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Peretzke R, Neher PF, Brandt GA, Fritze S, Volkmer S, Daub J, Northoff G, Bohn J, Kirchhoff Y, Roy S, Maier-Hein KH, Meyer-Lindenberg A, Hirjak D. Deciphering white matter microstructural alterations in catatonia according to ICD-11: replication and machine learning analysis. Mol Psychiatry 2025; 30:2095-2107. [PMID: 39623072 PMCID: PMC12014485 DOI: 10.1038/s41380-024-02821-0] [Citation(s) in RCA: 2] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/26/2024] [Revised: 10/31/2024] [Accepted: 11/01/2024] [Indexed: 04/24/2025]
Abstract
Catatonia is a severe psychomotor disorder characterized by motor, affective and cognitive-behavioral abnormalities. Although previous magnetic resonance imaging (MRI) studies suggested white matter (WM) dysconnectivity in the pathogenesis of catatonia, it is unclear whether microstructural alterations of WM tracts connecting psychomotor regions might contribute to a better classification of catatonia patients. Here, diffusion-weighted MRI data were collected from two independent cohorts (whiteCAT/replication cohort) of patients with (n = 45/n = 13) and without (n = 56/n = 26) catatonia according to ICD-11 criteria. Catatonia severity was examined using the Northoff (NCRS) and Bush-Francis (BFCRS) Catatonia Rating Scales. We used tract-based spatial statistics (TBSS), tractometry (TractSeg) and machine-learning (ML) to classify catatonia patients from tractometry values as well as tractomics features generated by the newly developed tool RadTract. Catatonia patients showed fractional anisotropy (FA) alterations measured via TractSeg in different corpus callosum segments (CC_1, CC_3, CC_4, CC_5 and CC_6) compared to non-catatonia patients across both cohorts. Our classification results indicated a higher level of performance when trained on tractomics as opposed to traditional tractometry values. Moreover, in the CC_6, we successfully trained two classifiers using the tractomics features identified in the whiteCAT data. These classifiers were applied separately to the whiteCAT and replication cohorts, demonstrating comparable performance with Area Under the Receiver Operating Characteristics (AUROC) values of 0.79 for the whiteCAT cohort and 0.76 for the replication cohort. In contrast, training on FA tractometry resulted in lower AUROC values of 0.66 for the whiteCAT cohort and 0.51 for the replication cohort. In conclusion, these findings underscore the significance of CC WM microstructural alterations in the pathophysiology of catatonia. The successful use of an ML based classification model to identify catatonia patients has the potential to improve diagnostic precision.
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Affiliation(s)
- Robin Peretzke
- Division of Medical Image Computing, German Cancer Research Center, Heidelberg, Germany
- Medical Faculty, Heidelberg University, Heidelberg, Germany
| | - Peter F Neher
- Division of Medical Image Computing, German Cancer Research Center, Heidelberg, Germany
- Pattern Analysis and Learning Group, Department of Radiation Oncology, Heidelberg University Hospital, Heidelberg, Germany
- German Cancer Consortium (DKTK), Heidelberg, Germany
| | - Geva A Brandt
- Department of Psychiatry and Psychotherapy, Central Institute of Mental Health, Medical Faculty Mannheim, Heidelberg University, Mannheim, Germany
- German Center for Mental Health (DZPG), partner site Mannheim-Heidelberg-Ulm, Mannheim, Germany
| | - Stefan Fritze
- Department of Psychiatry and Psychotherapy, Central Institute of Mental Health, Medical Faculty Mannheim, Heidelberg University, Mannheim, Germany
- German Center for Mental Health (DZPG), partner site Mannheim-Heidelberg-Ulm, Mannheim, Germany
| | - Sebastian Volkmer
- Department of Psychiatry and Psychotherapy, Central Institute of Mental Health, Medical Faculty Mannheim, Heidelberg University, Mannheim, Germany
- German Center for Mental Health (DZPG), partner site Mannheim-Heidelberg-Ulm, Mannheim, Germany
- Hector Institute for Artificial Intelligence in Psychiatry, Central Institute of Mental Health, Medical Faculty Mannheim, Heidelberg University, Mannheim, Germany
| | - Jonas Daub
- Department of Psychiatry and Psychotherapy, Central Institute of Mental Health, Medical Faculty Mannheim, Heidelberg University, Mannheim, Germany
- German Center for Mental Health (DZPG), partner site Mannheim-Heidelberg-Ulm, Mannheim, Germany
| | - Georg Northoff
- Mind, Brain Imaging and Neuroethics Research Unit, Institute of Mental Health Research, Faculty of Medicine, University of Ottawa, Ottawa, ON, Canada
| | - Jonas Bohn
- Division of Medical Image Computing, German Cancer Research Center, Heidelberg, Germany
- Faculty of Bioscience, Heidelberg University, Heidelberg, Germany
- National Center for Tumor Diseases (NCT), NCT Heidelberg, DKFZ and University Medical Center Heidelberg, Heidelberg, Germany
| | - Yannick Kirchhoff
- Division of Medical Image Computing, German Cancer Research Center, Heidelberg, Germany
- Faculty of Mathematics and Computer Science, Heidelberg University, Heidelberg, Germany
- HIDSS4Health - Helmholtz Information and Data Science School for Health, Karlsruhe/Heidelberg, Germany
| | - Saikat Roy
- Division of Medical Image Computing, German Cancer Research Center, Heidelberg, Germany
- Faculty of Mathematics and Computer Science, Heidelberg University, Heidelberg, Germany
| | - Klaus H Maier-Hein
- Division of Medical Image Computing, German Cancer Research Center, Heidelberg, Germany
- Medical Faculty, Heidelberg University, Heidelberg, Germany
- Pattern Analysis and Learning Group, Department of Radiation Oncology, Heidelberg University Hospital, Heidelberg, Germany
- German Cancer Consortium (DKTK), Heidelberg, Germany
- HIDSS4Health - Helmholtz Information and Data Science School for Health, Karlsruhe/Heidelberg, Germany
| | - Andreas Meyer-Lindenberg
- Department of Psychiatry and Psychotherapy, Central Institute of Mental Health, Medical Faculty Mannheim, Heidelberg University, Mannheim, Germany
- German Center for Mental Health (DZPG), partner site Mannheim-Heidelberg-Ulm, Mannheim, Germany
| | - Dusan Hirjak
- Department of Psychiatry and Psychotherapy, Central Institute of Mental Health, Medical Faculty Mannheim, Heidelberg University, Mannheim, Germany.
- German Center for Mental Health (DZPG), partner site Mannheim-Heidelberg-Ulm, Mannheim, Germany.
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2
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Markusson S, Raasakka A, Schröder M, Sograte‐Idrissi S, Rahimi AM, Asadpour O, Körner H, Lodygin D, Eichel‐Vogel MA, Chowdhury R, Sutinen A, Muruganandam G, Iyer M, Cooper MH, Weigel MK, Ambiel N, Werner HB, Zuchero JB, Opazo F, Kursula P. Nanobodies against the myelin enzyme CNPase as tools for structural and functional studies. J Neurochem 2025; 169:e16274. [PMID: 39655780 PMCID: PMC11629607 DOI: 10.1111/jnc.16274] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/27/2024] [Revised: 11/08/2024] [Accepted: 11/14/2024] [Indexed: 12/13/2024]
Abstract
2',3'-Cyclic nucleotide 3'-phosphodiesterase (CNPase) is an abundant constituent of central nervous system non-compact myelin, and its loss in mice and humans causes neurodegeneration. Additionally, CNPase is frequently used as a marker antigen for myelinating cells. The catalytic activity of CNPase, the 3'-hydrolysis of 2',3'-cyclic nucleotides, is well characterised in vitro, but the in vivo function of CNPase remains unclear. CNPase interacts with the actin cytoskeleton to counteract the developmental closure of cytoplasmic channels that travel through compact myelin; its enzymatic activity may be involved in adenosine metabolism and RNA degradation. We developed a set of high-affinity nanobodies recognising the phosphodiesterase domain of CNPase, and the crystal structures of each complex show that the five nanobodies have distinct epitopes. One of the nanobodies bound deep into the CNPase active site and acted as an inhibitor. Moreover, the nanobodies were characterised in imaging applications and as intrabodies, expressed in mammalian cells, such as primary oligodendrocytes. Fluorescently labelled nanobodies functioned in imaging of teased nerve fibres and whole brain tissue sections, as well as super-resolution microscopy. These anti-CNPase nanobodies provide new tools for structural and functional studies on myelin formation, dynamics, and disease, including high-resolution imaging of nerve tissue.
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Affiliation(s)
| | - Arne Raasakka
- Department of BiomedicineUniversity of BergenBergenNorway
- Neurosurgery DepartmentStanford University School of MedicineStanfordCaliforniaUSA
| | | | - Shama Sograte‐Idrissi
- Center for Biostructural Imaging of Neurodegeneration (BIN)University of Göttingen Medical CenterGöttingenGermany
| | - Amir Mohammad Rahimi
- Center for Biostructural Imaging of Neurodegeneration (BIN)University of Göttingen Medical CenterGöttingenGermany
| | - Ommolbanin Asadpour
- Center for Biostructural Imaging of Neurodegeneration (BIN)University of Göttingen Medical CenterGöttingenGermany
| | - Henrike Körner
- Department for Neuroimmunology and Multiple Sclerosis ResearchUniversity of Göttingen Medical CenterGöttingenGermany
| | - Dmitri Lodygin
- Department for Neuroimmunology and Multiple Sclerosis ResearchUniversity of Göttingen Medical CenterGöttingenGermany
| | - Maria A. Eichel‐Vogel
- Department of NeurogeneticsMax Planck Institute for Multidisciplinary SciencesGöttingenGermany
| | | | - Aleksi Sutinen
- Faculty of Biochemistry and Molecular Medicine & Biocenter OuluUniversity of OuluOuluFinland
| | - Gopinath Muruganandam
- VIB‐VUB Center for Structural BiologyVlaams Instituut voor BiotechnologieBrusselsBelgium
- Department of Bioengineering Sciences, Structural Biology BrusselsVrije Universiteit BrusselBrusselsBelgium
| | - Manasi Iyer
- Neurosurgery DepartmentStanford University School of MedicineStanfordCaliforniaUSA
| | - Madeline H. Cooper
- Neurosurgery DepartmentStanford University School of MedicineStanfordCaliforniaUSA
| | - Maya K. Weigel
- Neurosurgery DepartmentStanford University School of MedicineStanfordCaliforniaUSA
| | - Nicholas Ambiel
- Neurosurgery DepartmentStanford University School of MedicineStanfordCaliforniaUSA
| | - Hauke B. Werner
- Department of NeurogeneticsMax Planck Institute for Multidisciplinary SciencesGöttingenGermany
| | - J. Bradley Zuchero
- Neurosurgery DepartmentStanford University School of MedicineStanfordCaliforniaUSA
| | - Felipe Opazo
- Center for Biostructural Imaging of Neurodegeneration (BIN)University of Göttingen Medical CenterGöttingenGermany
- Institute of Neuro‐ and Sensory PhysiologyUniversity Medical Center GöttingenGöttingenGermany
- NanoTag Biotechnologies GmbHGöttingenGermany
| | - Petri Kursula
- Department of BiomedicineUniversity of BergenBergenNorway
- Faculty of Biochemistry and Molecular Medicine & Biocenter OuluUniversity of OuluOuluFinland
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3
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León-Rodríguez A, Grondona JM, Marín-Wong S, López-Aranda MF, López-Ávalos MD. Long-term reprogramming of primed microglia after moderate inhibition of CSF1R signaling. Glia 2025; 73:175-195. [PMID: 39448548 DOI: 10.1002/glia.24627] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/24/2024] [Revised: 10/01/2024] [Accepted: 10/07/2024] [Indexed: 10/26/2024]
Abstract
In acute neuroinflammation, microglia activate transiently, and return to a resting state later on. However, they may retain immune memory of such event, namely priming. Primed microglia are more sensitive to new stimuli and develop exacerbated responses, representing a risk factor for neurological disorders with an inflammatory component. Strategies to control the hyperactivation of microglia are, hence, of great interest. The receptor for colony stimulating factor 1 (CSF1R), expressed in myeloid cells, is essential for microglia viability, so its blockade with specific inhibitors (e.g. PLX5622) results in significant depletion of microglial population. Interestingly, upon inhibitor withdrawal, new naïve microglia repopulate the brain. Depletion-repopulation has been proposed as a strategy to reprogram microglia. However, substantial elimination of microglia is inadvisable in human therapy. To overcome such drawback, we aimed to reprogram long-term primed microglia by CSF1R partial inhibition. Microglial priming was induced in mice by acute neuroinflammation, provoked by intracerebroventricular injection of neuraminidase. After 3-weeks recovery, low-dose PLX5622 treatment was administrated for 12 days, followed by a withdrawal period of 7 weeks. Twelve hours before euthanasia, mice received a peripheral lipopolysaccharide (LPS) immune challenge, and the subsequent microglial inflammatory response was evaluated. PLX5622 provoked a 40%-50% decrease in microglial population, but basal levels were restored 7 weeks later. In the brain regions studied, hippocampus and hypothalamus, LPS induced enhanced microgliosis and inflammatory activation in neuraminidase-injected mice, while PLX5622 treatment prevented these changes. Our results suggest that PLX5622 used at low doses reverts microglial priming and, remarkably, prevents broad microglial depletion.
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Affiliation(s)
- Ana León-Rodríguez
- Departamento de Biología Celular, Genética y Fisiología, Facultad de Ciencias, Universidad de Málaga, Málaga, Spain
- Instituto de Investigación Biomédica de Málaga-IBIMA Plataforma Bionand, Málaga, Spain
| | - Jesús M Grondona
- Departamento de Biología Celular, Genética y Fisiología, Facultad de Ciencias, Universidad de Málaga, Málaga, Spain
- Instituto de Investigación Biomédica de Málaga-IBIMA Plataforma Bionand, Málaga, Spain
| | - Sonia Marín-Wong
- Departamento de Biología Celular, Genética y Fisiología, Facultad de Ciencias, Universidad de Málaga, Málaga, Spain
| | - Manuel F López-Aranda
- Departamento de Biología Celular, Genética y Fisiología, Facultad de Ciencias, Universidad de Málaga, Málaga, Spain
- Instituto de Investigación Biomédica de Málaga-IBIMA Plataforma Bionand, Málaga, Spain
| | - María D López-Ávalos
- Departamento de Biología Celular, Genética y Fisiología, Facultad de Ciencias, Universidad de Málaga, Málaga, Spain
- Instituto de Investigación Biomédica de Málaga-IBIMA Plataforma Bionand, Málaga, Spain
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Simons M, Gibson EM, Nave KA. Oligodendrocytes: Myelination, Plasticity, and Axonal Support. Cold Spring Harb Perspect Biol 2024; 16:a041359. [PMID: 38621824 PMCID: PMC11444305 DOI: 10.1101/cshperspect.a041359] [Citation(s) in RCA: 19] [Impact Index Per Article: 19.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 04/17/2024]
Abstract
The myelination of axons has evolved to enable fast and efficient transduction of electrical signals in the vertebrate nervous system. Acting as an electric insulator, the myelin sheath is a multilamellar membrane structure around axonal segments generated by the spiral wrapping and subsequent compaction of oligodendroglial plasma membranes. These oligodendrocytes are metabolically active and remain functionally connected to the subjacent axon via cytoplasmic-rich myelinic channels for movement of metabolites and macromolecules to and from the internodal periaxonal space under the myelin sheath. Increasing evidence indicates that oligodendrocyte numbers, specifically in the forebrain, and myelin as a dynamic cellular compartment can both respond to physiological demands, collectively referred to as adaptive myelination. This review summarizes our current understanding of how myelin is generated, how its function is dynamically regulated, and how oligodendrocytes support the long-term integrity of myelinated axons.
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Affiliation(s)
- Mikael Simons
- Institute of Neuronal Cell Biology, Technical University Munich, Munich 80802, Germany
- German Center for Neurodegenerative Diseases, Munich Cluster of Systems Neurology (SyNergy), Institute for Stroke and Dementia Research, Munich 81377, Germany
| | - Erin M Gibson
- Department of Psychiatry and Behavioral Sciences, Stanford University School of Medicine, Stanford 94305, California, USA
| | - Klaus-Armin Nave
- Department of Neurogenetics, Max Planck Institute for Multidisciplinary Sciences, Göttingen 37075, Germany
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5
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Hirjak D, Rogers JP, Wolf RC, Kubera KM, Fritze S, Wilson JE, Sambataro F, Fricchione G, Meyer-Lindenberg A, Ungvari GS, Northoff G. Catatonia. Nat Rev Dis Primers 2024; 10:49. [PMID: 39025858 DOI: 10.1038/s41572-024-00534-w] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 06/17/2024] [Indexed: 07/20/2024]
Abstract
Catatonia is a neuropsychiatric disorder characterized by motor, affective and cognitive-behavioural signs, which lasts from hours to days. Intensive research over the past two decades has led to catatonia being recognized as an independent diagnosis in the International Classification of Diseases, 11th Revision (ICD-11) since 2022. Catatonia is found in 5-18% of inpatients on psychiatric units and 3.3% of inpatients on medical units. However, in an unknown number of patients, catatonia remains unrecognized and these patients are at risk of life-threatening complications. Hence, recognizing the symptoms of catatonia early is crucial to initiate appropriate treatment to achieve a favourable outcome. Benzodiazepines such as lorazepam and diazepam, electroconvulsive therapy, and N-methyl-D-aspartate antagonists such as amantadine and memantine, are the cornerstones of catatonia therapy. In addition, dopamine-modulating second-generation antipsychotics (for example, clozapine and aripiprazole) are effective in some patient populations. Early and appropriate treatment combined with new screening assessments has the potential to reduce the high morbidity and mortality associated with catatonia in psychiatric and non-psychiatric settings.
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Affiliation(s)
- Dusan Hirjak
- Department of Psychiatry and Psychotherapy, Central Institute of Mental Health, Medical Faculty Mannheim, University of Heidelberg, Mannheim, Germany.
- German Centre for Mental Health (DZPG), Partner site Mannheim, Mannheim, Germany.
| | | | - Robert Christian Wolf
- Center for Psychosocial Medicine, Department of General Psychiatry, Heidelberg University, Heidelberg, Germany
| | - Katharina Maria Kubera
- Center for Psychosocial Medicine, Department of General Psychiatry, Heidelberg University, Heidelberg, Germany
| | - Stefan Fritze
- Department of Psychiatry and Psychotherapy, Central Institute of Mental Health, Medical Faculty Mannheim, University of Heidelberg, Mannheim, Germany
| | - Jo Ellen Wilson
- Critical Illness, Brain Dysfunction, and Survivorship Center, Vanderbilt University Medical Center, Nashville, TN, USA
- Department of Psychiatry and Behavioral Sciences, Vanderbilt University Medical Center, Nashville, TN, USA
- Geriatric Research, Education and Clinical Center (GRECC), Veterans Affairs, Tennessee Valley Healthcare System, Nashville, TN, USA
| | - Fabio Sambataro
- Department of Neuroscience (DNS), University of Padova, Padova, Italy
| | - Gregory Fricchione
- Benson-Henry Institute for Mind Body Medicine, Department of Psychiatry, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA
| | - Andreas Meyer-Lindenberg
- Department of Psychiatry and Psychotherapy, Central Institute of Mental Health, Medical Faculty Mannheim, University of Heidelberg, Mannheim, Germany
- German Centre for Mental Health (DZPG), Partner site Mannheim, Mannheim, Germany
| | - Gabor S Ungvari
- Division of Psychiatry, School of Medicine, University of Western Australia, Perth, Western Australia, Australia
- Section of Psychiatry, School of Medicine, University Notre Dame Australia, Fremantle, Western Australia, Australia
| | - Georg Northoff
- Mind, Brain Imaging and Neuroethics Research Unit, The Royal's Institute of Mental Health Research, University of Ottawa, Ottawa, Ontario, Canada
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6
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Markusson S, Raasakka A, Schröder M, Sograte-Idrissi S, Rahimi AM, Asadpour O, Körner H, Lodygin D, Eichel-Vogel MA, Chowdhury R, Sutinen A, Muruganandam G, Iyer M, Cooper MH, Weigel MK, Ambiel N, Werner HB, Zuchero JB, Opazo F, Kursula P. Nanobodies against the myelin enzyme CNPase as tools for structural and functional studies. BIORXIV : THE PREPRINT SERVER FOR BIOLOGY 2024:2024.05.25.595513. [PMID: 38826303 PMCID: PMC11142274 DOI: 10.1101/2024.05.25.595513] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 06/04/2024]
Abstract
2',3'-cyclic nucleotide 3'-phosphodiesterase (CNPase) is an abundant constituent of central nervous system non-compact myelin, frequently used as a marker antigen for myelinating cells. The catalytic activity of CNPase, the 3'-hydrolysis of 2',3'-cyclic nucleotides, is well characterised in vitro, but the in vivo function of CNPase remains unclear. CNPase interacts with the actin cytoskeleton to counteract the developmental closure of cytoplasmic channels that travel through compact myelin; its enzymatic activity may be involved in adenosine metabolism and RNA degradation. We developed a set of high-affinity nanobodies recognizing the phosphodiesterase domain of CNPase, and the crystal structures of each complex show that the five nanobodies have distinct epitopes. One of the nanobodies bound deep into the CNPase active site and acted as an inhibitor. Moreover, the nanobodies were characterised in imaging applications and as intrabodies, expressed in mammalian cells, such as primary oligodendrocytes. Fluorescently labelled nanobodies functioned in imaging of teased nerve fibers and whole brain tissue sections, as well as super-resolution microscopy. These anti-CNPase nanobodies provide new tools for structural and functional biology of myelination, including high-resolution imaging of nerve tissue.
