title: In vivo molecular neuroimaging of glucose utilization and its association with fibrillar amyloid-β load in aged APPPS1-21 mice.
abstract: BACKGROUND
  Radioligand imaging is a powerful in vivo method to assess the molecular basis of Alzheimer's Disease. We therefore aimed to visualize the pathological deposition of fibrillar amyloid-β and neuronal dysfunction in aged double transgenic mice.
  
  
  METHODS
  Using non-invasive positron emission tomography (PET) we assessed brain glucose utilization with [(18)F]FDG and fibrillar amyloidosis with [(11)C]PiB and [(18)F]AV45 in 12 month old APPPS1-21 (n = 10) mice and their age-matched wild-type controls (n = 15). PET scans were analyzed with statistical parametric mapping (SPM) to detect significant differences in tracer uptake between genotypes. After imaging, mice were sacrificed and ex vivo measures of amyloid-β burden with immunohistochemistry as well as glucose utilization with [(14)C]-2DG autoradiography were obtained as gold standards.
  
  
  RESULTS
  Voxel-wise SPM analysis revealed significantly decreased [(18)F]FDG uptake in aged APPPS1-21 mice in comparison to WT with the thalamus (96.96 %, maxT = 3.35) and striatum (61.21 %, maxT = 3.29) demonstrating the most widespread reductions at the threshold of p < 0.01. [(11)C]PiB binding was significantly increased in APPPS1-21 mice, most notably in the hippocampus (87.84 %, maxT = 7.15) and cortex (69.08 %, maxT = 7.95), as detected by SPM voxel-wise analysis at the threshold of p < 0.01. Using the same threshold [(18)F]AV45 uptake was comparably lower with less significant differences. Compared to their respective ex vivo equivalents [(18)F]FDG demonstrated significant positive correlation to [(14)C]2-DG autoradiography (r = 0.67, p <0.0001) while [(11)C]PiB and [(18)F]AV45 binding did not correlate to ex vivo immunohistochemistry for amyloid-β (r = 0.25, p = 0.07 and r = 0.17, p = 0.26 respectively). Lastly no correlation was observed between regions of high amyloid burden and those with decreased glucose utilization (r = 0.001, p = 0.99).
  
  
  CONCLUSIONS
  Our findings support that fibrillar amyloid-β deposition and reduced glucose utilization can be visualized and quantified with in vivo μPET imaging in aged APPPS1-21 mice. Therefore, the combined use of [(18)F]FDG and amyloid μPET imaging can shed light on the underlying relationship between fibrillar amyloid-β pathology and neuronal dysfunction.
authors.affiliation: Molecular Imaging Center Antwerp, University of Antwerp, Campus Drie Eiken - UC, Universiteitsplein 1, 2610, Wilrijk, Antwerp, Belgium. Ann-marie.waldron@uantwerpen.be.
authors.forename: Ann-Marie
authors.initials: AM
authors.lastname: Waldron
authors.affiliation: Neuroscience Research & Development, Janssen Pharmaceutica NV, Beerse, Belgium. Cwintmol@its.jnj.com.
authors.forename: Cindy
authors.initials: C
authors.lastname: Wintmolders
authors.affiliation: Neuroscience Research & Development, Janssen Pharmaceutica NV, Beerse, Belgium. Abottelb@its.jnj.com.
authors.forename: Astrid
authors.initials: A
authors.lastname: Bottelbergs
authors.affiliation: Neuroscience Research & Development, Janssen Pharmaceutica NV, Beerse, Belgium. Jkelley3@its.jnj.com.
authors.forename: Jonathan B
authors.initials: JB
authors.lastname: Kelley
authors.affiliation: Neuroscience Research & Development, Janssen Pharmaceutica NV, Beerse, Belgium. mschmid4@its.jnj.com.
authors.forename: Mark E
authors.initials: ME
authors.lastname: Schmidt
authors.affiliation: Molecular Imaging Center Antwerp, University of Antwerp, Campus Drie Eiken - UC, Universiteitsplein 1, 2610, Wilrijk, Antwerp, Belgium. Sigrid.Stroobants@uza.be.|Nuclear Medicine Department, University Hospital Antwerp, Antwerp, Belgium. Sigrid.Stroobants@uza.be.
authors.forename: Sigrid
authors.initials: S
authors.lastname: Stroobants
authors.affiliation: Neuroscience Research & Development, Janssen Pharmaceutica NV, Beerse, Belgium. Xlangloi@its.jnj.com.
authors.forename: Xavier
authors.initials: X
authors.lastname: Langlois
authors.affiliation: Molecular Imaging Center Antwerp, University of Antwerp, Campus Drie Eiken - UC, Universiteitsplein 1, 2610, Wilrijk, Antwerp, Belgium. steven.staelens@uantwerpen.be.
authors.forename: Steven
authors.initials: S
authors.lastname: Staelens
mesh_terms: D000544:Alzheimer Disease / Q000000981:diagnostic imaging* / Q000378:metabolism; D000682:Amyloid / Q000378:metabolism*; D016564:Amyloid beta-Protein Precursor / Q000235:genetics / Q000378:metabolism; D000814:Aniline Compounds; D000818:Animals; D001345:Autoradiography; D001921:Brain / Q000000981:diagnostic imaging* / Q000378:metabolism; D001931:Brain Mapping; D002250:Carbon Radioisotopes; D005026:Ethylene Glycols; D005260:Female; D019788:Fluorodeoxyglucose F18; D005947:Glucose / Q000378:metabolism*; D006801:Humans; D007150:Immunohistochemistry; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D010618:Phenanthrolines; D049268:Positron-Emission Tomography / Q000379:methods*; D019275:Radiopharmaceuticals; D013844:Thiazoles
chemical_list: C475519:2-(4'-(methylamino)phenyl)-6-hydroxybenzothiazole; C545487:APP protein, human; D000682:Amyloid; D016564:Amyloid beta-Protein Precursor; D000814:Aniline Compounds; D002250:Carbon Radioisotopes; D005026:Ethylene Glycols; D010618:Phenanthrolines; D019275:Radiopharmaceuticals; D013844:Thiazoles; D019788:Fluorodeoxyglucose F18; C545186:florbetapir; D005947:Glucose