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  1. Article ; Online: Synaptic injury in the inner plexiform layer of the retina is associated with progression in multiple sclerosis.

    Cordano, Christian / Werneburg, Sebastian / Abdelhak, Ahmed / Bennett, Daniel J / Beaudry-Richard, Alexandra / Duncan, Greg J / Oertel, Frederike C / Boscardin, W John / Yiu, Hao H / Jabassini, Nora / Merritt, Lauren / Nocera, Sonia / Sin, Jung H / Samana, Isaac P / Condor Montes, Shivany Y / Ananth, Kirtana / Bischof, Antje / Nourbakhsh, Bardia / Hauser, Stephen L /
    Cree, Bruce A C / Emery, Ben / Schafer, Dorothy P / Chan, Jonah R / Green, Ari J

    Cell reports. Medicine

    2024  Volume 5, Issue 4, Page(s) 101490

    Abstract: While neurodegeneration underlies the pathological basis for permanent disability in multiple sclerosis (MS), predictive biomarkers for progression are lacking. Using an animal model of chronic MS, we find that synaptic injury precedes neuronal loss and ... ...

    Abstract While neurodegeneration underlies the pathological basis for permanent disability in multiple sclerosis (MS), predictive biomarkers for progression are lacking. Using an animal model of chronic MS, we find that synaptic injury precedes neuronal loss and identify thinning of the inner plexiform layer (IPL) as an early feature of inflammatory demyelination-prior to symptom onset. As neuronal domains are anatomically segregated in the retina and can be monitored longitudinally, we hypothesize that thinning of the IPL could represent a biomarker for progression in MS. Leveraging our dataset with over 800 participants enrolled for more than 12 years, we find that IPL atrophy directly precedes progression and propose that synaptic loss is predictive of functional decline. Using a blood proteome-wide analysis, we demonstrate a strong correlation between demyelination, glial activation, and synapse loss independent of neuroaxonal injury. In summary, monitoring synaptic injury is a biologically relevant approach that reflects a potential driver of progression.
    MeSH term(s) Animals ; Humans ; Multiple Sclerosis/pathology ; Retina/pathology ; Neurons/pathology ; Models, Animal ; Atrophy/pathology
    Language English
    Publishing date 2024-04-03
    Publishing country United States
    Document type Journal Article
    ISSN 2666-3791
    ISSN (online) 2666-3791
    DOI 10.1016/j.xcrm.2024.101490
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  2. Article: Remyelination protects neurons from DLK-mediated neurodegeneration.

    Duncan, Greg J / Ingram, Samantha D / Emberley, Katie / Hill, Jo / Cordano, Christian / Abdelhak, Ahmed / McCane, Michael / Jabassini, Nora / Ananth, Kirtana / Ferrara, Skylar J / Stedelin, Brittany / Sivyer, Benjamin / Aicher, Sue A / Scanlan, Thomas / Watkins, Trent A / Mishra, Anusha / Nelson, Jonathan / Green, Ari J / Emery, Ben

    bioRxiv : the preprint server for biology

    2023  

    Abstract: Chronic demyelination is theorized to contribute to neurodegeneration and drive progressive disability in demyelinating diseases like multiple sclerosis. Here, we describe two genetic mouse models of inducible demyelination, one distinguished by ... ...

    Abstract Chronic demyelination is theorized to contribute to neurodegeneration and drive progressive disability in demyelinating diseases like multiple sclerosis. Here, we describe two genetic mouse models of inducible demyelination, one distinguished by effective remyelination, and the other by remyelination failure and persistent demyelination. By comparing these two models, we find that remyelination protects neurons from apoptosis, improves conduction, and promotes functional recovery. Chronic demyelination of neurons leads to activation of the mitogen-associated protein kinase (MAPK) stress pathway downstream of dual leucine zipper kinase (DLK), which ultimately induces the phosphorylation of c-Jun in the nucleus. Both pharmacological inhibition and CRISPR/Cas9-mediated disruption of DLK block c-Jun phosphorylation and the apoptosis of demyelinated neurons. These findings provide direct experimental evidence that remyelination is neuroprotective and identify DLK inhibition as a potential therapeutic strategy to protect chronically demyelinated neurons.
    Language English
    Publishing date 2023-10-12
    Publishing country United States
    Document type Preprint
    DOI 10.1101/2023.09.30.560267
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  3. Article ; Online: Neurofilament Light Chain Elevation and Disability Progression in Multiple Sclerosis.

