Molecular imaging of neuroinflammation in Alzheimer’s disease
Neuroinflammatory changes are observed in the brain of patients with Alzheimer’s disease (AD). Studies have shown the presence of activated microglia and astrocytes surrounding the amyloid plaques, along with the presence of cytokines and other mediators of inflammation. The role of inflammation in AD is not yet completely understood. More specifically, some inflammatory processes, such as the activation of microglia, may have detrimental or beneficial effects on the underlining neuropathology, by promoting inflammation and tissue damage or rather phagocytic activity and tissue repair. Imaging of neuroinflammation with positron emission tomography (PET) is the only technology that enables the visualization of microglia and astrocyte activation in the living human brain. PET studies with first- or second-generation radioligands binding to the 18-kDa translocator protein (TSPO) ([11C]-R-PK11195, [11C]DAA1106, [11C]PBR28, [18F]FEMPA, [18F]FEPPA) have shown some conflicting results, demonstrating on average a ~30 % higher TSPO availability in AD patients compared with controls, with a few studies showing no statistically significant difference between the two groups. Similar conflicting evidences have been shown when comparing subjects with mild cognitive impairment (MCI) and control subjects. Therefore, whether TSPO is a good marker for detecting in vivo microglia activation in AD is still a matter of debate. Imaging of MAO-B as a marker for astrocyte activation in AD is a valid alternative to TSPO imaging in the context of neuroinflammation. Only limited MAO-B imaging studies with [11C]l-deprenyl-D2 are available so far in AD and MCI, showing increased MAO-B binding in MCI patients compared with controls with a degree higher than that observed in AD. There are two unmet questions that are still under discussion. The first question is which neuroinflammatory process, microglia or astrocyte activation, occurs earlier in the natural course of AD from prodromal to dementia stage? Comparative studies using these two markers in MCI and AD could be important to clarify which marker can be used for earliest detection of neuroinflammatory changes in vivo. The second question is whether imaging of microglia or astrocytes per se is a useful marker of neuroinflammation associated with neurodegeneration. The development of new radioligands for other targets that are more directly associated with the pro- or anti-inflammatory activity of microglia could help in understanding the relevance of neuroinflammation in the pathological processes leading to neurodegeneration in AD. Molecular imaging with PET can be a useful tool to determine the nature and temporal evolution of inflammation in early stages of AD in relation to other pathological markers, such as deposition of amyloid plaques and tau as well as clinical presentation of the disease.
KeywordsTSPO Alzheimer Microglia Astrocytes
The work has been supported by funds from the Swedish Research Council (Project 05817), Karolinska Institutet Strategic Neuroscience program, the Stockholm County Council-Karolinska Institutet regional agreement on medical training and clinical research (ALF Grant), Swedish Brain Power, the Swedish Brain Foundation, the Alzheimer Foundation in Sweden, Karolinska Institutet’s Foundation for Aging Research, Swedish Foundation for Strategic Research (SFF), and by the EU project INMiND, FP7/2007-2013-no HEALTH-F2-2011-278850 (http://www.uni-muenster.de/InMind). Part of the work has been also supported by Bayer Healthcare, Berlin, Germany.
Andrea Varrone is responsible for literature search and review, content planning, manuscript writing and editing. Agneta Nordberg contributed to literature search and review, content planning, manuscript writing and editing.
Compliance with ethical standards
Conflict of interest
Andrea Varrone and Agneta Nordberg declare no conflicts of interest. The work performed using [18F]FEMPA has been supported by Bayer Healthcare, Berlin, Germany.
Human and animal studies
All procedures followed were in accordance with the ethical standards of the responsible committee on human experimentation (institutional and national) and with the Helsinki Declaration of 1975, as revised in 2008. Informed consent was obtained from all patients for being included in the study. In cases of animal studies, all institutional and national guidelines for the care and use of laboratory animals were followed.
