Neurofilament Light Research Articles

Safety and tolerability of tegoprubart in patients with amyotrophic lateral sclerosis: A Phase 2A clinical trial.

The interaction of CD40L and its receptor CD40 on activated T cells and B cells respectively control pro-inflammatory activation in the pathophysiology of autoimmunity and transplant rejection. Previous studies have implicated signaling pathways involving CD40L (interchangeably referred to as CD154), as well as adaptive and innate immune cell activation, in the induction of neuroinflammation in neurodegenerative diseases. This study aimed to assess the safety, tolerability, and impact on pro-inflammatory biomarker profiles of an anti CD40L antibody, tegoprubart, in individuals with amyotrophic lateral sclerosis (ALS). In this multicenter dose-escalating open-label Phase 2A study, 54 participants with a diagnosis of ALS received 6 infusions of tegoprubart administered intravenously every 2 weeks. The study was comprised of 4 dose cohorts: 1 mg/kg, 2 mg/kg, 4 mg/kg, and 8 mg/kg. The primary endpoint of the study was safety and tolerability. Exploratory endpoints assessed the pharmacokinetics of tegoprubart as well as anti-drug antibody (ADA) responses, changes in disease progression utilizing the Revised ALS Functional Rating Scale (ALSFRS-R), CD154 target engagement, changes in pro-inflammatory biomarkers, and neurofilament light chain (NFL). Seventy subjects were screened, and 54 subjects were enrolled in the study. Forty-nine of 54 subjects completed the study (90.7%) receiving all 6 infusions of tegoprubart and completing their final follow-up visit. The most common treatment emergent adverse events (TEAEs) overall (>10%) were fatigue (25.9%), falls (22.2%), headaches (20.4%), and muscle spasms (11.1%). Mean tegoprubart plasma concentrations increased proportionally with increasing dose with a half-life of approximately 24 days. ADA titers were low and circulating levels of tegoprubart were as predicted for all cohorts. Tegoprubart demonstrated dose dependent target engagement associated and a reduction in 18 pro-inflammatory biomarkers in circulation. Tegoprubart appeared to be safe and well tolerated in adults with ALS demonstrating dose-dependent reduction in pro-inflammatory chemokines and cytokines associated with ALS. These results warrant further clinical studies with sufficient power and duration to assess clinical outcomes as a potential treatment for adults with ALS. Clintrials.gov ID:NCT04322149.

Clinical trajectories of patients with multiple sclerosis from onset and their relationship with serum neurofilament light chain levels.

Serum neurofilament light chain (sNfL) is a biomarker of neuroaxonal destruction that correlates with acute inflammation (AI) in multiple sclerosis (MS). However, in the treatment era, progression without AI is the main driver of long-term disability. sNfL may provide added value in detecting ongoing axonal damage and neurological worsening in patients without AI. We conducted a prospective three-year study on patients with a first MS relapse to evaluate the basal cut-off value predicting early increased disability unrelated to relapses. sNfL levels and AI presence were measured every 6 months during the first year and the Expanded Disability Status Scale (EDSS) was monitored until the third year. Baseline cohorts were stratified by sNfL levels, using a cut-off derived from patients without AI (absence of clinical relapses, new/enlarging T2 lesions, or gadolinium enhancement in magnetic resonance imaging) at year one. Fifty-one patients were included. A sNfL cut-off of 11 pg/mL predicted sustained neurological worsening independent of AI. Patients exceeding this threshold exhibited features of highly active MS (higher proportion of AI, oligoclonal M bands and higher EDSS). Despite AI ablation, sNfL levels persisted elevated and were significantly associated with increased EDSS at baseline and year 3. Patients with low sNfL and concurrent AI (n = 8) experienced relapses in the optic nerve, brainstem, and spinal cord topographies. sNfL elevation may detect patients with increased disability even when AI is controlled. This may reveal mechanisms associated with early axonal degeneration and help identify patients at higher risk of progression.

Cumulative Socioeconomic Status Risk is Associated with Greater Increase in Serum Neurofilament Light Chain Levels Among Middle-Aged Black Adults.

