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  • 1
    Online Resource
    Online Resource
    Serum Neurofilament Light Association With Progression in Natalizumab-Treated Patients With Relapsing-Remitting Multiple Sclerosis
    Ovid Technologies (Wolters Kluwer Health) ; 2021
    In:  Neurology Vol. 97, No. 19 ( 2021-11-9), p. e1898-e1905
    Details
    In: Neurology, Ovid Technologies (Wolters Kluwer Health), Vol. 97, No. 19 ( 2021-11-9), p. e1898-e1905
    Abstract: To investigate the potential of serum neurofilament light (NfL) to reflect or predict progression mostly independent of acute inflammatory disease activity in patients with relapsing-remitting multiple sclerosis (RRMS) treated with natalizumab. Methods Patients were selected from a prospective observational cohort study initiated in 2006 at the VU University Medical Center Amsterdam, the Netherlands, including patients with RRMS treated with natalizumab. Selection criteria included an age of 18 years or older and a minimum follow-up of 3 years from natalizumab initiation. Clinical and MRI assessments were performed on a yearly basis, and serum NfL was measured at 5 time points during the follow-up, including on the day of natalizumab initiation (baseline), 3 months, 1 year, and 2 years after natalizumab initiation, and on last follow-up visit. Using general linear regression models, we compared the longitudinal dynamics of NfL between patients with and without confirmed Expanded Disability Status Scale (EDSS) progression between year 1 visit and last follow-up, and between individuals with and without EDSS + progression, a composite endpoint including the EDSS, 9-hole peg test, and timed 25-foot walk. Results Eighty-nine natalizumab-treated patients with RRMS were included. Median follow-up time was 5.2 years (interquartile range [IQR] 4.3–6.7, range 3.0–11.0) after natalizumab initiation, mean age at time of natalizumab initiation was 36.9 years (SD 8.5), and median disease duration was 7.4 years (IQR 3.8–12.1). Between year 1 and the last follow-up, 28/89 (31.5%) individuals showed confirmed EDSS progression. Data for the EDSS + endpoint was available for 73 out of the 89 patients and 35/73 (47.9%) showed confirmed EDSS + progression. We observed a significant reduction in NfL levels 3 months after natalizumab initiation, which reached its nadir of close to 50% of baseline levels 1 year after treatment initiation. We found no difference in the longitudinal dynamics of NfL in progressors vs nonprogressors. NfL levels at baseline and 1 year after natalizumab initiation did not predict progression at last follow-up. Conclusion In our cohort of natalizumab-treated patients with RRMS, NfL fails to capture or predict progression that occurs largely independently of clinical or radiologic signs of acute focal inflammatory disease activity. Additional biomarkers may thus be needed to monitor progression in these patients. Classification of Evidence This study provides Class II evidence that serum NfL levels are not associated with disease progression in natalizumab-treated patients with RRMS.
    Type of Medium: Online Resource
    ISSN: 0028-3878 , 1526-632X
    URL: Article
    DOI: 10.1212/WNL.0000000000012752
    RVK:
    XA 10000
    Language: English
    Publisher: Ovid Technologies (Wolters Kluwer Health)
    Publication Date: 2021
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  • 2
    Online Resource
    Online Resource
    Data_Sheet_1.xlsx
    Frontiers Media SA ; 2018
    In:  Frontiers in Molecular Neuroscience Vol. 11 ( 2018-10-31)
    Details
    In: Frontiers in Molecular Neuroscience, Frontiers Media SA, Vol. 11 ( 2018-10-31)
    Type of Medium: Online Resource
    ISSN: 1662-5099
    URL: Article
    URL: Article
    DOI: 10.3389/fnmol.2018.00371
    DOI: 10.3389/fnmol.2018.00371.s001
    Language: Unknown
    Publisher: Frontiers Media SA
    Publication Date: 2018
    detail.hit.zdb_id: 2452967-9
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  • 3
    Online Resource
    Online Resource
    Body fluid biomarkers for multiple sclerosis—the long road to clinical application
    Springer Science and Business Media LLC ; 2015
    In:  Nature Reviews Neurology Vol. 11, No. 10 ( 2015-10), p. 585-596
    Details
    In: Nature Reviews Neurology, Springer Science and Business Media LLC, Vol. 11, No. 10 ( 2015-10), p. 585-596
    Type of Medium: Online Resource
    ISSN: 1759-4758 , 1759-4766
    URL: Article
    DOI: 10.1038/nrneurol.2015.173
    Language: English
    Publisher: Springer Science and Business Media LLC
    Publication Date: 2015
    detail.hit.zdb_id: 2491518-X
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  • 4
