Validating a minipig model of reversible cerebral demyelination using human diagnostic modalities and electron microscopyResearch in context
Mihai Ancău,
Goutam Kumar Tanti,
Vicki Marie Butenschoen,
Jens Gempt,
Igor Yakushev,
Stephan Nekolla,
Mark Mühlau,
Christian Scheunemann,
Sebastian Heininger,
Benjamin Löwe,
Erik Löwe,
Silke Baer,
Johannes Fischer,
Judith Reiser,
Sai S. Ayachit,
Friederike Liesche-Starnecker,
Jürgen Schlegel,
Kaspar Matiasek,
Martina Schifferer,
Jan S. Kirschke,
Thomas Misgeld,
Tim Lueth,
Bernhard Hemmer
Affiliations
Mihai Ancău
Department of Neurology, Klinikum Rechts der Isar, School of Medicine and Health, Technical University of Munich, Munich, Germany; Munich Cluster for Systems Neurology (SyNergy), Munich, Germany; Institute of Neuronal Cell Biology, School of Medicine and Health, Technical University of Munich, Munich, Germany
Goutam Kumar Tanti
Department of Neurology, Klinikum Rechts der Isar, School of Medicine and Health, Technical University of Munich, Munich, Germany
Vicki Marie Butenschoen
Department of Neurosurgery, Klinikum Rechts der Isar, School of Medicine and Health, Technical University of Munich, Germany
Jens Gempt
Department of Neurosurgery, Klinikum Rechts der Isar, School of Medicine and Health, Technical University of Munich, Germany; Department of Neurosurgery, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
Igor Yakushev
Department of Nuclear Medicine, Klinikum Rechts der Isar, School of Medicine and Health, Technical University of Munich, Germany
Stephan Nekolla
Department of Nuclear Medicine, Klinikum Rechts der Isar, School of Medicine and Health, Technical University of Munich, Germany
Mark Mühlau
Department of Neurology, Klinikum Rechts der Isar, School of Medicine and Health, Technical University of Munich, Munich, Germany
Christian Scheunemann
Institute of Micro Technology and Medical Device Technology, Technical University of Munich, Garching, Germany; Ergosurg GmbH, Ismaning, Germany
Sebastian Heininger
Institute of Micro Technology and Medical Device Technology, Technical University of Munich, Garching, Germany; Ergosurg GmbH, Ismaning, Germany
Benjamin Löwe
Institute of Micro Technology and Medical Device Technology, Technical University of Munich, Garching, Germany; Ergosurg GmbH, Ismaning, Germany
Erik Löwe
Institute of Micro Technology and Medical Device Technology, Technical University of Munich, Garching, Germany; Ergosurg GmbH, Ismaning, Germany
Silke Baer
Centre for Preclinical Research, Department of Veterinary Medicine, Technical University of Munich, Munich, Germany
Johannes Fischer
Centre for Preclinical Research, Department of Veterinary Medicine, Technical University of Munich, Munich, Germany
Judith Reiser
Centre for Preclinical Research, Department of Veterinary Medicine, Technical University of Munich, Munich, Germany
Sai S. Ayachit
Department of Neurology, Klinikum Rechts der Isar, School of Medicine and Health, Technical University of Munich, Munich, Germany; Graduate School of Systemic Neurosciences, Ludwig Maximilian University of Munich, Germany
Friederike Liesche-Starnecker
Department of Neuropathology, Institute of Pathology, Technical University of Munich School of Medicine, Munich, Germany; Medical Faculty, Institute of Pathology and Molecular Diagnostics, University of Augsburg, Augsburg, Germany
Jürgen Schlegel
Department of Neuropathology, Institute of Pathology, Technical University of Munich School of Medicine, Munich, Germany
Kaspar Matiasek
Clinical and Comparative Neuropathology, Centre for Clinical Veterinary Medicine, Ludwig-Maximilians-University, Munich, Germany
Martina Schifferer
Munich Cluster for Systems Neurology (SyNergy), Munich, Germany; German Center for Neurodegenerative Diseases (DZNE), Munich, Germany
Jan S. Kirschke
Department of Neuroradiology, Klinikum Rechts der Isar, School of Medicine and Health, Technical University of Munich, Germany
Thomas Misgeld
Munich Cluster for Systems Neurology (SyNergy), Munich, Germany; German Center for Neurodegenerative Diseases (DZNE), Munich, Germany; Institute of Neuronal Cell Biology, School of Medicine and Health, Technical University of Munich, Munich, Germany
Tim Lueth
Institute of Micro Technology and Medical Device Technology, Technical University of Munich, Garching, Germany; Ergosurg GmbH, Ismaning, Germany
Bernhard Hemmer
Department of Neurology, Klinikum Rechts der Isar, School of Medicine and Health, Technical University of Munich, Munich, Germany; Munich Cluster for Systems Neurology (SyNergy), Munich, Germany; Corresponding author. Department of Neurology, Klinikum Rechts der Isar, School of Medicine and Health, Technical University of Munich, Munich, Germany.
Summary: Background: Inflammatory demyelinating diseases of the central nervous system, such as multiple sclerosis, are significant sources of morbidity in young adults despite therapeutic advances. Current murine models of remyelination have limited applicability due to the low white matter content of their brains, which restricts the spatial resolution of diagnostic imaging. Large animal models might be more suitable but pose significant technological, ethical and logistical challenges. Methods: We induced targeted cerebral demyelinating lesions by serially repeated injections of lysophosphatidylcholine in the minipig brain. Lesions were amenable to follow-up using the same clinical imaging modalities (3T magnetic resonance imaging, 11C-PIB positron emission tomography) and standard histopathology protocols as for human diagnostics (myelin, glia and neuronal cell markers), as well as electron microscopy (EM), to compare against biopsy data from two patients. Findings: We demonstrate controlled, clinically unapparent, reversible and multimodally trackable brain white matter demyelination in a large animal model. De-/remyelination dynamics were slower than reported for rodent models and paralleled by a degree of secondary axonal pathology. Regression modelling of ultrastructural parameters (g-ratio, axon thickness) predicted EM features of cerebral de- and remyelination in human data. Interpretation: We validated our minipig model of demyelinating brain diseases by employing human diagnostic tools and comparing it with biopsy data from patients with cerebral demyelination. Funding: This work was supported by the DFG under Germany's Excellence Strategy within the framework of the Munich Cluster for Systems Neurology (EXC 2145 SyNergy, ID 390857198) and TRR 274/1 2020, 408885537 (projects B03 and Z01).
