudinal utility of biomarkers such as neurofilament light chain and p-tau181 in DS. Gaps in our knowledge are highlighted, and a potential role for sex differences in biomarker outcomes is noted, along with recommendations for determining the appropriate context of use when translating biomarkers into clinical applications. HIGHLIGHTS: An overview of blood-based biomarkers for Alzheimer's disease (AD) was provided for consideration of their utility among individuals with Down syndrome when looking toward potential clinical applications. Longitudinal stability of many blood biomarkers and improvement in detection sensitivity make blood such as plasma a viable source for exploring AD pathology. Variability in reviewed findings regarding the application of blood biomarkers highlights the importance of understanding and defining the appropriate context of use, particularly when translating them into clinical practice.

Plasma Alzheimer's disease biomarker variability: Amyloid-independent and amyloid-dependent factors.

We aimed to investigate which factors affect plasma biomarker levels via amyloid beta (Aβ)-independent or Aβ-dependent effects and improve the predictive performance of these biomarkers for Aβ positivity on positron emission tomography (PET). A total of 2935 participants underwent blood sampling for measurements of plasma Aβ42/40 ratio, phosphorylated tau 217 (p-tau217; ALZpath), glial fibrillary acidic protein (GFAP), and neurofilament light chain (NfL) levels usingsingle-molecule array and Aβ PET. Laboratory findings were collected using a routine blood test battery. Aβ-independent factors included hemoglobin and estimated glomerular filtration rate (eGFR) for p-tau217 and hemoglobin, eGFR, and triiodothyronine (T3) for GFAP and NfL. Aβ-dependent factors included apolipoprotein E genotypes, body mass index status for Aβ42/40, p-tau217, GFAP, and NfL. However, these factors exhibited negligible or modest effects on Aβ positivity on PET. Our findings highlight the importance of accurately interpreting plasma biomarkers for predicting Aβ uptake in real-world settings. We investigated factor-Alzheimer's disease plasma biomarker associations in a large Korean cohort. Hemoglobin and estimated glomerular filtration rate affect the biomarkers independently of brain amyloid beta (Aβ). Apolipoprotein E genotypes and body mass index status affect the biomarkers dependent on brain Aβ. Addition of Aβ-independent factors shows negligible effect in predicting Aβ positivity. Adjusting for Aβ-dependent factors shows amodest effect in predicting Aβ positivity.

Biomarkers of response to ocrelizumab in relapsing–remitting multiple sclerosis

ObjectiveTo ascertain the changes of serum neurofilament light chain (sNfL) and glial fibrillary acidic protein (sGFAP) values in relapsing–remitting multiple sclerosis (RRMS) patients treated with ocrelizumab and their association with treatment response.MethodsMulticenter prospective study including 115 RRMS patients initiating ocrelizumab treatment between February 2020 and March 2022 followed during a year. Serum samples were collected at baseline and every 3 months to measure sNfL and sGFAP levels using single-molecule array (SIMOA) technology. Based on age and body mass index, sNfL values were standardized using z-score. NEDA (non-evidence of disease activity)-3 status was defined for patients free of disease activity after a year of follow-up. Inflammation (INFL) was considered when new relapses occurred during follow-up or new MRI lesions were found at 1-year exploration. PIRA (progression independent of relapse activity) was defined as disability progression occurring in the absence of relapses or new MRI activity.ResultsAfter a year on ocrelizumab, 85 patients (73.9%) achieved NEDA-3. Thirty patients did not achieve NEDA: 20 (17.4%) because of INFL and 10 (8.7%) because of PIRA. Of INFL patients, 6 (30.0%) had relapses, and 17 (85.0%) had at least one new MRI lesion at the 12-month examination. At baseline, INFL patients had higher sNfL (p = 0.0003) and sGFAP (p = 0.03) than the NEDA-3 group. PIRA patients mostly exhibited low sNfL and heterogeneous sGFAP levels. After a year, NEDA-3 and INFL patients showed similar decreases in sNfL (p &amp;lt; 0.0001) and sGFAP (p &amp;lt; 0.0001 for NEDA-3 and p = 0.001 for INFL ones). However, the decrease occurred earlier in NEDA-3 patients. Accordingly, sNfL &amp;gt; 1.5 z-score 3 months after ocrelizumab initiation indicated a higher risk of inflammation (OR = 13.6; p &amp;lt; 0.0001). Decrease in sGFAP values occurred later in both groups, with significant reductions observed at 12 months for INFL and 6 and 12 months for NEDA-3. No significant changes in sNfL or sGFAP were observed in PIRA patients.ConclusionOcrelizumab induced normalization of sNfL and sGFAP in the majority of NEDA-3 and inflammatory patients but did not cause changes in the PIRA group. Our data suggest that normalization of sNfL and sGFAP is associated with the lack of inflammatory-associated disease progression but it may not affect non-inflammatory PIRA.

