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| 2. |
- 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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| 6. |
- 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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| 8. |
- 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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| 10. |
- 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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| 11. |
- Khalil, M., et al.
(författare)
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Neurofilaments as biomarkers in neurological disorders
- 2018
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Ingår i: Nature Reviews Neurology. - : Springer Science and Business Media LLC. - 1759-4758 .- 1759-4766. ; 14:10, s. 577-589
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Tidskriftsartikel (refereegranskat)abstract
- Neuroaxonal damage is the pathological substrate of permanent disability in various neurological disorders. Reliable quantification and longitudinal follow-up of such damage are important for assessing disease activity, monitoring treatment responses, facilitating treatment development and determining prognosis. The neurofilament proteins have promise in this context because their levels rise upon neuroaxonal damage not only in the cerebrospinal fluid (CSF) but also in blood, and they indicate neuroaxonal injury independent of causal pathways. First-generation (immunoblot) and second-generation (enzyme-linked immunosorbent assay) neurofilament assays had limited sensitivity. Third-generation (electrochemiluminescence) and particularly fourth-generation (single-molecule array) assays enable the reliable measurement of neurofilaments throughout the range of concentrations found in blood samples. This technological advancement has paved the way to investigate neurofilaments in a range of neurological disorders. Here, we review what is known about the structure and function of neurofilaments, discuss analytical aspects and knowledge of age-dependent normal ranges of neurofilaments and provide a comprehensive overview of studies on neurofilament light chain as a marker of axonal injury in different neurological disorders, including multiple sclerosis, neurodegenerative dementia, stroke, traumatic brain injury, amyotrophic lateral sclerosis and Parkinson disease. We also consider work needed to explore the value of this axonal damage marker in managing neurological diseases in daily practice.
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| 12. |
- Barro, C., et al.
(författare)
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The blood biomarkers puzzle-A review of protein biomarkers in neurodegenerative diseases
- 2021
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Ingår i: Journal of Neuroscience Methods. - : Elsevier BV. - 0165-0270. ; 361
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Tidskriftsartikel (refereegranskat)abstract
- Neurodegenerative diseases are heterogeneous in their cause and clinical presentation making clinical assessment and disease monitoring challenging. Because of this, there is an urgent need for objective tools such as fluid biomarkers able to quantitate different aspects of the disease. In the last decade, technological improvements and awareness of the importance of biorepositories led to the discovery of an evolving number of fluid biomarkers covering the main characteristics of neurodegenerative diseases such as neurodegeneration, protein aggregates and inflammation. The ability to quantitate each aspect of the disease at a high definition enables a more precise stratification of the patients at inclusion in clinical trials, hence reducing the noise that may hamper the detection of therapeutical efficacy and allowing for smaller but likewise powered studies, which particularly improves the ability to start clinical trials for rare neurological diseases. Moreover, the use of fluid biomarkers has the potential to support a targeted therapeutical intervention, as it is now emerging for the treatment of amyloid-beta deposition in patients suffering from Alzheimer's disease. Here we review the knowledge that evolved from the measurement of fluid biomarker proteins in neurodegenerative conditions.
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| 13. |
- Barro, Lassina, et al.