This study examined the longitudinal relationship between cumulative socioeconomic status (SES) risk and serum neurofilament light chain (NfL) levels to better understand the association between social factors and a biomarker of neurodegeneration. We used data from the Family and Community Health Study (FACHS), collecting psychosocial and blood data at two waves (2008) and (2019) from 254 Black Americans (43 males and 211 females). Blood samples were analyzed at each wave for serum NfL concentrations. Regression analysis and mixed-effect modeling examined relationships between cumulative SES risk and serum NfL, controlling for covariates and assessing time effects. Utilizing 11-year longitudinal data, serum NfL levels increased with age. Higher cumulative SES risk at baseline correlated with elevated serum NfL at the 11-year follow-up and predicted a greater increase in NfL levels. Clinically, NfL is a sensitive biomarker for axonal injury and neurodegeneration, commonly used to detect early and preclinical stages of conditions such as Alzheimer's disease (AD), multiple sclerosis, and other neurodegenerative disorders. Our results suggest that exposure to cumulative SES risk among Black adults may contribute to elevated levels of NfL, indicating potential early neurodegeneration. Given the established role of NfL in detecting neurodegenerative processes, these findings underscore the importance of interventions that bolster social safety nets and social connectedness to enhance brain health and mitigate neurodegenerative risks.

Serum neurofilament light chain: a novel biomarker for cardiovascular diseases in individuals without hypertension

Serum neurofilament light chain (sNFL) is a biomarker for axonal injury. Previous studies have linked sNFL levels to cardiovascular risk factors such as diabetes and hypertension, but its association with cardiovascular diseases (CVD) remains unclear. This study aims to explore the association between sNFL and CVD and evaluates its predictive value. Utilizing NHANES 2013–2014 data, this study included 2,035 participants aged ≥ 20 years with measured sNFL quantified using a Siemens immunoassay. CVD was self-reported and included myocardial infarction, stroke, heart failure, coronary heart disease, or angina. Logistic regression models assessed the association between sNFL levels and CVD. The predictive value of sNFL for CVD was evaluated using area under the curve (AUC) and DeLong test. Participants with higher sNFL levels were typically older, male, non-Hispanic white, smokers, and had lower socioeconomic status, higher CVD, hypertension, and diabetes prevalence. Higher sNFL levels were significantly associated with increased odds of CVD (adjusted OR = 1.41, 95% CI: 1.05–1.88). The association was significant in non-hypertensive individuals (OR = 2.72, 95% CI: 1.61–4.62) but not in hypertensive individuals (OR = 1.13, 95% CI: 0.81–1.56). sNFL addition to traditional risk models improved predictive accuracy, especially in non-hypertensive individuals (AUC from 0.827 to 0.856). sNFL levels are significantly associated with CVD in the general population, with a strong predictive value in non-hypertensive individuals. Future longitudinal studies should validate sNFL’s efficacy in various populations and explore the underlying mechanisms of its relationship with hypertension and CVD.

Comparison of Serum and Cerebrospinal Fluid Neurofilament Light Chain Concentrations Measured by Ella™ and Lumipulse™ in Patients with Cognitive Impairment.

Neurofilament light chain proteins (NfLs) are considered a promising biomarker of neuroaxonal damage in several neurological diseases. Their measurement in the serum and cerebrospinal fluid (CSF) of patients with dementia may be especially useful. Our aim was to compare the NfL measurement performance of two advanced technologies, specifically the Ella™ microfluidic platform and the Lumipulse™ fully automated system, in patients with cognitive disorders. Thirty subjects with neurodegenerative cognitive disorders (10 with Alzheimer's Disease, 10 with Frontotemporal Dementia, and 10 with non-progressive Mild Cognitive Impairment) seen at the Cognitive Neurology Clinic of Modena University Hospital (Italy) underwent CSF and serum NfL measurement with both the Ella™ microfluidic platform (Bio-Techne, Minneapolis, MN, USA)) and the Lumipulse™ fully automated system for the CLEIA (Fujirebio Inc., Ghent, Belgium). Correlation and regression analyses were applied to assess the association between NfL concentrations obtained with the two assays in CSF and serum. The Passing-Bablok regression method was employed to evaluate the agreement between the assays. There were high correlations between the two assays (r = 0.976, 95% CI. 0.950-0.989 for CSF vs. r = 0.923, 95% CI 0.842-0.964 for serum). A Passing-Bablok regression model was estimated to explain the relationship between the two assays, allowing us to switch from one to the other when only one assay was available. We found a good degree of correlation between the two methods in patients with neurocognitive disorders. We also established a method that will allow comparisons between results obtained with either technique, allowing for meta-analyses and larger sample sizes.

Rethinking antisense oligonucleotide therapeutics for amyotrophic lateral sclerosis.

