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
- … show all 19 hide
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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).
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.
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.
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.
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- 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
Volume 32, Issue 5 , pp 593-600
- Cover Date
- Print ISSN
- Online ISSN
- Additional Links
- Small animal PET
- Transgenic mice
- β-Amyloid plaques
- Alzheimer’s disease
- Industry Sectors
- Hiroshi Toyama (1) (2)
- Daniel Ye (3)
- Masanori Ichise (2)
- Jeih-San Liow (2)
- Lisheng Cai (2)
- David Jacobowitz (4)
- John L. Musachio (2)
- Jinsoo Hong (2)
- Mathew Crescenzo (2)
- Dnyanesh Tipre (2)
- Jian-Qiang Lu (2)
- Sami Zoghbi (2)
- Douglass C. Vines (2)
- Jurgen Seidel (5)
- Kazuhiro Katada (1)
- Michael V. Green (5)
- Victor W. Pike (2)
- Robert M. Cohen (3)
- Robert B. Innis (2)
- Author Affiliations
- 1. Department of Radiology, Fujita Health University, 1-98, Dengakugakubo, Kutsukake, Toyoake, 470-1192, Aichi, Japan
- 2. Molecular Imaging Branch, National Institute of Mental Health, National Institutes of Health, Bethesda, Maryland, USA
- 3. Geriatric Psychiatry Branch, National Institute of Mental Health, National Institutes of Health, Bethesda, Maryland, USA
- 4. Department of Anatomy, Physiology, and Genetics, USUHS, Bethesda, Maryland, USA
- 5. Department of Nuclear Medicine, Warren Grant Magnuson Clinical Center, National Institutes of Health, Bethesda, Maryland, USA