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Affiliation(s)
| | - Arne Raasakka
- Department of Biomedicine, University of Bergen, Bergen, Norway
- Neurosurgery Department, Stanford University School of Medicine, Stanford, CA, USA
| | - Marcel Schröder
- Department of Biomedicine, University of Bergen, Bergen, Norway
| | - Shama Sograte-Idrissi
- Center for Biostructural Imaging of Neurodegeneration (BIN), University of Göttingen Medical Center, 37075 Göttingen, Germany
| | - Amir Mohammad Rahimi
- Center for Biostructural Imaging of Neurodegeneration (BIN), University of Göttingen Medical Center, 37075 Göttingen, Germany
| | - Ommolbanin Asadpour
- Center for Biostructural Imaging of Neurodegeneration (BIN), University of Göttingen Medical Center, 37075 Göttingen, Germany
| | - Henrike Körner
- Department for Neuroimmunology and Multiple Sclerosis Research, University of Göttingen Medical Center, 37075 Göttingen, Germany
| | - Dmitri Lodygin
- Department for Neuroimmunology and Multiple Sclerosis Research, University of Göttingen Medical Center, 37075 Göttingen, Germany
| | - Maria A. Eichel-Vogel
- Department of Neurogenetics, Max Planck Institute for Multidisciplinary Sciences, D-37075 Göttingen, Germany
| | - Risha Chowdhury
- Department of Biomedicine, University of Bergen, Bergen, Norway
| | - Aleksi Sutinen
- Faculty of Biochemistry and Molecular Medicine & Biocenter Oulu, University of Oulu, Finland
| | - Gopinath Muruganandam
- VIB-VUB Center for Structural Biology, Vlaams Instituut voor Biotechnologie, Brussels, Belgium
- Department of Bioengineering Sciences, Structural Biology Brussels, Vrije Universiteit Brussel, Brussel, Belgium
| | - Manasi Iyer
- Neurosurgery Department, Stanford University School of Medicine, Stanford, CA, USA
| | - Madeline H. Cooper
- Neurosurgery Department, Stanford University School of Medicine, Stanford, CA, USA
| | - Maya K. Weigel
- Neurosurgery Department, Stanford University School of Medicine, Stanford, CA, USA
| | - Nicholas Ambiel
- Neurosurgery Department, Stanford University School of Medicine, Stanford, CA, USA
| | - Hauke B. Werner
- Department of Neurogenetics, Max Planck Institute for Multidisciplinary Sciences, D-37075 Göttingen, Germany
| | - J. Bradley Zuchero
- Neurosurgery Department, Stanford University School of Medicine, Stanford, CA, USA
| | - Felipe Opazo
- Center for Biostructural Imaging of Neurodegeneration (BIN), University of Göttingen Medical Center, 37075 Göttingen, Germany
- Institute of Neuro- and Sensory Physiology, University Medical Center Göttingen, 37073 Göttingen, Germany
- NanoTag Biotechnologies GmbH, 37079 Göttingen, Germany
| | - Petri Kursula
- Department of Biomedicine, University of Bergen, Bergen, Norway
- Faculty of Biochemistry and Molecular Medicine & Biocenter Oulu, University of Oulu, Finland
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7
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Csihi L, Ungvari GS, Caroff SN, Gazdag G. First 150 years of catatonia: Looking back at its complicated history and forward to the road ahead. World J Psychiatry 2024; 14:600-606. [PMID: 38808080 PMCID: PMC11129151 DOI: 10.5498/wjp.v14.i5.600] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/27/2024] [Revised: 03/27/2024] [Accepted: 04/17/2024] [Indexed: 05/16/2024] Open
Abstract
Karl Ludwig Kahlbaum (1828-1899) was the first to conceptualize and describe the main clinical features of a novel psychiatric illness, which he termed catatonia in his groundbreaking monograph published 150 years ago. Although Kahlbaum postulated catatonia as a separate disease entity characterized by psychomotor symptoms and a cyclical course, a close examination of his 26 cases reveals that most of them presented with motor symptom complexes or syndromes associated with various psychiatric and medical conditions. In his classification system, Kraepelin categorized catatonic motor symptoms that occur in combination with psychotic symptoms and typically have a poor prognosis within his dementia praecox (schizophrenia) disease entity. Because of the substantial influence of Kraepelin's classification, catatonia was predominantly perceived as a component of schizophrenia for most of the 20th century. However, with the advent of the psychopharmacotherapy era starting from the early 1950s, interest in catatonia in both clinical practice and research subsided until the early 2000s. The past two decades have witnessed a resurgence of interest in catatonia. The Diagnostic and Statistical Manual of Mental Disorders Fifth Edition, marked a paradigmatic shift by acknowledging that catatonia can occur secondary to various psychiatric and medical conditions. The introduction of an independent diagnostic category termed "Catatonia Not Otherwise Specified" significantly stimulated research in this field. The authors briefly review the history and findings of recent catatonia research and highlight promising directions for future exploration.
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Affiliation(s)
- Levente Csihi
- Department of Psychiatry and Psychiatric Rehabilitation, Jahn Ferenc South Pest Hospital, Budapest 1204, Hungary
| | - Gabor S Ungvari
- Division of Psychiatry, School of Medicine, University of Western Australia, Crawley 6009, Western Australia, Australia
- Section of Psychiatry, University of Notre Dame, Fremantle 6160, Western Australia, Australia
| | - Stanley N Caroff
- Behavioral Health Service, Corporal Michael J Cresencz, Veterans Affairs Medical Center, Philadelphia, PA 19104, United States
- Department of Psychiatry, University of Pennsylvania, Perelman School of Medicine, Philadelphia, PA 19104, United States
| | - Gábor Gazdag
- Department of Psychiatry and Psychiatric Rehabilitation, Jahn Ferenc South Pest Hospital, Budapest 1204, Hungary
- Department of Psychiatry and Psychotherapy, Faculty of Medicine, Semmelweis University, Budapest 1083, Hungary
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8
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Hörner M, Popp S, Branchu J, Stevanin G, Darios F, Klebe S, Groh J, Martini R. Clinically approved immunomodulators ameliorate behavioral changes in a mouse model of hereditary spastic paraplegia type 11. Front Neurosci 2024; 18:1299554. [PMID: 38435059 PMCID: PMC10904495 DOI: 10.3389/fnins.2024.1299554] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/22/2023] [Accepted: 02/02/2024] [Indexed: 03/05/2024] Open
Abstract
We have previously demonstrated that neuroinflammation by the adaptive immune system acts as a robust and targetable disease amplifier in a mouse model of Spastic Paraplegia, type 11 (SPG11), a complicated form of Hereditary Spastic Paraplegia (HSP). While we identified an impact of neuroinflammation on distinct neuropathological changes and gait performance, neuropsychological features, typical and clinically highly relevant symptoms of complicated HSPs, were not addressed. Here we show that the corresponding SPG11 mouse model shows distinct behavioral abnormalities, particularly related to social behavior thus partially reflecting the neuropsychological changes in patients. We provide evidence that some behavioral abnormalities can be mitigated by genetic inactivation of the adaptive immune system. Translating this into a clinically applicable approach, we show that treatment with the established immunomodulators fingolimod or teriflunomide significantly attenuates distinct behavioral abnormalities, with the most striking effect on social behavior. This study links neuroinflammation to behavioral abnormalities in a mouse model of SPG11 and may thus pave the way for using immunomodulators as a treatment approach for SPG11 and possibly other complicated forms of HSP with neuropsychological involvement.
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Affiliation(s)
- Michaela Hörner
- Section of Developmental Neurobiology, Department of Neurology, University Hospital Würzburg, Würzburg, Germany
- Division of Neurodegenerative Diseases, Department of Neurology, Heidelberg University Hospital and Faculty of Medicine, Heidelberg, Germany
| | - Sandy Popp
- Section of Developmental Neurobiology, Department of Neurology, University Hospital Würzburg, Würzburg, Germany
- Center of Mental Health, Department of Psychiatry, Psychosomatics and Psychotherapy, University of Würzburg, Würzburg, Germany
- TSE Systems GmbH, Berlin, Germany
| | - Julien Branchu
- Institut du Cerveau – Paris Brain Institute, Inserm, Sorbonne Université, Paris, France
- EVerZom, Paris, France
| | - Giovanni Stevanin
- Institut du Cerveau – Paris Brain Institute, Inserm, Sorbonne Université, Paris, France
- INCIA, CNRS, EPHE, Université de Bordeaux, Bordeaux, France
| | - Frédéric Darios
- Institut du Cerveau – Paris Brain Institute, Inserm, Sorbonne Université, Paris, France
| | - Stephan Klebe
- Department of Neurology, University Hospital Essen, Essen, Germany
| | - Janos Groh
- Section of Developmental Neurobiology, Department of Neurology, University Hospital Würzburg, Würzburg, Germany
- Institute of Neuronal Cell Biology, Technical University Munich, Munich, Germany
| | - Rudolf Martini
- Section of Developmental Neurobiology, Department of Neurology, University Hospital Würzburg, Würzburg, Germany
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9
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Askew KE, Beverley J, Sigfridsson E, Szymkowiak S, Emelianova K, Dando O, Hardingham GE, Duncombe J, Hennessy E, Koudelka J, Samarasekera N, Salman RA, Smith C, Tavares AAS, Gomez‐Nicola D, Kalaria RN, McColl BW, Horsburgh K. Inhibiting CSF1R alleviates cerebrovascular white matter disease and cognitive impairment. Glia 2024; 72:375-395. [PMID: 37909242 PMCID: PMC10952452 DOI: 10.1002/glia.24481] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/02/2023] [Revised: 09/27/2023] [Accepted: 10/04/2023] [Indexed: 11/02/2023]
Abstract
White matter abnormalities, related to poor cerebral perfusion, are a core feature of small vessel cerebrovascular disease, and critical determinants of vascular cognitive impairment and dementia. Despite this importance there is a lack of treatment options. Proliferation of microglia producing an expanded, reactive population and associated neuroinflammatory alterations have been implicated in the onset and progression of cerebrovascular white matter disease, in patients and in animal models, suggesting that targeting microglial proliferation may exert protection. Colony-stimulating factor-1 receptor (CSF1R) is a key regulator of microglial proliferation. We found that the expression of CSF1R/Csf1r and other markers indicative of increased microglial abundance are significantly elevated in damaged white matter in human cerebrovascular disease and in a clinically relevant mouse model of chronic cerebral hypoperfusion and vascular cognitive impairment. Using the mouse model, we investigated long-term pharmacological CSF1R inhibition, via GW2580, and demonstrated that the expansion of microglial numbers in chronic hypoperfused white matter is prevented. Transcriptomic analysis of hypoperfused white matter tissue showed enrichment of microglial and inflammatory gene sets, including phagocytic genes that were the predominant expression modules modified by CSF1R inhibition. Further, CSF1R inhibition attenuated hypoperfusion-induced white matter pathology and rescued spatial learning impairments and to a lesser extent cognitive flexibility. Overall, this work suggests that inhibition of CSF1R and microglial proliferation mediates protection against chronic cerebrovascular white matter pathology and cognitive deficits. Our study nominates CSF1R as a target for the treatment of vascular cognitive disorders with broader implications for treatment of other chronic white matter diseases.
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Affiliation(s)
| | - Joshua Beverley
- Centre for Discovery Brain SciencesUniversity of EdinburghEdinburghUK
| | - Emma Sigfridsson
- Centre for Discovery Brain SciencesUniversity of EdinburghEdinburghUK
| | - Stefan Szymkowiak
- Centre for Discovery Brain SciencesUniversity of EdinburghEdinburghUK
- UK Dementia Research InstituteUniversity of EdinburghEdinburghUK
| | - Katherine Emelianova
- Centre for Discovery Brain SciencesUniversity of EdinburghEdinburghUK
- UK Dementia Research InstituteUniversity of EdinburghEdinburghUK
| | - Owen Dando
- Centre for Discovery Brain SciencesUniversity of EdinburghEdinburghUK
- UK Dementia Research InstituteUniversity of EdinburghEdinburghUK
| | - Giles E. Hardingham
- Centre for Discovery Brain SciencesUniversity of EdinburghEdinburghUK
- UK Dementia Research InstituteUniversity of EdinburghEdinburghUK
| | - Jessica Duncombe
- Centre for Discovery Brain SciencesUniversity of EdinburghEdinburghUK
| | - Edel Hennessy
- Centre for Discovery Brain SciencesUniversity of EdinburghEdinburghUK
| | - Juraj Koudelka
- Centre for Discovery Brain SciencesUniversity of EdinburghEdinburghUK
- UK Dementia Research InstituteUniversity of EdinburghEdinburghUK
| | - Neshika Samarasekera
- Centre for Clinical Brain Sciences and Sudden Death Brain BankUniversity of EdinburghEdinburghUK
| | - Rustam Al‐Shahi Salman
- Centre for Clinical Brain Sciences and Sudden Death Brain BankUniversity of EdinburghEdinburghUK
| | - Colin Smith
- Centre for Clinical Brain Sciences and Sudden Death Brain BankUniversity of EdinburghEdinburghUK
| | - Adriana A. S. Tavares
- British Heart Foundation Centre for Cardiovascular ScienceUniversity of EdinburghEdinburghUK
| | | | - Raj N. Kalaria
- Clinical and Translational Research InstituteNewcastle UniversityNewcastleUK
| | - Barry W. McColl
- Centre for Discovery Brain SciencesUniversity of EdinburghEdinburghUK
- UK Dementia Research InstituteUniversity of EdinburghEdinburghUK
| | - Karen Horsburgh
- Centre for Discovery Brain SciencesUniversity of EdinburghEdinburghUK
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10
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Mallien AS, Brandwein C, Vasilescu AN, Leenaars C, Bleich A, Inta D, Hirjak D, Gass P. A systematic scoping review of rodent models of catatonia: Clinical correlations, translation and future approaches. Schizophr Res 2024; 263:109-121. [PMID: 37524635 DOI: 10.1016/j.schres.2023.07.018] [Citation(s) in RCA: 2] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/31/2023] [Revised: 07/19/2023] [Accepted: 07/22/2023] [Indexed: 08/02/2023]
Abstract
Catatonia is a psychiatric disorder, which subsumes a plethora of affective, motor and behavioral symptoms. In the last two decades, the number of behavioral and neuroimaging studies on catatonia has steadily increased. The majority of behavioral and neuroimaging studies in psychiatric patients suggested aberrant higher-order frontoparietal networks which, on the biochemical level, are insufficiently modulated by gamma-aminobutyric acid (GABA)-ergic and glutamatergic transmission. However, the pathomechanisms of catatonic symptoms have rarely been studied using rodent models. Here, we performed a scoping review of literature available on PubMed for studies on rodent models of catatonia. We sought to identify what we could learn from pre-clinical animal models of catatonia-like symptoms, their underlying neuronal correlates, and the complex molecular (i.e. genes and neurotransmitter) mechanisms by which its modulation exerts its effects. What becomes evident is that although many transgenic models present catatonia-like symptoms, they have not been used to better understand the pathophysiological mechanisms underlying catatonia so far. However, the identified neuronal correlates of catatonia-like symptoms correlate to a great extent with findings from neuroscience research in psychiatric patients. This points us towards fundamental cortical-striatal-thalamocortical and associated networks modulated by white matter inflammation as well as aberrant dopaminergic, GABAergic, and glutamatergic neurotransmission that is involved in catatonia. Therefore, this scoping review opens up the possibility of finally using transgenic models to help with identifying novel target mechanisms for the development of new drugs for the treatment of catatonia.
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Affiliation(s)
- Anne S Mallien
- Department of Psychiatry and Psychotherapy, Central Institute of Mental Health, Medical Faculty Mannheim, University of Heidelberg, Heidelberg, Germany; Research Group Animal Models in Psychiatry, Central Institute of Mental Health, Medical Faculty Mannheim, University of Heidelberg, Heidelberg, Germany.
| | - Christiane Brandwein
- Department of Psychiatry and Psychotherapy, Central Institute of Mental Health, Medical Faculty Mannheim, University of Heidelberg, Heidelberg, Germany; Research Group Animal Models in Psychiatry, Central Institute of Mental Health, Medical Faculty Mannheim, University of Heidelberg, Heidelberg, Germany
| | - Andrei-Nicolae Vasilescu
- Department of Psychiatry and Psychotherapy, Central Institute of Mental Health, Medical Faculty Mannheim, University of Heidelberg, Heidelberg, Germany; Research Group Animal Models in Psychiatry, Central Institute of Mental Health, Medical Faculty Mannheim, University of Heidelberg, Heidelberg, Germany
| | - Cathalijn Leenaars
- Institute for Laboratory Animal Science, Hannover Medical School, 30625 Hannover, Germany; Department for Health Evidence, Radboud University Medical Centre, 6600 Nijmegen, The Netherlands
| | - André Bleich
- Institute for Laboratory Animal Science, Hannover Medical School, 30625 Hannover, Germany
| | - Dragos Inta
- Research Group Animal Models in Psychiatry, Central Institute of Mental Health, Medical Faculty Mannheim, University of Heidelberg, Heidelberg, Germany; Department of Biomedicine, University of Basel, Basel, Switzerland
| | - Dusan Hirjak
- Department of Psychiatry and Psychotherapy, Central Institute of Mental Health, Medical Faculty Mannheim, University of Heidelberg, Heidelberg, Germany
| | - Peter Gass
- Department of Psychiatry and Psychotherapy, Central Institute of Mental Health, Medical Faculty Mannheim, University of Heidelberg, Heidelberg, Germany; Research Group Animal Models in Psychiatry, Central Institute of Mental Health, Medical Faculty Mannheim, University of Heidelberg, Heidelberg, Germany
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11
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Beach SR, Luccarelli J, Praschan N, Fusunyan M, Fricchione GL. Molecular and immunological origins of catatonia. Schizophr Res 2024; 263:169-177. [PMID: 36966063 PMCID: PMC10517087 DOI: 10.1016/j.schres.2023.03.013] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/31/2022] [Revised: 03/03/2023] [Accepted: 03/05/2023] [Indexed: 03/27/2023]
Abstract
Catatonia occurs secondary to both primary psychiatric and neuromedical etiologies. Emerging evidence suggests possible linkages between causes of catatonia and neuroinflammation. These include obvious infectious and inflammatory etiologies, common neuromedical illnesses such as delirium, and psychiatric entities such as depression and autism-spectrum disorders. Symptoms of sickness behavior, thought to be a downstream effect of the cytokine response, are common in many of these etiologies and overlap significantly with symptoms of catatonia. Furthermore, there are syndromes that overlap with catatonia that some would consider variants, including neuroleptic malignant syndrome (NMS) and akinetic mutism, which may also have neuroinflammatory underpinnings. Low serum iron, a common finding in NMS and malignant catatonia, may be caused by the acute phase response. Cellular hits involving either pathogen-associated molecular patterns (PAMP) danger signals or the damage-associated molecular patterns (DAMP) danger signals of severe psychosocial stress may set the stage for a common pathway immunoactivation state that could lower the threshold for a catatonic state in susceptible individuals. Immunoactivation leading to dysfunction in the anterior cingulate cortex (ACC)/mid-cingulate cortex (MCC)/medial prefrontal cortex (mPFC)/paralimbic cortico-striato-thalamo-cortical (CSTC) circuit, involved in motivation and movement, may be particularly important in generating the motor and behavioral symptoms of catatonia.
