Oeckl et al., p1
Research article
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Different neuroinflammatory profile in ALS and FTD is linked to the
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clinical phase
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Patrick Oeckl PhD
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, Patrick Weydt MD
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, Petra Steinacker PhD
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, Sarah Anderl-Straub PhD
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,
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Frida Nordin MD
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, Alexander E. Volk MD
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, Janine Diehl-Schmid MD
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, Peter M. Andersen
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MD, PhD
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, Johannes Kornhuber MD
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, Adrian Danek MD
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, Klaus Fassbender MD
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, Klaus
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Fliessbach MD
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, German Consortium for Frontotemporal Lobar Degeneration
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, Holger Jahn
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MD
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, Martin Lauer MD
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, Kathrin Müller PhD
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, Antje Knehr
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, Johannes Prudlo MD
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, Anja
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Schneider MD
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, Dietmar R. Thal MD
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, Deniz Yilmazer-Hanke MD
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, Jochen H. Weishaupt
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MD
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, Albert C. Ludolph MD
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, Markus Otto MD
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Department of Neurology, Ulm University Hospital, Ulm, Germany
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Department of Pharmacology and Clinical Neurosciences, Umeå University, Umeå,
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Sweden.
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Institute of Human Genetics, University Medical Centre Hamburg-Eppendorf, Hamburg,
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Germany
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Department of Psychiatry, Technical University of Munich, Munich, Germany
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Department of Psychiatry, Friedrich-Alexander University Erlangen-Nuremberg, Erlangen,
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Germany
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Department of Neurology, LMU Munich, Munich, Germany
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Department of Neurology, Saarland University, Homburg, Germany
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Department of Neurodegenerative Diseases and Gerontopsychiatry, University of Bonn and
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DZNE Bonn, Bonn, Germany
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German Consortium for Frontotemporal Lobar Degeneration, University of Ulm, Ulm,
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Germany (www.ftld.de)
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Department of Psychiatry, University Hospital Hamburg, Germany
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Department of Psychiatry and Psychotherapy, University of Würzburg, Würzburg, Germany
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Department of Neurology, University of Rostock, and German Center for
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Neurodegenerative Diseases (DZNE), Rostock, Germany
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Department of Neuroscience, KU Leuven and Department of Pathology, UZ Leuven,
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Leuven, Belgium
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Laboratory of Neuropathology – Institute of Pathology, Ulm University, Ulm, Germany
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Oeckl et al., p2
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§current address: Department of Neurodegenerative Diseases and Gerontopsychiatry,
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University of Bonn, Germany
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Manuscript word count: 2836 words
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Corresponding author:
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Prof. Dr. med. Markus Otto
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Ulm University Hospital
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Department of Neurology
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Oberer Eselsberg 45
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D-89081 Ulm
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phone: +49-731-500-63010
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fax: +49-731-500-63012
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e-mail address: markus.otto@uni-ulm.de
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Oeckl et al., p3
Key Points
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Question: Is neuroinflammation present in the presymptomatic phase of ALS and FTD and
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is there a different profile between ALS and FTD.
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Findings: In this case-control study with ALS/FTD gene mutation carriers, CSF levels of
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neuroinflammatory markers (CHIT1, YKL-40, GFAP) were unchanged in asymptomatic
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mutation carriers. In contrast, levels were markedly increased in symptomatic ALS and FTD
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cases (genetic and sporadic) but with a different profile between ALS and FTD.
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Meaning: Neuroinflammation is linked to the symptomatic phase of ALS/FTD and the
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different profile between ALS and FTD could be one driver of the diverse presentations of the
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ALS/FTD syndrome.
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Oeckl et al., p4
Abstract
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Importance: Neuroinflammation plays a role in the pathogenesis of amyotrophic lateral
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sclerosis (ALS) and frontotemporal dementia (FTD) but its contribution to the early disease
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phase, differences between sporadic (sALS, sFTD) and genetic (gALS, gFTD) cases, or
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between ALS and FTD is unclear and data mainly based on non-human disease models.
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Objective: To investigate the role of neuroinflammation in asymptomatic and symptomatic
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ALS and FTD mutation carriers.
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Design: In this case-control study, individuals were recruited during 2011-2017 (Ulm,
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German Presymptomatic ALS study, German FTLD consortium) and 1987-2012 (Umeå).
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Setting: Multicenter study
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Participants: We investigated asymptomatic ALS/FTD mutation carriers (n=16), gALS
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(n=65), gFTD (n=23), sALS (n=64/70), and sFTD patients (n=20/26) and control patients
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without neurodegenerative diseases (n=36/32). Asymptomatic ALS/FTD mutation carriers
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were first-degree relatives of gALS patients.
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Main Measures: The neuroinflammatory markers chitotriosidase 1 (CHIT1), YKL-40, and
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GFAP were measured in CSF and blood.
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Results: CSF levels of CHIT1, YKL-40, and GFAP were unaffected in asymptomatic
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mutation carriers. CHIT1 and YKL-40 were increased in gALS whereas GFAP was not
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affected. ALS patients carrying a CHIT1 polymorphism had lower CHIT1 concentrations in
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CSF (-80%) whereas this polymorphism had no influence on neurofilament levels and age at
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disease onset. In gFTD, increased YKL-40 and GFAP was observed, whereas CHIT1 was
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nearly not affected. This could be confirmed in post-mortem spinal cord tissue. The same
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profile was observed in sALS and sFTD. GFAP showed a sensitivity and specificity of 75%
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and 83% to discriminate FTD from ALS.
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Conclusions: Our data indicate that neuroinflammation is linked to the symptomatic phase
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of ALS/FTD and shows a similar pattern in sporadic and genetic cases. ALS and FTD are
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characterized by a different neuroinflammatory profile, which might be one driver of the
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diverse presentations of the ALS/FTD syndrome and help in the differential diagnosis.
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Oeckl et al., p5
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Keywords: Neuroinflammation, amyotrophic lateral sclerosis, frontotemporal dementia
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