Antisense oligonucleotides, which are used to silence target genes, are gaining attention as a novel drug discovery modality for proteinopathies. However, while clinical trials for neurodegenerative diseases like amyotrophic lateral sclerosis have been conducted in recent years, the results have not always been favorable. The results from a Phase III trial of the antisense oligonucleotide, that is, tofersen, which targets SOD1 mRNA, showed decreased levels of cerebrospinal fluid SOD1 and plasma neurofilament light chain but no improvements in primary clinical endpoint. Moreover, case reports pertaining to patients with amyotrophic lateral sclerosis carrying FUS and C9orf72 mutations who received antisense oligonucleotide-based treatments have demonstrated a notable reduction in the targeted protein (thus providing the proof of mechanism) but with no discernible clinical benefits. There are several possible reasons why antisense oligonucleotides knockdown fails to achieve proof of concept, which need to be addressed: on-target adverse effects resulting from the loss of function of target gene and irreversible neuronal death cascade due to toxic protein accumulation, among other factors. This review provides an overview of the current status and discusses the prospects of antisense oligonucleotides treatment for amyotrophic lateral sclerosis.

Personality and Biomarkers of Neurodegeneration and Alzheimer’s Disease in Swedish Older Adults

Abstract Background Personality is associated with dementia risk. Neuroticism and conscientiousness may be involved in resistance and resilience to Alzheimer’s Disease (AD) pathology (ADP). These traits have also been associated with unspecific biomarkers of neurodegeneration; glial fibrillary acidic protein (GFAP) and neurofilament light (NfL). This study explores the role of personality in cognitive ageing. Methods We used data from the Swedish population-based studies H70 (individuals age 70 years only), and SNAC-K (individuals ages 60-104). Personality was assessed with the NEO-five-factor inventory. In H70, biomarkers of ADP were measured in cerebrospinal fluid (CSF, N = 305), except NfL which was also available in plasma (N = 1082). In SNAC-K (N = 1754), all biomarkers were measured in serum. We used multivariable regression models to evaluate the association between personality traits and ADP biomarkers, GFAP and NfL among individuals without dementia. We further examined if associations differed by age (SNAC-K only) and sex. Results In H70, higher neuroticism and was associated with lower Aβ42/Aβ40 ratio (B=-0.01, p = 0.02). In SNAC-K, higher openness was associated with lower NfL (B=-0.04, p = 0.03). For age 60-66, higher openness was associated with lower NfL (B=-0.09, p = 0.01), higher neuroticism was associated with higher GFAP (B = 0.09, p = 0.01), and NfL (B = 0.10, p = 0.003). For age >80, higher openness was associated with higher ptau-181, (B = 0.14, p = 0.01), and ptau-181/Aβ42 ratio (B = 0.15, p = 0.003). Conclusions Higher neuroticism and lower openness are associated with neurodegeneration. Higher openness may also be associated with resilience to AD-pathology. Key messages • Neuroticism may contribute to neurodegeneration in people <70. • Openness may contribute to cognitive resilience to ADP in people >80.

Neurodegeneration is highly associated with comorbidity burden in HFrEF patients

Abstract Background Heart failure (HF) is associated with cognitive decline and risk for dementia. Blood levels of amyloid beta 40 and 42 (Aβ40, Aβ42), tau protein (tau), and neurofilament light chain (NfL) have been found to be altered in neurodegenerative disease. Previous research has established a clear association between these neuromarkers and the risk of developing cognitive dysfunction and mortality in the general population. Objective The aim of this study was to investigate the association between the respective neuromarkers and comorbidity burden, as well as to explore whether comorbidity burden impacts the relationship between neuromarkers and outcome in HF patients. Methods Plasma levels of Aβ40, Aβ42, tau, and NfL were quantified using a single-molecule array assay. The primary outcome parameter was all-cause mortality. Results A total of 470 HFrEF patients were enrolled in the study, with a median age of 62 years (IQR: 52–72); 77% were male. Median NT-proBNP concentration was 1812 pg/ml (IQR: 718–3881). Elevated levels of all biomarkers were closely associated with comorbidity burden (Figure 1). All neuromarkers showed increased levels in individuals with chronic kidney disease (CKD) and known carotid artery stenosis (CAS), except for Aβ40, which did not show significant elevation in CAS (NfL: p<0.001 for both; t-tau: p<0.001 and p=0.041; Aβ40: p<0.001 and p=0.050; Aβ42: p<0.001 and p=0.033, respectively). In patients with type 2 diabetes mellitus (T2DM) and coronary artery disease (CAD), only NfL levels were significantly elevated (p<0.001 for both), whereas atrial fibrillation (AF) was associated with higher levels of NfL and t-tau (p<0.001 for both). In individuals with iron deficiency, only Aβ42 levels were significantly higher (p=0.025). All biomarkers showed significant associations with all-cause mortality [crude HR for an increase in 1-log unit (95%CI): NfL 4.44 (3.02-6.53), t-tau 5.04 (2.97-8.58), Aβ40 3.90 (2.27-6.72), Aβ42 5.14 (2.84-9.32); p<0.001 for all] (Figure 2). These associations remained statistically significant after adjusting for comorbidity burden including AF, T2DM, CAD, CKD, CAS and ID [adjusted HR for an increase in 1-log unit (95%CI): NfL 3.28 (1.93-5.57), t-tau 3.96 (2.07-7.57), Aβ40 2.42 (1.34-4.38), Aβ42 3.05 (1.56-5.97); p<0.01 for all]. Conclusion The findings suggest a close connection between elevated levels of markers of neurodegeneration and increased comorbidity burden in HFrEF patients. While this association may indicate the cumulative risk leading to neuronal injury and HFrEF progression, a causal relationship cannot be excluded. The observed accelerated neurodegeneration in HFrEF underscores the need for further investigation into this complex interplay.Figure 1Figure 2

