Downloaded from jnm.snmjournals.org by Erasmus Universiteit on May 26, 2014. For personal use only. Neuroinflammation in Patients with Chronic Fatigue Syndrome/Myalgic Encephalomyelitis: An 11C-(R)-PK11195 PET Study Yasuhito Nakatomi, Kei Mizuno, Akira Ishii, Yasuhiro Wada, Masaaki Tanaka, Shusaku Tazawa, Kayo Onoe, Sanae Fukuda, Joji Kawabe, Kazuhiro Takahashi, Yosky Kataoka, Susumu Shiomi, Kouzi Yamaguti, Masaaki Inaba, Hirohiko Kuratsune and Yasuyoshi Watanabe J Nucl Med. Published online: March 24, 2014. 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Journal of Nuclear Medicine, published on March 24, 2014 as doi:10.2967/jnumed.113.131045 Neuroinflammation in Patients with Chronic Fatigue Syndrome/Myalgic Encephalomyelitis: An 11C-(R)-PK11195 PET Study Yasuhito Nakatomi1,2, Kei Mizuno2–4, Akira Ishii2,3, Yasuhiro Wada2,3, Masaaki Tanaka2,3, Shusaku Tazawa2,3, Kayo Onoe2, Sanae Fukuda2,3, Joji Kawabe5, Kazuhiro Takahashi2,3, Yosky Kataoka2,3, Susumu Shiomi5, Kouzi Yamaguti3, Masaaki Inaba1, Hirohiko Kuratsune3,6,7, and Yasuyoshi Watanabe2,3 1Department of Metabolism, Endocrinology and Molecular Medicine, Osaka City University Graduate School of Medicine, Osaka, Japan; 2RIKEN Center for Life Science Technologies, Hyogo, Japan; 3Department of Physiology, Osaka City University Graduate School of Medicine, Osaka, Japan; 4Department of Medical Science on Fatigue, Osaka City University Graduate School of Medicine, Osaka, Japan; 5Department of Nuclear Medicine, Osaka City University Graduate School of Medicine, Osaka, Japan; 6Department of Health Science, Kansai University of Welfare Sciences, Osaka, Japan; and 7Graduate School of Agricultural and Life Sciences, University of Tokyo, Tokyo, Japan Chronic fatigue syndrome/myalgic encephalomyelitis (CFS/ME) is Chronic fatigue syndrome/myalgic encephalomyelitis (CFS/ a disease characterized by chronic, profound, disabling, and un- ME) is a disease characterized by chronic, profound, disabling, explained fatigue. Although it is hypothesized that brain inflammation and unexplained fatigue (1). CFS/ME patients experience neuro- is involved in the pathophysiology of CFS/ME, there is no direct psychologic symptoms, including cognitive impairment (thinking evidence of neuroinflammation in patients with CFS/ME. Activation of microglia or astrocytes is related to neuroinflammation. 11C-(R)- difficulty, decreased alertness, and impaired memory and concen- (2-chlorophenyl)-N-methyl-N-(1-methylpropyl)-3-isoquinoline-carbox- tration), chronic widespread pain (muscle pain, pain in multiple amide (11C-(R)-PK11195) is a ligand of PET for a translocator protein joints, headaches, and sore throat), and depressive symptoms (1). that is expressed by activated microglia or astrocytes. We used 11C-(R)- To date, no specific biomarkers for diagnosing and evaluating the PK11195 and PET to investigate the existence of neuroinflammation in severity of CFS/ME have been established. CFS/ME patients. Methods: Nine CFS/ME patients and 10 healthy The neuropsychologic symptoms in CFS/ME suggest that the 11 controls underwent C-(R)-PK11195 PET and completed question- central nervous system is involved in the pathophysiology, and naires about fatigue, fatigue sensation, cognitive impairments, pain, several studies including ours have shown central nervous and depression. To measure the density of translocator protein, non- system abnormalities in CFS/ME patients. Our previous study displaceable binding potential (BPND) values were determined using linear graphical analysis with the cerebellum as a reference region. (2) with PET showed hypoperfusion and reduction of biosyn- 11 Results: The BPND values of C-(R)-PK11195 in the cingulate cortex, thesis of neurotransmitters such as glutamate, aspartate, and hippocampus, amygdala, thalamus, midbrain, and pons were 45%– g-aminobutyric acid through acetylcarnitine in the frontal, cingulate, 199% higher in CFS/ME patients than in healthy controls. In CFS/ME temporal, and occipital cortices; basal ganglia; and hippocampus 11 R patients, the BPND values of C-( )-PK11195 in the amygdala, thala- in CFS/ME patients. CFS/ME patients also had a decrease in mus, and midbrain