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Frontiers in Immunology 2024Myelin oligodendrocyte glycoprotein (MOG) IgG is frequently elevated in pediatric patients with acquired demyelinating syndrome (ADS). However, no specific biomarkers...
BACKGROUND AND PURPOSE
Myelin oligodendrocyte glycoprotein (MOG) IgG is frequently elevated in pediatric patients with acquired demyelinating syndrome (ADS). However, no specific biomarkers exist for phenotype classification, symptom severity, prognosis, and treatment guidance of MOG-IgG-associated disease (MOGAD). This study evaluated neurofilament light chain (NfL) and endothelial growth factor receptor (EGFR) mRNA expression levels in serum and cerebrospinal fluid (CSF) as potential biomarkers for MOGAD in Chinese children.
METHODS
This was a cross-sectional and single-center study. We enrolled 22 consecutive pediatric patients hospitalized with MOGAD and 20 control pediatric patients hospitalized for noninflammatory neurological diseases in Hebei Children's Hospital. Serum and CSF were collected from MOGAD patients within 3 days before immunotherapy. The mRNA levels of NfL and EGFR in serum and CSF were measured by real-time polymerase chain reaction (qPCR), and the EGFR/NfL ratio mRNA was calculated. These measurement values were then compared between disease groups and among MOGAD phenotypes. In addition, the correlations between the mRNAs of three markers (NfL, EGFR, EGFR/NfL ratio), extended disability status scale (EDSS) scores, and clinical phenotypes were analyzed.
RESULTS
Serum and CSF NfL mRNA levels were significantly higher of acute-stage MOGAD patients than those of control patients ( 0.05 and 0.01, respectively), while the mRNA levels of serum EGFR and EGFR/NfL ratio were significantly lower of MOGAD patients than those of controls ( 0.05, 0.0001). Serum NfL mRNA was significantly correlated with mRNA of serum EGFR ( =0.480, < 0.05). Serum and CSF NfL mRNA levels in MOGAD patients with the ADEM-like phenotype were also significantly higher than those in control patients ( < 0.01, < 0.01) and optic neuritis (ON) phenotype ( < 0.05, < 0.05). Both mRNAs of NfL in CSF and EGFR/NfL ratio in serum were correlated with EDSS scores ( < 0.05, = 0.424; < 0.05, = -0.521).
CONCLUSION
The mRNA levels of elevated NfL in serum and CSF as well as lower EGFR and EGFR/NfL ratio in serum could help distinguish acute-phase MOGAD. Higher mRNA levels of NfL in serum and CSF of MOGAD patients help distinguish ADEM-like phenotype. In addition, serum EGFR/NfL mRNA ratio is indicative of disease severity in pediatric patients with MOGAD. Further investigations are warranted to elucidate the pathological mechanisms underlying these associations.
Topics: Humans; Male; Female; Biomarkers; Child; Neurofilament Proteins; Myelin-Oligodendrocyte Glycoprotein; RNA, Messenger; ErbB Receptors; Cross-Sectional Studies; Child, Preschool; Severity of Illness Index; Phenotype; Immunoglobulin G; Adolescent; Autoantibodies
PubMed: 38807603
DOI: 10.3389/fimmu.2024.1388734 -
International Journal of Molecular... May 2024The diagnostic and prognostic value of plasma glial fibrillary acidic protein (pl-GFAP) in sporadic Creutzfeldt-Jakob disease (sCJD) has never been assessed in the...
