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We have developed model S40RTS of shear-velocity variation in Earth's mantle using a new collection of Rayleigh wave phase velocity, teleseismic body-wave traveltime and normal-mode splitting function measurements. This data set is an order of magnitude larger than used for S20RTS and includes new data types. The data are related to shear-velocity perturbations from the (anisotropic) PREM model via kernel functions and ray paths that are computed using PREM. Contributions to phase delays and traveltimes from the heterogeneous crust are estimated using model CRUST2.0. We calculate crustal traveltimes from long-period synthetic waveforms rather than using ray theory. Shear-velocity perturbations are parametrized by spherical harmonics up to degree 40 and by 21 vertical spline functions for a total of 35 301 degrees of freedom. S40RTS is characterised by 8000 resolved unknowns. Since we compute the exact inverse, it is straightforward to determine models associated with fewer or more unknowns by adjusting the model damping. S40RTS shares many characteristics with S20RTS because it is based on the same data types and similar modelling procedures. However, S40RTS shows more clearly than S20RTS the abrupt change in the pattern of shear-velocity heterogeneity across the 660-km phase transition and it presents a more complex patern of shear-velocity heterogeneity in the lower mantle. Utilities to visualise S40RTS and software to analyse the resolution of S40RTS (or models for different damping parameters) are made available. [ABSTRACT FROM AUTHOR]

Background: Frontotemporal dementia (FTD) is pathologically heterogeneous, sometimes revealing intraneuronal inclusions of neurofilaments. We therefore measured CSF neurofilament profiles in patients with FTD, patients with early onset Alzheimer's disease (EAD) and healthy control subjects to explore the discriminative potential of CSF neurofilaments compared with the existing CSF biomarkers amyloid-beta(1-42), tau and tau phosphorylated at threonine-181. Methods: CSF levels of light chain, heavy chain and hyperphosphorylated heavy chain neurofilaments (NfL, t-NfH and P-NfH) were compared between 17 subjects with FTD, 20 with EAD and 25 cognitively healthy controls. Results: A subgroup of FTD patients had remarkably high CSF levels of both NfL and NfH. The degree of NfH phosphorylation was increased in FTD compared to both other groups. The levels of CSF NfL were significantly higher in EAD compared to controls. Conclusion: Differences in CSF biomarker profiles might reflect differential involvement of neurofilaments and tau in FTD and EAD. The subgroup of FTD patients with high CSF neurofilament levels may have a different neuropathological substrate and future studies addressing this specific issue are needed. Copyright (c) 2007 S. Karger AG, Basel. [ABSTRACT FROM AUTHOR]

