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- Meier, S, et al.
(författare)
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Serum Glial Fibrillary Acidic Protein Compared With Neurofilament Light Chain as a Biomarker for Disease Progression in Multiple Sclerosis
- 2023
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Ingår i: JAMA neurology. - : American Medical Association (AMA). - 2168-6157 .- 2168-6149. ; 80:3, s. 287-297
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Tidskriftsartikel (refereegranskat)abstract
- There is a lack of validated biomarkers for disability progression independent of relapse activity (PIRA) in multiple sclerosis (MS).ObjectiveTo determine how serum glial fibrillary acidic protein (sGFAP) and serum neurofilament light chain (sNfL) correlate with features of disease progression vs acute focal inflammation in MS and how they can prognosticate disease progression.Design, Setting, and ParticipantsData were acquired in the longitudinal Swiss MS cohort (SMSC; a consortium of tertiary referral hospitals) from January 1, 2012, to October 20, 2022. The SMSC is a prospective, multicenter study performed in 8 centers in Switzerland. For this nested study, participants had to meet the following inclusion criteria: cohort 1, patients with MS and either stable or worsening disability and similar baseline Expanded Disability Status Scale scores with no relapses during the entire follow-up; and cohort 2, all SMSC study patients who had initiated and continued B-cell–depleting treatment (ie, ocrelizumab or rituximab).ExposuresPatients received standard immunotherapies or were untreated.Main Outcomes and MeasuresIn cohort 1, sGFAP and sNfL levels were measured longitudinally using Simoa assays. Healthy control samples served as the reference. In cohort 2, sGFAP and sNfL levels were determined cross-sectionally.ResultsThis study included a total of 355 patients (103 [29.0%] in cohort 1: median [IQR] age, 42.1 [33.2-47.6] years; 73 female patients [70.9%]; and 252 [71.0%] in cohort 2: median [IQR] age, 44.3 [33.3-54.7] years; 156 female patients [61.9%]) and 259 healthy controls with a median [IQR] age of 44.3 [36.3-52.3] years and 177 female individuals (68.3%). sGFAP levels in controls increased as a function of age (1.5% per year; P < .001), were inversely correlated with BMI (−1.1% per BMI unit; P = .01), and were 14.9% higher in women than in men (P = .004). In cohort 1, patients with worsening progressive MS showed 50.9% higher sGFAP levels compared with those with stable MS after additional sNfL adjustment, whereas the 25% increase of sNfL disappeared after additional sGFAP adjustment. Higher sGFAP at baseline was associated with accelerated gray matter brain volume loss (per doubling: 0.24% per year; P < .001) but not white matter loss. sGFAP levels remained unchanged during disease exacerbations vs remission phases. In cohort 2, median (IQR) sGFAP z scores were higher in patients developing future confirmed disability worsening compared with those with stable disability (1.94 [0.36-2.23] vs 0.71 [−0.13 to 1.73]; P = .002); this was not significant for sNfL. However, the combined elevation of z scores of both biomarkers resulted in a 4- to 5-fold increased risk of confirmed disability worsening (hazard ratio [HR], 4.09; 95% CI, 2.04-8.18; P < .001) and PIRA (HR, 4.71; 95% CI, 2.05-9.77; P < .001).Conclusions and RelevanceResults of this cohort study suggest that sGFAP is a prognostic biomarker for future PIRA and revealed its complementary potential next to sNfL. sGFAP may serve as a useful biomarker for disease progression in MS in individual patient management and drug development.
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- Disanto, G., et al.
(författare)
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Serum Neurofilament Light: A Biomarker of Neuronal Damage in Multiple Sclerosis
- 2017
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Ingår i: Annals of Neurology. - : Wiley. - 0364-5134. ; 81:6, s. 857-870
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Tidskriftsartikel (refereegranskat)abstract
- Objective: Neurofilament light chains (NfL) are unique to neuronal cells, are shed to the cerebrospinal fluid (CSF), and are detectable at low concentrations in peripheral blood. Various diseases causing neuronal damage have resulted in elevated CSF concentrations. We explored the value of an ultrasensitive single-molecule array (Simoa) serum NfL (sNfL) assay in multiple sclerosis (MS). Methods: sNfL levels were measured in healthy controls (HC, n = 254) and two independent MS cohorts: (1) crosssectional with paired serum and CSF samples (n = 142), and (2) longitudinal with repeated serum sampling (n = 246, median follow-up = 3.1 years, interquartile range [IQR] = 2.0-4.0). We assessed their relation to concurrent clinical, imaging, and treatment parameters and to future clinical outcomes. Results: sNfL levels were higher in both MS cohorts than in HC (p < 0.001). We found a strong association between CSF NfL and sNfL (beta = 0.589, p < 0.001). Patients with either brain or spinal (43.4pg/ ml, IQR = 25.2-65.3) or both brain and spinal gadolinium-enhancing lesions (62.5pg/ml, IQR = 42.7-71.4) had higher sNfL than those without (29.6pg/ml, IQR = 20.9-41.8; beta = 1.461, p = 0.005 and beta = 1.902, p = 0.002, respectively). sNfL was independently associated with Expanded Disability Status Scale (EDSS) assessments (beta = 1.105, p < 0.001) and presence of relapses (beta = 1.430, p < 0.001). sNfL levels were lower under disease-modifying treatment (beta = 0.818, p = 0.003). Patients with sNfL levels above the 80th, 90th, 95th, 97.5th, and 99th HC-based percentiles had higher risk of relapses (97.5th percentile: incidence rate ratio = 1.94, 95% confidence interval [CI] = 1.21-3.10, p = 0.006) and EDSS worsening (97.5th percentile: OR = 2.41, 95% CI = 1.07-5.42, p = 0.034). Interpretation: These results support the value of sNfL as a sensitive and clinically meaningful blood biomarker to monitor tissue damage and the effects of therapies in MS.
