title: Magnetic Resonance Q Mapping Reveals a Decrease in Microvessel Density in the arcAβ Mouse Model of Cerebral Amyloidosis.
abstract: Alterations in density and morphology of the cerebral microvasculature have been reported to occur in Alzheimer's disease patients and animal models of the disease. In this study we compared magnetic resonance imaging (MRI) techniques for their utility to detect age-dependent changes of the cerebral vasculature in the arcAβ mouse model of cerebral amyloidosis. Dynamic susceptibility contrast (DSC)-MRI was performed by tracking the passage of a superparamagnetic iron oxide nanoparticle in the brain with dynamic gradient echo planar imaging (EPI). From this measurements relative cerebral blood volume [rCBV(DSC)] and relative cerebral blood flow (rCBF) were estimated. For the same animal maps of the relaxation shift index Q were computed from high resolution gradient echo and spin echo data that were acquired before and after superparamagnetic iron oxide (SPIO) nanoparticle injection. Q-values were used to derive estimates of microvessel density. The change in the relaxation rates [Formula: see text] obtained from pre- and post-contrast gradient echo data was used for the alternative determination of rCBV [rCBV([Formula: see text])]. Linear mixed effects modeling found no significant association between rCBV(DSC), rCBV([Formula: see text]), rCBF, and Q with genotype in 13-month old mice [compared to age-matched non-transgenic littermates (NTLs)] for any of the evaluated brain regions. In 24-month old mice there was a significant association for rCBV(DSC) with genotype in the cerebral cortex, and for rCBV([Formula: see text]) in the cerebral cortex and cerebellum. For rCBF there was a significant association in the cerebellum but not in other brain regions. Q-values in the olfactory bulb, cerebral cortex, striatum, hippocampus, and cerebellum in 24-month old mice were significantly associated with genotype. In those regions Q-values were reduced between 11 and 26% in arcAβ mice compared to age-matched NTLs. Vessel staining with CD31 immunohistochemistry confirmed a reduction of microvessel density in the old arcAβ mice. We further demonstrated a region-specific association between parenchymal and vascular deposition of β-amyloid and decreased vascular density, without a correlation with the amount of Aβ deposition. We found that Q mapping was more suitable than the hemodynamic read-outs to detect amyloid-related degeneration of the cerebral microvasculature.
authors.affiliation: Institute for Biomedical Engineering, ETH and University of Zurich Zurich, Switzerland.
authors.forename: Giovanna D
authors.initials: GD
authors.lastname: Ielacqua
authors.affiliation: Institute for Biomedical Engineering, ETH and University of ZurichZurich, Switzerland; Neuroscience Center Zurich, University of Zurich and ETH ZurichZurich, Switzerland.
authors.forename: Felix
authors.initials: F
authors.lastname: Schlegel
authors.affiliation: German Center for Neurodegenerative DiseasesBerlin, Germany; Department of Experimental Neurology, Charité - University Medicine BerlinBerlin, Germany.
authors.forename: Martina
authors.initials: M
authors.lastname: Füchtemeier
authors.affiliation: Institute for Biomedical Engineering, ETH and University of Zurich Zurich, Switzerland.
authors.forename: Jael
authors.initials: J
authors.lastname: Xandry
authors.affiliation: Institute for Biomedical Engineering, ETH and University of ZurichZurich, Switzerland; Neuroscience Center Zurich, University of Zurich and ETH ZurichZurich, Switzerland; Institute of Pharmacology and Toxicology, University of ZurichZurich, Switzerland.
authors.forename: Markus
authors.initials: M
authors.lastname: Rudin
authors.affiliation: Institute for Biomedical Engineering, ETH and University of ZurichZurich, Switzerland; Neuroscience Center Zurich, University of Zurich and ETH ZurichZurich, Switzerland.
authors.forename: Jan
authors.initials: J
authors.lastname: Klohs
keywords: Alzheimer's disease; cerebral amyloid angiopathy; cerebral amyloidosis; dynamic susceptibilty contrast MRI; microvessel density; relaxation rate shift index; superparamagnetic iron oxide nanoparticles
references.citation: Neurol Res. 2001 Jul;23(5):506-12
references.pmid: 11474807
references.citation: J Neuropathol Exp Neurol. 2006 Mar;65(3):235-44
references.pmid: 16651885
references.citation: J Neural Transm (Vienna). 2009 May;116(5):587-97
references.pmid: 19370387
references.citation: Alzheimers Res Ther. 2012 Feb 13;4(1):6
references.pmid: 22339927
references.citation: Neurobiol Aging. 2009 Dec;30(12):1936-48
references.pmid: 18359131
references.citation: Neurosci Lett. 2004 Jul 29;365(3):223-7
references.pmid: 15246553
references.citation: J Cereb Blood Flow Metab. 2011 Dec;31(12):2282-92
references.pmid: 21847134
references.citation: Neuroimage. 2012 Apr 2;60(2):958-66
references.pmid: 22227054