Background: Neurofilament light chain (NfL) is a biomarker for axonal damage in several neurological disorders. We studied the longitudinal changes in serum NfL in patients with Guillain-Barré syndrome (GBS) in relation to disease severity, electrophysiological subtype, treatment response, and prognosis., Methods: We included patients with GBS who participated in a double-blind, randomised, placebo-controlled trial that evaluated the effects of a second course of intravenous immunoglobulin (IVIg) on clinical outcomes. Serum NfL levels were measured before initiation of treatment and at one, two, four, and twelve weeks using a Simoa HD-X Analyzer. Serum NfL dynamics were analysed using linear mixed-effects models. Logistic regression was employed to determine the associations of serum NfL with clinical outcome and the prognostic value of serum NfL after correcting for known prognostic markers included in the modified Erasmus GBS Outcome Score (mEGOS)., Findings: NfL levels were tested in serum from 281 patients. Serum NfL dynamics were associated with disease severity and electrophysiological subtype. Strong associations were found between high levels of serum NfL at two weeks and inability to walk unaided at four weeks (OR = 1.74, 95% CI = 1.27-2.45), and high serum NfL levels at four weeks and inability to walk unaided at 26 weeks (OR = 2.79, 95% CI = 1.72-4.90). Baseline serum NfL had the most significant prognostic value for ability to walk, independent of predictors included in the mEGOS. The time to regain ability to walk unaided was significantly longer for patients with highest serum NfL levels at baseline (p = 0.0048) and week 2 (p < 0.0001). No differences in serum NfL were observed between patients that received a second IVIg course vs. IVIg and placebo., Interpretation: Serum NfL levels are associated with disease severity, axonal involvement, and poor outcome in GBS. Serum NfL potentially represents a biomarker to monitor neuronal damage in GBS and an intermediate endpoint to evaluate the effects of treatment., Funding: Prinses Beatrix Spierfonds W.OR19-24., Competing Interests: Declaration of interests Research of CT is supported by the European Commission (Marie Curie International Training Network, grant agreement No 860197 (MIRIADE), Innovative Medicines Initiatives 3TR (Horizon 2020, grant no 831434) EPND (IMI 2 Joint Undertaking (JU), grant No. 101034344) and JPND (bPRIDE), National MS Society (Progressive MS alliance), Alzheimer Drug Discovery Foundation, Alzheimer Association, Health Holland, the Dutch Research Council (ZonMW), The Selfridges Group Foundation, Alzheimer Netherlands. CT is recipient of ABOARD, which is a public-private partnership receiving funding from ZonMW2 (#73305095007) and Health ∼ Holland, Topsector Life Sciences & Health (PPP-allowance; #LSHM20106). CT is recipient of TAP-dementia, a ZonMw funded project (#10510032120003) in the context of the Dutch National Dementia Strategy. CT performed contract research for ADx Neurosciences, AC-Immune, Aribio, Axon Neurosciences, Beckman–Coulter, BioConnect, Bioorchestra, Brainstorm Therapeutics, Celgene, Cognition Therapeutics, EIP Pharma, Eisai, Eli Lilly Fujirebio, Grifols, Instant Nano Biosensors, Merck, Novo Nordisk, Olink, PeopleBio, Quanterix, Roche, Siemens, Toyama, and Vivoryon. CT received payment or honoraria for lectures, presentations or educational events from Roche, Novo Nordisk and Grifols. All payments were made to her institution. CT serves on editorial boards of Medidact Neurologie/Springer; and in Neurology: Neuroimmunology & Neuroinflammation. She is editor of Alzheimer Research and Therapy. RH reports institutional funding from the GBS-CIDP Foundation International, Stichting GBS, T2B collaboration project funded by PPP Allowance made available by Top Sector Life Sciences & Health to Samenwerkende Gezondheidsfondsen (SGF) under project number LSHM18055-SGF to stimulate public-private partnerships and co-financing by health foundations that are part of the SGF, NIH, and PANDIA collaboration project co-funded by BÜHLMANN Laboratories AG and the PPP Allowance made available by Health ∼ Holland, Top Sector Life Sciences & Health, to Prinses Beatrix Spierfonds to stimulate public-private partnerships under project number LSHM23017-SGF. She serves as editorial board member of the Journal of the Peripheral Nervous System and was board member of the Inflammatory Neuropathy Consortium. PD reports grants from the Prinses Beatrix Spierfonds and Sanquin to conduct the SID-GBS trial. PD reports consulting fees from Annexon and Roche, all paid to the institution. PD participates on a Data Safety Monitoring Board or Advisory Board for Argenx, Hansa, Octapharma and Sanofi. All fees go to the institution. He reports an unpaid leadership role in the Peripheral Nerve Society (PNS) and serves on the Medical advisory board for the GBS/CIDP Foundation International. BJ reports institutional funding from the GBS-CIDP Foundation International, Stichting GBS, Horizon 2020 (EU), Grifols, CSL-Behring, Annexon, Hoffmann-la Roche, Hansa Biopharma, BÜHLMANN Laboratories. BJ received institutional royalties, licences or consulting fees from Hansa Biopharma, Annexon and Hoffmann-la Roche. BJ received support from the GBS-CIDP Foundation International to cover travel expenses for their conference. BJ serves an unpaid role in the global Medical advisory board for the GBS-CIDP Foundation International, in the scientific review committee of Stichting MS research, and the scientific review committee of the Erasmus MC. All other authors declare no competing interests., (Copyright © 2024 The Author(s). Published by Elsevier B.V. All rights reserved.)