The diagnostic and prognostic value of plasma glial fibrillary acidic protein (pl-GFAP) in sporadic Creutzfeldt-Jakob disease (sCJD) has never been assessed in the clinical setting of rapidly progressive dementia (RPD). Using commercially available immunoassays, we assayed the plasma levels of GFAP, tau (pl-tau), and neurofilament light chain (pl-NfL) and the CSF total tau (t-tau), 14-3-3, NfL, phospho-tau181 (p-tau), and amyloid-beta isoforms 42 (Aβ) and 40 (Aβ) in sCJD ( = 132) and non-prion RPD (np-RPD) ( = 94) patients, and healthy controls (HC) ( = 54). We also measured the CSF GFAP in 67 sCJD patients. Pl-GFAP was significantly elevated in the sCJD compared to the np-RPD and HC groups and affected by the sCJD subtype. Its diagnostic accuracy (area under the curve (AUC) 0.760) in discriminating sCJD from np-RPD was higher than the plasma and CSF NfL (AUCs of 0.596 and 0.663) but inferior to the 14-3-3, t-tau, and pl-tau (AUCs of 0.875, 0.918, and 0.805). Pl-GFAP showed no association with sCJD survival after adjusting for known prognostic factors. Additionally, pl-GFAP levels were associated with 14-3-3, pl-tau, and pl-NfL but not with CSF GFAP, Aβ/Aβ, and p-tau. The diagnostic and prognostic value of pl-GFAP is inferior to established neurodegeneration biomarkers. Nonetheless, pl-GFAP noninvasively detects neuroinflammation and neurodegeneration in sCJD, warranting potential applications in disease monitoring.
Topics: Humans; Creutzfeldt-Jakob Syndrome; Female; Male; Glial Fibrillary Acidic Protein; Aged; Middle Aged; Prognosis; tau Proteins; Biomarkers; Dementia; Amyloid beta-Peptides; Neurofilament Proteins; Disease Progression; 14-3-3 Proteins
PubMed: 38791145
DOI: 10.3390/ijms25105106 -
International Journal of Alzheimer's... 2024Neurodegenerative disorders such as Alzheimer's disease (AD) represent an increasingly significant public health concern. As clinical diagnosis faces challenges,... (Review)
Review
Neurodegenerative disorders such as Alzheimer's disease (AD) represent an increasingly significant public health concern. As clinical diagnosis faces challenges, biomarkers are becoming increasingly important in research, trials, and patient assessments. While biomarkers like amyloid- peptide, tau proteins, CSF levels (A, tau, and p-tau), and neuroimaging techniques are commonly used in AD diagnosis, they are often limited and invasive in monitoring and diagnosis. For this reason, blood-based biomarkers are the optimal choice for detecting neurodegeneration in brain diseases due to their noninvasiveness, affordability, reliability, and consistency. This literature review focuses on plasma neurofilament light (NfL) and CSF NfL as blood-based biomarkers used in recent AD diagnosis. The findings revealed that the core CSF biomarkers of neurodegeneration (T-tau, P-tau, and A42), CSF NFL, and plasma T-tau were strongly associated with Alzheimer's disease, and the core biomarkers were strongly associated with mild cognitive impairment due to Alzheimer's disease. Elevated levels of plasma and cerebrospinal fluid NfL were linked to decreased [18F]FDG uptake in corresponding brain areas. In participants with A positivity (A+), NfL correlated with reduced metabolism in regions susceptible to Alzheimer's disease. In addition, CSF NfL levels correlate with brain atrophy and predict cognitive changes, while plasma total tau does not. Plasma P-tau, especially in combination with A42/A40, is promising for symptomatic AD stages. Though not AD-exclusive, blood NfL holds promise for neurodegeneration detection and assessing treatment efficacy. Given the consistent levels of T-tau, P-tau, A42, and NFL in CSF, their incorporation into both clinical practice and research is highly recommended.
PubMed: 38779175
DOI: 10.1155/2024/6668159 -
Behavioral and Brain Functions : BBF May 2024Subjective cognitive decline (SCD) is an early stage of dementia linked to Alzheimer's disease pathology. White matter changes were found in SCD using diffusion tensor...
BACKGROUND
Subjective cognitive decline (SCD) is an early stage of dementia linked to Alzheimer's disease pathology. White matter changes were found in SCD using diffusion tensor imaging, but there are known limitations in voxel-wise tensor-based methods. Fixel-based analysis (FBA) can help understand changes in white matter fibers and how they relate to neurodegenerative proteins and multidomain behavior data in individuals with SCD.
