title: In vivo evidence of a functional association between immune cells in blood and brain in healthy human subjects.
abstract: Microglia, the resident macrophages in the central nervous system, are thought to be maintained by a local self-renewal mechanism. Although preclinical and in vitro studies have suggested that the brain may contain immune cells also from peripheral origin, the functional association between immune cells in the periphery and brain at physiological conditions is poorly understood. We examined 32 healthy individuals using positron emission tomography (PET) and [(11)C]PBR28, a radioligand for the 18-kDa translocator protein (TSPO) which is expressed both in brain microglia and blood immune cells. In 26 individuals, two measurements were performed with varying time intervals. In a subgroup of 19 individuals, of which 12 had repeat examinations, leukocyte numbers in blood was measured on each day of PET measurements. All individuals were genotyped for TSPO polymorphism and categorized as high, mixed, and low affinity binders. We assessed TSPO binding expressed as total distribution volume of [(11)C]PBR28 in brain and in blood cells. TSPO binding in brain was strongly and positively correlated to binding in blood cells both at baseline and when analyzing change between two PET examinations. Furthermore, there was a significant correlation between change of leukocyte numbers and change in TSPO binding in brain, and a trend-level correlation to change in TSPO binding in blood cells. These in vivo findings indicate an association between immunological cells in blood and brain via intact BBB, suggesting a functional interaction between these two compartments, such as interchange of peripherally derived cells or a common regulatory mechanism. Measurement of radioligand binding in blood cells may be a way to control for peripheral immune function in PET studies using TSPO as a marker of brain immune activation.
authors.affiliation: Department of Clinical Neuroscience, Centre for Psychiatry Research, Karolinska Institutet, Stockholm, Sweden.
authors.forename: Naoki
authors.initials: N
authors.lastname: Kanegawa
authors.affiliation: Department of Clinical Neuroscience, Centre for Psychiatry Research, Karolinska Institutet, Stockholm, Sweden.
authors.forename: Karin
authors.initials: K
authors.lastname: Collste
authors.affiliation: Department of Clinical Neuroscience, Centre for Psychiatry Research, Karolinska Institutet, Stockholm, Sweden.
authors.forename: Anton
authors.initials: A
authors.lastname: Forsberg
authors.affiliation: Department of Clinical Neuroscience, Centre for Psychiatry Research, Karolinska Institutet, Stockholm, Sweden.
authors.forename: Martin
authors.initials: M
authors.lastname: Schain
authors.affiliation: Department of Clinical Neuroscience, Centre for Psychiatry Research, Karolinska Institutet, Stockholm, Sweden.
authors.forename: Ryosuke
authors.initials: R
authors.lastname: Arakawa
authors.affiliation: Department of Clinical Neuroscience, Centre for Psychiatry Research, Karolinska Institutet, Stockholm, Sweden.
authors.forename: Aurelija
authors.initials: A
authors.lastname: Jucaite
authors.affiliation: Department of Clinical Neuroscience, Osher Center for Integrative Medicine, Karolinska Institutet, Stockholm, Sweden; Stress Research Institute, Stockholm University, Stockholm, Sweden.
authors.forename: Mats
authors.initials: M
authors.lastname: Lekander
authors.affiliation: Department of Physiology and Pharmacology, Karolinska Institutet, Stockholm, Sweden; Department of Medicine Solna and CMM, Karolinska Institutet and Karolinska University Hospital Solna, Stockholm, Sweden.
authors.forename: Caroline
authors.initials: C
authors.lastname: Olgart Höglund
authors.affiliation: Department of Clinical Neuroscience, Osher Center for Integrative Medicine, Karolinska Institutet, Stockholm, Sweden.
authors.forename: Eva
authors.initials: E
authors.lastname: Kosek
authors.affiliation: Department of Medicine, Rheumatology Unit, Center of Molecular Medicine (CMM), Karolinska Institutet, Stockholm, Sweden.
authors.forename: Jon
authors.initials: J
authors.lastname: Lampa
authors.affiliation: Department of Clinical Neuroscience, Centre for Psychiatry Research, Karolinska Institutet, Stockholm, Sweden.
authors.forename: Christer
authors.initials: C
authors.lastname: Halldin
authors.affiliation: Department of Clinical Neuroscience, Centre for Psychiatry Research, Karolinska Institutet, Stockholm, Sweden.
authors.forename: Lars
authors.initials: L
authors.lastname: Farde
authors.affiliation: Department of Clinical Neuroscience, Centre for Psychiatry Research, Karolinska Institutet, Stockholm, Sweden.
authors.forename: Andrea
authors.initials: A
authors.lastname: Varrone
authors.affiliation: Department of Clinical Neuroscience, Centre for Psychiatry Research, Karolinska Institutet, Stockholm, Sweden. Electronic address: Simon.Cervenka@ki.se.
authors.forename: Simon
authors.initials: S
authors.lastname: Cervenka
mesh_terms: D000328:Adult; D000367:Age Factors; D015415:Biomarkers / Q000097:blood / Q000378:metabolism; D001812:Blood-Brain Barrier / Q000276:immunology* / Q000378:metabolism; D001921:Brain / Q000276:immunology* / Q000378:metabolism; D002250:Carbon Radioisotopes / Q000032:analysis; D015331:Cohort Studies; D005260:Female; D006801:Humans; D007958:Leukocyte Count; D008297:Male; D017628:Microglia / Q000276:immunology* / Q000378:metabolism; D008875:Middle Aged; D049268:Positron-Emission Tomography / Q000379:methods; D011485:Protein Binding; D019275:Radiopharmaceuticals / Q000032:analysis; D018079:Receptors, GABA / Q000097:blood / Q000276:immunology / Q000378:metabolism
chemical_list: D015415:Biomarkers; D002250:Carbon Radioisotopes; D019275:Radiopharmaceuticals; D018079:Receptors, GABA; C499229:TSPO protein, human
keywords: Blood immune cells; Microglia; PET; Translocator protein; [(11)C]PBR28