Background: Neurofilament light (NfL) has been identified as a biomarker for neuroaxonal damage in preterm infants, but its relation with bronchopulmonary dysplasia (BPD) has not been established. We hypothesized that BPD is associated with increased NfL levels at an early stage, indicative of early neuroaxonal damage., Methods: We included preterm infants born <30 weeks of gestation for assessment of NfL levels from cord blood and blood obtained at postnatal days 3, 7, 14, and 28. We used linear regression analysis to compare NfL levels between infants with moderate/severe BPD and infants with no/mild BPD, and linear mixed model analysis to compare the effect of time on NfL levels between groups., Results: Sixty-seven infants with a gestational age (GA) of 27 ± 1.3 weeks were included for analysis, of whom 19 (28%) developed moderate/severe BPD. Although NfL levels were higher at every time point in infants with BPD, statistical significance was lost after adjustment for GA, small for gestational age (SGA) and intraventricular hemorrhage (IVH). Groups did not differ in NfL change over time., Conclusions: The positive association between BPD and NfL in the first weeks of life could be explained by GA, SGA and IVH rather than by development of BPD., Impact: Neurofilament light chain (NfL) is a known biomarker for neuroaxonal damage. Biomarkers for brain damage during the first weeks of life in preterm infants developing BPD are lacking. NfL levels obtained during the first weeks of life did not differ between infants with and without BPD in analyses adjusted for GA, SGA, and IVH., (© 2022. The Author(s), under exclusive licence to the International Pediatric Research Foundation, Inc.)

The clinical overlap of frontotemporal dementia and primary psychiatric diseases hampers diagnostic distinction, leading to frequent misdiagnosis and diagnostic delay. Neurofilament light chain has shown great potential in CSF and blood for the distinction of frontotemporal dementia from primary psychiatric diseases. Measurement of neurofilament light chain in urine would be even more patient-friendly. We aimed to test the performance of neurofilament light chain urine measurements for diagnostics in frontotemporal dementia and to assess their correlation with serum levels. Fifty-five subjects ( n = 19 frontotemporal dementia, n = 19 primary psychiatric diseases and n = 17 controls) were included with available paired urine and serum samples. All subjects underwent standardized extensive diagnostic assessment. Samples were analysed with the ultrasensitive single molecule array neurofilament light chain assay. Neurofilament light chain group comparisons were performed adjusted for age, sex and geriatric depression scale. In the majority of the cohort, neurofilament light chain concentrations were not detectable in urine ( n = 6 samples above lower limit of detection (0.038 pg/ml): n = 5 frontotemporal dementia, n = 1 primary psychiatric disease). The frequency of a detectable neurofilament light chain level in urine in the frontotemporal dementia group did not differ from psychiatric disorders (Fisher Exact-test P = 0.180). In the individuals with detectable urine neurofilament light chain values, there was no correlation between the urine and serum neurofilament light chain levels. As expected, serum neurofilament light chain levels were higher in frontotemporal dementia compared to primary psychiatric diseases and controls ( P < 0.001), adjusted for age, sex and geriatric depression scale. Receiver operating characteristic curve analysis of serum neurofilament light chain of frontotemporal dementia versus primary psychiatric diseases showed an area under the curve of 0.978 95% confidence interval 0.941-1.000, P < 0.001. Urine is not suitable as a matrix for neurofilament light chain analysis and serum neurofilament light chain is still the most patient-friendly matrix for differentiation between frontotemporal dementia and primary psychiatric diseases., Competing Interests: The authors report no competing interests., (© The Author(s) 2023. Published by Oxford University Press on behalf of the Guarantors of Brain.)