METHODS
Healthy adults with normal cognition were recruited in the Northeastern Taiwan Community Medicine Research Cohort in 2018-2022 and divided into SCD and normal control (NC). Participants underwent evaluations to assess cognitive abilities, mental states, physical activity levels, and susceptibility to fatigue. Neurodegenerative proteins were measured using an immunomagnetic reduction technique. Multi-shell diffusion MRI data were collected and analyzed using whole-brain FBA, comparing results between groups and correlating them with multidomain assessments.
RESULTS
The final enrollment included 33 SCD and 46 NC participants, with no significant differences in age, sex, or education between the groups. SCD had a greater fiber-bundle cross-section than NC (pFWE < 0.05) at bilateral frontal superior longitudinal fasciculus II (SLFII). These white matter changes correlate negatively with plasma Aβ42 level (r = -0.38, p = 0.01) and positively with the AD8 score for subjective cognitive complaints (r = 0.42, p = 0.004) and the Hamilton Anxiety Rating Scale score for the degree of anxiety (Ham-A, r = 0.35, p = 0.019). The dimensional analysis of FBA metrics and blood biomarkers found positive correlations of plasma neurofilament light chain with fiber density at the splenium of corpus callosum (pFWE < 0.05) and with fiber-bundle cross-section at the right thalamus (pFWE < 0.05). Further examination of how SCD grouping interacts between the correlations of FBA metrics and multidomain assessments showed interactions between the fiber density at the corpus callosum with letter-number sequencing cognitive score (pFWE < 0.01) and with fatigue to leisure activities (pFWE < 0.05).
CONCLUSION
Based on FBA, our investigation suggests white matter structural alterations in SCD. The enlargement of SLFII's fiber cross-section is linked to plasma Aβ42 and neuropsychiatric symptoms, which suggests potential early axonal dystrophy associated with Alzheimer's pathology in SCD. The splenium of the corpus callosum is also a critical region of axonal degeneration and cognitive alteration for SCD.
Topics: Humans; Male; Female; White Matter; Cognitive Dysfunction; Biomarkers; Middle Aged; Aged; Diffusion Tensor Imaging; Amyloid beta-Peptides; Adult; Cohort Studies; Diagnostic Self Evaluation
PubMed: 38778325
DOI: 10.1186/s12993-024-00238-x -
Heliyon May 2024Neurofilaments are neuron specific skeleton proteins maintaining axon transduction speed, leaked into cerebrospinal fluid and serum after axonal injury or neuron death....
BACKGROUND
Neurofilaments are neuron specific skeleton proteins maintaining axon transduction speed, leaked into cerebrospinal fluid and serum after axonal injury or neuron death. Sleep duration change has long related to many health issues but lack laboratory examination.
METHODS
This study enrolled total 10,175 participants from 2013 to 2014 National Health and Nutrition Examination Survey and used a multi-variable linear model to analyze the relationship between sleep duration and serum neurofilament light chain (sNfL) level.
RESULTS
There was a fixed relationship between sleep duration and sNfL level (β = 0.65, = 0.0280). After adjusted for covariates, this relationship still (β = 0.82, = 0.0052). Segmented regression showed that the turning point of sleep duration was 7 h 1 h decrease in sleep duration was significantly associated with -1.26 higher sNfL level (95 % CI: 2.25, -0.28; = 0.0115) when sleep duration <7 h; however, 1 h increase in sleep duration was significantly associated with 3.20 higher sNfL level (95 % CI: 2.13, 4.27; < 0.0001) when sleep duration >7 h. Furthermore, the stratified analysis indicated that the associations between sleep duration and sNfL level were stronger among those normal body mass index and trouble sleeping (-interaction <0.0001 and 0.0003).
CONCLUSION
In summary, there was a J-shaped relationship between sleep duration and sNfL level in the United States of America representative group, these may suggest that extreme sleep duration can be deleterious judged by sNfL level. And still need large cohort study to determine the accurate relationship, and cluster analysis to infer the nervous disease connected with extreme sleep duration.