Abstract 4138781: Neuro-specific biomarkers for risk assessment of ischemic stroke and death in patients with atrial fibrillation not receiving oral anticoagulation

Background: Biomarkers measured in plasma reflecting cardiorenal dysfunction and inflammation are associated with clinical outcomes in atrial fibrillation (AF). We recently showed an association between the plasma level of the neuronal biomarker neurofilament light chain (NFL) and subsequent stroke and death in patients with AF not receiving oral anticoagulation (OAC). Purpose: We aimed to compare NFL with other circulating neuro-specific biomarkers, specifically glial fibrillary acidic protein (GFAP), tau, and ubiquitin carboxy-terminal hydrolase L1 (UCHL1), concerning associations with the risk of stroke and other outcomes in patients with AF. Methods: Concentrations of NFL, GFAP, tau, and UCHL1 were determined with Single Molecule Array (Simoa®) in plasma samples obtained at baseline from 967 patients with AF randomized to aspirin in the ACTIVE A trial. Median follow-up was 3.6 years. Associations between baseline biomarker concentrations, clinical variables (age, sex, body mass index, smoking, alcohol consumption, type of AF, cardiac rhythm at baseline, heart failure, hypertension, diabetes, prior stroke/transient ischemic attack, peripheral arterial disease, and myocardial infarction), and outcomes (ischemic stroke, cardiovascular and all-cause death) were analysed with Cox regression, adjusting for clinical variables and other biomarkers. Results: Increasing age and female sex were associated with elevated levels of all four biomarkers. Plasma levels of NFL were positively correlated with those of GFAP (r=0.67, p&lt;0.001), tau (r=0.12, p&lt;0.001), and UCHL1 (r=0.37, p&lt;0.001). NFL was independently associated with subsequent ischemic stroke (HR 1.27, 95% CI 1.03–1.56 for a doubling of NFL), cardiovascular death (HR 1.37, 95% CI 1.13–1.64 for a doubling of NFL), and all-cause death (HR 1.46, 95% CI 1.25–1.70 for a doubling of NFL) after adjustment for clinical factors and other biomarkers. In unadjusted analyses, GFAP was associated with ischemic stroke and death; tau and UCHL1 with death only, however, these associations were not significant after adjusting for clinical variables (Table). Conclusions: In patients with AF not receiving OAC, NFL was independently associated with ischemic stroke and death. Further investigation of NFL and its association with clinical outcomes in patients with cardiovascular disease is therefore warranted.

Sex differences in the association between repetitive negative thinking and neurofilament light.

Emerging evidence suggests that repetitive negative thinking (RNT; i.e., worry and ruminative brooding) is associated with biomarkers of Alzheimer's disease. Given that women have a greater risk of many neurodegenerative diseases, this study investigated whether worry and brooding are associated with general neurodegeneration and whether associations differ by sex. Exploratory analyses examined whether allostatic load, a marker of chronic stress, mediates any observed relationships. Baseline data from 134 cognitively healthy older adults in the Age-Well clinical trial were utilised. Worry and brooding were assessed using questionnaires. Plasma neurofilament light chain (NfL), a biomarker of neurodegeneration, was quantified using a Meso Scale Discovery assay. We found a positive interaction between brooding and sex on NfL, with higher brooding associated with greater NfL levels in women. No associations were observed between worry/ruminative brooding and allostatic load. These results offer preliminary support that RNT is associated with worse brain health, specifically in women.

Multimodal neuroimaging-based prediction of Parkinson's disease with mild cognitive impairment using machine learning technique.

This study aimed to identify potential markers that can predict Parkinson's disease with mild cognitive impairment (PDMCI). We retrospectively collected general demographic data, clinically relevant scales, plasma samples, and neuroimaging data (T1-weighted magnetic resonance imaging (MRI) data as well as resting-state functional MRI [Rs-fMRI] data) from 173 individuals. Subsequently, based on the aforementioned multimodal indices, a support vector machine was employed to investigate the machine learning (ML) classification of PD patients with normal cognition (PDNC) and PDMCI. The performance of 29 classifiers was assessed based on various combinations of indicators. Results demonstrated that the optimal classifier in the validation set was composed by clinical + Rs-fMRI+ neurofilament light chain, exhibiting a mean Accuracy of 0.762, a mean area under curve of 0.840, a mean sensitivity of 0.745, along with a mean specificity of 0.783. The ML algorithm based on multimodal data demonstrated enhanced discriminative ability between PDNC and PDMCI patients.