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Affiliation(s)
- Scott R Beach
- Department of Psychiatry, Massachusetts General Hospital, Boston, MA, USA; Harvard Medical School, Boston, MA, USA.
| | - James Luccarelli
- Department of Psychiatry, Massachusetts General Hospital, Boston, MA, USA; Harvard Medical School, Boston, MA, USA
| | - Nathan Praschan
- Department of Psychiatry, Massachusetts General Hospital, Boston, MA, USA; Harvard Medical School, Boston, MA, USA
| | - Mark Fusunyan
- Department of Psychiatry, Santa Clara Valley Medical Center, San Jose, CA, USA
| | - Gregory L Fricchione
- Department of Psychiatry, Massachusetts General Hospital, Boston, MA, USA; Harvard Medical School, Boston, MA, USA
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12
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Fricchione G. Brain evolution and the meaning of catatonia - An update. Schizophr Res 2024; 263:139-150. [PMID: 36754715 DOI: 10.1016/j.schres.2023.01.026] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/31/2022] [Revised: 01/16/2023] [Accepted: 01/18/2023] [Indexed: 02/10/2023]
Abstract
Back in 2004, in a chapter titled "Brain Evolution and the Meaning of Catatonia", a case was made that the syndrome's core meaning is embedded in millions of years of vertebrate brain evolution. (Fricchione, 2004) In this update, advances over the last almost 20 years, in catatonia theory and research in particular, and pertinent neuropsychiatry in general, will be applied to this question of meaning. The approach will rely heavily on a number of thought leaders, including Nicos Tinbergen, Paul MacLean, John Bowlby, M. Marsel Mesulam, Bruce McEwen and Karl Friston. Their guidance will be supplemented with a selected survey of 21sty century neuropsychiatry, neurophysiology, molecular biology, neuroimaging and neurotherapeutics as applied to the catatonic syndrome. In an attempt to address the question of the meaning of the catatonic syndrome in human life, we will employ two conceptual networks representing the intersubjectivity of the quantitative conceptual network of physical terms and the subjectivity of the qualitative conceptual network of mental and spiritual terms. In the process, a common referent providing extensional identity may emerge (Goodman, 1991). The goal of this exercise is to enhance our attunement with the experience of patients suffering with catatonia. A deeper understanding of catatonia's origins in brain evolution and of the challenges of individual epigenetic development in the setting of environmental events coupled with appreciation of what has been described as the most painful mammalian condition, that of separation, has the potential to foster greater efforts on the part of clinicians to diagnose and treat patients who present with catatonia. In addition, in this ancient and extreme tactic, evolved to provide safety from extreme survival threat, one can speculate what is at the core of human fear and the challenge it presents to all of us. And when the biology, psychology and sociology of catatonia are examined, the nature of solutions to the challenge may emerge.
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Affiliation(s)
- Gregory Fricchione
- Benson-Henry Institute for Mind Body Medicine Division of Psychiatry and Medicine Department of Psychiatry, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA.
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13
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Li J, Shangguan Z, Ye X, Wang Z, Liu W, Chen G. Modified FGF Hydrogel for Effective Axon Formation by Enhanced Regeneration of Myelin Sheath of Schwann Cells Using Rat Model. Int J Nanomedicine 2023; 18:7225-7236. [PMID: 38076728 PMCID: PMC10710222 DOI: 10.2147/ijn.s417723] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/05/2023] [Accepted: 11/09/2023] [Indexed: 12/18/2023] Open
Abstract
Introduction An acute spinal cord injury (SCI) is a debilitating event for which there is no targeted or effective treatment. Previous studies have shown that fibroblast growth factor (bFGF) and Schwann cells (SC) exert a protective effect on the injured tissues. Because of their easy injectability and strength, hydrogels are considered to be ideal candidates for creating loadable tissues. However, the application and mechanism of bFGF-hydrogels have not been explored. Methods We synthesized a new class of bFGF-hydrosol and evaluated its safety and biocompatibility in vitro and in vivo. Next, an SCI rat model was established to evaluate the effect of the hydrosol on an SCI by detecting various pro-inflammatory markers and evaluating the injury. The ability of hydrosol to promote axon formation was evaluated by detecting corresponding indexes, and its ability to promote remyelination was evaluated by detecting the corresponding indexes in Schwann cells. Results A novel in situ injectable hydrogel containing bFGF (HA-bFGF) was synthesized and found to have better biocompatibility than other gels. HA-bFGF helped to repair tissue damage after an SCI in vivo. Our mechanistic investigation also showed that HA-bFGF improved axon formation after an SCI by facilitating the regeneration of myelin sheath of Schwann cells. Conclusion In this study, we found that HA-bFGF could promote neural restoration and tissue recovery after an SCI. Our results indicate that hydrogels loaded with bFGF can alleviate a spinal cord injury by promoting the remyelination of Schwann cells, reducing inflammation at the injured site, and ultimately promoting axon generation.
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Affiliation(s)
- Jiandong Li
- Department of Orthopaedics, Fujian Medical University Union Hospital, Fuzhou, China
- Union Clinical College, Fujian Medical University, Fuzhou, China
| | - Zhitao Shangguan
- Department of Orthopaedics, Fujian Medical University Union Hospital, Fuzhou, China
- Union Clinical College, Fujian Medical University, Fuzhou, China
| | - Xiaoqing Ye
- Department of Orthopaedics, Fujian Medical University Union Hospital, Fuzhou, China
- Union Clinical College, Fujian Medical University, Fuzhou, China
| | - Zhenyu Wang
- Department of Orthopaedics, Fujian Medical University Union Hospital, Fuzhou, China
- Union Clinical College, Fujian Medical University, Fuzhou, China
| | - Wenge Liu
- Department of Orthopaedics, Fujian Medical University Union Hospital, Fuzhou, China
- Union Clinical College, Fujian Medical University, Fuzhou, China
| | - Gang Chen
- Department of Orthopaedics, Fujian Medical University Union Hospital, Fuzhou, China
- Union Clinical College, Fujian Medical University, Fuzhou, China
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14
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Affiliation(s)
- Stephan Heckers
- From the Department of Psychiatry and Behavioral Sciences, Vanderbilt University Medical Center, Nashville (S.H., S.W.); and the Translational Research Center, University Hospital of Psychiatry and Psychotherapy, University of Bern, Bern, Switzerland (S.W.)
| | - Sebastian Walther
- From the Department of Psychiatry and Behavioral Sciences, Vanderbilt University Medical Center, Nashville (S.H., S.W.); and the Translational Research Center, University Hospital of Psychiatry and Psychotherapy, University of Bern, Bern, Switzerland (S.W.)
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15
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Zhu H, Guan A, Liu J, Peng L, Zhang Z, Wang S. Noteworthy perspectives on microglia in neuropsychiatric disorders. J Neuroinflammation 2023; 20:223. [PMID: 37794488 PMCID: PMC10548593 DOI: 10.1186/s12974-023-02901-y] [Citation(s) in RCA: 37] [Impact Index Per Article: 18.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/15/2023] [Accepted: 09/22/2023] [Indexed: 10/06/2023] Open
Abstract
Microglia are so versatile that they not only provide immune surveillance for central nervous system, but participate in neural circuitry development, brain blood vessels formation, blood-brain barrier architecture, and intriguingly, the regulation of emotions and behaviors. Microglia have a profound impact on neuronal survival, brain wiring and synaptic plasticity. As professional phagocytic cells in the brain, they remove dead cell debris and neurotoxic agents via an elaborate mechanism. The functional profile of microglia varies considerately depending on age, gender, disease context and other internal or external environmental factors. Numerous studies have demonstrated a pivotal involvement of microglia in neuropsychiatric disorders, including negative affection, social deficit, compulsive behavior, fear memory, pain and other symptoms associated with major depression disorder, anxiety disorder, autism spectrum disorder and schizophrenia. In this review, we summarized the latest discoveries regarding microglial ontogeny, cell subtypes or state spectrum, biological functions and mechanistic underpinnings of emotional and behavioral disorders. Furthermore, we highlight the potential of microglia-targeted therapies of neuropsychiatric disorders, and propose outstanding questions to be addressed in future research of human microglia.
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Affiliation(s)
- Hongrui Zhu
- Department of Anesthesiology, First Affiliated Hospital of USTC, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, 230001, Anhui, China.
| | - Ao Guan
- School of Medicine, Xiamen University, Xiamen, 361102, China
| | - Jiayuan Liu
- Department of Anesthesiology, First Affiliated Hospital of USTC, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, 230001, Anhui, China
| | - Li Peng
- Department of Anesthesiology, First Affiliated Hospital of USTC, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, 230001, Anhui, China
| | - Zhi Zhang
- Department of Anesthesiology, First Affiliated Hospital of USTC, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, 230001, Anhui, China.
- Hefei National Laboratory for Physical Sciences at the Microscale, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, 230001, Anhui, China.
| | - Sheng Wang
- Department of Anesthesiology, First Affiliated Hospital of USTC, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, 230001, Anhui, China.
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16
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Jiang SM, Koepsell M, Patel B, Athanasiadi A. Recurrent Catatonia and Demyelinating Disorders. Cureus 2023; 15:e41656. [PMID: 37435012 PMCID: PMC10332807 DOI: 10.7759/cureus.41656] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 07/10/2023] [Indexed: 07/13/2023] Open
Abstract
Catatonia, a neuropsychiatric syndrome characterized by psychomotor and behavioral symptoms, can be associated with various underlying conditions, including demyelinating diseases such as multiple sclerosis. This paper presents a case study of a 47-year-old female with recurrent catatonic relapses and an underlying demyelinating disease. The patient exhibited symptoms of confusion, decreased oral intake, and difficulty with movement and speech. Neurological examinations, brain imaging, and laboratory tests were conducted to evaluate the etiology and guide treatment. The patient showed improvement with lorazepam and electroconvulsive therapy (ECT). However, relapses occurred after the abrupt withdrawal of medication. The case study highlights the potential connection between demyelinating diseases and catatonia and emphasizes the importance of considering demyelinating diseases in the workup, treatment, and relapse prevention of catatonia. Further research is needed to explore the mechanisms underlying the relationship between demyelination and catatonia and to investigate how different etiologies may impact the recurrence rates of catatonic episodes.
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Affiliation(s)
- Stephanie M Jiang
- Department of Psychiatry and Health Behavior, Augusta University Medical College of Georgia, Augusta, USA
| | - Marybeth Koepsell
- Department of Psychiatry and Health Behavior, Augusta University Medical College of Georgia, Augusta, USA
| | - Bhargav Patel
- Department of Psychiatry and Health Behavior, Augusta University Medical College of Georgia, Augusta, USA
| | - Argyro Athanasiadi
- Department of Psychiatry and Health Behavior, Augusta University Medical College of Georgia, Augusta, USA
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17
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Depp C, Sun T, Sasmita AO, Spieth L, Berghoff SA, Nazarenko T, Overhoff K, Steixner-Kumar AA, Subramanian S, Arinrad S, Ruhwedel T, Möbius W, Göbbels S, Saher G, Werner HB, Damkou A, Zampar S, Wirths O, Thalmann M, Simons M, Saito T, Saido T, Krueger-Burg D, Kawaguchi R, Willem M, Haass C, Geschwind D, Ehrenreich H, Stassart R, Nave KA. Myelin dysfunction drives amyloid-β deposition in models of Alzheimer's disease. Nature 2023; 618:349-357. [PMID: 37258678 PMCID: PMC10247380 DOI: 10.1038/s41586-023-06120-6] [Citation(s) in RCA: 183] [Impact Index Per Article: 91.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/30/2021] [Accepted: 04/21/2023] [Indexed: 06/02/2023]
Abstract
The incidence of Alzheimer's disease (AD), the leading cause of dementia, increases rapidly with age, but why age constitutes the main risk factor is still poorly understood. Brain ageing affects oligodendrocytes and the structural integrity of myelin sheaths1, the latter of which is associated with secondary neuroinflammation2,3. As oligodendrocytes support axonal energy metabolism and neuronal health4-7, we hypothesized that loss of myelin integrity could be an upstream risk factor for neuronal amyloid-β (Aβ) deposition, the central neuropathological hallmark of AD. Here we identify genetic pathways of myelin dysfunction and demyelinating injuries as potent drivers of amyloid deposition in mouse models of AD. Mechanistically, myelin dysfunction causes the accumulation of the Aβ-producing machinery within axonal swellings and increases the cleavage of cortical amyloid precursor protein. Suprisingly, AD mice with dysfunctional myelin lack plaque-corralling microglia despite an overall increase in their numbers. Bulk and single-cell transcriptomics of AD mouse models with myelin defects show that there is a concomitant induction of highly similar but distinct disease-associated microglia signatures specific to myelin damage and amyloid plaques, respectively. Despite successful induction, amyloid disease-associated microglia (DAM) that usually clear amyloid plaques are apparently distracted to nearby myelin damage. Our data suggest a working model whereby age-dependent structural defects of myelin promote Aβ plaque formation directly and indirectly and are therefore an upstream AD risk factor. Improving oligodendrocyte health and myelin integrity could be a promising target to delay development and slow progression of AD.
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Affiliation(s)
- Constanze Depp
- Department of Neurogenetics, Max Planck Institute for Multidisciplinary Sciences, Göttingen, Germany.
| | - Ting Sun
- Department of Neurogenetics, Max Planck Institute for Multidisciplinary Sciences, Göttingen, Germany
| | - Andrew Octavian Sasmita
- Department of Neurogenetics, Max Planck Institute for Multidisciplinary Sciences, Göttingen, Germany
| | - Lena Spieth
- Department of Neurogenetics, Max Planck Institute for Multidisciplinary Sciences, Göttingen, Germany
- Institute of Neuronal Cell Biology, Technical University Munich, Munich, Germany
- German Center for Neurodegenerative Diseases, Munich, Germany
| | - Stefan A Berghoff
- Department of Neurogenetics, Max Planck Institute for Multidisciplinary Sciences, Göttingen, Germany
- Institute of Neuronal Cell Biology, Technical University Munich, Munich, Germany
- German Center for Neurodegenerative Diseases, Munich, Germany
| | - Taisiia Nazarenko
- Department of Neurogenetics, Max Planck Institute for Multidisciplinary Sciences, Göttingen, Germany
| | - Katharina Overhoff
- Department of Neurogenetics, Max Planck Institute for Multidisciplinary Sciences, Göttingen, Germany
| | - Agnes A Steixner-Kumar
- Clinical Neuroscience, Max Planck Institute for Multidisciplinary Sciences, Göttingen, Germany
| | - Swati Subramanian
- Department of Neurogenetics, Max Planck Institute for Multidisciplinary Sciences, Göttingen, Germany
| | - Sahab Arinrad
- Clinical Neuroscience, Max Planck Institute for Multidisciplinary Sciences, Göttingen, Germany
| | - Torben Ruhwedel
- Department of Neurogenetics, Max Planck Institute for Multidisciplinary Sciences, Göttingen, Germany
| | - Wiebke Möbius
- Department of Neurogenetics, Max Planck Institute for Multidisciplinary Sciences, Göttingen, Germany
| | - Sandra Göbbels
- Department of Neurogenetics, Max Planck Institute for Multidisciplinary Sciences, Göttingen, Germany
| | - Gesine Saher
- Department of Neurogenetics, Max Planck Institute for Multidisciplinary Sciences, Göttingen, Germany
| | - Hauke B Werner
- Department of Neurogenetics, Max Planck Institute for Multidisciplinary Sciences, Göttingen, Germany
| | - Alkmini Damkou
- Institute of Neuronal Cell Biology, Technical University Munich, Munich, Germany
- German Center for Neurodegenerative Diseases, Munich, Germany
| | - Silvia Zampar
- Department of Psychiatry and Psychotherapy, University Medical Center, Georg-August University, Göttingen, Germany
| | - Oliver Wirths
- Department of Psychiatry and Psychotherapy, University Medical Center, Georg-August University, Göttingen, Germany
| | - Maik Thalmann
- Department of German Philology, Georg-August University, Göttingen, Germany
| | - Mikael Simons
- Institute of Neuronal Cell Biology, Technical University Munich, Munich, Germany
- German Center for Neurodegenerative Diseases, Munich, Germany
- Munich Cluster of Systems Neurology (SyNergy), Munich, Germany
| | - Takashi Saito
- Department of Neurocognitive Science, Institute of Brain Science, Nagoya City University Graduate School of Medical Sciences, Nagoya, Aichi, Japan
- Laboratory for Proteolytic Neuroscience, RIKEN Center for Brain Science, Wako, Saitama, Japan
| | - Takaomi Saido
- Laboratory for Proteolytic Neuroscience, RIKEN Center for Brain Science, Wako, Saitama, Japan
| | - Dilja Krueger-Burg
- Department of Psychiatry and Psychotherapy, University Medical Center, Georg-August University, Göttingen, Germany
- Department of Molecular Neurobiology, Max Planck Institute for Multidisciplinary Sciences, Göttingen, Germany
| | - Riki Kawaguchi
- Program in Neurogenetics, Department of Neurology, David Geffen School of Medicine, University of California Los Angeles, Los Angeles, CA, USA
| | - Michael Willem
- German Center for Neurodegenerative Diseases, Munich, Germany
- Munich Cluster of Systems Neurology (SyNergy), Munich, Germany
- Metabolic Biochemistry, Biomedical Center (BMC), Faculty of Medicine, Ludwig-Maximilians University of Munich, Munich, Germany
| | - Christian Haass
- German Center for Neurodegenerative Diseases, Munich, Germany
- Munich Cluster of Systems Neurology (SyNergy), Munich, Germany
- Metabolic Biochemistry, Biomedical Center (BMC), Faculty of Medicine, Ludwig-Maximilians University of Munich, Munich, Germany
| | - Daniel Geschwind
- Program in Neurogenetics, Department of Neurology, David Geffen School of Medicine, University of California Los Angeles, Los Angeles, CA, USA
| | - Hannelore Ehrenreich
- Clinical Neuroscience, Max Planck Institute for Multidisciplinary Sciences, Göttingen, Germany
| | - Ruth Stassart
- Department of Neurogenetics, Max Planck Institute for Multidisciplinary Sciences, Göttingen, Germany
- Paul-Flechsig-Institute of Neuropathology, University Clinic Leipzig, Leipzig, Germany
| | - Klaus-Armin Nave
- Department of Neurogenetics, Max Planck Institute for Multidisciplinary Sciences, Göttingen, Germany.
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18
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Arinrad S, Depp C, Siems SB, Sasmita AO, Eichel MA, Ronnenberg A, Hammerschmidt K, Lüders KA, Werner HB, Ehrenreich H, Nave KA. Isolated catatonia-like executive dysfunction in mice with forebrain-specific loss of myelin integrity. eLife 2023; 12:70792. [PMID: 36892455 PMCID: PMC9998085 DOI: 10.7554/elife.70792] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/28/2021] [Accepted: 01/24/2023] [Indexed: 03/10/2023] Open
Abstract
A key feature of advanced brain aging includes structural defects of intracortical myelin that are associated with secondary neuroinflammation. A similar pathology is seen in specific myelin mutant mice that model 'advanced brain aging' and exhibit a range of behavioral abnormalities. However, the cognitive assessment of these mutants is problematic because myelin-dependent motor-sensory functions are required for quantitative behavioral readouts. To better understand the role of cortical myelin integrity for higher brain functions, we generated mice lacking Plp1, encoding the major integral myelin membrane protein, selectively in ventricular zone stem cells of the mouse forebrain. In contrast to conventional Plp1 null mutants, subtle myelin defects were restricted to the cortex, hippocampus, and underlying callosal tracts. Moreover, forebrain-specific Plp1 mutants exhibited no defects of basic motor-sensory performance at any age tested. Surprisingly, several behavioral alterations reported for conventional Plp1 null mice (Gould et al., 2018) were absent and even social interactions appeared normal. However, with novel behavioral paradigms, we determined catatonia-like symptoms and isolated executive dysfunction in both genders. This suggests that loss of myelin integrity has an impact on cortical connectivity and underlies specific defects of executive function. These observations are likewise relevant for human neuropsychiatric conditions and other myelin-related diseases.
