PET imaging of brain with the β-amyloid probe, [11C]6-OH- BTA-1, in a transgenic mouse model of Alzheimer's disease

Hiroshi Toyama, Daniel Ye, Masanori Ichise, Jeih San Liow, Lisheng Cai, David Jacobowitz, John L. Musachio, Jinsoo Hong, Mathew Crescenzo, Dnyanesh Tipre, Jian Qiang Lu, Sami Zoghbi, Douglass C. Vines, Jurgen Seidel, Kazuhiro Katada, Michael V. Green, Victor W. Pike, Robert M. Cohen, Robert B. Innis

Research output: Contribution to journalArticle

117 Citations (Scopus)

Abstract

Purpose: The purpose of this study was to evaluate the capacity of [ 11C]6-OH-BTA-1 and positron emission tomography (PET) to quantify β-amyloid (Aβ) plaques in the Tg2576 mouse model of Alzheimer's disease (AD). Methods: PET imaging was performed with the NIH ATLAS small animal scanner in six elderly transgenic mice (Tg2576; age 22.0±1.8 months; 23.6±2.6 g) overexpressing a mutated form of human β-amyloid precursor protein (APP) known to result in the production of Aβ plaques, and in six elderly wild-type litter mates (age 21.8±1.6 months; 29.5±4.7 g). Dynamic PET scans were performed for 30 min in each mouse under 1% isoflurane inhalation anesthesia after a bolus injection of 13-46 MBq of [11C]6-OH-BTA-1. PET data were reconstructed with 3D OSEM. On the coronal PET image, irregular regions of interest (ROIs) were placed on frontal cortex (FR), parietal cortex (PA), striatum (ST), thalamus (TH), pons (PO), and cerebellum (CE), guided by a mouse stereotaxic atlas. Time-activity curves (TACs) (expressed as percent injected dose per gram normalized to body weight: % ID-kg/g) were obtained for FR, PA, ST, TH, PO, and CE. ROI-to-CE radioactivity ratios were also calculated. Following PET scans, sections of mouse brain prepared from anesthetized and fixative-perfused mice were stained with thioflavin-S. Results: TACs for [11C]6-OH-BTA-1 in all ROIs peaked early (at 30-55 s), with radioactivity washing out quickly thereafter in both transgenic and wild-type mice. Peak uptake in all regions was significantly lower in transgenic mice than in wild-type mice. During the later part of the washout phase (12-30 min), the mean FR/CE and PA/CE ratios were higher in transgenic than in wild-type mice (1.06±0.04 vs 0.98±0.07, p=0.04; 1.06±0.09 vs 0.93±0.08 p=0.02) while ST/CE, TH/CE, and PO/CE ratios were not. Ex vivo staining revealed widespread Aβ plaques in cortex, but not in cerebellum of transgenic mice or in any brain regions of wild-type mice. Conclusion: Marked reductions in brain uptake of this radioligand in transgenic mice may be due to reduced cerebral blood flow relative to that in wild-type mice. Specific [11C]6-OH-BTA-1 binding to Aβ plaques, if any, is probably very low, as reflected in the small FR/CE and PA/CE ratio differences. FR/CE and PA/CE ratios are considerably higher in AD patients while Aβ plaque densities in 22-month-old transgenic mice may be expected to show essentially the same density as is observed in the AD brain. This implies that the absence of tracer retention in 22-month-old transgenic mice may be due to the smaller number of Aβ plaque binding sites and/or to lower affinity of the binding sites for [11C]6-OH-BTA-1 as compared with AD patients. [11C]6-OH-BTA-1 shows excellent brain uptake in mice.

Original languageEnglish
Pages (from-to)593-600
Number of pages8
JournalEuropean Journal of Nuclear Medicine and Molecular Imaging
Volume32
Issue number5
DOIs
Publication statusPublished - 01-04-2005

Fingerprint

Amyloid
Neuroimaging
Positron-Emission Tomography
Cerebellum
Transgenic Mice
Alzheimer Disease
Parietal Lobe
Pons
Thalamus
Brain
hydroxide ion
2-(4'-(methylamino)phenyl)-6-hydroxybenzothiazole
Radioactivity
Cerebrovascular Circulation
Binding Sites
Inhalation Anesthesia
Fixatives
Amyloid beta-Protein Precursor
Atlases
Isoflurane

