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

Shigeyuki Yamamoto,Kei Mizuno,Tsuyoshi Tahara,Etsuji Yoshikawa,Yasuomi Ouchi,Hirohiko Kuratsune,Masao Iwase,Daisaku Nakatsuka,Hirotaka Onoe,Yasuyoshi Watanabe,Seiki Tajima,Kouzi Yamaguti,Hideo Tsukada,Francisco José Esteban

doi:10.1371/journal.pone.0051515

Abstract

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

Highlights

Neurotransmission at the muscarinic cholinergic receptor in the central nervous system is involved in cognitive function [1,2,3], motor control [4,5], and rapid eye movement sleep [6]
The present results demonstrate that serum autoantibody against the muscarinic cholinergic receptor (mAChR) can affect the brain mAChR without altering acetylcholinesterase activity and cognitive functions in chronic fatigue syndrome (CFS) patients
The mAChR was evaluated using a positron emission tomography (PET) ligand N-[11C]methyl-3piperidyl benzilate ([11C](+)3-MPB) [38], and acetylcholinesterase (AChE) activity was assessed with N-[11C]Methyl-4-piperidyl acetate ([11C]MP4A) [39,40,41]

Summary

Introduction

Neurotransmission at the muscarinic cholinergic receptor (mAChR) in the central nervous system is involved in cognitive function [1,2,3], motor control [4,5], and rapid eye movement sleep [6]. Five subtypes of mAChR, M1–5, have been identified by molecular cloning [19], and the M1 receptor has a significant role in cognitive function [3,20]. Necrosis factor, interleukin-1, interleukin-6 [27], increased markers of inflammation [28] and stressful life events prior to CFS onset [29,30] It has been established through in vitro and in vivo studies that BBB function was disrupted by tumour necrosis factor, interleukin-1 and interleukin-6 [31,32,33,34]. Increased levels of the serum autoantibody against the mAChR M1 have been reported in CFS patients [37] These lines of evidence led us to investigate the effect of autoantibody against the mAChR on the muscarinic cholinergic system in the brain in vivo. The mAChR was evaluated using a positron emission tomography (PET) ligand N-[11C]methyl-3piperidyl benzilate ([11C](+)3-MPB) [38], and acetylcholinesterase (AChE) activity was assessed with N-[11C]Methyl-4-piperidyl acetate ([11C]MP4A) [39,40,41]

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