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Affiliation(s)
- Sahab Arinrad
- Clinical Neuroscience, Max Planck Institute for Multidisciplinary Sciences, Göttingen, Germany
| | - Constanze Depp
- Neurogenetics, Max Planck Institute for Multidisciplinary Sciences, Göttingen, Germany
| | - Sophie B Siems
- Neurogenetics, Max Planck Institute for Multidisciplinary Sciences, Göttingen, Germany
| | | | - Maria A Eichel
- Neurogenetics, Max Planck Institute for Multidisciplinary Sciences, Göttingen, Germany
| | - Anja Ronnenberg
- Clinical Neuroscience, Max Planck Institute for Multidisciplinary Sciences, Göttingen, Germany
| | | | - Katja A Lüders
- Neurogenetics, Max Planck Institute for Multidisciplinary Sciences, Göttingen, Germany
| | - Hauke B Werner
- Neurogenetics, Max Planck Institute for Multidisciplinary Sciences, Göttingen, Germany
| | - Hannelore Ehrenreich
- Clinical Neuroscience, Max Planck Institute for Multidisciplinary Sciences, Göttingen, Germany
| | - Klaus-Armin Nave
- Neurogenetics, Max Planck Institute for Multidisciplinary Sciences, Göttingen, Germany
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19
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Montilla A, Zabala A, Er-Lukowiak M, Rissiek B, Magnus T, Rodriguez-Iglesias N, Sierra A, Matute C, Domercq M. Microglia and meningeal macrophages depletion delays the onset of experimental autoimmune encephalomyelitis. Cell Death Dis 2023; 14:16. [PMID: 36635255 PMCID: PMC9835747 DOI: 10.1038/s41419-023-05551-3] [Citation(s) in RCA: 35] [Impact Index Per Article: 17.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/08/2022] [Revised: 12/20/2022] [Accepted: 01/03/2023] [Indexed: 01/13/2023]
Abstract
In multiple sclerosis and the experimental autoimmune encephalomyelitis (EAE) model, both resident microglia and infiltrating macrophages contribute to demyelination as well as spontaneous remyelination. Nevertheless, the specific roles of microglia versus macrophages are unknown. We investigated the influence of microglia in EAE using the colony stimulating factor 1 receptor (CSF-1R) inhibitor, PLX5622, to deplete microglial population and Ccr2RFP/+ fmsEGFP/+ mice, to distinguish blood-derived macrophages from microglia. PLX5622 treatment depleted microglia and meningeal macrophages, and provoked a massive infiltration of CCR2+ macrophages into demyelinating lesions and spinal cord parenchyma, albeit it did not alter EAE chronic phase. In contrast, microglia and meningeal macrophages depletion reduced the expression of major histocompatibility complex II and CD80 co-stimulatory molecule in dendritic cells, macrophages and microglia. In addition, it diminished T cell reactivation and proliferation in the spinal cord parenchyma, inducing a significant delay in EAE onset. Altogether, these data point to a specific role of CNS microglia and meningeal macrophages in antigen presentation and T cell reactivation at initial stages of EAE.
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Affiliation(s)
- Alejandro Montilla
- Achucarro Basque Center for Neuroscience and Department of Neuroscience, University of the Basque Country UPV/EHU, E-48940, Leioa, Spain
- Centro de Investigación Biomédica en Red de Enfermedades Neurodegenerativas (CIBERNED), Leioa, Spain
| | - Alazne Zabala
- Achucarro Basque Center for Neuroscience and Department of Neuroscience, University of the Basque Country UPV/EHU, E-48940, Leioa, Spain
- Centro de Investigación Biomédica en Red de Enfermedades Neurodegenerativas (CIBERNED), Leioa, Spain
| | - Marco Er-Lukowiak
- Department of Neurology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany, 20251, Hamburg, Germany
| | - Björn Rissiek
- Department of Neurology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany, 20251, Hamburg, Germany
| | - Tim Magnus
- Department of Neurology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany, 20251, Hamburg, Germany
| | - Noelia Rodriguez-Iglesias
- Achucarro Basque Center for Neuroscience and Department of Neuroscience, University of the Basque Country UPV/EHU, E-48940, Leioa, Spain
| | - Amanda Sierra
- Achucarro Basque Center for Neuroscience and Department of Neuroscience, University of the Basque Country UPV/EHU, E-48940, Leioa, Spain
- Ikerbasque Foundation, E-48009, Bilbao, Spain
| | - Carlos Matute
- Achucarro Basque Center for Neuroscience and Department of Neuroscience, University of the Basque Country UPV/EHU, E-48940, Leioa, Spain.
- Centro de Investigación Biomédica en Red de Enfermedades Neurodegenerativas (CIBERNED), Leioa, Spain.
| | - María Domercq
- Achucarro Basque Center for Neuroscience and Department of Neuroscience, University of the Basque Country UPV/EHU, E-48940, Leioa, Spain.
- Centro de Investigación Biomédica en Red de Enfermedades Neurodegenerativas (CIBERNED), Leioa, Spain.
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20
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Walther S, Weiss F. [Catatonia Through the Ages - from Kahlbaum to the ICD-11]. FORTSCHRITTE DER NEUROLOGIE-PSYCHIATRIE 2023; 91:52-68. [PMID: 36693365 DOI: 10.1055/a-1942-3995] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/26/2023]
Abstract
For decades, the psychomotor syndrome of catatonia was considered exclusively a subtype of schizophrenia. The use of antipsychotics and changes in the teaching content in the further training of psychiatrists led to the fact that catatonia was hardly recognized anymore. Yet catatonia is in principle well treatable. The new status in ICD-11 will probably allow to better teach, recognize, and treat catatonia in the future.
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21
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Basilico B, Ferrucci L, Khan A, Di Angelantonio S, Ragozzino D, Reverte I. What microglia depletion approaches tell us about the role of microglia on synaptic function and behavior. Front Cell Neurosci 2022; 16:1022431. [PMID: 36406752 PMCID: PMC9673171 DOI: 10.3389/fncel.2022.1022431] [Citation(s) in RCA: 19] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/18/2022] [Accepted: 10/17/2022] [Indexed: 11/06/2022] Open
Abstract
Microglia are dynamic cells, constantly surveying their surroundings and interacting with neurons and synapses. Indeed, a wealth of knowledge has revealed a critical role of microglia in modulating synaptic transmission and plasticity in the developing brain. In the past decade, novel pharmacological and genetic strategies have allowed the acute removal of microglia, opening the possibility to explore and understand the role of microglia also in the adult brain. In this review, we summarized and discussed the contribution of microglia depletion strategies to the current understanding of the role of microglia on synaptic function, learning and memory, and behavior both in physiological and pathological conditions. We first described the available microglia depletion methods highlighting their main strengths and weaknesses. We then reviewed the impact of microglia depletion on structural and functional synaptic plasticity. Next, we focused our analysis on the effects of microglia depletion on behavior, including general locomotor activity, sensory perception, motor function, sociability, learning and memory both in healthy animals and animal models of disease. Finally, we integrated the findings from the reviewed studies and discussed the emerging roles of microglia on the maintenance of synaptic function, learning, memory strength and forgetfulness, and the implications of microglia depletion in models of brain disease.
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Affiliation(s)
| | - Laura Ferrucci
- Department of Physiology and Pharmacology, Sapienza University of Rome, Rome, Italy
| | - Azka Khan
- Department of Physiology and Pharmacology, Sapienza University of Rome, Rome, Italy
| | - Silvia Di Angelantonio
- Department of Physiology and Pharmacology, Sapienza University of Rome, Rome, Italy
- Center for Life Nano- and Neuro-Science, Istituto Italiano di Tecnologia, Rome, Italy
| | - Davide Ragozzino
- Laboratory Affiliated to Institute Pasteur Italia – Fondazione Cenci Bolognetti, Department of Physiology and Pharmacology, Sapienza University of Rome, Rome, Italy
- Santa Lucia Foundation (IRCCS Fondazione Santa Lucia), Rome, Italy
- *Correspondence: Davide Ragozzino,
| | - Ingrid Reverte
- Department of Physiology and Pharmacology, Sapienza University of Rome, Rome, Italy
- Santa Lucia Foundation (IRCCS Fondazione Santa Lucia), Rome, Italy
- Ingrid Reverte,
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22
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Ariza-Salamanca DF, Corrales-Hernández MG, Pachón-Londoño MJ, Hernández-Duarte I. Molecular and cellular mechanisms leading to catatonia: an integrative approach from clinical and preclinical evidence. Front Mol Neurosci 2022; 15:993671. [PMID: 36245923 PMCID: PMC9558725 DOI: 10.3389/fnmol.2022.993671] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/13/2022] [Accepted: 08/31/2022] [Indexed: 11/13/2022] Open
Abstract
This review aims to describe the clinical spectrum of catatonia, in order to carefully assess the involvement of astrocytes, neurons, oligodendrocytes, and microglia, and articulate the available preclinical and clinical evidence to achieve a translational understanding of the cellular and molecular mechanisms behind this disorder. Catatonia is highly common in psychiatric and acutely ill patients, with prevalence ranging from 7.6% to 38%. It is usually present in different psychiatric conditions such as mood and psychotic disorders; it is also a consequence of folate deficiency, autoimmunity, paraneoplastic disorders, and even autistic spectrum disorders. Few therapeutic options are available due to its complexity and poorly understood physiopathology. We briefly revisit the traditional treatments used in catatonia, such as antipsychotics, electroconvulsive therapy, and benzodiazepines, before assessing novel therapeutics which aim to modulate molecular pathways through different mechanisms, including NMDA antagonism and its allosteric modulation, and anti-inflammatory drugs to modulate microglia reaction and mitigate oxidative stress, such as lithium, vitamin B12, and NMDAr positive allosteric modulators.
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Affiliation(s)
- Daniel Felipe Ariza-Salamanca
- Medical and Health Sciences Education Research Group, School of Medicine and Health Sciences, Universidad del Rosario, Bogotá, Colombia
- Pharmacology Unit, Department of Biomedical Sciences, School of Medicine and Health Sciences, Universidad del Rosario, Bogotá, Colombia
- *Correspondence: Daniel Felipe Ariza-Salamanca
| | - María Gabriela Corrales-Hernández
- Pharmacology Unit, Department of Biomedical Sciences, School of Medicine and Health Sciences, Universidad del Rosario, Bogotá, Colombia
| | - María José Pachón-Londoño
- Pharmacology Unit, Department of Biomedical Sciences, School of Medicine and Health Sciences, Universidad del Rosario, Bogotá, Colombia
| | - Isabella Hernández-Duarte
- Pharmacology Unit, Department of Biomedical Sciences, School of Medicine and Health Sciences, Universidad del Rosario, Bogotá, Colombia
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23
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Ehrenreich H. For decades against the mainstream - From erythropoietin and hypoxia as novel treatment strategies to deep phenotyping in neuropsychiatric disorders. Psychiatry Res 2022; 317:114854. [PMID: 36170796 PMCID: PMC7613706 DOI: 10.1016/j.psychres.2022.114854] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/24/2022] [Revised: 09/14/2022] [Accepted: 09/15/2022] [Indexed: 01/06/2023]
Affiliation(s)
- Hannelore Ehrenreich
- Clinical Neuroscience, Max Planck Institute for Multidisciplinary Sciences - City Campus, Hermann-Rein-Str.3, Göttingen 37075, Germany.
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24
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Moore S, Amatya DN, Chu MM, Besterman AD. Catatonia in autism and other neurodevelopmental disabilities: a state-of-the-art review. NPJ MENTAL HEALTH RESEARCH 2022; 1:12. [PMID: 38609506 PMCID: PMC10955936 DOI: 10.1038/s44184-022-00012-9] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 05/31/2022] [Accepted: 08/26/2022] [Indexed: 04/14/2024]
Abstract
Individuals with neurodevelopmental disabilities (NDDs) may be at increased risk for catatonia, which can be an especially challenging condition to diagnose and treat. There may be symptom overlap between catatonia and NDD-associated behaviors, such as stereotypies. The diagnosis of catatonia should perhaps be adjusted to address symptom overlap and to include extreme behaviors observed in patients with NDDs, such as severe self-injury. Risk factors for catatonia in individuals with NDDs may include trauma and certain genetic variants, such as those that disrupt SHANK3. Common etiologic features between neurodevelopmental disabilities and catatonia, such as excitatory/inhibitory imbalance and neuroimmune dysfunction, may partially account for comorbidity. New approaches leveraging genetic testing and neuroimmunologic evaluation may allow for more precise diagnoses and effective treatments.
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Affiliation(s)
- Shavon Moore
- University of California San Diego, Department of Psychiatry, San Diego, CA, USA
- Rady Children's Hospital San Diego, Division of Behavioral Health Services, San Diego, CA, USA
| | - Debha N Amatya
- University of California San Diego, Department of Psychiatry, San Diego, CA, USA
- UCLA Semel Institute of Neuroscience and Human Behavior, Los Angeles, CA, USA
| | - Michael M Chu
- University of California San Diego, Department of Psychiatry, San Diego, CA, USA
- Rady Children's Hospital San Diego, Division of Behavioral Health Services, San Diego, CA, USA
- Children's Hospital of Orange County, Division of Child and Adolescent Psychiatry, Orange, CA, USA
- University of California Irvine, Department of Psychiatry, Irvine, CA, USA
| | - Aaron D Besterman
- University of California San Diego, Department of Psychiatry, San Diego, CA, USA.
- Rady Children's Hospital San Diego, Division of Behavioral Health Services, San Diego, CA, USA.
- Rady Children's Institute for Genomic Medicine, San Diego, CA, USA.
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25
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Badura Brzoza K, Główczyński P, Błachut M. Paralyzed by Fear?-A Case Report in the Context of Narrative Review on Catatonia. INTERNATIONAL JOURNAL OF ENVIRONMENTAL RESEARCH AND PUBLIC HEALTH 2022; 19:10161. [PMID: 36011796 PMCID: PMC9407999 DOI: 10.3390/ijerph191610161] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 06/12/2022] [Revised: 08/06/2022] [Accepted: 08/15/2022] [Indexed: 06/15/2023]
Abstract
In ICD-11, catatonia is a complex syndrome that includes psychomotor disorders (negativity, catalepsy, wax flexibility, mutism, automatism, mannerisms, or echolalia) and volitional processes affect modulation and action planning, which leads to hypofunctional, hyperfunctional, or parafunctional motor action. This is a very important clue that this state can be associated with both mental and somatic diseases. In order to create a narrative review, authors analyzed the diagnostic criteria of ICD-10 and ICD-11 and searched the PubMed medical base for articles on the diagnosis and different approaches to the treatment of catatonia. The treatment of catatonia is not standardized. It is based on the use of benzodiazepines, GABAa receptor antagonists, NMDA receptor antagonists, D2 receptor antagonist, and electroconvulsive therapy (ECT). The authors also would like to present the case of a patient in whom the diagnosis of catatonia was not so clear according to the diagnostic criteria, emphasizing the importance of the key diagnosis for the patient's recovery. The authors would also like to point out that the topic of catatonia should be of interest not only to psychiatrists, but also to doctors of other specialties, who may encounter cases of catatonia complicating somatic states in hospital wards.
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26
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Bullock G, Johnson GS, Mhlanga-Mutangadura T, Petesch SC, Thompson S, Goebbels S, Katz ML. Lysosomal storage disease associated with a CNP sequence variant in Dalmatian dogs. Gene X 2022; 830:146513. [PMID: 35447247 DOI: 10.1016/j.gene.2022.146513] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/14/2022] [Revised: 03/31/2022] [Accepted: 04/14/2022] [Indexed: 11/04/2022] Open
Abstract
A progressive neurological disorder was identified in purebred Dalmatian dogs. The disease is characterized by anxiety, pacing and circling, hypersensitivity, cognitive decline, sleep disturbance, loss of coordination, loss of control over urination and defecation, and visual impairment. Neurological signs first became apparent when the dogs were approximately 18 months of age and progressed slowly. Two affected littermates were euthanized at approximately 7 years, 5 months and 8 years, 2 months of age due to the severity of neurological impairment. The mother of the affected dogs and four other relatives exhibited milder, later-onset neurological signs. Pronounced accumulations of autofluorescent intracellular inclusions were found in cerebral cortex, cerebellum, optic nerve, and cardiac muscle of the affected dogs. These inclusions co-localized with immunolabeling of the lysosomal marker protein LAMP2 and bound antibodies to mitochondrial ATPase subunit c, indicating that the dogs suffered from a lysosomal storage disease with similarities to the neuronal ceroid lipofuscinoses. Ultrastructural analysis indicated that the storage bodies were surrounded by a single-layer membrane, but the storage granules were distinct from those reported for other lysosomal storage diseases. Whole genome sequences, generated with DNA from the two euthanized Dalmatians, both contained a rare, homozygous single-base deletion and reading-frame shift in CNP which encodes the enzyme CNPase (EC 3.1.4.37). The late-onset disease was exhibited by five of seven related Dalmatians that were heterozygous for the deletion allele and over 8 years of age, whereas none of 16 age-matched reference-allele homozygotes developed neurologic signs. No CNPase antigen could be detected with immunohistochemical labeling in tissues from the dogs with the earlier-onset disorder. Similar to the later-onset Dalmatians, autofluorescent storage granules were apparent in brain and cardiac tissue from transgenic mice that were nullizygous for Cnp. Based on the clinical signs, the histopathological, immunohistochemical, ultrastructural, and molecular-genetic findings, and the finding that nullizygous Cnp mice accumulate autofluorescent storage granules, we propose that the earlier-onset Dalmatian disorder is a novel lysosomal storage disease that results from a loss-of-function mutation in CNP and that shares features characteristic of the neuronal ceroid lipofuscinoses. That the later-onset disorder occurred only in dogs heterozygous for the CNP deletion variant suggests that this disorder is a result of the variant allele's presence.
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Affiliation(s)
- Garrett Bullock
- Department of Veterinary Pathobiology, College of Veterinary Medicine, University of Missouri, Columbia, MO, USA
| | - Gary S Johnson
- Department of Veterinary Pathobiology, College of Veterinary Medicine, University of Missouri, Columbia, MO, USA
| | - Tendai Mhlanga-Mutangadura
- Department of Veterinary Pathobiology, College of Veterinary Medicine, University of Missouri, Columbia, MO, USA
| | - Scott C Petesch
- University of Pennsylvania School of Veterinary Medicine, Philadelphia, PA, USA
| | | | - Sandra Goebbels
- Max Planck Institute of Experimental Medicine, Department of Neurogenetics, Hermann-Rein-Str. 3, 37075 Göttingen, Germany
| | - Martin L Katz
- Neurodegenerative Diseases Research Laboratory, University of Missouri School of Medicine, Columbia, MO, USA.
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27
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Gentry NW, McMahon T, Yamazaki M, Webb J, Arnold TD, Rosi S, Ptáček LJ, Fu YH. Microglia are involved in the protection of memories formed during sleep deprivation. Neurobiol Sleep Circadian Rhythms 2022; 12:100073. [PMID: 35028489 PMCID: PMC8741522 DOI: 10.1016/j.nbscr.2021.100073] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/04/2021] [Revised: 12/10/2021] [Accepted: 12/15/2021] [Indexed: 01/09/2023] Open
Abstract
Sleep deprivation can generate inflammatory responses in the central nervous system. In turn, this inflammation increases sleep drive, leading to a rebound in sleep duration. Microglia, the innate immune cells found exclusively in the CNS, have previously been found to release inflammatory signals and exhibit altered characteristics in response to sleep deprivation. Together, this suggests that microglia may be partially responsible for the brain's response to sleep deprivation through their inflammatory activity. In this study, we ablated microglia from the mouse brain and assessed resulting sleep, circadian, and sleep deprivation phenotypes. We find that microglia are dispensable for both homeostatic sleep and circadian function and the sleep rebound response to sleep deprivation. However, we uncover a phenomenon by which microglia appear to be essential for the protection of fear-conditioning memories formed during the recovery sleep period following a period of sleep deprivation. This phenomenon occurs potentially through the upregulation of synaptic-homeostasis related genes to protect nascent dendritic spines that may be otherwise removed or downscaled during recovery sleep. These findings further expand the list of known functions for microglia in synaptic modulation.