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    Deep gray matter volume loss drives disability worsening in multiple sclerosis
    Wiley ; 2018
    In:  Annals of Neurology Vol. 83, No. 2 ( 2018-02), p. 210-222
    Details
    In: Annals of Neurology, Wiley, Vol. 83, No. 2 ( 2018-02), p. 210-222
    Abstract: Gray matter (GM) atrophy occurs in all multiple sclerosis (MS) phenotypes. We investigated whether there is a spatiotemporal pattern of GM atrophy that is associated with faster disability accumulation in MS. Methods We analyzed 3,604 brain high‐resolution T1‐weighted magnetic resonance imaging scans from 1,417 participants: 1,214 MS patients (253 clinically isolated syndrome [CIS], 708 relapsing‐remitting [RRMS] , 128 secondary‐progressive [SPMS], and 125 primary‐progressive [PPMS] ), over an average follow‐up of 2.41 years (standard deviation [SD] = 1.97), and 203 healthy controls (HCs; average follow‐up = 1.83 year; SD = 1.77), attending seven European centers. Disability was assessed with the Expanded Disability Status Scale (EDSS). We obtained volumes of the deep GM (DGM), temporal, frontal, parietal, occipital and cerebellar GM, brainstem, and cerebral white matter. Hierarchical mixed models assessed annual percentage rate of regional tissue loss and identified regional volumes associated with time‐to‐EDSS progression. Results SPMS showed the lowest baseline volumes of cortical GM and DGM. Of all baseline regional volumes, only that of the DGM predicted time‐to‐EDSS progression (hazard ratio = 0.73; 95% confidence interval, 0.65, 0.82; p 〈 0.001): for every standard deviation decrease in baseline DGM volume, the risk of presenting a shorter time to EDSS worsening during follow‐up increased by 27%. Of all longitudinal measures, DGM showed the fastest annual rate of atrophy, which was faster in SPMS (–1.45%), PPMS (–1.66%), and RRMS (–1.34%) than CIS (–0.88%) and HCs (–0.94%; p 〈 0.01). The rate of temporal GM atrophy in SPMS (–1.21%) was significantly faster than RRMS (–0.76%), CIS (–0.75%), and HCs (–0.51%). Similarly, the rate of parietal GM atrophy in SPMS (–1.24‐%) was faster than CIS (–0.63%) and HCs (–0.23%; all p values 〈 0.05). Only the atrophy rate in DGM in patients was significantly associated with disability accumulation (beta = 0.04; p 〈 0.001). Interpretation This large, multicenter and longitudinal study shows that DGM volume loss drives disability accumulation in MS, and that temporal cortical GM shows accelerated atrophy in SPMS than RRMS. The difference in regional GM atrophy development between phenotypes needs to be taken into account when evaluating treatment effect of therapeutic interventions. Ann Neurol 2018;83:210–222
    Type of Medium: Online Resource
    ISSN: 0364-5134 , 1531-8249
    URL: Issue
    URL: Article
    DOI: 10.1002/ana.v83.2
    DOI: 10.1002/ana.25145
    Language: English
    Publisher: Wiley
    Publication Date: 2018
    detail.hit.zdb_id: 2037912-2
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  • 5
    Online Resource
    Online Resource
    Natalizumab-associated progressive multifocal leukoencephalopathy is not preceded by elevated drug concentrations
    SAGE Publications ; 2017
    In:  Multiple Sclerosis Journal Vol. 23, No. 7 ( 2017-06), p. 995-999
    Details
    In: Multiple Sclerosis Journal, SAGE Publications, Vol. 23, No. 7 ( 2017-06), p. 995-999
    Abstract: In recent years, a small but increasing number of neurologists choose to extend dose intervals of natalizumab with the aim of reducing the risk of progressive multifocal leukoencephalopathy (PML). This idea is based on the hypothesis that high drug concentrations increase the risk of PML. Objective: We investigated the relation between longitudinal natalizumab concentrations in patients who developed PML and patients who did not develop PML. Methods: In a prospective observational cohort study of 219 patients with relapsing–remitting multiple sclerosis treated with natalizumab, serum samples were taken every 12 weeks prior to natalizumab infusion. In this cohort, 5 patients developed PML and were matched with 10 patients from the cohort who did not develop PML. Natalizumab concentrations were measured in available samples, and the longitudinal results were compared between the two patient groups. Results: Mean natalizumab concentrations in the five patients developing PML was 18.9 µg/mL (standard deviation (SD): ±13.4) versus 23.8 µg/mL (SD: ±11.5) of the control patients. Furthermore, we did not observe a clear rise in concentration levels in patients subsequently developing PML. Conclusion: Our results provide preliminary evidence that contradicts the hypothesis that exposure to elevated concentrations of natalizumab is a relevant risk factor of developing PML.