Predictive and Explainable Artificial Intelligence for Neuroimaging Applications.

The aim of this review is to highlight the new advance of predictive and explainable artificial intelligence for neuroimaging applications. Data came from 30 original studies in PubMed with the following search terms: "neuroimaging" (title) together with "machine learning" (title) or "deep learning" (title). The 30 original studies were eligible according to the following criteria: the participants with the dependent variable of brain image or associated disease; the interventions/comparisons of artificial intelligence; the outcomes of accuracy, the area under the curve (AUC), and/or variable importance; the publication year of 2019 or later; and the publication language of English. The performance outcomes reported were within 58-96 for accuracy (%), 66-97 for sensitivity (%), 76-98 for specificity (%), and 70-98 for the AUC (%). The support vector machine and the convolutional neural network registered the best performance (AUC 98%) for the classifications of low- vs. high-grade glioma and brain conditions, respectively. Likewise, the random forest delivered the best performance (root mean square error 1) for the regression of brain conditions. The following factors were discovered to be major predictors of brain image or associated disease: (demographic) age, education, sex; (health-related) alpha desynchronization, Alzheimer's disease stage, CD4, depression, distress, mild behavioral impairment, RNA sequencing; (neuroimaging) abnormal amyloid-β, amplitude of low-frequency fluctuation, cortical thickness, functional connectivity, fractal dimension measure, gray matter volume, left amygdala activity, left hippocampal volume, plasma neurofilament light, right cerebellum, regional homogeneity, right middle occipital gyrus, surface area, sub-cortical volume. Predictive and explainable artificial intelligence provide an effective, non-invasive decision support system for neuroimaging applications.

Intrathecal IgG and IgM synthesis correlates with neurodegeneration markers and corresponds to meningeal B cell presence in MS

Intrathecal synthesis of immunoglobulins (Igs) is a key hallmark of multiple sclerosis (MS). B cells are known to accumulate in the leptomeninges of MS patients and associate with pathology in the underlying cortex and a more severe disease course. However, the role of locally produced antibodies in MS brain pathology is poorly understood. Here, we quantified the protein levels of IgA, IgM, IgG and albumin in serum and cerebrospinal fluid (CSF) samples of 80 MS patients and 28 neurological controls to calculate Ig indices. In addition, we quantified presence of meningeal IgA+, IgM+ and IgG+ B cells in post-mortem brain tissue of 20 MS patients and 6 controls using immunostainings. IgM and IgG, but not IgA, indices were increased in CSF of MS patients compared to controls, with no observed differences between MS disease types. Both IgM and IgG indices correlated significantly with neurofilament light (NfL) levels in CSF, but not with clinical or radiological parameters of disease. Similarly, IgG+ and IgM+ B cells were increased in MS meninges compared to controls, whereas IgA+ B cells were not. Neuronal loss did not differ between sections with low or high IgA+, IgM+ and IgG+ B cells, but was increased in sections with high numbers of all CD19+ meningeal B cells. Similarly, high presence of CD19+ meningeal B cells and IgG+ meningeal B cells associated with increased microglial density in the underlying cortex. Taken together, intrathecal synthesis of IgG and IgM is elevated in MS, which corresponds to an increased number of IgG+ and IgM+ B cells in MS meninges. The significant correlation between intrathecal IgG and IgM production and NfL levels, and increased microglial activation in cortical areas adjacent to meningeal infiltrates with high levels of IgG+ B cells indicate a role for intrathecal IgM- and IgG-producing B cells in neuroinflammatory and degenerative processes in MS.