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Affiliation(s)
- Nicholas W. Gentry
- Department of Neurology, University of California, San Francisco, San Francisco, CA, 94143, USA
| | - Thomas McMahon
- Department of Neurology, University of California, San Francisco, San Francisco, CA, 94143, USA
| | - Maya Yamazaki
- Department of Neurology, University of California, San Francisco, San Francisco, CA, 94143, USA
| | - John Webb
- Department of Neurology, University of California, San Francisco, San Francisco, CA, 94143, USA
| | - Thomas D. Arnold
- Department of Pediatrics, University of California, San Francisco, San Francisco, CA, 94143, USA
- Department of Physical Rehabilitation Science, University of California, San Francisco, San Francisco, CA, 94143, USA
- Department of Neurological Surgery, University of California, San Francisco, San Francisco, CA, 94143, USA
| | - Susanna Rosi
- Department of Physical Rehabilitation Science, University of California, San Francisco, San Francisco, CA, 94143, USA
- Department of Neurological Surgery, University of California, San Francisco, San Francisco, CA, 94143, USA
- Weill Institute for Neuroscience, University of California, San Francisco, San Francisco, CA, 94143, USA
- Kavli Institute for Fundamental Neuroscience, University of California, San Francisco, San Francisco, CA, 94143, USA
| | - Louis J. Ptáček
- Department of Neurology, University of California, San Francisco, San Francisco, CA, 94143, USA
- Institute for Human Genetics, University of California, San Francisco, San Francisco, CA, 94143, USA
- Weill Institute for Neuroscience, University of California, San Francisco, San Francisco, CA, 94143, USA
- Kavli Institute for Fundamental Neuroscience, University of California, San Francisco, San Francisco, CA, 94143, USA
| | - Ying-Hui Fu
- Department of Neurology, University of California, San Francisco, San Francisco, CA, 94143, USA
- Institute for Human Genetics, University of California, San Francisco, San Francisco, CA, 94143, USA
- Weill Institute for Neuroscience, University of California, San Francisco, San Francisco, CA, 94143, USA
- Kavli Institute for Fundamental Neuroscience, University of California, San Francisco, San Francisco, CA, 94143, USA
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28
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Yang Y, Ishima T, Wan X, Wei Y, Chang L, Zhang J, Qu Y, Hashimoto K. Microglial depletion and abnormalities in gut microbiota composition and short-chain fatty acids in mice after repeated administration of colony stimulating factor 1 receptor inhibitor PLX5622. Eur Arch Psychiatry Clin Neurosci 2022; 272:483-495. [PMID: 34480631 DOI: 10.1007/s00406-021-01325-0] [Citation(s) in RCA: 24] [Impact Index Per Article: 8.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/07/2021] [Accepted: 08/27/2021] [Indexed: 12/11/2022]
Abstract
PLX5622, a brain-penetrant highly specific inhibitor of the colony-stimulating factor 1 receptor (CSF1R), is used to eliminate microglia in the brain. Considering the role of microglia and gut microbiota in the brain homeostasis, this study was undertaken to investigate whether repeated intragastric administration of PLX5622 (65 mg/kg/day for consecutive 7 days) could affect the composition of gut microbiota and the concentration of short-chain fatty acids (SCFAs) in fresh feces of adult mice. Repeated administration of PLX5622 caused significant reductions of the expression of genes and proteins for microglial markers in the prefrontal cortex (PFC) and hippocampus compared to control mice although the elimination of brain's microglia was partial. There was a significant alteration in the β-diversity of intestine microbiota in the PLX5622-treated group. Linear discriminant analysis effect size identified eight significant enriched bacteria as microbial markers for PLX5622-treated group. Repeated administration of PLX5622 affected the relative abundance of several bacteria at the genus and species levels. Furthermore, repeated administration of PLX5622 caused a significant change in lactic acid compared to control group. Interestingly, we found significant correlations between microglial markers in the brain and the relative abundance of several bacteria, suggesting microbiome-microglia crosstalk through the brain-gut axis. These data demonstrate that repeated administration of PLX5622 leads to an abnormal composition of the gut microbiota and lactic acid in adult mice. Therefore, abnormalities in the composition of gut microbiota after repeated treatment of PLX5622 should be considered for behavioral and biological functions in animals treated with CSF1R inhibitors.
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Affiliation(s)
- Yong Yang
- Division of Clinical Neuroscience, Chiba University Center for Forensic Mental Health, Chiba, 260-8670, Japan
| | - Tamaki Ishima
- Division of Clinical Neuroscience, Chiba University Center for Forensic Mental Health, Chiba, 260-8670, Japan
| | - Xiayun Wan
- Division of Clinical Neuroscience, Chiba University Center for Forensic Mental Health, Chiba, 260-8670, Japan
| | - Yan Wei
- Division of Clinical Neuroscience, Chiba University Center for Forensic Mental Health, Chiba, 260-8670, Japan
| | - Lijia Chang
- Division of Clinical Neuroscience, Chiba University Center for Forensic Mental Health, Chiba, 260-8670, Japan
| | - Jiancheng Zhang
- Division of Clinical Neuroscience, Chiba University Center for Forensic Mental Health, Chiba, 260-8670, Japan
| | - Youge Qu
- Division of Clinical Neuroscience, Chiba University Center for Forensic Mental Health, Chiba, 260-8670, Japan
| | - Kenji Hashimoto
- Division of Clinical Neuroscience, Chiba University Center for Forensic Mental Health, Chiba, 260-8670, Japan.
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29
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Ziaei A, Garcia-Miralles M, Radulescu CI, Sidik H, Silvin A, Bae HG, Bonnard C, Yusof NABM, Ferrari Bardile C, Tan LJ, Ng AYJ, Tohari S, Dehghani L, Henry L, Yeo XY, Lee S, Venkatesh B, Langley SR, Shaygannejad V, Reversade B, Jung S, Ginhoux F, Pouladi MA. Ermin deficiency leads to compromised myelin, inflammatory milieu, and susceptibility to demyelinating insult. Brain Pathol 2022; 32:e13064. [PMID: 35285112 PMCID: PMC9425013 DOI: 10.1111/bpa.13064] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/16/2021] [Revised: 01/09/2022] [Accepted: 02/10/2022] [Indexed: 11/28/2022] Open
Abstract
Ermin is an actin-binding protein found almost exclusively in the central nervous system (CNS) as a component of myelin sheaths. Although Ermin has been predicted to play a role in the formation and stability of myelin sheaths, this has not been directly examined in vivo. Here, we show that Ermin is essential for myelin sheath integrity and normal saltatory conduction. Loss of Ermin in mice caused de-compacted and fragmented myelin sheaths and led to slower conduction along with progressive neurological deficits. RNA sequencing of the corpus callosum, the largest white matter structure in the CNS, pointed to inflammatory activation in aged Ermin-deficient mice, which was corroborated by increased levels of microgliosis and astrogliosis. The inflammatory milieu and myelin abnormalities were further associated with increased susceptibility to immune-mediated demyelination insult in Ermin knockout mice. Supporting a possible role of Ermin deficiency in inflammatory white matter disorders, a rare inactivating mutation in the ERMN gene was identified in multiple sclerosis patients. Our findings demonstrate a critical role for Ermin in maintaining myelin integrity. Given its near-exclusive expression in myelinating oligodendrocytes, Ermin deficiency represents a compelling "inside-out" model of inflammatory dysmyelination and may offer a new paradigm for the development of myelin stability-targeted therapies.
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Affiliation(s)
- Amin Ziaei
- Translational Laboratory in Genetic Medicine (TLGM), Agency for Science, Technology, and Research (A*STAR), Singapore, Singapore.,UCSF Weill Institute for Neurosciences, University of California, San Francisco, San Francisco, California, USA
| | - Marta Garcia-Miralles
- Translational Laboratory in Genetic Medicine (TLGM), Agency for Science, Technology, and Research (A*STAR), Singapore, Singapore
| | - Carola I Radulescu
- Translational Laboratory in Genetic Medicine (TLGM), Agency for Science, Technology, and Research (A*STAR), Singapore, Singapore
| | - Harwin Sidik
- Translational Laboratory in Genetic Medicine (TLGM), Agency for Science, Technology, and Research (A*STAR), Singapore, Singapore
| | - Aymeric Silvin
- Singapore Immunology Network (SIgN), A*STAR, Singapore, Singapore
| | - Han-Gyu Bae
- Institute of Molecular and Cell Biology, A*STAR, Biopolis, Singapore, Singapore.,Department of Life Sciences, Yeungnam University, Gyeongsan, South Korea
| | - Carine Bonnard
- Institute of Medical Biology, A*STAR, Singapore, Singapore
| | - Nur Amirah Binte Mohammad Yusof
- Translational Laboratory in Genetic Medicine (TLGM), Agency for Science, Technology, and Research (A*STAR), Singapore, Singapore
| | - Costanza Ferrari Bardile
- Translational Laboratory in Genetic Medicine (TLGM), Agency for Science, Technology, and Research (A*STAR), Singapore, Singapore.,Department of Medical Genetics, British Columbia Children's Hospital Research Institute, University of British Columbia, Vancouver, British Columbia, Canada
| | - Liang Juin Tan
- Translational Laboratory in Genetic Medicine (TLGM), Agency for Science, Technology, and Research (A*STAR), Singapore, Singapore
| | - Alvin Yu Jin Ng
- Institute of Molecular and Cell Biology, A*STAR, Biopolis, Singapore, Singapore
| | - Sumanty Tohari
- Institute of Molecular and Cell Biology, A*STAR, Biopolis, Singapore, Singapore
| | - Leila Dehghani
- Department of Neurology, Isfahan Neurosciences Research Centre, Faculty of Medicine, Isfahan University of Medical Sciences, Isfahan, Iran
| | - Lily Henry
- Translational Laboratory in Genetic Medicine (TLGM), Agency for Science, Technology, and Research (A*STAR), Singapore, Singapore
| | - Xin Yi Yeo
- Institute of Molecular and Cell Biology, A*STAR, Biopolis, Singapore, Singapore
| | - Sejin Lee
- Institute of Molecular and Cell Biology, A*STAR, Biopolis, Singapore, Singapore
| | - Byrappa Venkatesh
- Institute of Molecular and Cell Biology, A*STAR, Biopolis, Singapore, Singapore.,Department of Pediatrics, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore
| | - Sarah R Langley
- Lee Kong Chian School of Medicine, Nanyang Technological University, Singapore, Singapore
| | - Vahid Shaygannejad
- Department of Neurology, Isfahan Neurosciences Research Centre, Faculty of Medicine, Isfahan University of Medical Sciences, Isfahan, Iran
| | | | - Sangyong Jung
- Institute of Molecular and Cell Biology, A*STAR, Biopolis, Singapore, Singapore.,Department of Physiology, National University of Singapore, Singapore, Singapore
| | - Florent Ginhoux
- Singapore Immunology Network (SIgN), A*STAR, Singapore, Singapore.,Shanghai Institute of Immunology, Shanghai JiaoTong University School of Medicine, Shanghai, China.,Translational Immunology Institute, SingHealth Duke-NUS Academic Medical Centre, Singapore, Singapore
| | - Mahmoud A Pouladi
- Translational Laboratory in Genetic Medicine (TLGM), Agency for Science, Technology, and Research (A*STAR), Singapore, Singapore.,Department of Medical Genetics, British Columbia Children's Hospital Research Institute, University of British Columbia, Vancouver, British Columbia, Canada
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Liu X, Liu BL, Yang Q, Zhou X, Tang SJ. Microglial ablation does not affect opioid-induced hyperalgesia in rodents. Pain 2022; 163:508-517. [PMID: 34433775 PMCID: PMC8678393 DOI: 10.1097/j.pain.0000000000002376] [Citation(s) in RCA: 11] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/02/2021] [Accepted: 06/10/2021] [Indexed: 11/26/2022]
Abstract
ABSTRACT Opioids are the frontline analgesics in pain management. However, chronic use of opioid analgesics causes paradoxical pain that contributes to the decrease of their efficacy in pain control and the escalation of dose in long-term management of pain. The underling pathogenic mechanism is not well understood. Microglia have been commonly believed to play a critical role in the expression of opioid-induced hyperalgesia in animal models. We performed microglial ablation experiments using either genetic (CD11b-diphtheria toxin receptor transgenic mouse) or pharmacological (colony-stimulating factor-1 receptor inhibitor PLX5622) approaches. Surprisingly, ablating microglia using these specific and effective approaches did not cause detectable impairment in the expression of hyperalgesia induced by morphine. We confirmed this conclusion with a behavioral test of mechanical and thermal hyperalgesia, in male and female mice, and with different species (mouse and rat). These findings raise caution about the widely assumed contribution of microglia to the development of opioid-induced hyperalgesia.
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Affiliation(s)
- Xin Liu
- Department of Neuroscience and Cell Biology, University of Texas Medical Branch, Galveston, TX 77555, USA
| | - Bo-Long Liu
- Department of Neuroscience and Cell Biology, University of Texas Medical Branch, Galveston, TX 77555, USA
- Department of Urology, The Third Affiliated Hospital of the Sun Yat-Sen University, Guangzhou, China
| | - Qing Yang
- Department of Neuroscience and Cell Biology, University of Texas Medical Branch, Galveston, TX 77555, USA
| | - Xiangfu Zhou
- Department of Urology, The Third Affiliated Hospital of the Sun Yat-Sen University, Guangzhou, China
| | - Shao-Jun Tang
- Department of Neuroscience and Cell Biology, University of Texas Medical Branch, Galveston, TX 77555, USA
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NMDAR1 autoantibodies amplify behavioral phenotypes of genetic white matter inflammation: a mild encephalitis model with neuropsychiatric relevance. Mol Psychiatry 2022; 27:4974-4983. [PMID: 34866134 PMCID: PMC9763107 DOI: 10.1038/s41380-021-01392-8] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/16/2021] [Revised: 09/28/2021] [Accepted: 11/12/2021] [Indexed: 02/06/2023]
Abstract
Encephalitis has an estimated prevalence of ≤0.01%. Even with extensive diagnostic work-up, an infectious etiology is identified or suspected in <50% of cases, suggesting a role for etiologically unclear, noninfectious processes. Mild encephalitis runs frequently unnoticed, despite slight neuroinflammation detectable postmortem in many neuropsychiatric illnesses. A widely unexplored field in humans, though clearly documented in rodents, is genetic brain inflammation, particularly that associated with myelin abnormalities, inducing primary white matter encephalitis. We hypothesized that "autoimmune encephalitides" may result from any brain inflammation concurring with the presence of brain antigen-directed autoantibodies, e.g., against N-methyl-D-aspartate-receptor NR1 (NMDAR1-AB), which are not causal of, but may considerably shape the encephalitis phenotype. We therefore immunized young female Cnp-/- mice lacking the structural myelin protein 2'-3'-cyclic nucleotide 3'-phosphodiesterase (Cnp) with a "cocktail" of NMDAR1 peptides. Cnp-/- mice exhibit early low-grade inflammation of white matter tracts and blood-brain barrier disruption. Our novel mental-time-travel test disclosed that Cnp-/- mice are compromised in what-where-when orientation, but this episodic memory readout was not further deteriorated by NMDAR1-AB. In contrast, comparing wild-type and Cnp-/- mice without/with NMDAR1-AB regarding hippocampal learning/memory and motor balance/coordination revealed distinct stair patterns of behavioral pathology. To elucidate a potential contribution of oligodendroglial NMDAR downregulation to NMDAR1-AB effects, we generated conditional NR1 knockout mice. These mice displayed normal Morris water maze and mental-time-travel, but beam balance performance was similar to immunized Cnp-/-. Immunohistochemistry confirmed neuroinflammation/neurodegeneration in Cnp-/- mice, yet without add-on effect of NMDAR1-AB. To conclude, genetic brain inflammation may explain an encephalitic component underlying autoimmune conditions.
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32
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Uranova N, Vikhreva O, Rakhmanova V. Specific interactions between microglia and oligodendrocytes in white matter in continuous schizophrenia. Zh Nevrol Psikhiatr Im S S Korsakova 2022; 122:128-137. [DOI: 10.17116/jnevro2022122121128] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/24/2022]
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33
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Hosten N, Bülow R, Völzke H, Domin M, Schmidt CO, Teumer A, Ittermann T, Nauck M, Felix S, Dörr M, Markus MRP, Völker U, Daboul A, Schwahn C, Holtfreter B, Mundt T, Krey KF, Kindler S, Mksoud M, Samietz S, Biffar R, Hoffmann W, Kocher T, Chenot JF, Stahl A, Tost F, Friedrich N, Zylla S, Hannemann A, Lotze M, Kühn JP, Hegenscheid K, Rosenberg C, Wassilew G, Frenzel S, Wittfeld K, Grabe HJ, Kromrey ML. SHIP-MR and Radiology: 12 Years of Whole-Body Magnetic Resonance Imaging in a Single Center. Healthcare (Basel) 2021; 10:33. [PMID: 35052197 PMCID: PMC8775435 DOI: 10.3390/healthcare10010033] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/15/2021] [Revised: 12/17/2021] [Accepted: 12/20/2021] [Indexed: 12/16/2022] Open
Abstract
The Study of Health in Pomerania (SHIP), a population-based study from a rural state in northeastern Germany with a relatively poor life expectancy, supplemented its comprehensive examination program in 2008 with whole-body MR imaging at 1.5 T (SHIP-MR). We reviewed more than 100 publications that used the SHIP-MR data and analyzed which sequences already produced fruitful scientific outputs and which manuscripts have been referenced frequently. Upon reviewing the publications about imaging sequences, those that used T1-weighted structured imaging of the brain and a gradient-echo sequence for R2* mapping obtained the highest scientific output; regarding specific body parts examined, most scientific publications focused on MR sequences involving the brain and the (upper) abdomen. We conclude that population-based MR imaging in cohort studies should define more precise goals when allocating imaging time. In addition, quality control measures might include recording the number and impact of published work, preferably on a bi-annual basis and starting 2 years after initiation of the study. Structured teaching courses may enhance the desired output in areas that appear underrepresented.
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Affiliation(s)
- Norbert Hosten
- Institute of Diagnostic Radiology and Neuroradiology, University Medicine Greifswald, 17475 Greifswald, Germany; (N.H.); (R.B.); (M.D.); (K.H.); (C.R.)
| | - Robin Bülow
- Institute of Diagnostic Radiology and Neuroradiology, University Medicine Greifswald, 17475 Greifswald, Germany; (N.H.); (R.B.); (M.D.); (K.H.); (C.R.)
| | - Henry Völzke
- Institute for Community Medicine, University Medicine Greifswald, 17475 Greifswald, Germany; (H.V.); (C.O.S.); (A.T.); (T.I.); (W.H.); (J.-F.C.)
- German Centre for Cardiovascular Research (DZHK), Partner Site Greifswald, 10785 Berlin, Germany; (M.N.); (S.F.); (M.D.); (M.R.P.M.); (U.V.); (N.F.); (S.Z.); (A.H.)
| | - Martin Domin
- Institute of Diagnostic Radiology and Neuroradiology, University Medicine Greifswald, 17475 Greifswald, Germany; (N.H.); (R.B.); (M.D.); (K.H.); (C.R.)
| | - Carsten Oliver Schmidt
- Institute for Community Medicine, University Medicine Greifswald, 17475 Greifswald, Germany; (H.V.); (C.O.S.); (A.T.); (T.I.); (W.H.); (J.-F.C.)
| | - Alexander Teumer
- Institute for Community Medicine, University Medicine Greifswald, 17475 Greifswald, Germany; (H.V.); (C.O.S.); (A.T.); (T.I.); (W.H.); (J.-F.C.)