    Abdelhak, Ahmed / Benkert, Pascal / Schaedelin, Sabine / Boscardin, W John / Cordano, Christian / Oechtering, Johanna / Ananth, Kirtana / Granziera, Cristina / Melie-Garcia, Lester / Montes, Shivany Condor / Beaudry-Richard, Alexandra / Achtnichts, Lutz / Oertel, Frederike C / Lalive, Patrice H / Leppert, David / Müller, Stefanie / Henry, Roland G / Pot, Caroline / Matthias, Amandine /
    Salmen, Anke / Oksenberg, Jorge R / Disanto, Giulio / Zecca, Chiara / D'Souza, Marcus / Du Pasquier, Renaud / Bridel, Claire / Gobbi, Claudio / Kappos, Ludwig / Hauser, Stephen L / Cree, Bruce A C / Kuhle, Jens / Green, Ari J

    JAMA neurology

    2023  Volume 80, Issue 12, Page(s) 1317–1325

    Abstract: Importance: Mechanisms contributing to disability accumulation in multiple sclerosis (MS) are poorly understood. Blood neurofilament light chain (NfL) level, a marker of neuroaxonal injury, correlates robustly with disease activity in people with MS (MS) ...

    Abstract Importance: Mechanisms contributing to disability accumulation in multiple sclerosis (MS) are poorly understood. Blood neurofilament light chain (NfL) level, a marker of neuroaxonal injury, correlates robustly with disease activity in people with MS (MS); however, data on the association between NfL level and disability accumulation have been conflicting.
    Objective: To determine whether and when NfL levels are elevated in the context of confirmed disability worsening (CDW).
    Design, setting, and participants: This study included 2 observational cohorts: results from the Expression, Proteomics, Imaging, Clinical (EPIC) study at the University of California San Francisco (since 2004) were confirmed in the Swiss Multiple Sclerosis Cohort (SMSC), a multicenter study in 8 centers since 2012. Data were extracted from EPIC in April 2022 (sampling July 1, 2004, to December 20, 2016) and SMSC in December 2022 (sampling June 6, 2012, to September 2, 2021). The study included 2 observational cohorts in tertiary MS centers. All participants of both cohorts with available NfL results were included in the study, and no eligible participants were excluded or declined to participate.
    Exposure: Association between NfL z scores and CDW.
    Main outcome measures: CDW was defined as Expanded Disability Status Scale (EDSS) worsening that was confirmed after 6 or more months and classified into CDW associated with clinical relapses (CDW-R) or independent of clinical relapses (CDW-NR). Visits were classified in relation to the disability worsening events into CDW(-2) for 2 visits preceding event, CDW(-1) for directly preceding event, CDW(event) for first diagnosis of EDSS increase, and the confirmation visit. Mixed linear and Cox regression models were used to evaluate NfL dynamics and to assess the association of NfL with future CDW, respectively.
    Results: A total of 3906 EPIC visits (609 participants; median [IQR] age, 42.0 [35.0-50.0] years; 424 female [69.6%]) and 8901 SMSC visits (1290 participants; median [IQR] age, 41.2 [32.5-49.9] years; 850 female [65.9%]) were included. In CDW-R (EPIC, 36 events; SMSC, 93 events), NfL z scores were 0.71 (95% CI, 0.35-1.07; P < .001) units higher at CDW-R(-1) in EPIC and 0.32 (95% CI, 0.14-0.49; P < .001) in SMSC compared with stable MS samples. NfL elevation could be detected preceding CDW-NR (EPIC, 191 events; SMSC, 342 events) at CDW-NR(-2) (EPIC: 0.23; 95% CI, 0.01-0.45; P = .04; SMSC: 0.28; 95% CI, 0.18-0.37; P < .001) and at CDW-NR(-1) (EPIC: 0.27; 95% CI, 0.11-0.44; P < .001; SMSC: 0.09; 95% CI, 0-0.18; P = .06). Those findings were replicated in the subgroup with relapsing-remitting MS. Time-to-event analysis confirmed the association between NfL levels and future CDW-R within approximately 1 year and CDW-NR (in approximately 1-2 years).
    Conclusions and relevance: This cohort study documents the occurrence of NfL elevation in advance of clinical worsening and may hint to a potential window of ongoing dynamic central nervous system pathology that precedes the diagnosis of CDW.
    MeSH term(s) Adult ; Female ; Humans ; Biomarkers/blood ; Cohort Studies ; Disease Progression ; Multiple Sclerosis/diagnostic imaging ; Multiple Sclerosis/physiopathology ; Multiple Sclerosis, Relapsing-Remitting ; Neurofilament Proteins/blood ; Recurrence ; Disability Evaluation
    Chemical Substances Biomarkers ; Neurofilament Proteins
    Language English
    Publishing date 2023-11-06
    Publishing country United States
    Document type Observational Study ; Multicenter Study ; Journal Article
    ZDB-ID 2702023-X
    ISSN 2168-6157 ; 2168-6149
    ISSN (online) 2168-6157
    ISSN 2168-6149
    DOI 10.1001/jamaneurol.2023.3997
    Database MEDical Literature Analysis and Retrieval System OnLINE

