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Current Alzheimer Research


ISSN (Print): 1567-2050
ISSN (Online): 1875-5828

Research Article

[18F]-florbetaben PET/CT Imaging in the Alzheimer’s Disease Mouse Model APPswe/PS1dE9

Author(s): J. Stenzel, C. Rühlmann, T. Lindner, S. Polei, S. Teipel, J. Kurth, A. Rominger, B.J. Krause, B. Vollmar and A. Kuhla*

Volume 16, Issue 1, 2019

Page: [49 - 55] Pages: 7

DOI: 10.2174/1567205015666181022095904

Price: $65


Background: Positron-emission-tomography (PET) using 18F labeled florbetaben allows noninvasive in vivo-assessment of amyloid-beta (Aβ), a pathological hallmark of Alzheimer’s disease (AD). In preclinical research, [18F]-florbetaben-PET has already been used to test the amyloid-lowering potential of new drugs, both in humans and in transgenic models of cerebral amyloidosis. The aim of this study was to characterize the spatial pattern of cerebral uptake of [18F]-florbetaben in the APPswe/ PS1dE9 mouse model of AD in comparison to histologically determined number and size of cerebral Aβ plaques.

Methods: Both, APPswe/PS1dE9 and wild type mice at an age of 12 months were investigated by smallanimal PET/CT after intravenous injection of [18F]-florbetaben. High-resolution magnetic resonance imaging data were used for quantification of the PET data by volume of interest analysis. The standardized uptake values (SUVs) of [18F]-florbetaben in vivo as well as post mortem cerebral Aβ plaque load in cortex, hippocampus and cerebellum were analyzed.

Results: Visual inspection and SUVs revealed an increased cerebral uptake of [18F]-florbetaben in APPswe/ PS1dE9 mice compared with wild type mice especially in the cortex, the hippocampus and the cerebellum. However, SUV ratios (SUVRs) relative to cerebellum revealed only significant differences in the hippocampus between the APPswe/PS1dE9 and wild type mice but not in cortex; this differential effect may reflect the lower plaque area in the cortex than in the hippocampus as found in the histological analysis.

Conclusion: The findings suggest that histopathological characteristics of Aβ plaque size and spatial distribution can be depicted in vivo using [18F]-florbetaben in the APPswe/PS1dE9 mouse model.

Keywords: Alzheimer’s disease, positron emission tomography, [18F]-florbetaben, diagnosis, APPswe/PS1dE9 mouse model, Aβ plaque size.