All Science Journal Classification (ASJC) codes

  • Radiology Nuclear Medicine and imaging

Cite this

Toyama, Hiroshi ; Ye, Daniel ; Ichise, Masanori ; Liow, Jeih San ; Cai, Lisheng ; Jacobowitz, David ; Musachio, John L. ; Hong, Jinsoo ; Crescenzo, Mathew ; Tipre, Dnyanesh ; Lu, Jian Qiang ; Zoghbi, Sami ; Vines, Douglass C. ; Seidel, Jurgen ; Katada, Kazuhiro ; Green, Michael V. ; Pike, Victor W. ; Cohen, Robert M. ; Innis, Robert B. / PET imaging of brain with the β-amyloid probe, [11C]6-OH- BTA-1, in a transgenic mouse model of Alzheimer's disease. In: European Journal of Nuclear Medicine and Molecular Imaging. 2005 ; Vol. 32, No. 5. pp. 593-600.
@article{2aaa415055e34c92a38e716aee4cb00b,
title = "PET imaging of brain with the β-amyloid probe, [11C]6-OH- BTA-1, in a transgenic mouse model of Alzheimer's disease",
abstract = "Purpose: The purpose of this study was to evaluate the capacity of [ 11C]6-OH-BTA-1 and positron emission tomography (PET) to quantify β-amyloid (Aβ) plaques in the Tg2576 mouse model of Alzheimer's disease (AD). Methods: PET imaging was performed with the NIH ATLAS small animal scanner in six elderly transgenic mice (Tg2576; age 22.0±1.8 months; 23.6±2.6 g) overexpressing a mutated form of human β-amyloid precursor protein (APP) known to result in the production of Aβ plaques, and in six elderly wild-type litter mates (age 21.8±1.6 months; 29.5±4.7 g). Dynamic PET scans were performed for 30 min in each mouse under 1{\%} isoflurane inhalation anesthesia after a bolus injection of 13-46 MBq of [11C]6-OH-BTA-1. PET data were reconstructed with 3D OSEM. On the coronal PET image, irregular regions of interest (ROIs) were placed on frontal cortex (FR), parietal cortex (PA), striatum (ST), thalamus (TH), pons (PO), and cerebellum (CE), guided by a mouse stereotaxic atlas. Time-activity curves (TACs) (expressed as percent injected dose per gram normalized to body weight: {\%} ID-kg/g) were obtained for FR, PA, ST, TH, PO, and CE. ROI-to-CE radioactivity ratios were also calculated. Following PET scans, sections of mouse brain prepared from anesthetized and fixative-perfused mice were stained with thioflavin-S. Results: TACs for [11C]6-OH-BTA-1 in all ROIs peaked early (at 30-55 s), with radioactivity washing out quickly thereafter in both transgenic and wild-type mice. Peak uptake in all regions was significantly lower in transgenic mice than in wild-type mice. During the later part of the washout phase (12-30 min), the mean FR/CE and PA/CE ratios were higher in transgenic than in wild-type mice (1.06±0.04 vs 0.98±0.07, p=0.04; 1.06±0.09 vs 0.93±0.08 p=0.02) while ST/CE, TH/CE, and PO/CE ratios were not. Ex vivo staining revealed widespread Aβ plaques in cortex, but not in cerebellum of transgenic mice or in any brain regions of wild-type mice. Conclusion: Marked reductions in brain uptake of this radioligand in transgenic mice may be due to reduced cerebral blood flow relative to that in wild-type mice. Specific [11C]6-OH-BTA-1 binding to Aβ plaques, if any, is probably very low, as reflected in the small FR/CE and PA/CE ratio differences. FR/CE and PA/CE ratios are considerably higher in AD patients while Aβ plaque densities in 22-month-old transgenic mice may be expected to show essentially the same density as is observed in the AD brain. This implies that the absence of tracer retention in 22-month-old transgenic mice may be due to the smaller number of Aβ plaque binding sites and/or to lower affinity of the binding sites for [11C]6-OH-BTA-1 as compared with AD patients. [11C]6-OH-BTA-1 shows excellent brain uptake in mice.",
author = "Hiroshi Toyama and Daniel Ye and Masanori Ichise and Liow, {Jeih San} and Lisheng Cai and David Jacobowitz and Musachio, {John L.} and Jinsoo Hong and Mathew Crescenzo and Dnyanesh Tipre and Lu, {Jian Qiang} and Sami Zoghbi and Vines, {Douglass C.} and Jurgen Seidel and Kazuhiro Katada and Green, {Michael V.} and Pike, {Victor W.} and Cohen, {Robert M.} and Innis, {Robert B.}",
year = "2005",
month = "4",
day = "1",
doi = "10.1007/s00259-005-1780-5",
language = "English",
volume = "32",
pages = "593--600",
journal = "European Journal of Nuclear Medicine and Molecular Imaging",
issn = "1619-7070",
publisher = "Springer Verlag",
number = "5",