(författare)
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A double-virally-inactivated (Intercept-solvent/detergent) human platelet lysate for in vitro expansion of human mesenchymal stromal cells
- 2019
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Ingår i: Transfusion. - : John Wiley & Sons. - 0041-1132 .- 1537-2995. ; 59:6, s. 2061-2073
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Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND Pooled human platelet lysate (HPL) can replace fetal bovine serum (FBS) as xeno-free supplement for ex vivo expansion of mesenchymal stromal cells (MSCs). We evaluate here whether a double-virally-inactivated HPL (DVI-HPL) prepared from expired Intercept-treated platelet concentrates (PCs) and treated by solvent/detergent (S/D) can be used for MSC expansion. STUDY DESIGN AND METHODS Expired Intercept-treated PCs in 65% platelet (PLT) additive solution were pooled and subjected to a 1% tri-n-butyl phosphate/1% Triton X-45 treatment followed by soybean oil, hydrophobic interaction chromatography purification, and sterile filtration. Bone marrow-derived MSCs (BM-MSCs) were expanded for four passages in growth medium containing 10% DVI-HPL, I-HPL (from Intercept-PC only), untreated HPL, and FBS. MSC morphology, doubling time, immunophenotype, immunosuppressive activity, and differentiation capacity were compared. RESULTS Expanded cells had typical spindle morphology and showed higher viability in all HPL conditions than in FBS. The DVI-HPL and FBS-expanded cells were morphologically larger than in I-HPL and HPL supplements. The cumulative population doubling was lower using DVI-HPL than with HPL and I-HPL, but significantly higher than using FBS. Immunophenotype was not affected by the supplements used. Immunosuppressive activity was maintained with all supplements. Differentiation capacity into chondrocytes and osteocytes was more effective in DVI-HPL but less toward adipocytes compared to other supplements. CONCLUSIONS Human PLT lysate made from Intercept-PCs subjected to S/D treatment may be an alternative to untreated HPL and to I-HPL for BM-MSC expansion. This finding reinforces the potential of HPL as a virally safe alternative to FBS for clinical grade MSC expansion protocols.
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| 14. |
- Barro, Lassina, et al.
(författare)
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Nanofiltration of growth media supplemented with human platelet lysates for pathogen-safe xeno-free expansion of mesenchymal stromal cells
- 2020
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Ingår i: Cytotherapy. - : Elsevier BV. - 1465-3249 .- 1477-2566. ; 22:8, s. 458-472
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Tidskriftsartikel (refereegranskat)abstract
- Background aims: Human platelet lysate can replace fetal bovine serum (FBS) for xeno-free ex vivo expansion of mesenchymal stromal cells (MSCs), but pooling of platelet concentrates (PCs) increases risks of pathogen transmission. We evaluated the feasibility of performing nanofiltration of platelet lysates and determined the impact on expansion of bone marrow-derived MSCs. Methods: Platelet lysates were prepared by freeze-thawing of pathogen-reduced (Intercept) PCs suspended in 65% storage solution (SPP+) and 35% plasma, and by serum-conversion of PCs suspended in 100% plasma. Lysates were added to the MSC growth media at 10% (v/v), filtered and subjected to cascade nanofiltration on 35- and 19-nm Planova filters. Media supplemented with 10% starting platelet lysates or FBS were used as the controls. Impacts of nanofiltration on the growth media composition, removal of platelet extracellular vesicles (PEVs) and MSC expansion were evaluated. Results: Nanofiltration did not detrimentally affect contents of total protein and growth factors or the biochemical composition. The clearance factor of PEVs was >3 log values. Expansion, proliferation, membranemarkers, differentiation potential and immunosuppressive properties of cells in nanofiltered media were consistently better than those expanded in FBS-supplemented media. Compared with FBS, chondrogenesis and osteogenesis genes were expressed more in nanofiltered media, and there were fewer senescent cells over six passages. Conclusions: Nanofiltration of growth media supplemented with two types of platelet lysates, including one prepared from pathogen-reduced PCs, is technically feasible. These data support the possibility of developing pathogen-reduced xeno-free growth media for clinical-grade propagation of human cells.
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| 15. |
- Cook, David C., et al.
(författare)
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Plant biosecurity policy-making modelled on the human immune system: What would it look like?
- 2014
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Ingår i: Environmental Science and Policy. - : Elsevier BV. - 1462-9011. ; 41, s. 1-10
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Tidskriftsartikel (refereegranskat)abstract
- This paper takes inspiration from the field of bio-mimicry to suggest what a plant biosecurity system might look like if it was modelled on the human immune system. We suggest structural and institutional changes to current biosecurity systems that would facilitate adaptive preparation and response policies, focusing particularly on the Australian plant biosecurity system. By improving information exchanges, interpretation and managing overlapping complementary response capabilities of this system, novel policies emerge that increase resilience to harmful weeds, pests and diseases. This is achieved by adding an element of flexibility in invasion response to cope with different circumstances and contexts, rather than a 'one size fits all' approach. While we find bio-mimicry to be a potentially useful system design tool, there are key differences between the immune and biosecurity systems that the analogy makes clear. Perhaps the most important of these stems from the inability of immune systems to imagine future threats. (C) 2014 Elsevier Ltd. All rights reserved.