- 11.Jimenez S, Baglietto-Vargas D, Caballero C, Moreno-Gonzalez I, Torres M, Sanchez-Varo R et al (2008) Inflammatory response in the hippocampus of PS1M146L/APP751SL mouse model of Alzheimer’s disease: age-dependent switch in the microglial phenotype from alternative to classic. J Neurosci 28:11650–11661. doi: 10.1523/JNEUROSCI.3024-08.2008 CrossRefPubMedGoogle Scholar
- 13.Cosenza-Nashat M, Zhao ML, Suh HS, Morgan J, Natividad R, Morgello S et al (2009) Expression of the translocator protein of 18 kDa by microglia, macrophages and astrocytes based on immunohistochemical localization in abnormal human brain. Neuropathol Appl Neurobiol 35:306–328. doi: 10.1111/j.1365-2990.2008.01006.x CrossRefPubMedGoogle Scholar
- 28.Fowler JS, Wolf AP, MacGregor RR, Dewey SL, Logan J, Schlyer DJ et al (1988) Mechanistic positron emission tomography studies: demonstration of a deuterium isotope effect in the monoamine oxidase-catalyzed binding of [11C]l-deprenyl in living baboon brain. J Neurochem 51:1524–1534CrossRefPubMedGoogle Scholar
- 36.Yasuno F, Ota M, Kosaka J, Ito H, Higuchi M, Doronbekov TK et al (2008) Increased binding of peripheral benzodiazepine receptor in Alzheimer’s disease measured by positron emission tomography with [11C]DAA1106. Biol Psychiatry 64:835–841. doi: 10.1016/j.biopsych.2008.04.021 CrossRefPubMedGoogle Scholar
- 37.Varrone A, Mattsson P, Forsberg A, Takano A, Nag S, Gulyas B et al (2013) In vivo imaging of the 18-kDa translocator protein (TSPO) with [18F]FEDAA1106 and PET does not show increased binding in Alzheimer’s disease patients. Eur J Nucl Med Mol Imaging 40:921–931. doi: 10.1007/s00259-013-2359-1 CrossRefPubMedGoogle Scholar
- 39.Varrone A, Oikonen V, Forsberg A, Joutsa J, Takano A, Solin O et al (2015) Positron emission tomography imaging of the 18-kDa translocator protein (TSPO) with [18F]FEMPA in Alzheimer’s disease patients and control subjects. Eur J Nucl Med Mol Imaging 42:438–446. doi: 10.1007/s00259-014-2955-8 CrossRefPubMedGoogle Scholar
- 40.Golla SS, Boellaard R, Oikonen V, Hoffmann A, van Berckel BN, Windhorst AD et al (2015) Quantification of [18F]DPA-714 binding in the human brain: initial studies in healthy controls and Alzheimer’s disease patients. J Cereb Blood Flow Metab 35:766–772. doi: 10.1038/jcbfm.2014.261 CrossRefPubMedPubMedCentralGoogle Scholar
- 44.Kropholler MA, Boellaard R, van Berckel BN, Schuitemaker A, Kloet RW, Lubberink MJ et al (2007) Evaluation of reference regions for (R)-[(11)C]PK11195 studies in Alzheimer’s disease and mild cognitive impairment. J Cereb Blood Flow Metab 27:1965–1974. doi: 10.1038/sj.jcbfm.9600488 CrossRefPubMedGoogle Scholar
- 45.Tomasi G, Edison P, Bertoldo A, Roncaroli F, Singh P, Gerhard A et al (2008) Novel reference region model reveals increased microglial and reduced vascular binding of 11C-(R)-PK11195 in patients with Alzheimer’s disease. J Nucl Med 49:1249–1256. doi: 10.2967/jnumed.108.050583 CrossRefPubMedGoogle Scholar
- 46.Yaqub M, van Berckel BN, Schuitemaker A, Hinz R, Turkheimer FE, Tomasi G et al (2012) Optimization of supervised cluster analysis for extracting reference tissue input curves in (R)-[(11)C]PK11195 brain PET studies. J Cereb Blood Flow Metab 32:1600–1608. doi: 10.1038/jcbfm.2012.59 CrossRefPubMedPubMedCentralGoogle Scholar
- 48.Versijpt JJ, Dumont F, Van Laere KJ, Decoo D, Santens P, Audenaert K et al (2003) Assessment of neuroinflammation and microglial activation in Alzheimer’s disease with radiolabelled PK11195 and single photon emission computed tomography. A pilot study. Eur Neurol 50:39–47CrossRefPubMedGoogle Scholar