    Type of Medium: Online Resource
    ISSN: 1352-4585 , 1477-0970
    URL: Article
    DOI: 10.1177/1352458516684023
    Language: English
    Publisher: SAGE Publications
    Publication Date: 2017
    detail.hit.zdb_id: 2008225-3
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  • 6
    Online Resource
    Online Resource
    The majority of natalizumab-treated MS patients have high natalizumab concentrations at time of re-dosing
    SAGE Publications ; 2018
    In:  Multiple Sclerosis Journal Vol. 24, No. 6 ( 2018-05), p. 805-810
    Details
    In: Multiple Sclerosis Journal, SAGE Publications, Vol. 24, No. 6 ( 2018-05), p. 805-810
    Abstract: Natalizumab is efficacious in the treatment of relapsing-remitting multiple sclerosis. All patients receive the same treatment regimen of 300 mg every 4 weeks, despite differences in pharmacokinetics between individual patients. Objective: To give neurologists insight into natalizumab concentrations at time of re-dosing, we investigated longitudinal natalizumab concentrations in 80 patients in relation to disease activity, with possible influencing factors. Methods: In a prospective observational cohort study, natalizumab trough serum concentrations were measured in 80 patients. Data on demographics, duration of treatment, Expanded Disability Status Scale, clinical exacerbations, brain magnetic resonance imaging (MRI), and body weight were collected. Results: We measured high (≥10 µg/mL) natalizumab trough concentrations in 94% of patients. Intra-individual concentrations were stable. The spread in concentrations was substantial and did not correlate with disease activity. We found a negative association between natalizumab concentration and body weight (β = −0.30, p = 0.010). Interpretation: The majority of patients showed high natalizumab serum concentrations at time of re-dosing. Alternative treatment regimens could lead to more efficient use of natalizumab, but caution is warranted regarding the possibility of recurrence of disease activity. Prospective clinical trials are needed to establish the safety of extended dose intervals in natalizumab treatment.
    Type of Medium: Online Resource
    ISSN: 1352-4585 , 1477-0970
    URL: Article
    DOI: 10.1177/1352458517708464
    Language: English
    Publisher: SAGE Publications
    Publication Date: 2018
    detail.hit.zdb_id: 2008225-3
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  • 7
    Online Resource
    Online Resource
    Switching natalizumab to fingolimod within 6 weeks reduces recurrence of disease activity in MS patients
    SAGE Publications ; 2018
    In:  Multiple Sclerosis Journal Vol. 24, No. 11 ( 2018-10), p. 1453-1460
    Details
    In: Multiple Sclerosis Journal, SAGE Publications, Vol. 24, No. 11 ( 2018-10), p. 1453-1460
    Abstract: Natalizumab is an effective treatment in relapsing-remitting multiple sclerosis (MS). Mainly because of the risk of progressive multifocal leukoencephalopathy (PML), a substantial proportion of John Cunningham (JC) virus–positive patients switch to fingolimod. Previous reports show a clear benefit when the duration of a washout (WO) period of natalizumab is 0–3 months in comparison to longer WO periods. However, there is no consensus regarding the optimal duration of a WO period under 3 months. Objective: We compared MS disease activity after different WO periods. In addition, we investigated several factors that possibly influence recurrence of disease activity, including serum natalizumab concentration and lymphocyte counts. Methods: From a prospective observational cohort study of natalizumab-treated patients, we selected 52 patients who switched to fingolimod. We divided the patients in three groups ( 〈 6 weeks, 6–8 weeks, 〉 8 weeks WO). Serum natalizumab concentration and lymphocyte count were assessed during and after natalizumab treatment. Results: Patients with a WO period of 〉 8 weeks had a significant higher recurrence of disease activity (odds ratio, 6.8; 95% confidence interval, 1.4–32.8) compared to patients with a WO period of 〈 6 weeks. Serum natalizumab concentration and lymphocyte count did not predict recurrence of disease activity. Interpretation: A short WO period decreases the risk of recurrence of disease activity. The possible impact of a short WO period on the risk of carry-over PML in JC virus–positive patients remains uncertain.