PubMed: 38770343
DOI: 10.1016/j.heliyon.2024.e30699 -
Nature Communications May 2024The multifaceted nature of multiple sclerosis requires quantitative biomarkers that can provide insights related to diverse physiological pathways. To this end,...
The multifaceted nature of multiple sclerosis requires quantitative biomarkers that can provide insights related to diverse physiological pathways. To this end, proteomic analysis of deeply-phenotyped serum samples, biological pathway modeling, and network analysis were performed to elucidate inflammatory and neurodegenerative processes, identifying sensitive biomarkers of multiple sclerosis disease activity. Here, we evaluated the concentrations of > 1400 serum proteins in 630 samples from three multiple sclerosis cohorts for association with clinical and radiographic new disease activity. Twenty proteins were associated with increased clinical and radiographic multiple sclerosis disease activity for inclusion in a custom assay panel. Serum neurofilament light chain showed the strongest univariate correlation with gadolinium lesion activity, clinical relapse status, and annualized relapse rate. Multivariate modeling outperformed univariate for all endpoints. A comprehensive biomarker panel including the twenty proteins identified in this study could serve to characterize disease activity for a patient with multiple sclerosis.
Topics: Humans; Biomarkers; Multiple Sclerosis; Female; Male; Adult; Proteomics; Middle Aged; Neurofilament Proteins; Blood Proteins; Magnetic Resonance Imaging; Inflammation; Cohort Studies
PubMed: 38769309
DOI: 10.1038/s41467-024-48602-9 -
Alzheimer's Research & Therapy May 2024Alzheimer's disease (AD) is characterized by the accumulation of amyloid-β (Aβ) plaques, neurofibrillary tau tangles, and neurodegeneration in the brain parenchyma....
Blood biomarkers of neurodegeneration associate differently with amyloid deposition, medial temporal atrophy, and cerebrovascular changes in APOE ε4-enriched cognitively unimpaired elderly.
BACKGROUND
Alzheimer's disease (AD) is characterized by the accumulation of amyloid-β (Aβ) plaques, neurofibrillary tau tangles, and neurodegeneration in the brain parenchyma. Here, we aimed to (i) assess differences in blood and imaging biomarkers used to evaluate neurodegeneration among cognitively unimpaired APOE ε4 homozygotes, heterozygotes, and non-carriers with varying risk for sporadic AD, and (ii) to determine how different cerebral pathologies (i.e., Aβ deposition, medial temporal atrophy, and cerebrovascular pathology) contribute to blood biomarker concentrations in this sample.
METHODS
Sixty APOE ε4 homozygotes (n = 19), heterozygotes (n = 21), and non-carriers (n = 20) ranging from 60 to 75 years, were recruited in collaboration with Auria biobank (Turku, Finland). Participants underwent Aβ-PET ([C]PiB), structural brain MRI including T1-weighted and T2-FLAIR sequences, and blood sampling for measuring serum neurofilament light chain (NfL), plasma total tau (t-tau), plasma N-terminal tau fragments (NTA-tau) and plasma glial fibrillary acidic protein (GFAP). [C]PiB standardized uptake value ratio was calculated for regions typical for Aβ accumulation in AD. MRI images were analysed for regional volumes, atrophy scores, and volumes of white matter hyperintensities. Differences in biomarker levels and associations between blood and imaging biomarkers were tested using uni- and multivariable linear models (unadjusted and adjusted for age and sex).
RESULTS
Serum NfL concentration was increased in APOE ε4 homozygotes compared with non-carriers (mean 21.4 pg/ml (SD 9.5) vs. 15.5 pg/ml (3.8), p = 0.013), whereas other blood biomarkers did not differ between the groups (p > 0.077 for all). From imaging biomarkers, hippocampal volume was significantly decreased in APOE ε4 homozygotes compared with non-carriers (6.71 ml (0.86) vs. 7.2 ml (0.7), p = 0.029). In the whole sample, blood biomarker levels were differently predicted by the three measured cerebral pathologies; serum NfL concentration was associated with cerebrovascular pathology and medial temporal atrophy, while plasma NTA-tau associated with medial temporal atrophy. Plasma GFAP showed significant association with both medial temporal atrophy and Aβ pathology. Plasma t-tau concentration did not associate with any of the measured pathologies.