Diagnosing central nervous system (CNS) infections quickly is often difficult. Neurofilament light chain (NfL) is a component of the axonal cytoskeleton and identified as marker of neuronal damage in several CNS diseases. We evaluated the diagnostic accuracy of NfL for diagnosing CNS infections. We included patients from a prospective cohort of consecutive patients in whom a lumbar puncture was performed for suspected CNS infection in an academic hospital in The Netherlands. The index test was NfL in cerebrospinal fluid (CSF) and reference standard the final clinical diagnosis. Diagnostic accuracy was determined using the area-under-the-curve (AUC) with 95% confidence intervals (CI). The association of CSF NfL with clinical characteristics, diagnosis and outcome was evaluated. Between 2012 and 2015, 273 episodes in adults of which sufficient CSF was available were included. CNS infection was diagnosed in 26%(n = 70), CNS inflammatory disease in 7%(n = 20), systemic infection in 32%(n = 87), and other neurological disorders in 33%(n = 90). Median CSF NfL level was 593 pg/ml (IQR 249-1569) and did not discriminate between diagnostic categories or CNS infection subcategories. AUC for diagnosing any CNS infection compared to patients without CNS infections was 0.50 (95% CI 0.42-0.59). Patients presenting with an altered mental status had higher NfL levels compared to other patients. We concluded that NfL cannot discriminate between causes in patients suspected of CNS infections. High concentrations of NfL are associated with severe neurological disease and the prognostic value of NfL in patients with CNS infections should be investigated in future research., (© 2022. The Author(s).)

Metachromatic leukodystrophy is a lethal metabolic leukodystrophy, with emerging treatments for early disease stages. Biomarkers to measure disease activity are required for clinical assessment and treatment follow-up. This retrospective study compared neurofilament light chain and glial fibrillary acidic protein (GFAP) levels in CSF (n = 11) and blood (n = 92) samples of 40 patients with metachromatic leukodystrophy (aged 0-42 years) with 38 neurologically healthy children (aged 0-17 years) and 38 healthy adults (aged 18-45 years), and analysed the associations between these levels with clinical phenotype and disease evolution in untreated and transplanted patients. Metachromatic leukodystrophy subtype was determined based on the (expected) age of symptom onset. Disease activity was assessed by measuring gross motor function deterioration and brain MRI. Longitudinal analyses with measurements up to 23 years after diagnosis were performed using linear mixed models. CSF and blood neurofilament light chain and GFAP levels in paediatric controls were negatively associated with age (all P < 0.001). Blood neurofilament light chain level at diagnosis (median, interquartile range; picograms per millilitre) was significantly increased in both presymptomatic (14.7, 10.6-56.7) and symptomatic patients (136, 40.8-445) compared to controls (5.6, 4.5-7.1), and highest among patients with late-infantile (456, 201-854) or early-juvenile metachromatic leukodystrophy (291.0, 104-445) and those ineligible for treatment based on best practice (291, 57.4-472). GFAP level (median, interquartile range; picogram per millilitre) was only increased in symptomatic patients (591, 224-1150) compared to controls (119, 78.2-338) and not significantly associated with treatment eligibility (P = 0.093). Higher blood neurofilament light chain and GFAP levels at diagnosis were associated with rapid disease progression in late-infantile (P = 0.006 and P = 0.051, respectively) and early-juvenile patients (P = 0.048 and P = 0.039, respectively). Finally, blood neurofilament light chain and GFAP levels decreased during follow-up in untreated and transplanted patients but remained elevated compared with controls. Only neurofilament light chain levels were associated with MRI deterioration (P < 0.001). This study indicates that both proteins may be considered as non-invasive biomarkers for clinical phenotype and disease stage at clinical assessment, and that neurofilament light chain might enable neurologists to make better informed treatment decisions. In addition, neurofilament light chain holds promise assessing treatment response. Importantly, both biomarkers require paediatric reference values, given that their levels first decrease before increasing with advancing age., (© The Author(s) (2021). Published by Oxford University Press on behalf of the Guarantors of Brain.)

