title: In Vivo Detection of Age- and Disease-Related Increases in Neuroinflammation by 18F-GE180 TSPO MicroPET Imaging in Wild-Type and Alzheimer's Transgenic Mice.
abstract: Alzheimer's disease (AD) is the most common cause of dementia. Neuroinflammation appears to play an important role in AD pathogenesis. Ligands of the 18 kDa translocator protein (TSPO), a marker for activated microglia, have been used as positron emission tomography (PET) tracers to reflect neuroinflammation in humans and mouse models. Here, we used the novel TSPO-targeted PET tracer (18)F-GE180 (flutriciclamide) to investigate differences in neuroinflammation between young and old WT and APP/PS1dE9 transgenic (Tg) mice. In vivo PET scans revealed an overt age-dependent elevation in whole-brain uptake of (18)F-GE180 in both WT and Tg mice, and a significant increase in whole-brain uptake of (18)F-GE180 (peak-uptake and retention) in old Tg mice compared with young Tg mice and all WT mice. Similarly, the (18)F-GE180 binding potential in hippocampus was highest to lowest in old Tg > old WT > young Tg > young WT mice using MRI coregistration. Ex vivo PET and autoradiography analysis further confirmed our in vivo PET results: enhanced uptake and specific binding (SUV75%) of (18)F-GE180 in hippocampus and cortex was highest in old Tg mice followed by old WT, young Tg, and finally young WT mice. (18)F-GE180 specificity was confirmed by an in vivo cold tracer competition study. We also examined (18)F-GE180 metabolites in 4-month-old WT mice and found that, although total radioactivity declined over 2 h, of the remaining radioactivity, ∼90% was due to parent (18)F-GE180. In conclusion, (18)F-GE180 PET scans may be useful for longitudinal monitoring of neuroinflammation during AD progression and treatment.
  
  
  CONCLUSIONS
  Microglial activation, a player in Alzheimer's disease (AD) pathogenesis, is thought to reflect neuroinflammation. Using in vivo microPET imaging with a novel TSPO radioligand, (18)F-GE180, we detected significantly enhanced neuroinflammation during normal aging in WT mice and in response to AD-associated pathology in APP/PS1dE9 Tg mice, an AD mouse model. Increased uptake and specific binding of (18)F-GE180 in whole brain and hippocampus were confirmed by ex vivo PET and autoradiography. The binding specificity and stability of (18)F-GE180 was further confirmed by a cold tracer competition study and a metabolite study, respectively. Therefore, (18)F-GE180 PET imaging may be useful for longitudinal monitoring of neuroinflammation during AD progression and treatment and may also be useful for other neurodegenerative diseases.
authors.affiliation: Department of Neurology, Ann Romney Center for Neurologic Diseases, and Harvard Medical School, Boston, Massachusetts 02115.
authors.forename: Bin
authors.initials: B
authors.lastname: Liu
authors.affiliation: Department of Neurology, Ann Romney Center for Neurologic Diseases, and.
authors.forename: Kevin X
authors.initials: KX
authors.lastname: Le
authors.affiliation: Department of Radiology, Brigham and Women's Hospital, Boston, Massachusetts 02115, Harvard Medical School, Boston, Massachusetts 02115.
authors.forename: Mi-Ae
authors.initials: MA
authors.lastname: Park
authors.affiliation: Department of Radiology, Brigham and Women's Hospital, Boston, Massachusetts 02115.
authors.forename: Shuyan
authors.initials: S
authors.lastname: Wang
authors.affiliation: Department of Radiology, Brigham and Women's Hospital, Boston, Massachusetts 02115, Harvard Medical School, Boston, Massachusetts 02115.
authors.forename: Anthony P
authors.initials: AP
authors.lastname: Belanger
authors.affiliation: Department of Radiology, Brigham and Women's Hospital, Boston, Massachusetts 02115, Harvard Medical School, Boston, Massachusetts 02115.
authors.forename: Shipra
authors.identifier: http://orcid.org/0000-0003-1008-3041
authors.initials: S
authors.lastname: Dubey
authors.affiliation: Department of Neurology, Ann Romney Center for Neurologic Diseases, and.
authors.forename: Jeffrey L
authors.initials: JL
authors.lastname: Frost
authors.affiliation: Department of Radiology, Brigham and Women's Hospital, Boston, Massachusetts 02115, Harvard Medical School, Boston, Massachusetts 02115.
authors.forename: Peter
authors.initials: P
authors.lastname: Holton
authors.affiliation: GE Healthcare, Princeton, New Jersey 08540-6231, and.
authors.forename: Vladimir
authors.initials: V
authors.lastname: Reiser
authors.affiliation: GE Healthcare, Amersham HP7 9LL, United Kingdom.
authors.forename: Paul A
authors.identifier: http://orcid.org/0000-0002-8385-1702
authors.initials: PA
authors.lastname: Jones
authors.affiliation: GE Healthcare, Amersham HP7 9LL, United Kingdom.
authors.forename: William
authors.identifier: http://orcid.org/0000-0003-4046-0813
authors.initials: W
authors.lastname: Trigg
authors.affiliation: Department of Radiology, Brigham and Women's Hospital, Boston, Massachusetts 02115, Harvard Medical School, Boston, Massachusetts 02115.
authors.forename: Marcelo F
authors.initials: MF
authors.lastname: Di Carli
authors.affiliation: Department of Neurology, Ann Romney Center for Neurologic Diseases, and Harvard Medical School, Boston, Massachusetts 02115, clemere@partners.org.
authors.forename: Cynthia A
authors.identifier: http://orcid.org/0000-0002-2983-7870
authors.initials: CA
authors.lastname: Lemere
mesh_terms: D000375:Aging / Q000378:metabolism* / Q000473:pathology; D000544:Alzheimer Disease / Q000000981:diagnostic imaging / Q000378:metabolism*; D000818:Animals; D002227:Carbazoles / Q000378:metabolism*; D018450:Disease Progression; D005462:Fluorine Radioisotopes / Q000378:metabolism*; D006801:Humans; D007249:Inflammation / Q000175:diagnosis / Q000000981:diagnostic imaging; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D049268:Positron-Emission Tomography / Q000379:methods*; D018079:Receptors, GABA / Q000378:metabolism*
chemical_list: C463819:Bzrp protein, mouse; D002227:Carbazoles; D005462:Fluorine Radioisotopes; C571664:GE-180; D018079:Receptors, GABA
keywords: Alzheimer's disease; GE180 PET tracer; TSPO; microglia; neuroinflammation