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      Increased heterogeneity of brain perfusion is an early marker of central nervous system involvement in antiphospholipid antibody carriers

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          Abstract

          Objective

          The non-criteria neuropsychiatric manifestations of antiphospholipid syndrome include headache, dizziness, vertigo, seizure, depression and psychosis. There were still no objective methods qualified to detect the early central nervous system involvement in non-criteria antiphospholipid syndrome. We evaluated the effectiveness of Tc-99m ECD SPECT in assessing circulatory insufficiency in the brains of patients with antiphospholipid antibodies and neuropsychiatric symptoms but without thromboembolism.

          Materials and methods

          Patients with a history of positive antiphospholipid antibodies and neuropsychiatric symptoms composed the case group; patients without antiphospholipid antibody served as the control group. Subjects with a history of thromboembolism or autoantibodies to extractable nuclear antigens were excluded. All patients received Tc-99m ECD SPECT studies and were classified by the number of positive antiphospholipid antibodies they carried. The heterogeneity of brain perfusion was defined as the coefficient of variation of the SPECT signals. Analysis of variance (ANOVA) was applied to evaluate the differences between the groups.

          Results

          Total 60 adult patients were included in this study. There were 54 patients in the case group and 6 patients in the control group. The mean age was 38.3 ± 11.5 years. There were 52 women and 8 men. There was no significant difference in the mean brain perfusion between groups ( P = 0.69). However, Tc-99m ECD SPECT demonstrated significant heterogeneity of brain perfusion in relation to the number of antiphospholipid antibodies ( P = 0.01).

          Conclusions

          This is the first study demonstrating that Tc-99m ECD SPECT can early detect the increased heterogeneity of brain circulation in non-criteria antiphospholipid antibody carriers.

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          Most cited references29

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          The pathogenesis of the antiphospholipid syndrome.

          Bill Giannakopoulos, Steven A Krilis (2013)
          Article 0 comments Cited 185 times – based on 0 reviews     Review now
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            Pathogenesis of antiphospholipid syndrome: understanding the antibodies.

            Pier Meroni, Anna Borghi, Francesco Saverio Tedesco … (2011)
            Antiphospholipid antibodies (aPL) are both diagnostic markers for, and pathogenic drivers of, antiphospholipid syndrome (APS). Although the presence of aPL is a necessary pre-condition, APS-associated clotting is seemingly triggered by an additional 'second hit', frequently related to innate inflammatory immune responses. β(2) glycoprotein I (β(2)GPI)-dependent aPL, the most important subset of these antibodies, mediate several--not necessarily alternative--thrombogenic mechanisms, mainly on the basis of their reactivity with β(2)GPI expressed on the membrane of cells that participate in the coagulation cascade. Recurrent pregnancy complications associated with aPL cannot be explained solely by thrombosis, and alternative pathogenic mechanisms have been reported. Although one in vivo model of fetal loss suggests a mechanism of aPL-mediated acute placental inflammation, other models and the histopathological examination of APS placentae do not support a widespread inflammatory signature. β(2)GPI-dependent aPL are thought to recognize their antigen on placental tissues, inhibit the growth and differentiation of trophoblasts, and eventually cause defective placentation. Why antibodies with similar antigen specificity produce different clinical manifestations is not clear. Characterization of the molecular basis of the pathogenic mechanisms involved, including the putative second hits and the role of complement activation, might offer an answer to this question.
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              Antiphospholipid antibodies and risk of myocardial infarction and ischaemic stroke in young women in the RATIO study: a case-control study.