Plasma biomarkers that reflect specific amyloid beta (Abeta) proteoforms provide an insight in the treatment effects of Alzheimer's disease (AD) therapies. Our aim was to develop and validate ready-to-use Simoa 'Amyblood' assays that measure full length Abeta 1-42 and Abeta 1-40 and compare their performance with two commercial assays. Linearity, intra- and inter-assay %CV were compared between Amyblood, Quanterix Simoa triplex, and Euroimmun ELISA. Sensitivity and selectivity were assessed for Amyblood and the Quanterix triplex. Clinical performance was assessed in CSF biomarker confirmed AD (n = 43, 68 ± 6 years) and controls (n = 42, 62 ± 5 years). Prototype and Amyblood showed similar calibrator curves and differentiation (20 AD vs 20 controls, p < 0.001). Amyblood, Quanterix triplex, and ELISA showed similar linearity (96%-122%) and intra-assay %CVs (≤ 3.1%). A minor non-specific signal was measured with Amyblood of + 2.4 pg/mL Abeta 1-42 when incubated with 60 pg/mL Abeta 1-40 . A substantial non-specific signal of + 24.7 pg/mL Abeta x-42 was obtained when 40 pg/mL Abeta 3-42 was measured with the Quanterix triplex. Selectivity for Abeta 1-42 at physiological Abeta 1-42 and Abeta 1-40 concentrations was 125% for Amyblood and 163% for Quanterix. Amyblood and Quanterix ratios (p < 0.001) and ELISA Abeta 1-42 concentration (p = 0.025) could differentiate AD from controls. We successfully developed and upscaled a prototype to the Amyblood assays with similar technical and clinical performance as the Quanterix triplex and ELISA, but better specificity and selectivity than the Quanterix triplex assay. These results suggest leverage of this specific assay for monitoring treatment response in trials.

Objective: We investigated the association of plasma amyloid beta (Abeta)40, Abeta42, and total tau (tTau) with the presence of Alzheimer pathological changes in cognitively normal individuals with subjective cognitive decline (SCD)., Methods: We included 248 subjects with SCD (61 ± 9 years, 42% female, Mini-Mental State Examination = 28 ± 2) from the SCIENCe project and Amsterdam Dementia Cohort. Subjects were dichotomized as amyloid abnormal by cerebrospinal fluid (CSF) and positron emission tomography (PET). Baseline plasma Abeta40, Abeta42, and tTau were measured using Simoa technology. Associations between plasma levels and amyloid status were assessed using logistic regression analyses and receiver operating characteristic analyses. Association of plasma levels with risk of clinical progression to mild cognitive impairment (MCI) or dementia was assessed using Cox proportional hazard models., Results: Fifty-seven (23%) subjects were CSF-amyloid abnormal. Plasma Abeta42/Abeta40 ratio and plasma Abeta42 alone, but not tTau, identified abnormal CSF-amyloid status (plasma ratio: area under the curve [AUC] = 77%, 95% confidence interval [CI] = 69-84%; plasma Abeta42: AUC = 66%, 95% CI: 58-74%). Combining plasma ratio with age and apolipoprotein E resulted in AUC = 83% (95% CI = 77-89%). The Youden cutoff of the plasma ratio gave a sensitivity of 76% and specificity of 75%, and applying this as a prescreener would reduce the number of lumbar punctures by 51%. Using PET as outcome, a comparable reduction in number of PET scans would be achieved when applying the plasma ratio as prescreener. In addition, low plasma ratio was associated with clinical progression to MCI or dementia (hazard ratio = 2.0, 95% CI = 1.4-2.3)., Interpretation: Plasma Abeta42/Abeta40 ratio has potential as a prescreener to identify Alzheimer pathological changes in cognitively normal individuals with SCD. Ann Neurol 2018;84:656-666., (© 2018 The Authors. Annals of Neurology published by Wiley Periodicals, Inc. on behalf of American Neurological Association.)

Systematic analyses of earthquake-generated seismic waves have resulted in models of three-dimensional elastic wavespeed structure in Earth's mantle. This paper describes the development and the dominant characteristics of one of the most recently developed models. This model is based on seismic wave travel times and wave shapes from over 100,000 ground motion recordings of earthquakes that occurred between 1980 and 1998. It shows signatures of plate tectonic processes to a depth of about 1,200 km in the mantle, and it demonstrates the presence of large-scale structure throughout the lower 2,000 km of the mantle. Seismological analyses make it increasingly more convincing that geologic processes shaping Earth's surface are intimately linked to physical processes in the deep mantle.