Neurovascular unit, neuroinflammation and neurodegeneration markers in brain disorders.

Neurovascular unit (NVU) inflammation via activation of glial cells and neuronal damage plays a critical role in neurodegenerative diseases. Though the exact mechanism of disease pathogenesis is not understood, certain biomarkers provide valuable insight into the disease pathogenesis, severity, progression and therapeutic efficacy. These markers can be used to assess pathophysiological status of brain cells including neurons, astrocytes, microglia, oligodendrocytes, specialized microvascular endothelial cells, pericytes, NVU, and blood-brain barrier (BBB) disruption. Damage or derangements in tight junction (TJ), adherens junction (AdJ), and gap junction (GJ) components of the BBB lead to increased permeability and neuroinflammation in various brain disorders including neurodegenerative disorders. Thus, neuroinflammatory markers can be evaluated in blood, cerebrospinal fluid (CSF), or brain tissues to determine neurological disease severity, progression, and therapeutic responsiveness. Chronic inflammation is common in age-related neurodegenerative disorders including Alzheimer's disease (AD), Parkinson's disease (PD), and dementia. Neurotrauma/traumatic brain injury (TBI) also leads to acute and chronic neuroinflammatory responses. The expression of some markers may also be altered many years or even decades before the onset of neurodegenerative disorders. In this review, we discuss markers of neuroinflammation, and neurodegeneration associated with acute and chronic brain disorders, especially those associated with neurovascular pathologies. These biomarkers can be evaluated in CSF, or brain tissues. Neurofilament light (NfL), ubiquitin C-terminal hydrolase-L1 (UCHL1), glial fibrillary acidic protein (GFAP), Ionized calcium-binding adaptor molecule 1 (Iba-1), transmembrane protein 119 (TMEM119), aquaporin, endothelin-1, and platelet-derived growth factor receptor beta (PDGFRβ) are some important neuroinflammatory markers. Recent BBB-on-a-chip modeling offers promising potential for providing an in-depth understanding of brain disorders and neurotherapeutics. Integration of these markers in clinical practice could potentially enhance early diagnosis, monitor disease progression, and improve therapeutic outcomes.

Neuronal plasma biomarkers in acute ischemic stroke.

Early imaging-based detection of acute ischemic stroke (AIS) has improved in the era of reperfusion therapy. Despite of this, prognosis of outcome after AIS remains a challenge. Therefore, parameters that support clinical decision making are sought. Blood-based biomarkers have the potential to provide valuable information in addition to the established prognostic factors. Neuronal biomarkers of acute or degenerative neuronal injury have shown to be reliably detected in plasma. These biomarkers are well-established in neurodegenerative pathology, such as Alzheimer's disease. In this study, we explored the association between stroke diameter and plasma biomarkers for neuronal injury and tau pathophysiology (brain-derived tau [BD-tau], phosphorylated-tau-217 [p-tau21] and neurofilament light [NfL]) in patients (n = 193) admitted to the acute ward, Akershus University Hospital. All patients received a final diagnosis of AIS, transient ischemic attack or stroke mimics. Blood samples were obtained the day after admission. We find that levels of BD-tau (p = .004) and NfL (p = .011) were higher after AIS than in patients with stroke mimics. The cortical stroke diameter correlated with BD-tau (tau-b = 0.64, p < .001) and p-tau217 (tau-b = 0.36, p = .003). Linear regression confirmed BD-tau to be the strongest variable associated with stroke diameter, pointing to the potential clinical value of plasma BD-tau in outcome prediction after AIS.

Cognitive status and demographics modify the association between subjective cognition and amyloid.

This study examined the effect of cognitive status, education, and sex on the association between subjective cognitive decline (SCD) and Alzheimer's disease (AD) biomarkers in non-demented older adults. Vanderbilt Memory and Aging Project participants (n = 129), dementia or stroke free, completed fasting lumbar puncture, SCD assessment, and cognitive assessment. Cerebrospinal fluid (CSF) biomarkers for AD were analyzed. Linear regression models related SCD to CSF AD biomarkers and follow-up models assessed interactions of SCD × cognitive status, sex, reading level, and education on AD biomarkers. In main effect models, higher SCD was associated with more amyloidosis (p-values <0.004). SCD was not associated with tau, p-tau, or neurofilament light (NFL) levels (p-values >0.38). SCD score interacted with cognitive status (p < 0.02), sex (p = 0.03), and education (p-values <0.005) on amyloidosis. In stratified models, higher SCD was associated with more amyloid in cognitively unimpaired (p-values <0.003), men (p = 0.0003), and higher education. No SCD score × reading-level interaction was found (p-values >0.51) though SCD related to amyloid markers in the higher reading-level group (p-values <0.004). Higher SCD was associated with greater cerebral amyloid accumulation, one of the earliest pathological AD changes. SCD appears most useful in detecting early AD-related brain changes prior to objective cognitive impairment, in men, and those with higher quantity and quality of education and highlight the importance of considering these factors.