              Rolf T. Urbanus, Bob Siegerink, Mark Roest … (2009)
              Arterial thrombosis is a major clinical manifestation of the antiphospholipid syndrome, which is an autoimmune disease found mostly in young women. Although the presence of circulating antiphospholipid antibodies in individuals who have a thrombotic event is a prerequisite for the diagnosis of the antiphospholipid syndrome, the risk of arterial thrombosis associated with antiphospholipid antibodies in the general population is unclear. In RATIO (Risk of Arterial Thrombosis In relation to Oral contraceptives), a large multicentre population-based case-control study, we enrolled women aged under 50 years who were admitted to hospital at 16 centres with first ischaemic stroke or myocardial infarction between January, 1990, and October, 1995. An additional 59 women who presented with ischaemic stroke at the University Medical Centre Utrecht between 1996 and 2001 were also enrolled. Information on cardiovascular risk factors (such as oral contraceptive use, smoking, and hypertension) were assessed with a standard questionnaire. During the second phase (1998-2002), blood samples were taken to measure antiphospholipid antibody profiles (lupus anticoagulant, anticardiolipin IgG, anti-beta(2)-glycoprotein I IgG, and antiprothrombin IgG) and to determine genetic prothrombotic risk factors (factor V G1691A variant, prothrombin G20210A variant, and factor XIII 204Phe allele). 175 patients with ischaemic stroke, 203 patients with myocardial infarction, and 628 healthy controls were included. Patients were frequency matched with controls for age, residence area, and index year. Lupus anticoagulant was found in 30 (17%) patients with ischaemic stroke, six (3%) patients with myocardial infarction, and four (0.7%) in the control group. The odds ratio for myocardial infarction was 5.3 (95% CI 1.4-20.8), which increased to 21.6 (1.9-242.0) in women who used oral contraceptives and 33.7 (6.0-189.0) in those who smoked. The odds ratio for ischaemic stroke was 43.1 (12.2-152.0), which increased to 201.0 (22.1-1828.0) in women who used oral contraceptives and 87.0 (14.5-523.0) in those who smoked. In women who had anti-beta(2)-glycoprotein I antibodies, the risk of ischaemic stroke was 2.3 (1.4-3.7), but the risk of myocardial infarction was not increased (0.9, 0.5-1.6). Neither anticardiolipin nor antiprothrombin antibodies affected the risk of myocardial infarction or ischaemic stroke. Our results suggest that lupus anticoagulant is a major risk factor for arterial thrombotic events in young women, and the presence of other cardiovascular risk factors increases the risk even further. Netherlands Heart Foundation and Leducq Foundation.
              Article 0 comments Cited 81 times – based on 0 reviews     Review now
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                Author and article information

                Contributors
                Christophe Leroyer: Role: Editor
                Journal
                Journal ID (nlm-ta): PLoS One
                Journal ID (iso-abbrev): PLoS ONE
                Journal ID (publisher-id): plos
                Journal ID (pmc): plosone
                Title: PLoS ONE
                Publisher: Public Library of Science (San Francisco, CA USA )
                ISSN (Electronic): 1932-6203
                Publication date (Electronic): 1 August 2017
                Publication date Collection: 2017
                Volume: 12
                Issue: 8
                Electronic Location Identifier: e0182344
                Affiliations
                [1 ] Department of Internal Medicine, National Taiwan University Hospital, Yun-Lin Branch, Yun-Lin, Taiwan
                [2 ] Institute of Clinical Medicine, National Taiwan University College of Medicine, Taipei City, Taiwan
                [3 ] Department of Nuclear Medicine, National Taiwan University Hospital, Yun-Lin Branch, Yun-Lin, Taiwan
                [4 ] Department of Nuclear Medicine, National Taiwan University Hospital and National Taiwan University College of Medicine, Taipei City, Taiwan
                [5 ] Department of Medical Research, National Taiwan University Hospital, Taipei City, Taiwan
                [6 ] Department of Internal Medicine, National Taiwan University Hospital, Taipei City, Taiwan
                [7 ] Cardiology Division of Cardiovascular Medical Center and Department of Nuclear Medicine, Far Eastern Memorial Hospital, New Taipei City, Taiwan
                [8 ] Yang-Ming University School of Medicine, Taipei City, Taiwan
                [9 ] Department of Laboratory Medicine, National Taiwan University Hospital, Yun-Lin Branch, Yun-Lin, Taiwan
                Universite de Bretagne Occidentale, FRANCE
                Author notes

                Competing Interests: The authors have declared that no competing interests exist.

                • Conceptualization: TSL SCH.

                • Data curation: PYH CLK YWW RFY YCH.

                • Formal analysis: CHC.

                • Funding acquisition: YMK TSL.

                • Investigation: TSL.

                • Methodology: PYH.

                • Project administration: SCH.

                • Resources: CHW KJL SCH.

                • Software: PYH.

                • Supervision: SCH.

                • Validation: RFY CHW.

                • Visualization: TSL.

                • Writing – original draft: TSL.

                • Writing – review & editing: TSL.