    Type of Medium: Online Resource
    ISSN: 1352-4585 , 1477-0970
    URL: Article
    DOI: 10.1177/1352458517726381
    Language: English
    Publisher: SAGE Publications
    Publication Date: 2018
    detail.hit.zdb_id: 2008225-3
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  • 8
    Online Resource
    Online Resource
    Cerebrospinal fluid mtDNA concentration is elevated in multiple sclerosis disease and responds to treatment
    SAGE Publications ; 2018
    In:  Multiple Sclerosis Journal Vol. 24, No. 4 ( 2018-04), p. 472-480
    Details
    In: Multiple Sclerosis Journal, SAGE Publications, Vol. 24, No. 4 ( 2018-04), p. 472-480
    Abstract: Mitochondrial dysfunction is increasingly recognized as an important feature of multiple sclerosis (MS) pathology and may be relevant for clinical disease progression. However, it is unknown whether mitochondrial DNA (mtDNA) levels in the cerebrospinal fluid (CSF) associate with disease progression and therapeutic response. Objectives: To evaluate whether CSF concentrations of mtDNA in MS patients can serve as a marker of ongoing neuropathology and may be helpful to differentiate between MS disease subtypes. To explore the effect of disease-modifying therapies on mtDNA levels in the CSF. Methods: CSF mtDNA was measured using a digital polymerase chain reaction (PCR) CSF mtDNA in two independent MS cohorts. The cohorts included 92 relapsing-remitting multiple sclerosis (RRMS) patients, 40 progressive multiple sclerosis (PMS) patients (27 secondary progressive and 13 primary progressive), 50 various neurologic disease controls, and 5 healthy controls. Results: Patients with PMS showed a significant increase in CSF mtDNA compared to non-inflammatory neurologic disease controls. Patients with higher T2 lesion volumes and lower normalized brain volumes showed increased concentration of mtDNA. Patients treated with fingolimod had significantly lower mtDNA copy levels at follow-up compared to baseline. Conclusion: Our results showed a non-specific elevation of concentration of mtDNA in PMS patients. mtDNA concentrations respond to fingolimod and may be used to monitor biological effect of this treatment.
    Type of Medium: Online Resource
    ISSN: 1352-4585 , 1477-0970
    URL: Article
    DOI: 10.1177/1352458517699874
    Language: English
    Publisher: SAGE Publications
    Publication Date: 2018
    detail.hit.zdb_id: 2008225-3
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  • 9
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    Online Resource
    Plasma proteome in multiple sclerosis disease progression
    Wiley ; 2019
    In:  Annals of Clinical and Translational Neurology Vol. 6, No. 9 ( 2019-09), p. 1582-1594
    Details
    In: Annals of Clinical and Translational Neurology, Wiley, Vol. 6, No. 9 ( 2019-09), p. 1582-1594
    Abstract: The pathophysiology of multiple sclerosis disease progression remains undetermined. The aim of this study was to identify differences in plasma proteome during different stages of MS disease progression. Methods We used a multiplex aptamer proteomics platform (Somalogic) for sensitive detection of 1129 proteins in plasma. MS patients were selected and categorized based on baseline and a 4‐year follow‐up EDSS (delta EDSS ) scores; relapse‐onset ( RO ) slow progression ( n  = 31), RO with rapid progression ( n  = 29), primary progressive ( n  = 30), and healthy controls ( n  = 20). The relation of baseline plasma protein levels with delta EDSS and different MRI progression parameters were assessed using linear regression models. Results Regression analyses of plasma proteins with delta EDSS showed six significant associations. Strong associations were found for the proteins LGLAS 8 ( P  = 7.64 × 10 −5 , q  = 0.06), CCL 3 ( P  = 0.0001, q  = 0.06), and RGMA ( P  = 0.0005, q  = 0.09). In addition, associations of plasma proteins were found with percentage brain volume for C3 ( P  = 2,08 × 10 −9 , q  = 1,70 × 10 −6 ), FGF 9 ( P  = 3,42 × 10 −9 , q  = 1,70 × 10 −6 ), and EHMT 2 ( P  = 0.0007, q  = 0.01). Most of the significant markers were associated with cell‐cell and cell‐extracellular matrix adhesion, immune system communication, immune system activation, and complement pathways. Conclusions Our results revealed eight novel biomarkers related to clinical and radiological progression in MS . These results indicate that changes in immune system, complement pathway and ECM remodeling proteins contribute to MS progression and may therefore be further explored for use in prognosis of MS .
    Type of Medium: Online Resource
    ISSN: 2328-9503 , 2328-9503
    URL: Issue
    URL: Article
    DOI: 10.1002/acn3.v6.9
    DOI: 10.1002/acn3.771
    Language: English
    Publisher: Wiley
    Publication Date: 2019
    detail.hit.zdb_id: 2740696-9
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  • 10
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    Detection and localization of early- and late-stage cancers using platelet RNA
    Elsevier BV ; 2022
    In:  Cancer Cell Vol. 40, No. 9 ( 2022-09), p. 999-1009.e6
    Details
    In: Cancer Cell, Elsevier BV, Vol. 40, No. 9 ( 2022-09), p. 999-1009.e6
    Type of Medium: Online Resource
    ISSN: 1535-6108
    URL: Article
    DOI: 10.1016/j.ccell.2022.08.006
    Language: English
    Publisher: Elsevier BV
    Publication Date: 2022
    detail.hit.zdb_id: 2074034-7
    detail.hit.zdb_id: 2078448-X
    SSG: 12
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