NCOG-27. HIGHER LEVELS OF SERUM ICAM-1 AND IL-10 ARE ASSOCIATED WITH COGNITIVE DYSFUNCTION IN BOTH IDH-WILDTYPE AND IDH-MUTANT GLIOMA

Abstract BACKGROUND Cognitive dysfunction is common among glioma patients, but the contribution of specific mechanisms to the development of cognitive symptoms is unclear. Circulating levels of proteins linked to neurodegeneration, inflammation, and vascular damage have been associated with cognitive symptoms in neurological diseases and aging, but their prognostic value in glioma is unknown. Here, we examined associations between cognitive symptoms and serum levels of protein biomarkers in glioma patients. METHODS Cognitive function was evaluated using the Montreal Cognitive Assessment (MoCA, scores ≤ 25 = cognitive dysfunction). Cytokines (interleukin-1β [IL-1β], IL-2, IL-4, IL-6, IL-8, IL-10, IL-12p70, IL-13, interferon-γ [IFN-γ], tumor necrosis factor-α [TNF-α]), and neurodegeneration (neurofilament light chain [NfL], tau, glial fibrillary acidic protein [GFAP]), and vascular damage markers (Serum amyloid A [SAA], C-reactive protein [CRP], vascular cell adhesion molecule 1 [VCAM-1], and intercellular adhesion molecule 1 [ICAM-1]) were measured using ultrasensitive assays (Meso Scale Discovery). RESULTS Patients (n=73) were predominantly male (58%), white (74%), with a median age of 44 (range=24,74). Cognitive dysfunction was found in 53% of the patients. Levels of NfL (p=0.035), IL-6 (p=0.006), IL-10 (p=0.007), TNF-α (p=0.035), IFN-γ (p=0.011), CRP (p=0.016), VCAM-1 (p=0.012), and ICAM-1 (p&amp;lt;0.001) were higher in patients with cognitive dysfunction when compared to those with normal cognition. After adjusting for isocitrate dehydrogenase (IDH) tumor mutation status, age, tumor grade, and number of surgeries, higher levels of ICAM-1 and IL-10, but not other markers, remained associated with cognitive dysfunction. MoCA scores were negatively correlated with GFAP (r=-0.24, p=0.038), IFN-γ (r=-0.31, p=0.008), IL-6 (r=-0.29, p=0.014), IL-10 (r=-0.24, p=0.039), and ICAM-1 (r=-0.39, p&amp;lt;0.001). CONCLUSIONS ICAM-1 and IL-10 levels were higher in patients with MOCA determined cognitive dysfunction, suggesting an association between cognitive symptoms and inflammation and vascular impairment in glioma patients. Future analyses in larger longitudinal cohorts are warranted to assess the predictive value of protein biomarkers.

Neuroglial Biomarkers for Risk Assessment of Ischemic Stroke and Other Cardiovascular Events in Patients with Atrial Fibrillation Not Receiving Oral Anticoagulation.

Cardiac biomarkers improve risk prediction in patients with atrial fibrillation (AF). We recently demonstrated that the neuron-specific protein neurofilament light chain (NFL) was associated with ischemic stroke in patients with AF not receiving oral anticoagulation (OAC). The association of other neuroglial biomarkers reflecting brain injury, i.e., glial fibrillary acidic protein (GFAP), total tau (tau), and ubiquitin carboxy-terminal hydrolase L1 (UCHL1) with the risk of stroke and other cardiovascular outcomes in AF is unknown. Baseline plasma samples were available from 967 patients with AF not receiving OAC treatment. Concentrations of NFL, GFAP, tau, and UCHL1 were determined with Single Molecule Array (Simoa®). Associations between baseline biomarker level, clinical characteristics, and outcomes (ischemic stroke, hospitalization for heart failure, and all-cause death) were analyzed with multivariable Cox regression adjusted for clinical characteristics and other biomarkers. Higher levels of all four neuroglial biomarkers correlated with increasing age and female sex. During a median follow-up of 3.6 years, NFL was associated with increased risk of ischemic stroke (for a doubling in NFL, hazard ratio [HR] 1.27 95% confidence interval [CI] 1.03-1.56) and death (HR 1.46 95% CI 1.25-1.70). In adjusted analyses, GFAP, tau, and UCHL1 were not associated with stroke or death. NFL, tau, and UCHL1 were significantly associated with hospitalization for heart failure. In patients with AF not receiving OAC, NFL was the only neuroglial biomarker significantly and independently associated with the risk of ischemic stroke and death. Further studies evaluating NFL for stroke risk assessment in patients with AF and the impact of contemporary OAC treatment are warranted.

Development of a Novel Microphysiological System for Peripheral Neurotoxicity Prediction Using Human iPSC-Derived Neurons with Morphological Deep Learning

A microphysiological system (MPS) is an in vitro culture technology that reproduces the physiological microenvironment and functionality of humans and is expected to be applied for drug screening. In this study, we developed an MPS for the structured culture of human iPSC-derived sensory neurons and then predicted drug-induced neurotoxicity by morphological deep learning. Using human iPSC-derived sensory neurons, after the administration of representative anti-cancer drugs, the toxic effects on soma and axons were evaluated by an AI model with neurite images. Significant toxicity was detected in positive drugs and could be classified by different effects on soma or axons, suggesting that the current method provides an effective evaluation of chemotherapy-induced peripheral neuropathy. The results of neurofilament light chain expression changes in the MPS device also agreed with clinical reports. Therefore, the present MPS combined with morphological deep learning is a useful platform for in vitro peripheral neurotoxicity assessment.