CONCLUSIONS
Only increased serum NfL concentrations and decreased hippocampal volume was observed in cognitively unimpaired APOEε4 homozygotes compared to non-carriers. In the whole population the concentrations of blood biomarkers were affected in distinct ways by different pathologies.
Topics: Humans; Female; Male; Aged; Biomarkers; Atrophy; Middle Aged; Apolipoprotein E4; tau Proteins; Positron-Emission Tomography; Amyloid beta-Peptides; Magnetic Resonance Imaging; Neurofilament Proteins; Temporal Lobe; Alzheimer Disease; Heterozygote; Glial Fibrillary Acidic Protein; Aniline Compounds; Thiazoles
PubMed: 38762725
DOI: 10.1186/s13195-024-01477-w -
Neuroscience May 2024It is increasingly evident that blood biomarkers have potential to improve the diagnosis and management of both acute and chronic neurological disorders. The most...
It is increasingly evident that blood biomarkers have potential to improve the diagnosis and management of both acute and chronic neurological disorders. The most well-studied candidates, and arguably those with the broadest utility, are proteins that are highly enriched in neural tissues and released into circulation upon cellular damage. It is currently unknown how the brain expression levels of these proteins is influenced by demographic factors such as sex, race, and age. Given that source tissue abundance is likely a key determinant of the levels observed in the blood during neurological pathology, understanding such influences is important in terms of identifying potential clinical scenarios that could produce diagnostic bias. In this study, we leveraged existing mRNA sequencing data originating from 2,642 normal brain specimens harvested from 382 human donors to examine potential demographic variability in the expression levels genes which code for 28 candidate blood biomarkers of neurological damage. Existing mass spectrometry data originating from 26 additional normal brain specimens harvested from 26 separate human donors was subsequently used to tentatively assess whether observed transcriptional variance was likely to produce corresponding variance in terms of protein abundance. Genes associated with several well-studied or emerging candidate biomarkers including neurofilament light chain (NfL), ubiquitin carboxyl-terminal hydrolase isozyme L1 (UCH-L1), neuron-specific enolase (NSE), and synaptosomal-associated protein 25 (SNAP-25) exhibited significant differences in expression with respect to sex, race, and age. In many instances, these differences in brain expression align well with and provide a mechanistic explanation for previously reported differences in blood levels.
PubMed: 38762083
DOI: 10.1016/j.neuroscience.2024.05.017 -
Scientific Reports May 2024We aimed to assess diagnostic accuracy of plasma p-tau181 and NfL separately and in combination in discriminating Subjective Cognitive Decline (SCD) and Mild Cognitive...
Future perspective and clinical applicability of the combined use of plasma phosphorylated tau 181 and neurofilament light chain in Subjective Cognitive Decline and Mild Cognitive Impairment.
We aimed to assess diagnostic accuracy of plasma p-tau181 and NfL separately and in combination in discriminating Subjective Cognitive Decline (SCD) and Mild Cognitive Impairment (MCI) patients carrying Alzheimer's Disease (AD) pathology from non-carriers; to propose a flowchart for the interpretation of the results of plasma p-tau181 and NfL. We included 43 SCD, 41 MCI and 21 AD-demented (AD-d) patients, who underwent plasma p-tau181 and NfL analysis. Twenty-eight SCD, 41 MCI and 21 AD-d patients underwent CSF biomarkers analysis (Aβ1-42, Aβ1-42/1-40, p-tau, t-tau) and were classified as carriers of AD pathology (AP+) it they were A+/T+ , or non-carriers (AP-) when they were A-, A+/T-/N-, or A+/T-/N+ according to the A/T(N) system. Plasma p-tau181 and NfL separately showed a good accuracy (AUC = 0.88), while the combined model (NfL + p-tau181) showed an excellent accuracy (AUC = 0.92) in discriminating AP+ from AP- patients. Plasma p-tau181 and NfL results were moderately concordant (Coehn's k = 0.50, p < 0.001). Based on a logistic regression model, we estimated the risk of AD pathology considering the two biomarkers: 10.91% if both p-tau181 and NfL were negative; 41.10 and 76.49% if only one biomarker was positive (respectively p-tau18 and NfL); 94.88% if both p-tau181 and NfL were positive. Considering the moderate concordance and the risk of presenting an underlying AD pathology according to the positivity of plasma p-tau181 and NfL, we proposed a flow chart to guide the combined use of plasma p-tau181 and NfL and the interpretation of biomarker results to detect AD pathology.