references.citation: Neurosci Biobehav Rev. 1994 Fall;18(3):397-401
references.pmid: 7984357
references.citation: Magn Reson Med. 2001 Oct;46(4):735-47
references.pmid: 11590650
references.citation: J Cereb Blood Flow Metab. 2011 Aug;31(8):1687-95
references.pmid: 21468091
references.citation: PLoS One. 2010 May 10;5(5):e10561
references.pmid: 20479943
references.citation: Nat Rev Neurosci. 2004 May;5(5):347-60
references.pmid: 15100718
references.citation: J Neurosci. 2014 Oct 8;34(41):13780-9
references.pmid: 25297104
references.citation: Magn Reson Med. 2000 Jun;43(6):845-53
references.pmid: 10861879
references.citation: Neurobiol Aging. 2007 Sep;28(9):1297-306
references.pmid: 16876915
references.citation: Neurobiol Aging. 2011 Mar;32(3):407-18
references.pmid: 19398247
references.citation: Neurobiol Aging. 2012 Sep;33(9):1995-2005
references.pmid: 22079157
references.citation: Front Aging Neurosci. 2014 Mar 13;6:32
references.pmid: 24659966
references.citation: J Neurosci. 2003 Sep 17;23(24):8453-9
references.pmid: 13679413
references.citation: J Cereb Blood Flow Metab. 2016 Sep;36(9):1614-24
references.pmid: 26661253
references.citation: MAGMA. 2010 Feb;23(1):53-64
references.pmid: 20066469
references.citation: Amyloid. 1999 Sep;6(3):157-64
references.pmid: 10524279
references.citation: Brain. 2011 Feb;134(Pt 2):335-44
references.pmid: 21257651
references.citation: Acta Neuropathol. 1990;79(6):672-9
references.pmid: 2360411
references.citation: Am J Pathol. 2005 Aug;167(2):505-15
references.pmid: 16049335
references.citation: Brain Struct Funct. 2013 Sep;218(5):1085-98
references.pmid: 22892904
references.citation: Magn Reson Med. 1996 Sep;36(3):415-9
references.pmid: 8875412
references.citation: Cerebrovasc Dis. 2012;33(4):303-9
references.pmid: 22343905
references.citation: NMR Biomed. 2004 Nov;17(7):507-12
references.pmid: 15523704
references.citation: Nat Rev Mol Cell Biol. 2007 Feb;8(2):101-12
references.pmid: 17245412
references.citation: J Neurochem. 1997 Mar;68(3):1135-41
references.pmid: 9048759
references.citation: J Neurochem. 1998 Jan;70(1):216-23
references.pmid: 9422365
references.citation: Alzheimer Dis Assoc Disord. 1987;1(1):19-37
references.pmid: 3453741
references.citation: Nature. 1996 Mar 14;380(6570):168-71
references.pmid: 8600393
references.citation: J Magn Reson Imaging. 2005 Dec;22(6):710-7
references.pmid: 16261573
references.citation: Proc Natl Acad Sci U S A. 2008 Mar 4;105(9):3587-92
references.pmid: 18305170
references.citation: PLoS One. 2013 Jun 19;8(6):e66097
references.pmid: 23840405
references.citation: Transl Psychiatry. 2012 Nov 13;2:e183
references.pmid: 23149447
references.citation: Stroke. 1987 Mar-Apr;18(2):311-24
references.pmid: 3551211
references.citation: Brain Res Bull. 2005 Apr 30;65(4):317-22
references.pmid: 15811597
references.citation: Magn Reson Med. 2009 Jul;62(1):35-45
references.pmid: 19449370
references.citation: Ann N Y Acad Sci. 1997 Sep 26;826:7-24
references.pmid: 9329677
references.citation: J Neurosci. 2012 Feb 1;32(5):1705-13
references.pmid: 22302811
references.citation: Phys Med Biol. 2003 Mar 7;48(5):N83-8
references.pmid: 12696805
references.citation: Magn Reson Med. 2013 Jan;69(1):18-26
references.pmid: 22431289
references.citation: Neurobiol Aging. 2009 Mar;30(3):337-52
references.pmid: 17869382
references.citation: Neurobiol Aging. 2013 Jun;34(6):1644-52
references.pmid: 23273599
references.citation: J Magn Reson Imaging. 2000 Sep;12(3):411-6
references.pmid: 10992308
references.citation: Proc Natl Acad Sci U S A. 1997 Nov 25;94(24):13287-92
references.pmid: 9371838
references.citation: Int J Dev Neurosci. 2006 Apr-May;24(2-3):187-93
references.pmid: 16423498
references.citation: J Neuroinflammation. 2011 Mar 25;8:26
references.pmid: 21439035
references.citation: AJNR Am J Neuroradiol. 2004 Oct;25(9):1524-32
references.pmid: 15502131
references.citation: Magn Reson Med. 2000 Aug;44(2):224-30
references.pmid: 10918321
references.citation: Acta Neuropathol. 2011 Sep;122(3):293-311
references.pmid: 21688176
references.citation: Nat Rev Neurosci. 2011 Nov 03;12(12):723-38
references.pmid: 22048062
references.citation: Radiology. 2005 Mar;234(3):851-9
references.pmid: 15734937
references.citation: Am J Manag Care. 2011 Nov;17 Suppl 13:S339-45
references.pmid: 22214391
references.citation: Neurobiol Aging. 2013 Apr;34(4):1018-31
references.pmid: 23084084
references.citation: Can J Neurol Sci. 1986 Nov;13(4 Suppl):456-61
references.pmid: 3791062
references.citation: J Neurosci. 2011 Jan 19;31(3):1023-31
references.pmid: 21248127
references.citation: PLoS One. 2011 May 05;6(5):e19592
references.pmid: 21573168
references.citation: Neuroimage. 2005 Dec;28(4):1014-21
references.pmid: 16129627
references.citation: PLoS One. 2011;6(8):e23789
references.pmid: 21909359
references.citation: Comput Methods Programs Biomed. 2010 May;98(2):204-13
references.pmid: 20060614
references.citation: Ann Neurol. 1995 Aug;38(2):254-9
references.pmid: 7654074