- 49.Gulyas B, Vas A, Toth M, Takano A, Varrone A, Cselenyi Z et al (2011) Age and disease related changes in the translocator protein (TSPO) system in the human brain: positron emission tomography measurements with [11C]vinpocetine. Neuroimage 56:1111–1121. doi: 10.1016/j.neuroimage.2011.02.020 CrossRefPubMedGoogle Scholar
- 51.Yasuno F, Kosaka J, Ota M, Higuchi M, Ito H, Fujimura Y et al (2012) Increased binding of peripheral benzodiazepine receptor in mild cognitive impairment-dementia converters measured by positron emission tomography with [(1)(1)C]DAA1106. Psychiatry Res 203:67–74. doi: 10.1016/j.pscychresns.2011.08.013 CrossRefPubMedGoogle Scholar
- 54.Wiley CA, Lopresti BJ, Venneti S, Price J, Klunk WE, DeKosky ST et al (2009) Carbon 11-labeled Pittsburgh Compound B and carbon 11-labeled (R)-PK11195 positron emission tomographic imaging in Alzheimer disease. Arch Neurol 66:60–67. doi: 10.1001/archneurol.2008.511 CrossRefPubMedPubMedCentralGoogle Scholar
- 55.Schuitemaker A, Kropholler MA, Boellaard R, van der Flier WM, Kloet RW, van der Doef TF et al (2013) Microglial activation in Alzheimer’s disease: an (R)-[(1)(1)C]PK11195 positron emission tomography study. Neurobiol Aging 34:128–136. doi: 10.1016/j.neurobiolaging.2012.04.021 CrossRefPubMedGoogle Scholar
- 57.Lyoo CH, Ikawa M, Liow JS, Zoghbi SS, Morse CL, Pike VW et al (2015) Cerebellum can serve as a pseudo-reference region in Alzheimer disease to detect neuroinflammation measured with pet radioligand binding to translocator protein. J Nucl Med 56:701–706. doi: 10.2967/jnumed.114.146027 CrossRefPubMedPubMedCentralGoogle Scholar
- 61.Gulyas B, Makkai B, Kasa P, Gulya K, Bakota L, Varszegi S et al (2009) A comparative autoradiography study in post mortem whole hemisphere human brain slices taken from Alzheimer patients and age-matched controls using two radiolabelled DAA1106 analogues with high affinity to the peripheral benzodiazepine receptor (PBR) system. Neurochem Int 54:28–36. doi: 10.1016/j.neuint.2008.10.001 CrossRefPubMedGoogle Scholar
- 64.Marutle A, Gillberg PG, Bergfors A, Yu W, Ni R, Nennesmo I et al (2013) (3)H-deprenyl and (3)H-PIB autoradiography show different laminar distributions of astroglia and fibrillar beta-amyloid in Alzheimer brain. J Neuroinflammation 10:90. doi: 10.1186/1742-2094-10-90 CrossRefPubMedPubMedCentralGoogle Scholar
- 65.Hirvonen J, Kailajarvi M, Haltia T, Koskimies S, Nagren K, Virsu P et al (2009) Assessment of MAO-B occupancy in the brain with PET and [11C]-l-deprenyl-D2: a dose-finding study with a novel MAO-B inhibitor, EVT 301. Clin Pharmacol Ther 85:506–512. doi: 10.1038/clpt.2008.241 CrossRefPubMedGoogle Scholar
- 67.Carter SF, Scholl M, Almkvist O, Wall A, Engler H, Langstrom B et al (2012) Evidence for astrocytosis in prodromal Alzheimer disease provided by 11C-deuterium-l-deprenyl: a multitracer PET paradigm combining 11C-Pittsburgh compound B and 18F-FDG. J Nucl Med 53:37–46. doi: 10.2967/jnumed.110.087031 CrossRefPubMedGoogle Scholar
- 68.Choo IL, Carter SF, Scholl ML, Nordberg A (2014) Astrocytosis measured by (1)(1)C-deprenyl PET correlates with decrease in gray matter density in the parahippocampus of prodromal Alzheimer’s patients. Eur J Nucl Med Mol Imaging 41:2120–2126. doi: 10.1007/s00259-014-2859-7 CrossRefPubMedGoogle Scholar
- 70.Rodriguez-Vieitez E, Ni R, Gulyas B, Toth M, Haggkvist J, Halldin C et al (2015) Astrocytosis precedes amyloid plaque deposition in Alzheimer APPswe transgenic mouse brain: a correlative positron emission tomography and in vitro imaging study. Eur J Nucl Med Mol Imaging 42:1119–1132. doi: 10.1007/s00259-015-3047-0 CrossRefPubMedPubMedCentralGoogle Scholar