Circulating Blood-Brain Barrier Proteins for Differentiating Ischaemic Stroke Patients from Stroke Mimics

Background: Stroke is one of the leading causes of death and disability worldwide. The diagnosis of stroke remains largely clinical, yet widely used stroke scoring systems and brain imaging do not satisfactorily allow the distinction of ischaemic stroke (IS) patients from stroke mimics (SMs). Blood biomarkers are promising tools that could facilitate clinical triage. Methods: This study recruited 66 patients with IS and 24 SMs. The levels of Glial fibrillary acidic protein (GFAP), Neuron-specific enolase (NSE), Neurofilament light chain (NfL) and blood-brain barrier (BBB) proteins [Occludin (OCLN), Zonula occludens 1 (ZO-1), Claudin-5] in blood serum were measured by enzyme-linked immunosorbent assay technique. Biomarker levels in IS patients and SMs were compared using the Mann–Whitney U test. Multivariable logistic regression analysis was used to evaluate the diagnostic performance of biomarkers in combination with the National Institutes of Health Stroke Scale (NIHSS) score. Results: More significant differences in circulating GFAP, NfL, OCLN, ZO-1, and Claudin-5 but not NSE were found in IS patients compared to SMs. A combination of circulating ZO-1, Claudin-5, and OCLN with NIHSS score gives the highest diagnostic accuracy, sensitivity, and specificity. Conclusions: A prediction model with circulating BBB proteins in combination with NIHSS score differentiates between IS patients and SMs.

Blood biomarkers for Alzheimer’s disease with the Lumipulse automated platform: Age-effect and clinical value interpretation

BackgroundAdvances in analytical methods have recently paved the way to Alzheimer’s disease (AD) biomarkers testing in blood along with the more established CSF testing. To ensure a forthcoming application of this low-invasive diagnostic that might allow to recognize early onset of dementia, appropriate pathological cut-points need to be defined. MethodsIn this cross-sectional study we measured blood and CSF neurofilament light chain (NFL), phosphorylated tau (pTau 181), Amyloid-β1-42 (AB 1–42) and Amyloid-β1-40 (AB 1–40) on a fully automated chemiluminescent platform (Lumipulse, Fujirebio) in 80 cognitively impaired patients and 55 cognitively unimpaired subjects. Clinical cut points were calculated with receiver-operator characteristic (ROC) curve analysis and a head-to-head comparison of blood and CSF testing was performed. ResultsBlood NFL best discriminant thresholds to distinguish neurodegenerative diseases from controls varied age-dependently, being 19 and 33 pg/mL in subjects 50–65 years and > 65 years respectively. AD was best framed by AB 1–42/1–40 ratio < 0.079 and ptau181 > 1 pg/mL. Though a strong correlation for all biomarkers, only blood AB ratio was equal to CSF testing for AD diagnosis. ConclusionsThe specific context of use might be considered to define the cut-offs of blood biomarkers of neurodegenerative diseases. Future efforts towards reference materials for each AD blood biomarker will improve clinical cut-offs.

The Association Between Constipation and Positron Emission Tomography and Blood-Based Biomarkers in Older Cognitively Unimpaired Adults with Higher Amyloid-β Burden.