positively correlated with cognitive impairment serotonin transporter densities in the rostral sector of the anterior score, the BPND values in the cingulate cortex and thalamus positively cingulate cortex, and the serotonin transporter density in the correlated with pain score, and the BP value in the hippocampus ND middle sector of the cingulate cortex was negatively correlated positively correlated with depression score. Conclusion: Neuroinflam- mation is present in widespread brain areas in CFS/ME patients and with pain score (3). Furthermore, our voxel-based morphometry was associated with the severity of neuropsychologic symptoms. studies demonstrated volume reduction of the bilateral prefrontal Evaluation of neuroinflammation in CFS/ME patients may be essen- cortices in CFS/ME patients, and the volume reduction level in tial for understanding the core pathophysiology and for developing the right prefrontal cortex was associated with the severity of objectivediagnosticcriteriaandeffectivemedicaltreatments. fatigue (4). Key Words: neuroinflammation; chronic fatigue syndrome (CFS); Other fatigue-related neurologic diseases such as multiple myalgic encephalomyelitis (ME); 11C-(R)-PK11195; positron emission sclerosis, Parkinson disease, and postpolio fatigue syndrome are tomography (PET) also thought to arise from dysfunction of the central nervous J Nucl Med 2014; 55:1–6 system (5,6), and it has been suggested that neuroinflammation DOI: 10.2967/jnumed.113.131045 is involved in the pathogenesis or progression of these diseases (7). There are also related reports that the levels of proinflam- matory cytokines in the peripheral blood and cerebral spinal Received Aug. 15, 2013; revision accepted Jan. 14, 2014. fluid, which might be indicative of neuroinflammation, are For correspondence or reprints contact: Yasuyoshi Watanabe, RIKEN higher in CFS/ME patients than in healthy controls (8,9), sug- Center for Life Science Technologies, 6-7-3 Minatojima-minamimachi, Chuo-ku, Kobe, Hyogo 650-0047, Japan. gesting that neuroinflammation may also be related to the patho- E-mail: [email protected] physiology of CFS/ME (10). However, to prove the existence of Published online ▪▪▪▪▪▪▪▪▪▪▪▪. COPYRIGHT © 2014 by the Society of Nuclear Medicine and Molecular neuroinflammation and its possible contribution to the patho- Imaging, Inc. physiology of CFS/ME, it is necessary to directly evaluate NEUROINFLAMMATION IN CFS/ME • Nakatomi et al. 1 jnm131045-sn n 3/20/14 Downloaded from jnm.snmjournals.org by Erasmus Universiteit on May 26, 2014. For personal use only. neuroinflammation using a neuroimaging technique such as PET The severity of neuropsychologic symptoms was measured using and to investigate the relations between neuroinflammation and the following questionnaires: a visual analog scale (VAS) for fatigue symptom severity. sensation (14), the Chalder fatigue scale, the Center for Epidemiolog- Neuroinflammation is evidenced by activation of microglia or ical Studies depression scale (CES-D), cognitive impairment and pain astrocytes, and activated glial cells exhibit an increase in scores, and duration of disease. The VAS for fatigue sensation ranges expression of the 18-kDa translocator protein (TSPO). 11C- from 0 (no fatigue) to 100 (complete exhaustion). The Chalder fatigue (R)-(2-chlorophenyl)-N-methyl-N-(1-methylpropyl)-3-isoquino- scale (15) consists of 11 questions rated on a 4-point Likert scale. The line-carboxamide (11C-(R)-PK11195) is a ligand of PET for the total score ranges from 0 to 33, with higher scores indicating a greater TSPO that is expressed in activated microglia or astrocytes and degree of daily fatigue. The CES-D consists of 20 questions rated on a 4- point Likert scale. The total score ranges from 0 to 60, with higher scores is widely used to assess neuroinflammation in neurologic dis- indicating a greater degree of depression (16). The cognitive impairment eases (7). Recently, it has been reported that although TSPO score was assessed using 4 questions on thinking difficulty, inability to polymorphisms affect the affinities of second-generation TSPO 11 concentrate, impairment in memory, and absence of alertness.