Topics: Humans; tau Proteins; Cognitive Dysfunction; Male; Female; Neurofilament Proteins; Aged; Biomarkers; Phosphorylation; Alzheimer Disease; Middle Aged; Amyloid beta-Peptides
PubMed: 38760423
DOI: 10.1038/s41598-024-61655-6 -
Alzheimer's Research & Therapy May 2024Plasma biomarkers of Alzheimer's disease (AD) pathology, neurodegeneration, and neuroinflammation are ideally suited for secondary prevention programs in self-sufficient... (Comparative Study)
Comparative Study
BACKGROUND
Plasma biomarkers of Alzheimer's disease (AD) pathology, neurodegeneration, and neuroinflammation are ideally suited for secondary prevention programs in self-sufficient persons at-risk of dementia. Plasma biomarkers have been shown to be highly correlated with traditional imaging biomarkers. However, their comparative predictive value versus traditional AD biomarkers is still unclear in cognitively unimpaired (CU) subjects and with mild cognitive impairment (MCI).
METHODS
Plasma (Aβ42/40, p-tau181, p-tau231, NfL, and GFAP) and neuroimaging (hippocampal volume, centiloid of amyloid-PET, and tau-SUVR of tau-PET) biomarkers were assessed at baseline in 218 non-demented subjects (CU = 140; MCI = 78) from the Geneva Memory Center. Global cognition (MMSE) was evaluated at baseline and at follow-ups up to 5.7 years. We used linear mixed-effects models and Cox proportional-hazards regression to assess the association between biomarkers and cognitive decline. Lastly, sample size calculations using the linear mixed-effects models were performed on subjects positive for amyloid-PET combined with tau-PET and plasma biomarker positivity.
RESULTS
Cognitive decline was significantly predicted in MCI by baseline plasma NfL (β=-0.55), GFAP (β=-0.36), hippocampal volume (β = 0.44), centiloid (β=-0.38), and tau-SUVR (β=-0.66) (all p < 0.05). Subgroup analysis with amyloid-positive MCI participants also showed that only NfL and GFAP were the only significant predictors of cognitive decline among plasma biomarkers. Overall, NfL and tau-SUVR showed the highest prognostic values (hazard ratios of 7.3 and 5.9). Lastly, we demonstrated that adding NfL to the inclusion criteria could reduce the sample sizes of future AD clinical trials by up to one-fourth in subjects with amyloid-PET positivity or by half in subjects with amyloid-PET and tau-PET positivity.
CONCLUSIONS
Plasma NfL and GFAP predict cognitive decline in a similar manner to traditional imaging techniques in amyloid-positive MCI patients. Hence, even though they are non-specific biomarkers of AD, both can be implemented in memory clinic workups as important prognostic biomarkers. Likewise, future clinical trials might employ plasma biomarkers as additional inclusion criteria to stratify patients at higher risk of cognitive decline to reduce sample sizes and enhance effectiveness.
Topics: Humans; Male; Female; Biomarkers; Cognitive Dysfunction; Aged; tau Proteins; Amyloid beta-Peptides; Positron-Emission Tomography; Middle Aged; Neuroimaging; Neurofilament Proteins; Hippocampus; Peptide Fragments; Glial Fibrillary Acidic Protein
PubMed: 38755703
DOI: 10.1186/s13195-024-01478-9