Constipation may be linked to cognitive decline and a higher risk of Alzheimer's disease (AD). We aimed to investigate the association between constipation and positron emission tomography (PET) and blood-based AD biomarkers in older cognitively unimpaired (CU) adults with higher Aβ burden. Constipation was diagnosed according to Rome IV criteria and the severity of constipation was evaluated by using a validated self-reported questionnaire. The participants underwent the examination of plasma AD biomarkers and 18F-florbetapir PET and 18F-MK6240 PET scans; the latter was only performed in the validation cohort. Correlation and multiple linear regression analyses were used to investigate the association between constipation and AD biomarkers. Two cohorts were included in our study. A total of 404 older participants with 126 of whom Aβ-PET positive were enrolled in the development cohort. Multiple linear regression analysis showed constipation was associated with plasma t-Tau, p-Tau-181, and neurofilament light chain (NfL) in participants with Aβ-PET (+). Meanwhile, no/mild constipation was associated with lower Aβ-PET standard uptake value ratio. The association between constipation and plasma biomarkers was different in the subgroups stratified by age, sex and APOE ε4 genotype. The above associations were further validated in the validation cohort containing 36 Aβ-PET (+) participants. Importantly, no/mild constipation was associated with lessTau burden evaluated by 18F-MK6240 PET Braak stages. Our data indicate that no/mild constipation may be associated with lower plasma t-Tau, p-Tau-181, and NfL as well as less Aβ and Tau burden in older CU adults with Aβ deposition. Improving constipation and being away from defecation disorders may help reduce the risk of AD development.

CSF and blood levels of Neurofilaments, T-Tau, P-Tau, and Abeta-42 in amyotrophic lateral sclerosis: a systematic review and meta-analysis.

Recent literature suggests that markers of neuroaxonal damage, such as neurofilaments and tau protein, might serve as potential biomarkers for ALS. We conducted this systematic review and meta-analysis study to compare cerebrospinal fluid (CSF) and blood levels of total tau (t-tau), phosphorylated tau (p-tau), amyloid beta peptide 42 (Abeta-42), and neurofilaments in ALS patients and controls. A systematic search of Cochrane Library, PubMed, Embase, and ISI Web of Science was conducted on March 18, 2022, and updated on January 26, 2023. Observational studies that compared the concentrations of neurofilament light chain (NfL), neurofilament heavy chain (NFH), t-tau, p-tau, or Abeta-42 in CSF or peripheral blood of ALS patients and controls were included. Data from relevant studies were independently extracted and screened for quality using a standard tool, by at least two authors. Meta-analysis was conducted when a minimum of 3 studies reported the same biomarker within the same biofluid. A total of 100 studies were eligible for at least one meta-analysis. CSF and blood levels of NfL (standardized mean difference (SMD) [95% CI]; CSF: 1.46 [1.25-1.68]; blood: 1.35 [1.09-1.60]) and NFH (CSF: 1.32 [1.13-1.50], blood: 0.90 [0.58-1.22]) were significantly higher in ALS patients compared with controls. The pooled differences between ALS patients and controls were not significant for CSF t-tau, blood t-tau, and CSF Abeta-42, but CSF p-tau was lower in ALS patients (-0.27 [-0.47- -0.07]). Significantly decreased p-tau/t-tau ratios were found in ALS patients compared with controls (-0.84 [-1.16- -0.53]). Heterogeneity was considerable in most of our meta-analyses. CSF and blood neurofilament levels, as well as the CSF p-tau/t-tau ratio, might be potential candidates for improving ALS diagnosis. Further research is warranted to better understand the underlying mechanisms and the clinical implications of these biomarker alterations.

Blood‐based biomarkers of Alzheimer's disease: Standardization and comprehensiveness

AbstractPopulation aging is sweeping across the globe, resulting in a striking prevalence of Alzheimer's disease (AD) and dementia and a heavy economic burden. Given the time window of 10–20 years from pathological initiation to clinically detected cognitive impairment, early detection can significantly impact the prevention and control of AD. The invasiveness and high cost of cerebrospinal fluid biomarkers and positron emission tomography‐computed tomography imaging limit large‐scale disease screening. However, blood‐based biomarkers (BBMs) lack these disadvantages, shedding light on their usefulness in the large‐scale identification and prevention of AD. Prominent advancement has recently been made regarding BBMs of AD co‐pathology (amyloid β, tau protein, neurofilament light polypeptide, and glial fibrillary acidic protein) to improve their accuracy as clinical diagnostics of AD to a level comparable to that of canonical methods, facilitating the large‐scale clinical implementation of diagnostic tests with higher precision. To briefly summarize, the prospects of AD BBMs rely on standardization and comprehensiveness. Calibrating the sample collection procedure and clarifying the boundaries for indices and abnormalities are beneficial for constructing a canonical diagnostic assay. The comprehensive assembly of heterogeneous clinical evidence guarantees the accuracy of diagnosis and improves the workflow for early identification.

Plasma neurofilament light chain as prognostic marker of cognitive decline in neurodegenerative diseases, a clinical setting study.

