Reduction of [11C](+)3-MPB Binding in Brain of Chronic Fatigue Syndrome with Serum Autoantibody against Muscarinic Cholinergic Receptor

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Abstract

Background

Numerous associations between brain-reactive antibodies and neurological or psychiatric symptoms have been proposed. Serum autoantibody against the muscarinic cholinergic receptor (mAChR) was increased in some patients with chronic fatigue syndrome (CFS) or psychiatric disease. We examined whether serum autoantibody against mAChR affected the central cholinergic system by measuring brain mAChR binding and acetylcholinesterase activity using positron emission tomography (PET) in CFS patients with positive [CFS(+)] and negative [CFS(−)] autoantibodies.

Methodology

Five CFS(+) and six CFS(−) patients, as well as 11 normal control subjects underwent a series of PET measurements with N-[ ¹¹C]methyl-3-piperidyl benzilate [ ¹¹C](+)3-MPB for the mAChR binding and N-[ ¹¹C]methyl-4-piperidyl acetate [ ¹¹C]MP4A for acetylcholinesterase activity. Cognitive function of all subjects was assessed by neuropsychological tests. Although the brain [ ¹¹C](+)3-MPB binding in CFS(−) patients did not differ from normal controls, CFS(+) patients showed significantly lower [ ¹¹C](+)3-MPB binding than CFS(−) patients and normal controls. In contrast, the [ ¹¹C]MP4A index showed no significant differences among these three groups. Neuropsychological measures were similar among groups.

Conclusion

The present results demonstrate that serum autoantibody against the mAChR can affect the brain mAChR without altering acetylcholinesterase activity and cognitive functions in CFS patients.

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Most cited references 56

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Pharmacological data clearly indicate that both muscarinic and nicotinic acetylcholine receptors have a role in the encoding of new memories. Localized lesions and antagonist infusions demonstrate the anatomical locus of these cholinergic effects, and computational modeling links the function of cholinergic modulation to specific cellular effects within these regions. Acetylcholine has been shown to increase the strength of afferent input relative to feedback, to contribute to theta rhythm oscillations, activate intrinsic mechanisms for persistent spiking, and increase the modification of synapses. These effects might enhance different types of encoding in different cortical structures. In particular, the effects in entorhinal and perirhinal cortex and hippocampus might be important for encoding new episodic memories.

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Estimation of premorbid IQ in individuals with Alzheimer's disease using Japanese ideographic script (Kanji) compound words: Japanese version of National Adult Reading Test.

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The National Adult Reading Test (NART) is widely used as a measure of premorbid IQ of the English-speaking patients with dementia. The purpose of the present study was to develop a Japanese version of the NART (JART), using 50 Japanese irregular words, all of which are Kanji (ideographic script) compound words. Reading performance based on JART and IQ as measured by the Wechsler Adult Intelligence Scale-Revised (WAIS-R) was examined in a sample of 100 normal elderly (NE) persons and in 70 age-, sex-, and education-matched patients with Alzheimer's disease (AD). The NE group was randomly divided into the NE calculation group (n=50) and the NE validation group (n=50). Using the NE calculation group, a linear regression equation was obtained in which the observed full-scale IQ (FSIQ) was regressed on the reading errors of the JART. When the regressed equation computed from the NE calculation group was applied to the NE validation group, the predicted FSIQ adequately fit the observed FSIQ (R2=0.78). Further, independent t-tests showed that the JART-predicted IQs were not significantly different between the NE and AD groups, whereas the AD group performed worse in the observed IQs. The reading ability of Kanji compound words is well-preserved in Japanese patients with AD. The JART is a valid scale for evaluating premorbid IQ in patients with AD.

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Loss of blood-brain barrier (BBB) integrity is believed to be an early and significant event in lesion pathogenesis in the inflammatory demyelinating disease multiple sclerosis (MS), and understanding mechanisms involved may lead to novel therapeutic avenues for this disorder. Well-differentiated endothelium forms the basis of the BBB, while astrocytes control the balance between barrier stability and permeability via production of factors that restrict or promote vessel plasticity. In this study, we report that the proinflammatory cytokine IL-1beta, which is prominently expressed in active MS lesions, causes a shift in the expression of these factors to favor plasticity and permeability. The transcription factor, hypoxia inducible factor-1 (HIF-1), plays a significant role in this switch. Using a microarray-based approach, we found that in human astrocytes, IL-1beta induced the expression of genes favoring vessel plasticity, including HIF-1alpha and its target, vascular endothelial growth factor-A (VEGF-A). Demonstrating relevance to MS, we showed that HIF-1alpha and VEGF-A were expressed by reactive astrocytes in active MS lesions, while the VEGF receptor VEGFR2/flk-1 localized to endothelium and IL-1 to microglia/macrophages. Suggesting functional significance, we found that expression of IL-1beta in the brain induced astrocytic expression of HIF-1alpha, VEGF-A, and BBB permeability. In addition, we confirmed VEGF-A to be a potent inducer of BBB permeability and angiogenesis, and demonstrated the importance of IL-1beta-induced HIF-1alpha in its regulation. These results suggest that IL-1beta contributes to BBB permeability in MS via reactivation of the HIF-VEGF axis. This pathway may represent a potential therapeutic target to restrict lesion formation.

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Author and article information

Contributors

Francisco José Esteban: 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, USA )

ISSN (Electronic): 1932-6203

Publication date Collection: 2012

Publication date (Electronic): 11 December 2012

Volume: 7

Issue: 12

Electronic Location Identifier: e51515

Affiliations

[1 ]Department of Physiology, Osaka City University Graduate School of Medicine, Abeno-ku, Osaka, Japan

[2 ]Central Research Laboratory, Hamamatsu Photonics KK, Hamakita, Shizuoka, Japan

[3 ]Molecular Imaging Frontier Research Center, Hamamatsu University School of Medicine, Hamamatsu, Japan

[4 ]RIKEN Center for Molecular Imaging Science (CMIS), Kobe, Hyogo, Japan

[5 ]Psychiatry, Department of Clinical Neuroscience, Osaka University Graduate School of Medicine, Suita, Japan

[6 ]Department of Health Sciences, Faculty of Health Sciences for Welfare, Kansai University of Welfare Sciences, Kashiwara, Japan

University of Jaén, Spain

Author notes

* E-mail: yywata@ 123456riken.jp

Competing Interests: The authors have read the journal’s policy and have the following conflicts: SY, EY and HT are employees of Hamamatsu Photonics KK. This does not alter the authors’ adherence to all the PLOS ONE policies on sharing data and materials.

Conceived and designed the experiments: YW. Performed the experiments: SY YO DN TT ST EY HT MI KY HK. Analyzed the data: SY TT KM ST EY. Wrote the paper: SY YO KM HO YW.

Article

Publisher ID: PONE-D-11-26092

DOI: 10.1371/journal.pone.0051515

PMC ID: 3519853

PubMed ID: 23240035

SO-VID: 44c61e0c-9810-4910-a329-96e51d7d1348

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 : 29 December 2011

Date accepted : 3 September 2012

Page count

Pages: 7

Funding

This work was supported in part by Special Coordination Funds for Promoting Science and Technology, the 21st Century COE Program “Base to Overcome Fatigue” from the Japanese Ministry of Education, Culture, Sports, Science, and Technology, and grants from Japanese Ministry of Health, Labor, and Welfare. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. No additional external funding received for this study.