}

Toyama, H, Ye, D, Ichise, M, Liow, JS, Cai, L, Jacobowitz, D, Musachio, JL, Hong, J, Crescenzo, M, Tipre, D, Lu, JQ, Zoghbi, S, Vines, DC, Seidel, J, Katada, K, Green, MV, Pike, VW, Cohen, RM & Innis, RB 2005, 'PET imaging of brain with the β-amyloid probe, [11C]6-OH- BTA-1, in a transgenic mouse model of Alzheimer's disease', European Journal of Nuclear Medicine and Molecular Imaging, vol. 32, no. 5, pp. 593-600. https://doi.org/10.1007/s00259-005-1780-5

PET imaging of brain with the β-amyloid probe, [11C]6-OH- BTA-1, in a transgenic mouse model of Alzheimer's disease. / Toyama, Hiroshi; Ye, Daniel; Ichise, Masanori; Liow, Jeih San; Cai, Lisheng; Jacobowitz, David; Musachio, John L.; Hong, Jinsoo; Crescenzo, Mathew; Tipre, Dnyanesh; Lu, Jian Qiang; Zoghbi, Sami; Vines, Douglass C.; Seidel, Jurgen; Katada, Kazuhiro; Green, Michael V.; Pike, Victor W.; Cohen, Robert M.; Innis, Robert B.

In: European Journal of Nuclear Medicine and Molecular Imaging, Vol. 32, No. 5, 01.04.2005, p. 593-600.

Research output: Contribution to journalArticle

TY - JOUR

T1 - PET imaging of brain with the β-amyloid probe, [11C]6-OH- BTA-1, in a transgenic mouse model of Alzheimer's disease

AU - Toyama, Hiroshi

AU - Ye, Daniel

AU - Ichise, Masanori

AU - Liow, Jeih San

AU - Cai, Lisheng

AU - Jacobowitz, David

AU - Musachio, John L.

AU - Hong, Jinsoo

AU - Crescenzo, Mathew

AU - Tipre, Dnyanesh

AU - Lu, Jian Qiang

AU - Zoghbi, Sami

AU - Vines, Douglass C.

AU - Seidel, Jurgen

AU - Katada, Kazuhiro

AU - Green, Michael V.

AU - Pike, Victor W.

AU - Cohen, Robert M.

AU - Innis, Robert B.

PY - 2005/4/1

Y1 - 2005/4/1

N2 - Purpose: The purpose of this study was to evaluate the capacity of [ 11C]6-OH-BTA-1 and positron emission tomography (PET) to quantify β-amyloid (Aβ) plaques in the Tg2576 mouse model of Alzheimer's disease (AD). Methods: PET imaging was performed with the NIH ATLAS small animal scanner in six elderly transgenic mice (Tg2576; age 22.0±1.8 months; 23.6±2.6 g) overexpressing a mutated form of human β-amyloid precursor protein (APP) known to result in the production of Aβ plaques, and in six elderly wild-type litter mates (age 21.8±1.6 months; 29.5±4.7 g). Dynamic PET scans were performed for 30 min in each mouse under 1% isoflurane inhalation anesthesia after a bolus injection of 13-46 MBq of [11C]6-OH-BTA-1. PET data were reconstructed with 3D OSEM. On the coronal PET image, irregular regions of interest (ROIs) were placed on frontal cortex (FR), parietal cortex (PA), striatum (ST), thalamus (TH), pons (PO), and cerebellum (CE), guided by a mouse stereotaxic atlas. Time-activity curves (TACs) (expressed as percent injected dose per gram normalized to body weight: % ID-kg/g) were obtained for FR, PA, ST, TH, PO, and CE. ROI-to-CE radioactivity ratios were also calculated. Following PET scans, sections of mouse brain prepared from anesthetized and fixative-perfused mice were stained with thioflavin-S. Results: TACs for [11C]6-OH-BTA-1 in all ROIs peaked early (at 30-55 s), with radioactivity washing out quickly thereafter in both transgenic and wild-type mice. Peak uptake in all regions was significantly lower in transgenic mice than in wild-type mice. During the later part of the washout phase (12-30 min), the mean FR/CE and PA/CE ratios were higher in transgenic than in wild-type mice (1.06±0.04 vs 0.98±0.07, p=0.04; 1.06±0.09 vs 0.93±0.08 p=0.02) while ST/CE, TH/CE, and PO/CE ratios were not. Ex vivo staining revealed widespread Aβ plaques in cortex, but not in cerebellum of transgenic mice or in any brain regions of wild-type mice. Conclusion: Marked reductions in brain uptake of this radioligand in transgenic mice may be due to reduced cerebral blood flow relative to that in wild-type mice. Specific [11C]6-OH-BTA-1 binding to Aβ plaques, if any, is probably very low, as reflected in the small FR/CE and PA/CE ratio differences. FR/CE and PA/CE ratios are considerably higher in AD patients while Aβ plaque densities in 22-month-old transgenic mice may be expected to show essentially the same density as is observed in the AD brain. This implies that the absence of tracer retention in 22-month-old transgenic mice may be due to the smaller number of Aβ plaque binding sites and/or to lower affinity of the binding sites for [11C]6-OH-BTA-1 as compared with AD patients. [11C]6-OH-BTA-1 shows excellent brain uptake in mice.