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    Ui II Zs.191: Show issues Location:
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  4. Article ; Online: An autoantibody signature predictive for multiple sclerosis.

    Zamecnik, Colin R / Sowa, Gavin M / Abdelhak, Ahmed / Dandekar, Ravi / Bair, Rebecca D / Wade, Kristen J / Bartley, Christopher M / Kizer, Kerry / Augusto, Danillo G / Tubati, Asritha / Gomez, Refujia / Fouassier, Camille / Gerungan, Chloe / Caspar, Colette M / Alexander, Jessica / Wapniarski, Anne E / Loudermilk, Rita P / Eggers, Erica L / Zorn, Kelsey C /
    Ananth, Kirtana / Jabassini, Nora / Mann, Sabrina A / Ragan, Nicholas R / Santaniello, Adam / Henry, Roland G / Baranzini, Sergio E / Zamvil, Scott S / Sabatino, Joseph J / Bove, Riley M / Guo, Chu-Yueh / Gelfand, Jeffrey M / Cuneo, Richard / von Büdingen, H-Christian / Oksenberg, Jorge R / Cree, Bruce A C / Hollenbach, Jill A / Green, Ari J / Hauser, Stephen L / Wallin, Mitchell T / DeRisi, Joseph L / Wilson, Michael R

    Nature medicine

    2024  Volume 30, Issue 5, Page(s) 1300–1308

    Abstract: Although B cells are implicated in multiple sclerosis (MS) pathophysiology, a predictive or diagnostic autoantibody remains elusive. In this study, the Department of Defense Serum Repository (DoDSR), a cohort of over 10 million individuals, was used to ... ...

    Abstract Although B cells are implicated in multiple sclerosis (MS) pathophysiology, a predictive or diagnostic autoantibody remains elusive. In this study, the Department of Defense Serum Repository (DoDSR), a cohort of over 10 million individuals, was used to generate whole-proteome autoantibody profiles of hundreds of patients with MS (PwMS) years before and subsequently after MS onset. This analysis defines a unique cluster in approximately 10% of PwMS who share an autoantibody signature against a common motif that has similarity with many human pathogens. These patients exhibit antibody reactivity years before developing MS symptoms and have higher levels of serum neurofilament light (sNfL) compared to other PwMS. Furthermore, this profile is preserved over time, providing molecular evidence for an immunologically active preclinical period years before clinical onset. This autoantibody reactivity was validated in samples from a separate incident MS cohort in both cerebrospinal fluid and serum, where it is highly specific for patients eventually diagnosed with MS. This signature is a starting point for further immunological characterization of this MS patient subset and may be clinically useful as an antigen-specific biomarker for high-risk patients with clinically or radiologically isolated neuroinflammatory syndromes.
    MeSH term(s) Humans ; Multiple Sclerosis/immunology ; Multiple Sclerosis/blood ; Autoantibodies/blood ; Autoantibodies/immunology ; Neurofilament Proteins/blood ; Neurofilament Proteins/immunology ; Biomarkers/blood ; Cohort Studies ; Female ; Male ; Adult ; Middle Aged
    Chemical Substances neurofilament protein L
    Language English
    Publishing date 2024-04-19
    Publishing country United States
    Document type Journal Article
    ZDB-ID 1220066-9
    ISSN 1546-170X ; 1078-8956
    ISSN (online) 1546-170X
    ISSN 1078-8956
    DOI 10.1038/s41591-024-02938-3
    Database MEDical Literature Analysis and Retrieval System OnLINE