Czech C, Tremp G, Pradier L. Presenilins and Alzheimer’s disease: biological functions and pathogenic mechanisms. Prog Neurobiol 60: 363-84. (2000).
Hyman BT. The neuropathological diagnosis of Alzheimer’s disease: clinical-pathological studies. Neurobiol Aging 18(4)(Suppl.): S27-32. (1997).
Villars H, Gillioz AS, Hein C, Voisin T, Nourhashemi F, Soto ME, et al. Alzheimer’s disease and syndromes related to the severe stage. Rev Neurol (Paris) 164(Spec No 2): F98-F106. (2008).
Ziegler-Graham K, Brookmeyer R, Johnson E, Arrighi HM. Worldwide variation in the doubling time of Alzheimer’s disease incidence rates. Alzheimers Dement 4: 316-23. (2008).
Ferreira LK, Busatto GF. Neuroimaging in Alzheimer’s disease: current role in clinical practice and potential future applications. Clinics (São Paulo) 66(Suppl. 1): 19-24. (2011).
Bateman RJ, Xiong C, Benzinger TL, Fagan AM, Goate A, Fox NC, et al. Clinical and biomarker changes in dominantly inherited Alzheimer’s disease. N Engl J Med 367: 795-804. (2012).
Rinne JO, Brooks DJ, Rossor MN, Fox NC, Bullock R, Klunk WE, et al. 11C-PiB PET assessment of change in fibrillar amyloid-β load in patients with Alzheimer’s disease treated with bapineuzumab: a phase 2, double-blind, placebo-controlled, ascending-dose study. Lancet Neurol 9: 363-72. (2010).
Braak H, Braak E. Diagnostic criteria for neuropathologic assessment of Alzheimer’s disease. Neurobiol Aging 18(4)(Suppl.): S85-8. (1997).
Mirra SS, Heyman A, McKeel D, Sumi SM, Crain BJ, Brownlee LM, et al. The consortium to establish a registry for Alzheimer’s disease (CERAD). Part II. Standardization of the neuropathologic assessment of Alzheimer’s disease. Neurology 41: 479-86. (1991).
Newell KL, Hyman BT, Growdon JH, Hedley-Whyte ET. Application of the National Institute on Aging (NIA)-Reagan Institute criteria for the neuropathological diagnosis of Alzheimer disease. J Neuropathol Exp Neurol 58: 1147-55. (1999).
Dubois B, Feldman HH, Jacova C, Hampel H, Molinuevo JL, Blennow K, et al. Advancing research diagnostic criteria for Alzheimer’s disease: the IWG-2 criteria. Lancet Neurol 13: 614-29. (2014).
Jack CR Jr, Albert MS, Knopman DS, McKhann GM, Sperling RA, Carrillo MC, et al. Introduction to the recommendations from the National Institute on Aging-Alzheimer’s Association workgroups on diagnostic guidelines for Alzheimer’s disease. Alzheimers Dement 7: 257-62. (2011).
Vlassenko AG, Benzinger TL, Morris JC. PET amyloid-beta imaging in preclinical Alzheimer’s disease. Biochim Biophys Acta 1822: 370-9. (2012).
Brockschnieder D, Schmitt-Willich H, Heinrich T, Varrone A, Gulyás B, Toth M, et al. Preclinical characterization of a novel class of 18F-labeled PET tracers for amyloid-β. J Nucl Med 53: 1794-801. (2012).
Quigley H, Colloby SJ, O’Brien JT. PET imaging of brain amyloid in dementia: a review. Int J Geriatr Psychiatry 26: 991-9.
[ (2011).]
Klunk WE, Engler H, Nordberg A, Wang Y, Blomqvist G, Holt DP, et al. Imaging brain amyloid in Alzheimer’s disease with Pittsburgh Compound-B. Ann Neurol 55: 306-19. (2004).
Nordberg A. PET imaging of amyloid in Alzheimer’s disease. Lancet Neurol 3: 519-27. (2004).
Rowe CC, Ng S, Ackermann U, Gong SJ, Pike K, Savage G, et al. Imaging beta-amyloid burden in aging and dementia. Neurology 68: 1718-25. (2007).
Mintun MA, Larossa GN, Sheline YI, Dence CS, Lee SY, Mach RH, et al. [11C]PIB in a nondemented population: potential antecedent marker of Alzheimer disease. Neurology 67: 446-52. (2006).
Villemagne VL, Pike KE, Chételat G, Ellis KA, Mulligan RS, Bourgeat P, et al. Longitudinal assessment of Aβ and cognition in aging and Alzheimer disease. Ann Neurol 69: 181-92. (2011).
Rowe CC, Ackerman U, Browne W, Mulligan R, Pike KL, O’Keefe G, et al. Imaging of amyloid β in Alzheimer’s disease with 18F-BAY94-9172, a novel PET tracer: proof of mechanism. Lancet Neurol 7: 129-35. (2008).