AB - Purpose: The purpose of this study was to evaluate the capacity of [ 11C]6-OH-BTA-1 and positron emission tomography (PET) to quantify β-amyloid (Aβ) plaques in the Tg2576 mouse model of Alzheimer's disease (AD). Methods: PET imaging was performed with the NIH ATLAS small animal scanner in six elderly transgenic mice (Tg2576; age 22.0±1.8 months; 23.6±2.6 g) overexpressing a mutated form of human β-amyloid precursor protein (APP) known to result in the production of Aβ plaques, and in six elderly wild-type litter mates (age 21.8±1.6 months; 29.5±4.7 g). Dynamic PET scans were performed for 30 min in each mouse under 1% isoflurane inhalation anesthesia after a bolus injection of 13-46 MBq of [11C]6-OH-BTA-1. PET data were reconstructed with 3D OSEM. On the coronal PET image, irregular regions of interest (ROIs) were placed on frontal cortex (FR), parietal cortex (PA), striatum (ST), thalamus (TH), pons (PO), and cerebellum (CE), guided by a mouse stereotaxic atlas. Time-activity curves (TACs) (expressed as percent injected dose per gram normalized to body weight: % ID-kg/g) were obtained for FR, PA, ST, TH, PO, and CE. ROI-to-CE radioactivity ratios were also calculated. Following PET scans, sections of mouse brain prepared from anesthetized and fixative-perfused mice were stained with thioflavin-S. Results: TACs for [11C]6-OH-BTA-1 in all ROIs peaked early (at 30-55 s), with radioactivity washing out quickly thereafter in both transgenic and wild-type mice. Peak uptake in all regions was significantly lower in transgenic mice than in wild-type mice. During the later part of the washout phase (12-30 min), the mean FR/CE and PA/CE ratios were higher in transgenic than in wild-type mice (1.06±0.04 vs 0.98±0.07, p=0.04; 1.06±0.09 vs 0.93±0.08 p=0.02) while ST/CE, TH/CE, and PO/CE ratios were not. Ex vivo staining revealed widespread Aβ plaques in cortex, but not in cerebellum of transgenic mice or in any brain regions of wild-type mice. Conclusion: Marked reductions in brain uptake of this radioligand in transgenic mice may be due to reduced cerebral blood flow relative to that in wild-type mice. Specific [11C]6-OH-BTA-1 binding to Aβ plaques, if any, is probably very low, as reflected in the small FR/CE and PA/CE ratio differences. FR/CE and PA/CE ratios are considerably higher in AD patients while Aβ plaque densities in 22-month-old transgenic mice may be expected to show essentially the same density as is observed in the AD brain. This implies that the absence of tracer retention in 22-month-old transgenic mice may be due to the smaller number of Aβ plaque binding sites and/or to lower affinity of the binding sites for [11C]6-OH-BTA-1 as compared with AD patients. [11C]6-OH-BTA-1 shows excellent brain uptake in mice.

UR - http://www.scopus.com/inward/record.url?scp=24044535149&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=24044535149&partnerID=8YFLogxK

U2 - 10.1007/s00259-005-1780-5

DO - 10.1007/s00259-005-1780-5

M3 - Article

C2 - 15791432

AN - SCOPUS:24044535149

VL - 32

SP - 593

EP - 600

JO - European Journal of Nuclear Medicine and Molecular Imaging

JF - European Journal of Nuclear Medicine and Molecular Imaging

SN - 1619-7070

IS - 5

ER -