- German Centre for Cardiovascular Research (DZHK), Partner Site Greifswald, 10785 Berlin, Germany; (M.N.); (S.F.); (M.D.); (M.R.P.M.); (U.V.); (N.F.); (S.Z.); (A.H.)
| | - Till Ittermann
- Institute for Community Medicine, University Medicine Greifswald, 17475 Greifswald, Germany; (H.V.); (C.O.S.); (A.T.); (T.I.); (W.H.); (J.-F.C.)
| | - Matthias Nauck
- German Centre for Cardiovascular Research (DZHK), Partner Site Greifswald, 10785 Berlin, Germany; (M.N.); (S.F.); (M.D.); (M.R.P.M.); (U.V.); (N.F.); (S.Z.); (A.H.)
- Institute of Clinical Chemistry and Laboratory Medicine, University Medicine Greifswald, 17475 Greifswald, Germany
| | - Stephan Felix
- German Centre for Cardiovascular Research (DZHK), Partner Site Greifswald, 10785 Berlin, Germany; (M.N.); (S.F.); (M.D.); (M.R.P.M.); (U.V.); (N.F.); (S.Z.); (A.H.)
- Department of Internal Medicine B, University Medicine Greifswald, 17475 Greifswald, Germany
| | - Marcus Dörr
- German Centre for Cardiovascular Research (DZHK), Partner Site Greifswald, 10785 Berlin, Germany; (M.N.); (S.F.); (M.D.); (M.R.P.M.); (U.V.); (N.F.); (S.Z.); (A.H.)
- Department of Internal Medicine B, University Medicine Greifswald, 17475 Greifswald, Germany
| | - Marcello Ricardo Paulista Markus
- German Centre for Cardiovascular Research (DZHK), Partner Site Greifswald, 10785 Berlin, Germany; (M.N.); (S.F.); (M.D.); (M.R.P.M.); (U.V.); (N.F.); (S.Z.); (A.H.)
- Department of Internal Medicine B, University Medicine Greifswald, 17475 Greifswald, Germany
| | - Uwe Völker
- German Centre for Cardiovascular Research (DZHK), Partner Site Greifswald, 10785 Berlin, Germany; (M.N.); (S.F.); (M.D.); (M.R.P.M.); (U.V.); (N.F.); (S.Z.); (A.H.)
- Interfaculty Institute of Genetics and Functional Genomics, University Medicine Greifswald, 17475 Greifswald, Germany
| | - Amro Daboul
- Department of Prosthetic Dentistry, Gerodontology and Biomaterials, University Medicine Greifswald, 17475 Greifswald, Germany; (A.D.); (C.S.); (T.M.); (S.S.); (R.B.)
| | - Christian Schwahn
- Department of Prosthetic Dentistry, Gerodontology and Biomaterials, University Medicine Greifswald, 17475 Greifswald, Germany; (A.D.); (C.S.); (T.M.); (S.S.); (R.B.)
| | - Birte Holtfreter
- Department of Restorative Dentistry, Periodontology, Endodontology, and Preventive and Pediatric Dentistry, University Medicine Greifswald, 17475 Greifswald, Germany; (B.H.); (T.K.)
| | - Torsten Mundt
- Department of Prosthetic Dentistry, Gerodontology and Biomaterials, University Medicine Greifswald, 17475 Greifswald, Germany; (A.D.); (C.S.); (T.M.); (S.S.); (R.B.)
| | - Karl-Friedrich Krey
- Department of Orthodontics, University Medicine Greifswald, 17475 Greifswald, Germany;
| | - Stefan Kindler
- Department of Oral and Maxillofacial Surgery/Plastic Surgery, University Medicine Greifswald, 17475 Greifswald, Germany; (S.K.); (M.M.)
| | - Maria Mksoud
- Department of Oral and Maxillofacial Surgery/Plastic Surgery, University Medicine Greifswald, 17475 Greifswald, Germany; (S.K.); (M.M.)
| | - Stefanie Samietz
- Department of Prosthetic Dentistry, Gerodontology and Biomaterials, University Medicine Greifswald, 17475 Greifswald, Germany; (A.D.); (C.S.); (T.M.); (S.S.); (R.B.)
| | - Reiner Biffar
- Department of Prosthetic Dentistry, Gerodontology and Biomaterials, University Medicine Greifswald, 17475 Greifswald, Germany; (A.D.); (C.S.); (T.M.); (S.S.); (R.B.)
| | - Wolfgang Hoffmann
- Institute for Community Medicine, University Medicine Greifswald, 17475 Greifswald, Germany; (H.V.); (C.O.S.); (A.T.); (T.I.); (W.H.); (J.-F.C.)
- German Centre for Cardiovascular Research (DZHK), Partner Site Greifswald, 10785 Berlin, Germany; (M.N.); (S.F.); (M.D.); (M.R.P.M.); (U.V.); (N.F.); (S.Z.); (A.H.)
- German Centre for Neurodegenerative Diseases (DZNE), Partner Site Rostock/Greifswald, 17489 Greifswald, Germany
| | - Thomas Kocher
- Department of Restorative Dentistry, Periodontology, Endodontology, and Preventive and Pediatric Dentistry, University Medicine Greifswald, 17475 Greifswald, Germany; (B.H.); (T.K.)
| | - Jean-Francois Chenot
- Institute for Community Medicine, University Medicine Greifswald, 17475 Greifswald, Germany; (H.V.); (C.O.S.); (A.T.); (T.I.); (W.H.); (J.-F.C.)
| | - Andreas Stahl
- Clinic of Ophthalmology, University Medicine Greifswald, 17475 Greifswald, Germany; (A.S.); (F.T.)
| | - Frank Tost
- Clinic of Ophthalmology, University Medicine Greifswald, 17475 Greifswald, Germany; (A.S.); (F.T.)
| | - Nele Friedrich
- German Centre for Cardiovascular Research (DZHK), Partner Site Greifswald, 10785 Berlin, Germany; (M.N.); (S.F.); (M.D.); (M.R.P.M.); (U.V.); (N.F.); (S.Z.); (A.H.)
- Institute of Clinical Chemistry and Laboratory Medicine, University Medicine Greifswald, 17475 Greifswald, Germany
| | - Stephanie Zylla
- German Centre for Cardiovascular Research (DZHK), Partner Site Greifswald, 10785 Berlin, Germany; (M.N.); (S.F.); (M.D.); (M.R.P.M.); (U.V.); (N.F.); (S.Z.); (A.H.)
- Institute of Clinical Chemistry and Laboratory Medicine, University Medicine Greifswald, 17475 Greifswald, Germany
| | - Anke Hannemann
- German Centre for Cardiovascular Research (DZHK), Partner Site Greifswald, 10785 Berlin, Germany; (M.N.); (S.F.); (M.D.); (M.R.P.M.); (U.V.); (N.F.); (S.Z.); (A.H.)
- Institute of Clinical Chemistry and Laboratory Medicine, University Medicine Greifswald, 17475 Greifswald, Germany
| | - Martin Lotze
- Functional Imaging Unit, Institute of Diagnostic Radiology and Neuroradiology, University Medicine Greifswald, 17475 Greifswald, Germany;
| | - Jens-Peter Kühn
- Institute and Policlinic of Diagnostic and Interventional Radiology, Medical University, Carl-Gustav Carus, 01307 Dresden, Germany;
| | - Katrin Hegenscheid
- Institute of Diagnostic Radiology and Neuroradiology, University Medicine Greifswald, 17475 Greifswald, Germany; (N.H.); (R.B.); (M.D.); (K.H.); (C.R.)
| | - Christian Rosenberg
- Institute of Diagnostic Radiology and Neuroradiology, University Medicine Greifswald, 17475 Greifswald, Germany; (N.H.); (R.B.); (M.D.); (K.H.); (C.R.)
| | - Georgi Wassilew
- Clinic of Orthopedics, University Medicine Greifswald, 17475 Greifswald, Germany;
| | - Stefan Frenzel
- Department of Psychiatry and Psychotherapy, University Medicine Greifswald, 17475 Greifswald, Germany; (S.F.); (K.W.); (H.J.G.)
| | - Katharina Wittfeld
- Department of Psychiatry and Psychotherapy, University Medicine Greifswald, 17475 Greifswald, Germany; (S.F.); (K.W.); (H.J.G.)
- German Center of Neurodegenerative Diseases (DZNE), Rostock/Greifswald, Site Greifswald, 17489 Greifswald, Germany
| | - Hans J. Grabe
- Department of Psychiatry and Psychotherapy, University Medicine Greifswald, 17475 Greifswald, Germany; (S.F.); (K.W.); (H.J.G.)
- German Center of Neurodegenerative Diseases (DZNE), Rostock/Greifswald, Site Greifswald, 17489 Greifswald, Germany
| | - Marie-Luise Kromrey
- Institute of Diagnostic Radiology and Neuroradiology, University Medicine Greifswald, 17475 Greifswald, Germany; (N.H.); (R.B.); (M.D.); (K.H.); (C.R.)
- Correspondence:
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Rao Y, Du S, Yang B, Wang Y, Li Y, Li R, Zhou T, Du X, He Y, Wang Y, Zhou X, Yuan TF, Mao Y, Peng B. NeuroD1 induces microglial apoptosis and cannot induce microglia-to-neuron cross-lineage reprogramming. Neuron 2021; 109:4094-4108.e5. [PMID: 34875233 DOI: 10.1016/j.neuron.2021.11.008] [Citation(s) in RCA: 44] [Impact Index Per Article: 11.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/03/2021] [Revised: 06/28/2021] [Accepted: 09/24/2021] [Indexed: 11/21/2022]
Abstract
The regenerative capacity of neurons is limited in the central nervous system (CNS), with irreversible neuronal loss upon insult. In contrast, microglia exhibit extraordinary capacity for repopulation. Matsuda et al. (2019) recently reported NeuroD1-induced microglia-to-neuron conversion, aiming to provide an "unlimited" source to regenerate neurons. However, the extent to which NeuroD1 can exert cross-lineage reprogramming of microglia (myeloid lineage) to neurons (neuroectodermal lineage) is unclear. In this study, we unexpectedly found that NeuroD1 cannot convert microglia to neurons in mice. Instead, NeuroD1 expression induces microglial cell death. Moreover, lineage tracing reveals non-specific leakage of similar lentiviruses as previously used for microglia-to-neuron conversion, which confounds the microglia-to-neuron observation. In summary, we demonstrated that NeuroD1 cannot induce microglia-to-neuron cross-lineage reprogramming. We here propose rigid principles for verifying glia-to-neuron conversion. This Matters Arising paper is in response to Matsuda et al. (2019), published in Neuron.
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Affiliation(s)
- Yanxia Rao
- Shanghai Key Laboratory of Psychotic Disorders, Shanghai Mental Health Center, Shanghai Jiao Tong University School of Medicine, Shanghai 201108, China.
| | - Siling Du
- Shanghai Key Laboratory of Psychotic Disorders, Shanghai Mental Health Center, Shanghai Jiao Tong University School of Medicine, Shanghai 201108, China; Department of Neurosurgery, Huashan Hospital, Institute for Translational Brain Research, State Key Laboratory of Medical Neurobiology, MOE Frontiers Center for Brain Science, Fudan University, Shanghai 200032, China
| | - Baozhi Yang
- Shanghai Key Laboratory of Psychotic Disorders, Shanghai Mental Health Center, Shanghai Jiao Tong University School of Medicine, Shanghai 201108, China; Department of Neurosurgery, Huashan Hospital, Institute for Translational Brain Research, State Key Laboratory of Medical Neurobiology, MOE Frontiers Center for Brain Science, Fudan University, Shanghai 200032, China; School of Basic Medical Sciences, Jinzhou Medical University, Jinzhou, Liaoning 121001, China
| | - Yuqing Wang
- Shanghai Key Laboratory of Psychotic Disorders, Shanghai Mental Health Center, Shanghai Jiao Tong University School of Medicine, Shanghai 201108, China; Department of Neurosurgery, Huashan Hospital, Institute for Translational Brain Research, State Key Laboratory of Medical Neurobiology, MOE Frontiers Center for Brain Science, Fudan University, Shanghai 200032, China; School of Basic Medical Sciences, Jinzhou Medical University, Jinzhou, Liaoning 121001, China
| | - Yuxin Li
- Department of Neurosurgery, Huashan Hospital, Institute for Translational Brain Research, State Key Laboratory of Medical Neurobiology, MOE Frontiers Center for Brain Science, Fudan University, Shanghai 200032, China
| | - Ruofan Li
- Shanghai Key Laboratory of Psychotic Disorders, Shanghai Mental Health Center, Shanghai Jiao Tong University School of Medicine, Shanghai 201108, China
| | - Tian Zhou
- Shenzhen Institute of Advanced Technology, Chinese Academy of Sciences, Shenzhen, Guangdong 518055, China
| | - Xiangjuan Du
- Department of Neurosurgery, Huashan Hospital, Institute for Translational Brain Research, State Key Laboratory of Medical Neurobiology, MOE Frontiers Center for Brain Science, Fudan University, Shanghai 200032, China
| | - Yang He
- Department of Neurosurgery, Huashan Hospital, Institute for Translational Brain Research, State Key Laboratory of Medical Neurobiology, MOE Frontiers Center for Brain Science, Fudan University, Shanghai 200032, China
| | - Yafei Wang
- Department of Neurosurgery, Huashan Hospital, Institute for Translational Brain Research, State Key Laboratory of Medical Neurobiology, MOE Frontiers Center for Brain Science, Fudan University, Shanghai 200032, China
| | - Xin Zhou
- Department of Neurosurgery, Huashan Hospital, Institute for Translational Brain Research, State Key Laboratory of Medical Neurobiology, MOE Frontiers Center for Brain Science, Fudan University, Shanghai 200032, China
| | - Ti-Fei Yuan
- Shanghai Key Laboratory of Psychotic Disorders, Shanghai Mental Health Center, Shanghai Jiao Tong University School of Medicine, Shanghai 201108, China; Co-innovation Center of Neuroregeneration, Nantong University, Nantong, Jiangsu 226001, China.
| | - Ying Mao
- Department of Neurosurgery, Huashan Hospital, Institute for Translational Brain Research, State Key Laboratory of Medical Neurobiology, MOE Frontiers Center for Brain Science, Fudan University, Shanghai 200032, China.
| | - Bo Peng
- Department of Neurosurgery, Huashan Hospital, Institute for Translational Brain Research, State Key Laboratory of Medical Neurobiology, MOE Frontiers Center for Brain Science, Fudan University, Shanghai 200032, China; Co-innovation Center of Neuroregeneration, Nantong University, Nantong, Jiangsu 226001, China.
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Pieters LE, Nadesalingam N, Walther S, van Harten PN. A systematic review of the prognostic value of motor abnormalities on clinical outcome in psychosis. Neurosci Biobehav Rev 2021; 132:691-705. [PMID: 34813828 DOI: 10.1016/j.neubiorev.2021.11.027] [Citation(s) in RCA: 30] [Impact Index Per Article: 7.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/12/2021] [Revised: 11/09/2021] [Accepted: 11/17/2021] [Indexed: 02/07/2023]
Abstract
Schizophrenia spectrum disorders have heterogeneous outcomes and currently no marker predicts the course of illness. Motor abnormalities (MAs) are inherent to psychosis, the risk of psychosis, symptom severity, and brain alterations. However, the prognostic value of MAs is still unresolved. Here, we provide a systematic review of longitudinal studies on the prognostic role of MAs spanning individuals at clinical high risk for psychosis (CHR), patients with first-episode psychosis (FEP), and chronic schizophrenia. We included 68 studies for a total of 23,630 subjects that assessed neurological soft signs (NSS), hypo- or hyperkinetic movement disorders and/or catatonia as a prognostic factor on clinical and functional outcomes. We found increased levels of MAs, in particular NSS, parkinsonism, and dyskinesia, were related to deteriorating symptomatic and poor functional outcome over time. Collectively, the findings emphasize the clinical, prognostic and scientific relevance of MA assessment and detection in individuals with or at risk of psychosis. In the future, instrumental measures of MA are expected to further augment detection, early intervention and treatment strategies in psychosis.
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Affiliation(s)
- Lydia E Pieters
- Psychiatric Center GGz Centraal, Amersfoort, Research Department, Postbus 3051, 3800 DB Amersfoort, The Netherlands; Department of Psychiatry, School for Mental Health and Neuroscience, Maastricht University Medical Center, P.O. Box 616, 6200 MD Maastricht, The Netherlands
| | - Niluja Nadesalingam
- Translational Research Center, University Hospital of Psychiatry and Psychotherapy, University of Bern, Bolligenstrasse 111, CH-3000 Bern 60, Switzerland
| | - Sebastian Walther
- Translational Research Center, University Hospital of Psychiatry and Psychotherapy, University of Bern, Bolligenstrasse 111, CH-3000 Bern 60, Switzerland
| | - Peter N van Harten
- Psychiatric Center GGz Centraal, Amersfoort, Research Department, Postbus 3051, 3800 DB Amersfoort, The Netherlands; Department of Psychiatry, School for Mental Health and Neuroscience, Maastricht University Medical Center, P.O. Box 616, 6200 MD Maastricht, The Netherlands.
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36
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Catatonia: Clinical Overview of the Diagnosis, Treatment, and Clinical Challenges. Neurol Int 2021; 13:570-586. [PMID: 34842777 PMCID: PMC8628989 DOI: 10.3390/neurolint13040057] [Citation(s) in RCA: 52] [Impact Index Per Article: 13.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/25/2021] [Accepted: 10/26/2021] [Indexed: 12/29/2022] Open
Abstract
Catatonia is a syndrome that has been associated with several mental illness disorders but that has also presented as a result of other medical conditions. Schizophrenia and other psychiatric disorders such as mania and depression are known to be associated with catatonia; however, several case reports have been published of certain medical conditions inducing catatonia, including hyponatremia, cerebral venous sinus thrombosis, and liver transplantation. Neuroleptic Malignant Syndrome and anti-NMDA receptor encephalitis are also prominent causes of catatonia. Patients taking benzodiazepines or clozapine are also at risk of developing catatonia following the withdrawal of these medications—it is speculated that the prolonged use of these medications increases gamma-aminobutyric acid (GABA) activity and that discontinuation may increase excitatory neurotransmission, leading to catatonia. The treatment of catatonia often involves the use of benzodiazepines, such as lorazepam, that can be used in combination therapy with antipsychotics. Definitive treatment may be found with electroconvulsive therapy (ECT). Aberrant neuronal activity in different motor pathways, defective neurotransmitter regulation, and impaired oligodendrocyte function have all been proposed as the pathophysiology behind catatonia. There are many clinical challenges that come with catatonia and, as early treatment is associated with better outcomes, it becomes imperative to understand these challenges. The purpose of this manuscript is to provide an overview of these challenges and to look at clinical studies regarding the pathophysiology, diagnosis, and treatment of as well as the complications and risk factors associated with catatonia.
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Chitu V, Biundo F, Stanley ER. Colony stimulating factors in the nervous system. Semin Immunol 2021; 54:101511. [PMID: 34743926 DOI: 10.1016/j.smim.2021.101511] [Citation(s) in RCA: 29] [Impact Index Per Article: 7.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/14/2021] [Accepted: 10/23/2021] [Indexed: 01/02/2023]
Abstract
Although traditionally seen as regulators of hematopoiesis, colony-stimulating factors (CSFs) have emerged as important players in the nervous system, both in health and disease. This review summarizes the cellular sources, patterns of expression and physiological roles of the macrophage (CSF-1, IL-34), granulocyte-macrophage (GM-CSF) and granulocyte (G-CSF) colony stimulating factors within the nervous system, with a particular focus on their actions on microglia. CSF-1 and IL-34, via the CSF-1R, are required for the development, proliferation and maintenance of essentially all CNS microglia in a temporal and regional specific manner. In contrast, in steady state, GM-CSF and G-CSF are mainly involved in regulation of microglial function. The alterations in expression of these growth factors and their receptors, that have been reported in several neurological diseases, are described and the outcomes of their therapeutic targeting in mouse models and humans are discussed.
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Affiliation(s)
- Violeta Chitu
- Department of Developmental and Molecular Biology, Albert Einstein College of Medicine, Bronx, NY 10461, USA.
| | - Fabrizio Biundo
- Department of Developmental and Molecular Biology, Albert Einstein College of Medicine, Bronx, NY 10461, USA.
| | - E Richard Stanley
- Department of Developmental and Molecular Biology, Albert Einstein College of Medicine, Bronx, NY 10461, USA.