Analysis of selected research cohorts has highlighted an association between plasma neurofilament light (NfL) protein and cross-sectional cognitive impairment as well as longitudinal cognitive decline. However, the findings have yielded inconsistent results regarding its possible application in clinical practice. Despite its potential prognostic significance, the role of plasma NfL in daily clinical practice with unselected patients suffering from cognitive impairment remains largely unexplored. This retrospective, cross-sectional and longitudinal monocentric study enrolled 320 patients with Alzheimer's disease ([AD], n = 158), dementia with Lewy body ([DLB], n = 30), frontotemporal dementia ([FTD], n = 32), non-neurodegenerative diseases ([NND], n = 59) or subjective cognitive decline ([SCD], n = 41). Plasma NfL levels were measured at baseline on the Simoa platform. AD, DLB, and FTD patients were also analyzed altogether as a 'degenerative conditions' subgroup, whereas SCD and NND were grouped as a 'non-degenerative conditions' subgroup. We assessed the relationship between plasma NfL levels and cross-sectional cognitive performance, including global cognition and six specific cognitive domains. A subset of 239 patients had follow-up mini-mental state examinations (MMSE) up to 60 months. Models were adjusted on age, education level, glomerular filtration rate and body mass index. In 320 patients, baseline plasma NfL levels were negatively associated with global cognition (β=-1.28 (-1.81 ; -0.75) P < 0.001), memory (β=-1.48 (-2.38 ; -0.59), P = 0.001), language (β=-1.72(-2.49 ; -0.95) P < 0.001), praxis (β=-2.02 (-2.91 ; -1.13) P < 0.001) and executive functions (β=-0.81, P < 0.001). Across diagnosis, plasma NfL levels were negatively associated with cross-sectional global cognition in all but the SCD subgroup, specifically with executive functions and memory in AD (respectively β=-0.71(-1.21 ; -0.211), P = 0.005 and β=-1.29 (-2.17 ; -0.42), P = 0.004), and with attention in LBD (β=-0.81(-1.16 ; -0.002), P = 0.03). Linear mixed-effects models showed that plasma NfL predicted MMSE decline in the global population (βPlasmaNfLxTime=-0.15 (-0.26 ; -0.04), P = 0.006), as in the neurodegenerative condition subgroup (βPlasmaNfLxTime=-0.21 (-0.37 ; - 0.06), P = 0.007), but not in non-neurodegenerative condition subgroup. In our clinical cohort, plasma NfL was associated with faster cognitive decline in neurodegenerative dementia, which corroborates data obtained in research cohorts. Yet, plasma NfL was not predictive of accelerated cognitive decline in individuals without neurodegeneration, suggesting its use as a neurodegeneration-specific predictive biomarker.

Serum Glial Fibrillary Acidic Protein and Neurofilament Light Chain Levels Reflect Different Mechanisms of Disease Progression under B-Cell Depleting Treatment in Multiple Sclerosis.

To investigate the longitudinal dynamics of serum glial fibrillary acidic protein (sGFAP) and serum neurofilament light chain (sNfL) levels in people with multiple sclerosis (pwMS) under B-cell depleting therapy (BCDT) and their capacity to prognosticate future progression independent of relapse activity (PIRA) events. A total of 362 pwMS (1,480 samples) starting BCDT in the Swiss Multiple Sclerosis (MS) Cohort were included. sGFAP levels in 2,861 control persons (4,943 samples) provided normative data to calculate adjusted Z scores. Elevated sGFAP levels (Z score >1) at 1 year were associated with a higher hazard for PIRA (hazard ratio [HR]: 1.80 [95% CI: 1.17-2.78]; p = 0.0079) than elevated sNfL levels (HR, 1.45 [0.95-2.24], p = 0.0886) in a combined model. Independent of PIRA events, sGFAP levels longitudinally increased by 0.49 Z score units per 10 years follow-up (estimate, 0.49 [0.29, 0.69], p < 0.0001). In patients experiencing PIRA, sGFAP Z scores were 0.52 Z score units higher versus stable patients (0.52 [0.22, 0.83], p = 0.0009). Different sNfL Z score trajectories were found in pwMS with versus without PIRA (interaction p = 0.0028), with an average decrease of 0.92 Z score units per 10 years observed without PIRA (-0.92 [-1.23, -0.60], p < 0.0001), whereas levels in patients with PIRA remained high. Elevated sGFAP and lack of drop in sNfL after BCDT start are associated with increased risk of future PIRA. These findings provide a rationale for combined monitoring of sNfL and sGFAP in pwMS starting BCDT to predict the risk of PIRA, and to use sGFAP as an outcome in clinical trials aiming to impact on MS progressive disease biology. ANN NEUROL 2024.