Wong DF, Rosenberg PB, Zhou Y, Kumar A, Raymont V, Ravert HT, et al. In vivo imaging of amyloid deposition in Alzheimer disease using the radioligand [18F]-AV-45 (florbetapir [corrected] F 18). J Nucl Med 51: 913-20. (2010).
Vandenberghe R, Van Laere K, Ivanoiu A, Salmon E, Bastin C, Triau E, et al. 18F-Flutemetamol amyloid imaging in Alzheimer disease and mild cognitive impairment: a phase 2 trial. Ann Neurol 68: 319-29. (2010).
Villemagne VL, Ong K, Mulligan RS, Holl G, Pejoska S, Jones G, et al. Amyloid imaging with 18F-Florbetaben in Alzheimer disease and other dementias. J Nucl Med 52: 1210-7. (2011).
Barthel H, Gertz HJ, Dresel S, Peters O, Bartenstein P, Buerger K, et al. Cerebral amyloid-β PET with florbetaben (18F) in patients with Alzheimer’s disease and healthy controls: a multicentre phase 2 diagnostic study. Lancet Neurol 10: 424-35. (2011).
Yousefi BH, von Reutern B, Scherübl D, Manook A, Schwaiger M, Grimmer T, et al. FIBT versus florbetaben and PiB: a preclinical comparison study with amyloid-PET in transgenic mice. EJNMMI Res 5: 20. (2015).
Ni R, Gillberg PG, Bergfors A, Marutle A, Nordberg A. Amyloid tracers detect multiple binding sites in Alzheimer’s disease brain tissue. Brain 136: 2217-27. (2013).
Fodero-Tavoletti MT, Brockschnieder D, Villemagne VL, Martin L, Connor AR, Thiele A, et al. In vitro characterization of [18F]-florbetaben, an Aβ imaging radiotracer. Nucl Med Biol 39: 1042-8. (2012).
Rominger A, Brendel M, Burgold S, Keppler K, Baumann K, Xiong G, et al. Longitudinal assessment of cerebral Aβ deposition in mice overexpressing Swedish mutant Aβ precursor protein using 18F-florbetaben PET. J Nucl Med 54: 1127-34. (2013).
Brendel M, Jaworska A, Grießinger E, Rötzer C, Burgold S, Gildehaus FJ, et al. Cross-sectional comparison of small animal [18F]-florbetaben amyloid-PET between transgenic AD mouse models. PLoS One 10: e0116678. (2015).
Brendel M, Jaworska A, Herms J, Trambauer J, Rötzer C, Gildehaus FJ, et al. Amyloid-PET predicts inhibition of de novo plaque formation upon chronic γ-secretase modulator treatment. Mol Psychiatry 20: 1179-87. (2015).
Malm T, Koistinaho J, Kanninen K. Utilization of APPswe/PS1dE9 Transgenic Mice in Research of Alzheimer’s Disease: focus on Gene Therapy and Cell-Based Therapy Applications. Int J Alzheimers Dis 2011: 517160. (2011).
Jankowsky JL, Younkin LH, Gonzales V, Fadale DJ, Slunt HH, Lester HA, et al. Rodent A beta modulates the solubility and distribution of amyloid deposits in transgenic mice. J Biol Chem 282: 22707-20. (2007).
Xiong H, Callaghan D, Wodzinska J, Xu J, Premyslova M, Liu QY, et al. Biochemical and behavioral characterization of the double transgenic mouse model (APPswe/PS1dE9) of Alzheimer’s disease. Neurosci Bull 27: 221-32. (2011).
Kuhla A, Rühlmann C, Lindner T, Polei S, Hadlich S, Krause BJ, et al. APPswe/PS1dE9 mice with cortical amyloid pathology show a reduced NAA/Cr ratio without apparent brain atrophy: A MRS and MRI study. Neuroimage Clin 15: 581-6. (2017).
Poisnel G, Dhilly M, Moustié O, et al. PET imaging with [18F]AV-45 in an APP/PS1-21 murine model of amyloid plaque deposition. Neurobiol Aging 33: 2561-71. (2012).
Overhoff F, Brendel M, Jaworska A, Korzhova V, Delker A, Probst F, et al. Automated spatial brain normalization and hindbrain white matter reference tissue give improved [18F]-Florbetaben PET quantitation in Alzheimer’s model mice. Front Neurosci 10: 45. (2016).
Chiaravalloti A, Danieli R, Lacanfora A, Palumbo B, Caltagirone C, Schillaci O. Usefulness of 18F florbetaben in diagnosis of Alzheimer’s disease and other types of dementia. Curr Alzheimer Res 14: 154-60. (2017).
Sabri O, Seibyl J, Rowe C, Barthel H. Beta-amyloid imaging with florbetaben. Clin Transl Imaging 3: 13-26. (2015).
Snellman A, Rokka J, López-Picón FR, Eskola O, Salmona M, Forloni G, et al. In vivo PET imaging of beta-amyloid deposition in mouse models of Alzheimer’s disease with a high specific activity PET imaging agent [18F]flutemetamol. EJNMMI Res 4: 37. (2014).

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