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| 16. |
- Delcoigne, Bénédicte, et al.
(författare)
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Blood neurofilament light levels segregate treatment effects in multiple sclerosis
- 2020
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Ingår i: Neurology. - 1526-632X. ; 94
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Tidskriftsartikel (refereegranskat)abstract
- Copyright © 2020 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the American Academy of Neurology. OBJECTIVE: To determine factors (including the role of specific disease modulatory treatments [DMTs]) associated with (1) baseline, (2) on-treatment, and (3) change (from treatment start to on-treatment assessment) in plasma neurofilament light chain (pNfL) concentrations in relapsing-remitting multiple sclerosis (RRMS). METHODS: Data including blood samples analyses and long-term clinical follow-up information for 1,261 Swedish patients with RRMS starting novel DMTs were analyzed using linear regressions to model pNfL and changes in pNfL concentrations as a function of clinical variables and DMTs (alemtuzumab, dimethyl fumarate, fingolimod, natalizumab, rituximab, and teriflunomide). RESULTS: The baseline pNfL concentration was positively associated with relapse rate, Expanded Disability Status Scale score, Age-Related MS Severity Score, and MS Impact Score (MSIS-29), and negatively associated with Symbol Digit Modalities Test performance and the number of previously used DMTs. All analyses, which used inverse propensity score weighting to correct for differences in baseline factors at DMT start, highlighted that both the reduction in pNfL concentration from baseline to on-treatment measurement and the on-treatment pNfL level differed across DMTs. Patients starting alemtuzumab displayed the highest reduction in pNfL concentration and lowest on-treatment pNfL concentrations, while those starting teriflunomide had the smallest decrease and highest on-treatment levels, but also starting from lower values. Both on-treatment pNfL and decrease in pNfL concentrations were highly dependent on baseline concentrations. CONCLUSION: Choice of DMT in RRMS is significantly associated with degree of reduction in pNfL, which supports a role for pNfL as a drug response marker.
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| 20. |
- Manouchehrinia, A., et al.
(författare)
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Plasma neurofilament light levels are associated with risk of disability in multiple sclerosis
- 2020
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Ingår i: Neurology. - : Ovid Technologies (Wolters Kluwer Health). - 0028-3878 .- 1526-632X. ; 94:23
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Tidskriftsartikel (refereegranskat)abstract
- ObjectiveTo investigate the association between plasma neurofilament light chain (pNfL) levels and the risk of developing sustained disability worsening.MethodsConcentrations of pNfL were determined in 4,385 persons with multiple sclerosis (MS) and 1,026 randomly selected population-based sex- and age-matched controls using the highly sensitive Single Molecule Array (SimoaTM) NF-Light Advantage Kit. We assessed the impact of age-stratified pNfL levels above the 80th, 95th, and 99th percentiles among controls on the risk of Expanded Disability Status Scale (EDSS) worsening within the following year and reaching sustained EDSS scores of 3.0, 4.0, and 6.0 and conversion to secondary progressive multiple sclerosis (SPMS).ResultsThe median (interquartile range [IQR]) pNfL was 7.5 (4.1) pg/mL in controls and 11.4 (9.6) pg/mL in MS (p < 0.001). The median (IQR) duration of follow-up was 5 (5.1) years. High pNfL was associated with increased adjusted rates of EDSS worsening ranging between 1.4 (95% confidence intervals [CIs]: 1.1-1.8) and 1.7 (95% CI: 1.4-2.3). High pNfL was also associated with the risk of reaching a sustained EDSS score of 3.0, with adjusted rates ranging between 1.5 (95% CI: 1.2-1.8) and 1.55 (95% CI: 1.3-1.8) over all percentile cutoffs (all p < 0.001). Similar increases were observed for the risk of sustained EDSS score 4.0. In contrast, the risk of reaching sustained EDSS score 6.0 and conversion to SPMS was not consistently significant.ConclusionsElevated pNfL levels at early stages of MS are associated with an increased risk of reaching sustained disability worsening. Hence, pNfL may serve as a prognostic tool to assess the risk of developing permanent disability in MS.
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