                Author information
                http://orcid.org/0000-0002-2101-0887
                Article
                Publisher ID: PONE-D-16-48125
                DOI: 10.1371/journal.pone.0182344
                PMC ID: 5538638
                PubMed ID: 28763503
                SO-VID: b4944563-762e-4e1d-8e77-99af8bdd8b20
                Copyright © © 2017 Lin et al
                License:

                This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

                History
                Date received : 5 December 2016
                Date accepted : 17 July 2017
                Page count
                Figures: 2, Tables: 2, Pages: 9
                Funding
                Funded by: National Taiwan University Hospital Yun-Lin Branch
                Award ID: NTUHYL104.I004
                Award Recipient :
                ORCID: http://orcid.org/0000-0002-2101-0887
                Funded by research grant from National Taiwan University Hospital, Yun-Lin Branch Grant number:NTUHYL104.I004 to TSL. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.
                Categories
                Subject: Research Article
                Subject: Research and Analysis Methods
                Subject: Imaging Techniques
                Subject: Neuroimaging
                Subject: Single Photon Emission Computed Tomography
                Subject: Biology and Life Sciences
                Subject: Neuroscience
                Subject: Neuroimaging
                Subject: Single Photon Emission Computed Tomography
                Subject: Medicine and Health Sciences
                Subject: Diagnostic Medicine
                Subject: Diagnostic Radiology
                Subject: Tomography
                Subject: Single Photon Emission Computed Tomography
                Subject: Research and Analysis Methods
                Subject: Imaging Techniques
                Subject: Diagnostic Radiology
                Subject: Tomography
                Subject: Single Photon Emission Computed Tomography
                Subject: Medicine and Health Sciences
                Subject: Radiology and Imaging
                Subject: Diagnostic Radiology
                Subject: Tomography
                Subject: Single Photon Emission Computed Tomography
                Subject: Medicine and Health Sciences
                Subject: Vascular Medicine
                Subject: Thromboembolism
                Subject: Medicine and Health Sciences
                Subject: Otorhinolaryngology
                Subject: Otology
                Subject: Vertigo
                Subject: Biology and Life Sciences
                Subject: Neuroscience
                Subject: Cognitive Science
                Subject: Cognitive Neuroscience
                Subject: Cognitive Neurology
                Subject: Neuropsychological Testing
                Subject: Biology and Life Sciences
                Subject: Neuroscience
                Subject: Cognitive Neuroscience
                Subject: Cognitive Neurology
                Subject: Neuropsychological Testing
                Subject: Medicine and Health Sciences
                Subject: Neurology
                Subject: Cognitive Neurology
                Subject: Neuropsychological Testing
                Subject: Biology and Life Sciences
                Subject: Neuroscience
                Subject: Neuropsychology
                Subject: Neuropsychological Testing
                Subject: Biology and Life Sciences
                Subject: Psychology
                Subject: Neuropsychology
                Subject: Neuropsychological Testing
                Subject: Social Sciences
                Subject: Psychology
                Subject: Neuropsychology
                Subject: Neuropsychological Testing
                Subject: Research and Analysis Methods
                Subject: Immunologic Techniques
                Subject: Immunoassays
                Subject: Enzyme-Linked Immunoassays
                Subject: Medicine and Health Sciences
                Subject: Diagnostic Medicine
                Subject: Diagnostic Radiology
                Subject: Magnetic Resonance Imaging
                Subject: Research and Analysis Methods
                Subject: Imaging Techniques
                Subject: Diagnostic Radiology
                Subject: Magnetic Resonance Imaging
                Subject: Medicine and Health Sciences
                Subject: Radiology and Imaging
                Subject: Diagnostic Radiology
                Subject: Magnetic Resonance Imaging
                Subject: Biology and Life Sciences
                Subject: Anatomy
                Subject: Nervous System
                Subject: Central Nervous System
                Subject: Medicine and Health Sciences
                Subject: Anatomy
                Subject: Nervous System
                Subject: Central Nervous System
                Subject: Medicine and Health Sciences
                Subject: Diagnostic Medicine
                Subject: Signs and Symptoms
                Subject: Headaches
                Subject: Medicine and Health Sciences
                Subject: Pathology and Laboratory Medicine
                Subject: Signs and Symptoms
                Subject: Headaches
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