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38
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Berdowski WM, Sanderson LE, van Ham TJ. The multicellular interplay of microglia in health and disease: lessons from leukodystrophy. Dis Model Mech 2021; 14:dmm048925. [PMID: 34282843 PMCID: PMC8319551 DOI: 10.1242/dmm.048925] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/20/2023] Open
Abstract
Microglia are highly dynamic cells crucial for developing and maintaining lifelong brain function and health through their many interactions with essentially all cellular components of the central nervous system. The frequent connection of microglia to leukodystrophies, genetic disorders of the white matter, has highlighted their involvement in the maintenance of white matter integrity. However, the mechanisms that underlie their putative roles in these processes remain largely uncharacterized. Microglia have also been gaining attention as possible therapeutic targets for many neurological conditions, increasing the demand to understand their broad spectrum of functions and the impact of their dysregulation. In this Review, we compare the pathological features of two groups of genetic leukodystrophies: those in which microglial dysfunction holds a central role, termed 'microgliopathies', and those in which lysosomal or peroxisomal defects are considered to be the primary driver. The latter are suspected to have notable microglia involvement, as some affected individuals benefit from microglia-replenishing therapy. Based on overlapping pathology, we discuss multiple ways through which aberrant microglia could lead to white matter defects and brain dysfunction. We propose that the study of leukodystrophies, and their extensively multicellular pathology, will benefit from complementing analyses of human patient material with the examination of cellular dynamics in vivo using animal models, such as zebrafish. Together, this will yield important insight into the cell biological mechanisms of microglial impact in the central nervous system, particularly in the development and maintenance of myelin, that will facilitate the development of new, and refinement of existing, therapeutic options for a range of brain diseases.
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Affiliation(s)
| | | | - Tjakko J. van Ham
- Department of Clinical Genetics, Erasmus MC University Medical Center, PO Box 2040, 3000 CA, Rotterdam, The Netherlands
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Wilke JBH, Hindermann M, Moussavi A, Butt UJ, Dadarwal R, Berghoff SA, Sarcheshmeh AK, Ronnenberg A, Zihsler S, Arinrad S, Hardeland R, Seidel J, Lühder F, Nave KA, Boretius S, Ehrenreich H. Inducing sterile pyramidal neuronal death in mice to model distinct aspects of gray matter encephalitis. Acta Neuropathol Commun 2021; 9:121. [PMID: 34215338 PMCID: PMC8253243 DOI: 10.1186/s40478-021-01214-6] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/11/2021] [Accepted: 06/07/2021] [Indexed: 02/07/2023] Open
Abstract
Up to one person in a population of 10,000 is diagnosed once in lifetime with an encephalitis, in 50-70% of unknown origin. Recognized causes amount to 20-50% viral infections. Approximately one third of affected subjects develops moderate and severe subsequent damage. Several neurotropic viruses can directly infect pyramidal neurons and induce neuronal death in cortex and hippocampus. The resulting encephalitic syndromes are frequently associated with cognitive deterioration and dementia, but involve numerous parallel and downstream cellular and molecular events that make the interpretation of direct consequences of sudden pyramidal neuronal loss difficult. This, however, would be pivotal for understanding how neuroinflammatory processes initiate the development of neurodegeneration, and thus for targeted prophylactic and therapeutic interventions. Here we utilized adult male NexCreERT2xRosa26-eGFP-DTA (= 'DTA') mice for the induction of a sterile encephalitis by diphtheria toxin-mediated ablation of cortical and hippocampal pyramidal neurons which also recruits immune cells into gray matter. We report multifaceted aftereffects of this defined process, including the expected pathology of classical hippocampal behaviors, evaluated in Morris water maze, but also of (pre)frontal circuit function, assessed by prepulse inhibition. Importantly, we modelled in encephalitis mice novel translationally relevant sequelae, namely altered social interaction/cognition, accompanied by compromised thermoreaction to social stimuli as convenient readout of parallel autonomic nervous system (dys)function. High resolution magnetic resonance imaging disclosed distinct abnormalities in brain dimensions, including cortical and hippocampal layering, as well as of cerebral blood flow and volume. Fluorescent tracer injection, immunohistochemistry and brain flow cytometry revealed persistent blood-brain-barrier perturbance and chronic brain inflammation. Surprisingly, blood flow cytometry showed no abnormalities in circulating major immune cell subsets and plasma high-mobility group box 1 (HMGB1) as proinflammatory marker remained unchanged. The present experimental work, analyzing multidimensional outcomes of direct pyramidal neuronal loss, will open new avenues for urgently needed encephalitis research.
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Affiliation(s)
- Justus B H Wilke
- Clinical Neuroscience, Max Planck Institute of Experimental Medicine, Hermann-Rein-Str.3, 37075, Göttingen, Germany
| | - Martin Hindermann
- Clinical Neuroscience, Max Planck Institute of Experimental Medicine, Hermann-Rein-Str.3, 37075, Göttingen, Germany
| | - Amir Moussavi
- Functional Imaging Laboratory, German Primate Center, Leibniz Institute for Primate Research, Kellnerweg 4, 37077, Göttingen, Germany
| | - Umer Javed Butt
- Clinical Neuroscience, Max Planck Institute of Experimental Medicine, Hermann-Rein-Str.3, 37075, Göttingen, Germany
| | - Rakshit Dadarwal
- Functional Imaging Laboratory, German Primate Center, Leibniz Institute for Primate Research, Kellnerweg 4, 37077, Göttingen, Germany
- Georg August University, Göttingen, Germany
| | - Stefan A Berghoff
- Department of Neurogenetics, Max Planck Institute of Experimental Medicine, Göttingen, Germany
| | - Aref Kalantari Sarcheshmeh
- Functional Imaging Laboratory, German Primate Center, Leibniz Institute for Primate Research, Kellnerweg 4, 37077, Göttingen, Germany
| | - Anja Ronnenberg
- Clinical Neuroscience, Max Planck Institute of Experimental Medicine, Hermann-Rein-Str.3, 37075, Göttingen, Germany
| | - Svenja Zihsler
- Clinical Neuroscience, Max Planck Institute of Experimental Medicine, Hermann-Rein-Str.3, 37075, Göttingen, Germany
| | - Sahab Arinrad
- Clinical Neuroscience, Max Planck Institute of Experimental Medicine, Hermann-Rein-Str.3, 37075, Göttingen, Germany
| | - Rüdiger Hardeland
- Johann Friedrich Blumenbach Institute of Zoology & Anthropology, University of Göttingen, Göttingen, Germany
| | - Jan Seidel
- Clinical Neuroscience, Max Planck Institute of Experimental Medicine, Hermann-Rein-Str.3, 37075, Göttingen, Germany
| | - Fred Lühder
- Institute for Neuroimmunology and Multiple Sclerosis Research, University Medical Center Göttingen, Göttingen, Germany
| | - Klaus-Armin Nave
- Department of Neurogenetics, Max Planck Institute of Experimental Medicine, Göttingen, Germany
| | - Susann Boretius
- Functional Imaging Laboratory, German Primate Center, Leibniz Institute for Primate Research, Kellnerweg 4, 37077, Göttingen, Germany.
- Georg August University, Göttingen, Germany.
| | - Hannelore Ehrenreich
- Clinical Neuroscience, Max Planck Institute of Experimental Medicine, Hermann-Rein-Str.3, 37075, Göttingen, Germany.
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40
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Hirjak D, Meyer-Lindenberg A, Sambataro F, Christian Wolf R. Sensorimotor Neuroscience in Mental Disorders: Progress, Perspectives and Challenges. Schizophr Bull 2021; 47:880-882. [PMID: 33940630 PMCID: PMC8266597 DOI: 10.1093/schbul/sbab053] [Citation(s) in RCA: 16] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/29/2022]
Affiliation(s)
- Dusan Hirjak
- Department of Psychiatry and Psychotherapy, Central Institute of Mental Health, Medical Faculty Mannheim, University of Heidelberg, Mannheim, Germany,To whom correspondence should be addressed; Department of Psychiatry and Psychotherapy, Central Institute of Mental Health, D-68159 Mannheim, Germany; tel: +49-621-1703-0, fax: +49-621-1703-2305, e-mail:
| | - Andreas Meyer-Lindenberg
- Department of Psychiatry and Psychotherapy, Central Institute of Mental Health, Medical Faculty Mannheim, University of Heidelberg, Mannheim, Germany
| | - Fabio Sambataro
- Department of Neuroscience (DNS), University of Padua, Padua, Italy,Padua Neuroscience Center, University of Padua, Padua, Italy
| | - Robert Christian Wolf
- Center for Psychosocial Medicine, Department of General Psychiatry, University of Heidelberg, Heidelberg, Germany
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41
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Nishiyama A, Serwanski DR, Pfeiffer F. Many roles for oligodendrocyte precursor cells in physiology and pathology. Neuropathology 2021; 41:161-173. [PMID: 33913208 DOI: 10.1111/neup.12732] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/03/2020] [Revised: 01/15/2021] [Accepted: 01/15/2021] [Indexed: 12/12/2022]
Abstract
Oligodendrocyte precursor cells (OPCs) are a fourth resident glial cell population in the mammalian central nervous system. They are evenly distributed throughout the gray and white matter and continue to proliferate and generate new oligodendrocytes (OLs) throughout life. They were understudied until a few decades ago when immunolabeling for NG2 and platelet-derived growth factor receptor alpha revealed cells that are distinct from mature OLs, astrocytes, neurons, and microglia. In this review, we provide a summary of the known properties of OPCs with some historical background, followed by highlights from recent studies that suggest new roles for OPCs in certain pathological conditions.
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Affiliation(s)
- Akiko Nishiyama
- Department of Physiology and Neurobiology, University of Connecticut, Storrs, Connecticut, USA.,Institute for Systems Genomics, University of Connecticut, Storrs, Connecticut, USA.,The Connecticut Institute for the Brain and Cognitive Sciences, University of Connecticut, Storrs, Connecticut, USA
| | - David R Serwanski
- Department of Physiology and Neurobiology, University of Connecticut, Storrs, Connecticut, USA
| | - Friederike Pfeiffer
- Department of Physiology and Neurobiology, University of Connecticut, Storrs, Connecticut, USA.,Department of Neurophysiology, Eberhard Karls University of Tübingen, Tübingen, Germany
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42
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Morrens M, Coppens V, Walther S. Do Immune Dysregulations and Oxidative Damage Drive Mood and Psychotic Disorders? Neuropsychobiology 2021; 79:251-254. [PMID: 30991415 DOI: 10.1159/000496622] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/01/2018] [Accepted: 01/07/2019] [Indexed: 12/18/2022]
Affiliation(s)
- Manuel Morrens
- Collaborative Antwerp Psychiatric Research Institute (CAPRI), Faculty of Medicine and Health Sciences, Campus Drie Eiken, University of Antwerp, Antwerp, Belgium, .,University Department of Psychiatry, Campus Duffel, Duffel, Belgium,
| | - Violette Coppens
- Collaborative Antwerp Psychiatric Research Institute (CAPRI), Faculty of Medicine and Health Sciences, Campus Drie Eiken, University of Antwerp, Antwerp, Belgium.,University Department of Psychiatry, Campus Duffel, Duffel, Belgium
| | - Sebastian Walther
- Translational Research Center, University Hospital of Psychiatry, University of Bern, Bern, Switzerland
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Marzan DE, Brügger-Verdon V, West BL, Liddelow S, Samanta J, Salzer JL. Activated microglia drive demyelination via CSF1R signaling. Glia 2021; 69:1583-1604. [PMID: 33620118 DOI: 10.1002/glia.23980] [Citation(s) in RCA: 102] [Impact Index Per Article: 25.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/09/2019] [Revised: 02/04/2021] [Accepted: 02/05/2021] [Indexed: 02/06/2023]
Abstract
Microgliosis is a prominent pathological feature in many neurological diseases including multiple sclerosis (MS), a progressive auto-immune demyelinating disorder. The precise role of microglia, parenchymal central nervous system (CNS) macrophages, during demyelination, and the relative contributions of peripheral macrophages are incompletely understood. Classical markers used to identify microglia do not reliably discriminate between microglia and peripheral macrophages, confounding analyses. Here, we use a genetic fate mapping strategy to identify microglia as predominant responders and key effectors of demyelination in the cuprizone (CUP) model. Colony-stimulating factor 1 (CSF1), also known as macrophage colony-stimulating factor (M-CSF) - a secreted cytokine that regulates microglia development and survival-is upregulated in demyelinated white matter lesions. Depletion of microglia with the CSF1R inhibitor PLX3397 greatly abrogates the demyelination, loss of oligodendrocytes, and reactive astrocytosis that results from CUP treatment. Electron microscopy (EM) and serial block face imaging show myelin sheaths remain intact in CUP treated mice depleted of microglia. However, these CUP-damaged myelin sheaths are lost and robustly phagocytosed upon-repopulation of microglia. Direct injection of CSF1 into CNS white matter induces focal microgliosis and demyelination indicating active CSF1 signaling can promote demyelination. Finally, mice defective in adopting a toxic astrocyte phenotype that is driven by microglia nevertheless demyelinate normally upon CUP treatment implicating microglia rather than astrocytes as the primary drivers of CUP-mediated demyelination. Together, these studies indicate activated microglia are required for and can drive demyelination directly and implicate CSF1 signaling in these events.
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Affiliation(s)
- Dave E Marzan
- Neuroscience Institute and Department of Neuroscience and Physiology, NYU Grossman School of Medicine, New York, New York, USA.,Translational Neuroscience Program, University of Pennsylvania, Philadelphia, PA, USA
| | - Valérie Brügger-Verdon
- Neuroscience Institute and Department of Neuroscience and Physiology, NYU Grossman School of Medicine, New York, New York, USA
| | | | - Shane Liddelow
- Neuroscience Institute and Department of Neuroscience and Physiology, NYU Grossman School of Medicine, New York, New York, USA
| | - Jayshree Samanta
- Department of Comparative Biosciences, School of Veterinary Medicine, University of Wisconsin, Madison, Wisconsin, USA
| | - James L Salzer
- Neuroscience Institute and Department of Neuroscience and Physiology, NYU Grossman School of Medicine, New York, New York, USA
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44
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Cawkwell PB, Mayor ID, Shaw RJ. Catatonia in a 6-year-old Patient Following Disseminated Group A Streptococcus Infection. INNOVATIONS IN CLINICAL NEUROSCIENCE 2021; 18:17-20. [PMID: 34150358 PMCID: PMC8195556] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Subscribe] [Scholar Register] [Indexed: 06/13/2023]
Abstract
Pediatric catatonia is a complex entity that is easily missed in the hospital setting and seldom reported in the literature. Here, we present the case of a 6-year-old previously healthy female patient who was initially thought to have intractable delirium secondary to disseminated Group A streptococcus (GAS) infection. Careful examination, utilization of the Pediatric Catatonia Rating Scale, and lorazepam challenge were key to elucidating the diagnosis. While GAS is most often associated with pediatric acute-onset neuropsychiatric syndrome (PANS) in the child and adolescent population, we reviewed the limited literature to suggest a mechanism by which it can lead to catatonia. Further systematic study of catatonia in the pediatric population is warranted to better understand pathogenesis and long-term neuropsychiatric outcomes.
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Affiliation(s)
- Philip B Cawkwell
- Drs. Cawkwell and Shaw and Mr. Mayor are with the Department of Psychiatry and Behavioral Sciences, Division of Child and Adolescent Psychiatry, at the Stanford University School of Medicine in Palo Alto, California
| | - Ivan Daniel Mayor
- Drs. Cawkwell and Shaw and Mr. Mayor are with the Department of Psychiatry and Behavioral Sciences, Division of Child and Adolescent Psychiatry, at the Stanford University School of Medicine in Palo Alto, California
| | - Richard J Shaw
- Drs. Cawkwell and Shaw and Mr. Mayor are with the Department of Psychiatry and Behavioral Sciences, Division of Child and Adolescent Psychiatry, at the Stanford University School of Medicine in Palo Alto, California
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45
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Autoantibodies against NMDA receptor 1 modify rather than cause encephalitis. Mol Psychiatry 2021; 26:7746-7759. [PMID: 34331009 PMCID: PMC8872987 DOI: 10.1038/s41380-021-01238-3] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/28/2021] [Revised: 07/06/2021] [Accepted: 07/09/2021] [Indexed: 02/07/2023]
Abstract
The etiology and pathogenesis of "anti-N-methyl-D-aspartate-receptor (NMDAR) encephalitis" and the role of autoantibodies (AB) in this condition are still obscure. While NMDAR1-AB exert NMDAR-antagonistic properties by receptor internalization, no firm evidence exists to date that NMDAR1-AB by themselves induce brain inflammation/encephalitis. NMDAR1-AB of all immunoglobulin classes are highly frequent across mammals with multiple possible inducers and boosters. We hypothesized that "NMDAR encephalitis" results from any primary brain inflammation coinciding with the presence of NMDAR1-AB, which may shape the encephalitis phenotype. Thus, we tested whether following immunization with a "cocktail" of 4 NMDAR1 peptides, induction of a spatially and temporally defined sterile encephalitis by diphtheria toxin-mediated ablation of pyramidal neurons ("DTA" mice) would modify/aggravate the ensuing phenotype. In addition, we tried to replicate a recent report claiming that immunizing just against the NMDAR1-N368/G369 region induced brain inflammation. Mice after DTA induction revealed a syndrome comprising hyperactivity, hippocampal learning/memory deficits, prefrontal cortical network dysfunction, lasting blood brain-barrier impairment, brain inflammation, mainly in hippocampal and cortical regions with pyramidal neuronal death, microgliosis, astrogliosis, modest immune cell infiltration, regional atrophy, and relative increases in parvalbumin-positive interneurons. The presence of NMDAR1-AB enhanced the hyperactivity (psychosis-like) phenotype, whereas all other readouts were identical to control-immunized DTA mice. Non-DTA mice with or without NMDAR1-AB were free of any encephalitic signs. Replication of the reported NMDAR1-N368/G369-immunizing protocol in two large independent cohorts of wild-type mice completely failed. To conclude, while NMDAR1-AB can contribute to the behavioral phenotype of an underlying encephalitis, induction of an encephalitis by NMDAR1-AB themselves remains to be proven.
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46
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Berve K, West BL, Martini R, Groh J. Sex- and region-biased depletion of microglia/macrophages attenuates CLN1 disease in mice. J Neuroinflammation 2020; 17:323. [PMID: 33115477 PMCID: PMC7594417 DOI: 10.1186/s12974-020-01996-x] [Citation(s) in RCA: 19] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/19/2020] [Accepted: 10/12/2020] [Indexed: 12/16/2022] Open
Abstract
BACKGROUND The neuronal ceroid lipofuscinoses (CLN diseases) are fatal lysosomal storage diseases causing neurodegeneration in the CNS. We have previously shown that neuroinflammation comprising innate and adaptive immune reactions drives axonal damage and neuron loss in the CNS of palmitoyl protein thioesterase 1-deficient (Ppt1-/-) mice, a model of the infantile form of the diseases (CLN1). Therefore, we here explore whether pharmacological targeting of innate immune cells modifies disease outcome in CLN1 mice. METHODS We applied treatment with PLX3397 (150 ppm in the chow), a potent inhibitor of the colony stimulating factor-1 receptor (CSF-1R) to target innate immune cells in CLN1 mice. Experimental long-term treatment was non-invasively monitored by longitudinal optical coherence tomography and rotarod analysis, as well as analysis of visual acuity, myoclonic jerks, and survival. Treatment effects regarding neuroinflammation, neural damage, and neurodegeneration were subsequently analyzed by histology and immunohistochemistry. RESULTS We show that PLX3397 treatment attenuates neuroinflammation in CLN1 mice by depleting pro-inflammatory microglia/macrophages. This leads to a reduction of T lymphocyte recruitment, an amelioration of axon damage and neuron loss in the retinotectal system, as well as reduced thinning of the inner retina and total brain atrophy. Accordingly, long-term treatment with the inhibitor also ameliorates clinical outcomes in CLN1 mice, such as impaired motor coordination, visual acuity, and myoclonic jerks. However, we detected a sex- and region-biased efficacy of CSF-1R inhibition, with male microglia/macrophages showing higher responsiveness toward depletion, especially in the gray matter of the CNS. This results in a better treatment outcome in male Ppt1-/- mice regarding some histopathological and clinical readouts and reflects heterogeneity of innate immune reactions in the diseased CNS. CONCLUSIONS Our results demonstrate a detrimental impact of innate immune reactions in the CNS of CLN1 mice. These findings provide insights into CLN pathogenesis and may guide in the design of immunomodulatory treatment strategies.