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- Wilke, C., et al.
(författare)
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Correlations between serum and CSF pNfH levels in ALS, FTD and controls: A comparison of three analytical approaches
- 2019
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Ingår i: Clinical Chemistry and Laboratory Medicine. - : Walter de Gruyter GmbH. - 1434-6621 .- 1437-4331. ; 57:10, s. 1556-1564
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Tidskriftsartikel (refereegranskat)abstract
- Phosphorylated neurofilament heavy (pNfH), a neuronal cytoskeleton protein, might provide a promising blood biomarker of neuronal damage in neurodegenerative diseases (NDDs). The best analytical approaches to measure pNfH levels and whether serum levels correlate with cerebrospinal fluid (CSF) levels in NDDs remain to be determined. We here compared analytical sensitivity and reliability of three novel analytical approaches (homebrew Simoa, commercial Simoa and ELISA) for quantifying pNfH in both CSF and serum in samples of amyotrophic lateral sclerosis (ALS), frontotemporal dementia (FTD) and control subjects. While all three assays showed highly correlated CSF measurements, Simoa assays also yielded high between-assay correlations for serum measurements (± = 0.95). Serum levels also correlated strongly with CSF levels for Simoa-based measurements (both ± = 0.62). All three assays allowed distinguishing ALS from controls by increased CSF pNfH levels, and Simoa assays also by increased serum pNfH levels. pNfH levels were also increased in FTD. pNfH concentrations in CSF and, if measured by Simoa assays, in blood might provide a sensitive and reliable biomarker of neuronal damage, with good between-assay correlations. Serum pNfH levels measured by Simoa assays closely reflect CSF levels, rendering serum pNfH an easily accessible blood biomarker of neuronal damage in NDDs. ©2019 Walter de Gruyter GmbH, Berlin/Boston.
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- Grazian, A., et al.
(författare)
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Lyman continuum escape fraction of faint galaxies at z similar to 3.3 in the CANDELS/GOODS-North, EGS, and COSMOS fields with LBC
- 2017
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Ingår i: Astronomy and Astrophysics. - : EDP Sciences. - 0004-6361 .- 1432-0746. ; 602
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Tidskriftsartikel (refereegranskat)abstract
- Context. The reionization of the Universe is one of the most important topics of present-day astrophysical research. The most plausible candidates for the reionization process are star-forming galaxies, which according to the predictions of the majority of the theoretical and semi-analytical models should dominate the H I ionizing background at z greater than or similar to 3. Aims. We measure the Lyman continuum escape fraction, which is one of the key parameters used to compute the contribution of star-forming galaxies to the UV background. It provides the ratio between the photons produced at lambda <= 912 angstrom rest-frame and those that are able to reach the inter-galactic medium, i.e. that are not absorbed by the neutral hydrogen or by the dust of the galaxy's inter-stellar medium. Methods. We used ultra-deep U-band imaging (U = 30.2 mag at 1 sigma) from Large Binocular Camera at the Large Binocular Telescope (LBC/LBT) in the CANDELS/GOODS-North field and deep imaging in the COSMOS and EGS fields in order to estimate the Lyman continuum escape fraction of 69 star-forming galaxies with secure spectroscopic redshifts at 3.27 <= z <= 3.40 to faint magnitude limits (L = 0.2L*, or equivalently M-1500 similar to -19). The narrow redshift range implies that the LBC U-band filter exclusively samples the lambda <= 912 angstrom rest-frame wavelengths. Results. We measured through stacks a stringent upper limit (<1.7% at 1 sigma) for the relative escape fraction of H I ionizing photons from bright galaxies (L > L*), while for the faint population (L = 0.2L*) the limit to the escape fraction is less than or similar to 10%. We computed the contribution of star-forming galaxies to the observed UV background at z similar to 3 and find that it is not sufficient to keep the Universe ionized at these redshifts unless their escape fraction increases significantly (>= 10%) at low luminosities (M-1500 >= -19). Conclusions. We compare our results on the Lyman continuum escape fraction of high-z galaxies with recent estimates in the literature, and discuss future prospects to shed light on the end of the Dark Ages. In the future, strong gravitational lensing will be fundamental in order to measure the Lyman continuum escape fraction down to faint magnitudes (M-1500 similar to -16) that are inaccessible with the present instrumentation on blank fields. These results will be important in order to quantify the role of faint galaxies to the reionization budget.
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