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    In stock of ZB MED Cologne/Königswinter

    Zs.A 4212: Show issues Location:
    Je nach Verfügbarkeit (siehe Angabe bei Bestand)
    bis Jg. 1994: Bestellungen von Artikeln über das Online-Bestellformular
    Jg. 1995 - 2021: Lesesall (2.OG)
    ab Jg. 2022: Lesesaal (EG)
    Zs.MG 39: Show issues

    Order via subito

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  5. Article: A Predictive Autoantibody Signature in Multiple Sclerosis.

    Zamecnik, Colin R / Sowa, Gavin M / Abdelhak, Ahmed / Dandekar, Ravi / Bair, Rebecca D / Wade, Kristen J / Bartley, Christopher M / Tubati, Asritha / Gomez, Refujia / Fouassier, Camille / Gerungan, Chloe / Alexander, Jessica / Wapniarski, Anne E / Loudermilk, Rita P / Eggers, Erica L / Zorn, Kelsey C / Ananth, Kirtana / Jabassini, Nora / Mann, Sabrina A /
    Ragan, Nicholas R / Santaniello, Adam / Henry, Roland G / Baranzini, Sergio E / Zamvil, Scott S / Bove, Riley M / Guo, Chu-Yueh / Gelfand, Jeffrey M / Cuneo, Richard / von Büdingen, H-Christian / Oksenberg, Jorge R / Cree, Bruce Ac / Hollenbach, Jill A / Green, Ari J / Hauser, Stephen L / Wallin, Mitchell T / DeRisi, Joseph L / Wilson, Michael R

    medRxiv : the preprint server for health sciences

    2023  

    Abstract: Although B cells are implicated in multiple sclerosis (MS) pathophysiology, a predictive or diagnostic autoantibody remains elusive. Here, the Department of Defense Serum Repository (DoDSR), a cohort of over 10 million individuals, was used to generate ... ...

    Abstract Although B cells are implicated in multiple sclerosis (MS) pathophysiology, a predictive or diagnostic autoantibody remains elusive. Here, the Department of Defense Serum Repository (DoDSR), a cohort of over 10 million individuals, was used to generate whole-proteome autoantibody profiles of hundreds of patients with MS (PwMS) years before and subsequently after MS onset. This analysis defines a unique cluster of PwMS that share an autoantibody signature against a common motif that has similarity with many human pathogens. These patients exhibit antibody reactivity years before developing MS symptoms and have higher levels of serum neurofilament light (sNfL) compared to other PwMS. Furthermore, this profile is preserved over time, providing molecular evidence for an immunologically active prodromal period years before clinical onset. This autoantibody reactivity was validated in samples from a separate incident MS cohort in both cerebrospinal fluid (CSF) and serum, where it is highly specific for patients eventually diagnosed with MS. This signature is a starting point for further immunological characterization of this MS patient subset and may be clinically useful as an antigen-specific biomarker for high-risk patients with clinically- or radiologically-isolated neuroinflammatory syndromes.
    Language English
    Publishing date 2023-05-15
    Publishing country United States
    Document type Preprint
    DOI 10.1101/2023.05.01.23288943
    Database MEDical Literature Analysis and Retrieval System OnLINE

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