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Affiliation(s)
- Kristina Berve
- Department of Neurology, Section of Developmental Neurobiology, University Hospital Würzburg, Würzburg, Germany
- Present address: Theodor-Kocher-Institute, University of Bern, Bern, Switzerland
| | | | - Rudolf Martini
- Department of Neurology, Section of Developmental Neurobiology, University Hospital Würzburg, Würzburg, Germany
| | - Janos Groh
- Department of Neurology, Section of Developmental Neurobiology, University Hospital Würzburg, Würzburg, Germany.
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47
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Zhou FC, Lee JWY, Zhang QH, Sun ZL, Bo Q, He XX, Han T, Xiong M, Li C, Wang CY. Higher Serum C-Reactive Protein Levels in Catatonic Patients: A Comparison to Non-catatonic Patients and Healthy Controls. Schizophr Bull 2020; 46:1155-1164. [PMID: 32219399 PMCID: PMC7505189 DOI: 10.1093/schbul/sbaa041] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/14/2022]
Abstract
Catatonia is a psychomotor syndrome defined by a constellation of predominantly motor symptoms. The aim of the present study was to determine whether recently admitted psychiatric patients with catatonia exhibited higher serum C-reactive protein (hs-CRP) levels compared to non-catatonic psychiatric patients and healthy controls (HCs). Recently admitted psychiatric patients were screened and evaluated for the catatonia syndrome using the Bush-Francis Catatonia Rating Scale and the Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition (DSM-5). The study sample was formed by 150 individuals (39 male and 111 female), including 51 catatonic patients, 55 non-catatonic patients, and 44 HCs. Serum hs-CRP levels were processed with the enzyme-linked immunosorbent assay. Serum levels of creatine kinase (CK), adrenocorticotropic hormone (ACTH), immunoglobulin G (IgG), complement component 3 (C3), and complement component 4 (C4) were also determined. There was a significantly higher percentage of patients with high inflammatory levels (hs-CRP > 3000ng/ml) in the catatonic (43.1%) than in the non-catatonic (14.5%) or HCs group (9.1%) (χ 2 =18.9, P < .001). Logistic regression showed that catatonic patients had significantly higher hs-CRP levels compared to non-catatonic patients even after controlling for other clinical and laboratory variables (OR = 3.52, P = .015, 95% CI 1.28-9.79). Multiple linear regression analysis revealed that log-transformed hs-CRP was independently predicted by body mass index and log-transformed C4, ACTH, and Cortisol in catatonic patients. Findings of the present study suggest that catatonia is specifically linked to a higher level of systemic inflammation, not merely attributable to the overall psychopathology, or alterations in the stress level and complement system.
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Affiliation(s)
- Fu-Chun Zhou
- The National Clinical Research Center for Mental Disorders & Beijing Key Laboratory of Mental Disorders, Beijing Anding Hospital, Capital Medical University, Beijing, China
- Advanced Innovation Center for Human Brain Protection, Capital Medical University, Beijing, China
| | - Joseph W Y Lee
- Division of Psychiatry, Faculty of Health and Medical Sciences, University of Western Australia, Perth, Australia
| | - Qi-Hang Zhang
- The National Clinical Research Center for Mental Disorders & Beijing Key Laboratory of Mental Disorders, Beijing Anding Hospital, Capital Medical University, Beijing, China
- Advanced Innovation Center for Human Brain Protection, Capital Medical University, Beijing, China
| | - Zuo-Li Sun
- The National Clinical Research Center for Mental Disorders & Beijing Key Laboratory of Mental Disorders, Beijing Anding Hospital, Capital Medical University, Beijing, China
- Advanced Innovation Center for Human Brain Protection, Capital Medical University, Beijing, China
| | - Qijing Bo
- The National Clinical Research Center for Mental Disorders & Beijing Key Laboratory of Mental Disorders, Beijing Anding Hospital, Capital Medical University, Beijing, China
- Advanced Innovation Center for Human Brain Protection, Capital Medical University, Beijing, China
| | - Xiao-Xiao He
- The National Clinical Research Center for Mental Disorders & Beijing Key Laboratory of Mental Disorders, Beijing Anding Hospital, Capital Medical University, Beijing, China
- Advanced Innovation Center for Human Brain Protection, Capital Medical University, Beijing, China
| | - Tian Han
- The National Clinical Research Center for Mental Disorders & Beijing Key Laboratory of Mental Disorders, Beijing Anding Hospital, Capital Medical University, Beijing, China
- Advanced Innovation Center for Human Brain Protection, Capital Medical University, Beijing, China
| | - Min Xiong
- Department of Psychiatry, Beijing Daxing Xin Kang hospital, Beijing, China
| | - Chaohui Li
- Department of Psychiatry, Beijing Daxing Xin Kang hospital, Beijing, China
| | - Chuan-Yue Wang
- The National Clinical Research Center for Mental Disorders & Beijing Key Laboratory of Mental Disorders, Beijing Anding Hospital, Capital Medical University, Beijing, China
- Advanced Innovation Center for Human Brain Protection, Capital Medical University, Beijing, China
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48
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Amouri J, Andrews PS, Heckers S, Ely EW, Wilson JE. A Case of Concurrent Delirium and Catatonia in a Woman With Coronavirus Disease 2019. J Acad Consult Liaison Psychiatry 2020; 62:109-114. [PMID: 33069380 PMCID: PMC7491455 DOI: 10.1016/j.psym.2020.09.002] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/03/2020] [Revised: 09/10/2020] [Accepted: 09/10/2020] [Indexed: 12/26/2022]
Affiliation(s)
- Jamelleh Amouri
- Department of Psychiatry and Behavioral Sciences, Vanderbilt University Medical Center, Nashville, TN
| | - Patricia S Andrews
- Department of Psychiatry and Behavioral Sciences, Vanderbilt University Medical Center, Nashville, TN; Critical Illness, Brain Dysfunction and Survivorship (CIBS) Center, Vanderbilt University Medical Center, Nashville, TN
| | - Stephan Heckers
- Department of Psychiatry and Behavioral Sciences, Vanderbilt University Medical Center, Nashville, TN
| | - E Wesley Ely
- Critical Illness, Brain Dysfunction and Survivorship (CIBS) Center, Vanderbilt University Medical Center, Nashville, TN; Veteran's Affairs TN Valley, Geriatrics Research, Education and Clinical Center (GRECC), Nashville, TN; Division of General Internal Medicine and Public Health, Department of Medicine, Vanderbilt University Medical Center, Nashville, TN
| | - Jo Ellen Wilson
- Department of Psychiatry and Behavioral Sciences, Vanderbilt University Medical Center, Nashville, TN; Critical Illness, Brain Dysfunction and Survivorship (CIBS) Center, Vanderbilt University Medical Center, Nashville, TN; Veteran's Affairs TN Valley, Geriatrics Research, Education and Clinical Center (GRECC), Nashville, TN.
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49
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Weinberger T, Esfandyari D, Messerer D, Percin G, Schleifer C, Thaler R, Liu L, Stremmel C, Schneider V, Vagnozzi RJ, Schwanenkamp J, Fischer M, Busch K, Klapproth K, Ishikawa-Ankerhold H, Klösges L, Titova A, Molkentin JD, Kobayashi Y, Engelhardt S, Massberg S, Waskow C, Perdiguero EG, Schulz C. Ontogeny of arterial macrophages defines their functions in homeostasis and inflammation. Nat Commun 2020; 11:4549. [PMID: 32917889 PMCID: PMC7486394 DOI: 10.1038/s41467-020-18287-x] [Citation(s) in RCA: 53] [Impact Index Per Article: 10.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/24/2019] [Accepted: 08/12/2020] [Indexed: 12/22/2022] Open
Abstract
Arterial macrophages have different developmental origins, but the association of macrophage ontogeny with their phenotypes and functions in adulthood is still unclear. Here, we combine macrophage fate-mapping analysis with single-cell RNA sequencing to establish their cellular identity during homeostasis, and in response to angiotensin-II (AngII)-induced arterial inflammation. Yolk sac erythro-myeloid progenitors (EMP) contribute substantially to adventitial macrophages and give rise to a defined cluster of resident immune cells with homeostatic functions that is stable in adult mice, but declines in numbers during ageing and is not replenished by bone marrow (BM)-derived macrophages. In response to AngII inflammation, increase in adventitial macrophages is driven by recruitment of BM monocytes, while EMP-derived macrophages proliferate locally and provide a distinct transcriptional response that is linked to tissue regeneration. Our findings thus contribute to the understanding of macrophage heterogeneity, and associate macrophage ontogeny with distinct functions in health and disease. Arterial macrophages develop from either yolk sac or bone marrow progenitors. Here, the author show that ageing-induced reduction of arterial macrophages is not replenished by bone marrow-derived cells, but under inflammatory conditions circulating monocytes are recruited to maintain homeostasis, while arterial macrophages of yolk sac origin carry out tissue repair.
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Affiliation(s)
- Tobias Weinberger
- Medizinische Klinik und Poliklinik I, Klinikum der Universität München, Ludwig-Maximilians-Universität, Marchioninistrasse 15, 81377, Munich, Germany.,DZHK (German Centre for Cardiovascular Research), partner site Munich Heart Alliance, 80802, Munich, Germany
| | - Dena Esfandyari
- DZHK (German Centre for Cardiovascular Research), partner site Munich Heart Alliance, 80802, Munich, Germany.,Institute of Pharmacology and Toxicology, Technische Universität München, Biedersteiner Strasse 29, 80802, Munich, Germany
| | - Denise Messerer
- Medizinische Klinik und Poliklinik I, Klinikum der Universität München, Ludwig-Maximilians-Universität, Marchioninistrasse 15, 81377, Munich, Germany.,DZHK (German Centre for Cardiovascular Research), partner site Munich Heart Alliance, 80802, Munich, Germany
| | - Gulce Percin
- Regeneration in Hematopoiesis, Leibniz-Institute on Aging - Fritz-Lipmann-Institute (FLI), Beutenbergstrasse 11, 07745, Jena, Germany
| | - Christian Schleifer
- Medizinische Klinik und Poliklinik I, Klinikum der Universität München, Ludwig-Maximilians-Universität, Marchioninistrasse 15, 81377, Munich, Germany.,DZHK (German Centre for Cardiovascular Research), partner site Munich Heart Alliance, 80802, Munich, Germany
| | - Raffael Thaler
- Medizinische Klinik und Poliklinik I, Klinikum der Universität München, Ludwig-Maximilians-Universität, Marchioninistrasse 15, 81377, Munich, Germany.,DZHK (German Centre for Cardiovascular Research), partner site Munich Heart Alliance, 80802, Munich, Germany
| | - Lulu Liu
- Medizinische Klinik und Poliklinik I, Klinikum der Universität München, Ludwig-Maximilians-Universität, Marchioninistrasse 15, 81377, Munich, Germany.,DZHK (German Centre for Cardiovascular Research), partner site Munich Heart Alliance, 80802, Munich, Germany
| | - Christopher Stremmel
- Medizinische Klinik und Poliklinik I, Klinikum der Universität München, Ludwig-Maximilians-Universität, Marchioninistrasse 15, 81377, Munich, Germany.,DZHK (German Centre for Cardiovascular Research), partner site Munich Heart Alliance, 80802, Munich, Germany
| | - Vanessa Schneider
- Medizinische Klinik und Poliklinik I, Klinikum der Universität München, Ludwig-Maximilians-Universität, Marchioninistrasse 15, 81377, Munich, Germany.,DZHK (German Centre for Cardiovascular Research), partner site Munich Heart Alliance, 80802, Munich, Germany
| | - Ronald J Vagnozzi
- Department of Pediatrics, Cincinnati Children's Hospital Medical Center, Cincinnati, OH, 45229, USA
| | - Jennifer Schwanenkamp
- Department of Pediatrics, Cincinnati Children's Hospital Medical Center, Cincinnati, OH, 45229, USA
| | - Maximilian Fischer
- Medizinische Klinik und Poliklinik I, Klinikum der Universität München, Ludwig-Maximilians-Universität, Marchioninistrasse 15, 81377, Munich, Germany.,DZHK (German Centre for Cardiovascular Research), partner site Munich Heart Alliance, 80802, Munich, Germany
| | - Katrin Busch
- Division of Cellular Immunology, German Cancer Research Center (DKFZ), Im Neuenheimer Feld 280, 69120, Heidelberg, Germany
| | - Kay Klapproth
- Division of Cellular Immunology, German Cancer Research Center (DKFZ), Im Neuenheimer Feld 280, 69120, Heidelberg, Germany
| | - Hellen Ishikawa-Ankerhold
- Medizinische Klinik und Poliklinik I, Klinikum der Universität München, Ludwig-Maximilians-Universität, Marchioninistrasse 15, 81377, Munich, Germany.,DZHK (German Centre for Cardiovascular Research), partner site Munich Heart Alliance, 80802, Munich, Germany
| | - Lukas Klösges
- Medizinische Klinik und Poliklinik I, Klinikum der Universität München, Ludwig-Maximilians-Universität, Marchioninistrasse 15, 81377, Munich, Germany.,DZHK (German Centre for Cardiovascular Research), partner site Munich Heart Alliance, 80802, Munich, Germany
| | - Anna Titova
- Medizinische Klinik und Poliklinik I, Klinikum der Universität München, Ludwig-Maximilians-Universität, Marchioninistrasse 15, 81377, Munich, Germany.,DZHK (German Centre for Cardiovascular Research), partner site Munich Heart Alliance, 80802, Munich, Germany
| | - Jeffery D Molkentin
- Department of Pediatrics, Cincinnati Children's Hospital Medical Center, Cincinnati, OH, 45229, USA.,Howard Hughes Medical Institute, Cincinnati Children's Hospital Medical Center, Cincinnati, OH, USA
| | - Yasuhiro Kobayashi
- Institute for Oral Science, Matsumoto Dental University, 1780 Hiro-Oka Gobara Shiojiri, Nagano, 390-0781, Japan
| | - Stefan Engelhardt
- DZHK (German Centre for Cardiovascular Research), partner site Munich Heart Alliance, 80802, Munich, Germany.,Institute of Pharmacology and Toxicology, Technische Universität München, Biedersteiner Strasse 29, 80802, Munich, Germany
| | - Steffen Massberg
- Medizinische Klinik und Poliklinik I, Klinikum der Universität München, Ludwig-Maximilians-Universität, Marchioninistrasse 15, 81377, Munich, Germany.,DZHK (German Centre for Cardiovascular Research), partner site Munich Heart Alliance, 80802, Munich, Germany
| | - Claudia Waskow
- Regeneration in Hematopoiesis, Leibniz-Institute on Aging - Fritz-Lipmann-Institute (FLI), Beutenbergstrasse 11, 07745, Jena, Germany.,Faculty of Biological Sciences, Friedrich-Schiller-University Jena, 07737 Jena, 07745, Jena, Germany
| | - Elisa Gomez Perdiguero
- Institut Pasteur, Macrophages and Endothelial cells, Département de Biologie du Développement et Cellules Souches, UMR3738 CNRS, Paris, 75015, France
| | - Christian Schulz
- Medizinische Klinik und Poliklinik I, Klinikum der Universität München, Ludwig-Maximilians-Universität, Marchioninistrasse 15, 81377, Munich, Germany. .,DZHK (German Centre for Cardiovascular Research), partner site Munich Heart Alliance, 80802, Munich, Germany. .,Walter-Brendel-Center for Experimental Medicine, Ludwig Maximilian University, Marchioninistrasse 27, 81377, Munich, Germany.
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50
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Wasserthal J, Maier-Hein KH, Neher PF, Northoff G, Kubera KM, Fritze S, Harneit A, Geiger LS, Tost H, Wolf RC, Hirjak D. Multiparametric mapping of white matter microstructure in catatonia. Neuropsychopharmacology 2020; 45:1750-1757. [PMID: 32369829 PMCID: PMC7419514 DOI: 10.1038/s41386-020-0691-2] [Citation(s) in RCA: 55] [Impact Index Per Article: 11.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/01/2020] [Revised: 04/20/2020] [Accepted: 04/22/2020] [Indexed: 12/13/2022]
Abstract
Catatonia is characterized by motor, affective and behavioral abnormalities. To date, the specific role of white matter (WM) abnormalities in schizophrenia spectrum disorders (SSD) patients with catatonia is largely unknown. In this study, diffusion magnetic resonance imaging (dMRI) data were collected from 111 right-handed SSD patients and 28 healthy controls. Catatonic symptoms were examined on the Northoff Catatonia Rating Scale (NCRS). We used whole-brain tract-based spatial statistics (TBSS), tractometry (along tract statistics using TractSeg) and graph analytics (clustering coefficient-CCO, local betweenness centrality-BC) to provide a framework of specific WM microstructural abnormalities underlying catatonia in SSD. Following a categorical approach, post hoc analyses showed differences in fractional anisotrophy (FA) measured via tractometry in the corpus callosum, corticospinal tract and thalamo-premotor tract as well as increased CCO as derived by graph analytics of the right superior parietal cortex (SPC) and left caudate nucleus in catatonic patients (NCRS total score ≥ 3; n = 30) when compared to non-catatonic patients (NCRS total score = 0; n = 29). In catatonic patients according to DSM-IV-TR (n = 43), catatonic symptoms were associated with FA variations (tractometry) of the left corticospinal tract and CCO of the left orbitofrontal cortex, primary motor cortex, supplementary motor area and putamen. This study supports the notion that structural reorganization of WM bundles connecting orbitofrontal/parietal, thalamic and striatal regions contribute to catatonia in SSD patients.
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Affiliation(s)
- Jakob Wasserthal
- Division of Medical Imaging Computing (MIC), German Cancer Research Center (DKFZ), Heidelberg, Germany
- Medical Faculty Heidelberg, Heidelberg University, Heidelberg, Germany
| | - Klaus H Maier-Hein
- Division of Medical Imaging Computing (MIC), German Cancer Research Center (DKFZ), Heidelberg, Germany
- Section of Automated Image Analysis, Heidelberg University Hospital, Heidelberg, Germany
| | - Peter F Neher
- Division of Medical Imaging Computing (MIC), German Cancer Research Center (DKFZ), Heidelberg, Germany
- Medical Faculty Heidelberg, Heidelberg University, Heidelberg, Germany
| | - Georg Northoff
- Mind, Brain Imaging and Neuroethics Research Unit, The Royal's Institute of Mental Health Research, University of Ottawa, Ottawa, ON, Canada
| | - Katharina M Kubera
- Center for Psychosocial Medicine, Department of General Psychiatry, Heidelberg University, Heidelberg, Germany
| | - Stefan Fritze
- Department of Psychiatry and Psychotherapy, Central Institute of Mental Health, Medical Faculty Mannheim, Heidelberg University, Mannheim, Germany
| | - Anais Harneit
- Department of Psychiatry and Psychotherapy, Research Group System Neuroscience in Psychiatry, Central Institute of Mental Health, Medical Faculty Mannheim, Heidelberg University, Mannheim, Germany
| | - Lena S Geiger
- Department of Psychiatry and Psychotherapy, Research Group System Neuroscience in Psychiatry, Central Institute of Mental Health, Medical Faculty Mannheim, Heidelberg University, Mannheim, Germany
| | - Heike Tost
- Department of Psychiatry and Psychotherapy, Research Group System Neuroscience in Psychiatry, Central Institute of Mental Health, Medical Faculty Mannheim, Heidelberg University, Mannheim, Germany
| | - Robert C Wolf
- Center for Psychosocial Medicine, Department of General Psychiatry, Heidelberg University, Heidelberg, Germany
| | - Dusan Hirjak
- Department of Psychiatry and Psychotherapy, Central Institute of Mental Health, Medical Faculty Mannheim, Heidelberg University, Mannheim, Germany.
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