Voxel-Based Analysis of Amyloid-Burden Measured with [11C]PiB PET in a Double Transgenic Mouse Model of Alzheimer’s Disease

Reutern, Boris von; Grünecker, Barbara; Yousefi, Behrooz H.; Henriksen, Gjermund; Czisch, Michael; Drzezga, Alexander

doi:10.1007/s11307-013-0625-z

Cited by 16 publications

(14 citation statements)

References 33 publications

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“…Thus far, reports using in vivo PET and MRI in transgenic animal models of AD using [ 11 10,11,21,24 . These approaches lack PET quantification or require transient opening of the blood-brain barrier for MRI contrast agents [2][3][4]8,25,26 .…”

Section: Discussionmentioning

confidence: 99%

“…These approaches lack PET quantification or require transient opening of the blood-brain barrier for MRI contrast agents [2][3][4]8,25,26 . Quantifying the β-amyloid burden in small rodents is of paramount interest for the evaluation of new treatment strategies targeting β-amyloid; however, to our knowledge, there have only been a few encouraging reports on β-amyloid imaging using [ 11 C]PIB-PET in transgenic mice that have demonstrated the feasibility of this strategy 10,11,21,24 . Current in vivo MRI methodology is unable to quantify individual plaques in 3D data sets, especially in APPPS1 mice, which have a plaque diameter of ~2-22 µm 27 .…”

Section: Discussionmentioning

confidence: 99%

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Longitudinal PET-MRI reveals β-amyloid deposition and rCBF dynamics and connects vascular amyloidosis to quantitative loss of perfusion

Maier

Wehrl

Schmid

et al. 2014

Nat Med

113

110

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The dynamics of β-amyloid deposition and related second-order physiological effects, such as regional cerebral blood flow (rCBF), are key factors for a deeper understanding of Alzheimer's disease (AD). We present longitudinal in vivo data on the dynamics of β-amyloid deposition and the decline of rCBF in two different amyloid precursor protein (APP) transgenic mouse models of AD. Using a multiparametric positron emission tomography and magnetic resonance imaging approach, we demonstrate that in the presence of cerebral β-amyloid angiopathy (CAA), β-amyloid deposition is accompanied by a decline of rCBF. Loss of perfusion correlates with the growth of β-amyloid plaque burden but is not related to the number of CAA-induced microhemorrhages. However, in a mouse model of parenchymal β-amyloidosis and negligible CAA, rCBF is unchanged. Because synaptically driven spontaneous network activity is similar in both transgenic mouse strains, we conclude that the disease-related decline of rCBF is caused by CAA.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Longitudinal PET-MRI reveals β-amyloid deposition and rCBF dynamics and connects vascular amyloidosis to quantitative loss of perfusion

Maier

Wehrl

Schmid

et al. 2014

Nat Med

113

110

View full text Add to dashboard Cite

show abstract

“…So far, only few reports have demonstrated the feasibility of 11 C-PIB PET in fundamental research applications using smallanimal models of cerebral b-amyloidosis, although this method is gathering momentum (11,12,17,23). On the other hand, other groups have shown the feasibility of using high-resolution microscopic MR imaging to detect single amyloid plaques (1,9,(24)(25)(26).…”

Section: Discussionmentioning

confidence: 99%

“…In the past, the feasibility of arterial spin labeling (ASL) MR imaging for the non-invasive quantification of rCBF in the brain of AD mice has been demonstrated (16) and specific 11 C-PIB binding has been compared with control animals using voxel-based analysis (17). However, to our knowledge, quantitative rCBF has never been compared with 11 C-PIB PET on a voxelwise basis in transgenic AD mice.…”

mentioning

confidence: 99%

Quantification of β-Amyloidosis and rCBF with Dedicated PET, 7 T MR Imaging, and High-Resolution Microscopic MR Imaging at 16.4 T in APP23 Mice

et al. 2015

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We present a combined PET/7 T MR imaging and 16.4 T microscopic MR imaging dual-modality imaging approach enabling quantification of the amyloid load at high sensitivity and high resolution, and of regional cerebral blood flow (rCBF) in the brain of transgenic APP23 mice. Moreover, we demonstrate a novel, voxel-based correlative data analysis method for in-depth evaluation of amyloid PET and rCBF data. Methods: We injected 11 C-Pittsburgh compound B (PIB) intravenously in transgenic and control APP23 mice and performed dynamic PET measurements. rCBF data were recorded with a flow-sensitive alternating inversion recovery approach at 7 T. Subsequently, the animals were sacrificed and their brains harvested for ex vivo microscopic MR imaging at 16.4 T with a T 2 *-weighted gradient-echo sequence at 30-μm spatial resolution. Additionally, correlative amyloid histology was performed. The 11 C-PIB PET data were quantified to nondisplaceable binding potentials (BP ND ) using the Logan graphical analysis; flow-sensitive alternating inversion recovery data were quantified with a simplified version of the Bloch equation. Results: Amyloid load assessed by both 11 C-PIB PET and amyloid histology was highest in the frontal cortex of transgenic mice ( 11 C-PIB BP ND : 0.93 ± 0.08; amyloid histology: 15.1% ± 1.5%), followed by the temporoparietal cortex ( 11 C-PIB BP ND : 0.75 ± 0.08; amyloid histology: 13.9% ± 0.7%) and the hippocampus ( 11 C-PIB BP ND : 0.71 ± 0.09; amyloid histology: 9.2% ± 0.9%), and was lowest in the thalamus ( 11 C-PIB BP ND : 0.40 ± 0.07; amyloid histology: 6.6% ± 0.6%). However, 11 C-PIB BP ND and amyloid histology linearly correlated (R 2 5 0.82, P , 0.05) and were significantly higher in transgenic animals (P , 0.01). Similarly, microscopic MR imaging allowed quantifying the amyloid load, in addition to the detection of substructures within single amyloid plaques correlating with amyloid deposition density and the measurement of hippocampal atrophy. Finally, we found an inverse relationship between 11 C-PIB BP ND and rCBF MR imaging in the voxel-based analysis that was absent in control mice (slope tg : −0.11 ± 0.03; slope co : 0.004 ± 0.005; P 5 0.014). Conclusion: Our dual-modality imaging approach using 11 C-PIB PET/7 T MR imaging and 16.4 T microscopic MR imaging allowed amyloid-load quantification with high sensitivity and high resolution, the identification of substructures within single amyloid plaques, and the quantification of rCBF.

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“…Previous studies showed voxel-based analysis of amyloid plaques using PET 18 and MRI 13,19 in AD mouse models, which mostly focused on detecting amyloid plaques in the comparison of WT and AD mice. We showed the feasibility of our voxel-based method as a noninvasive imaging tool for detecting amyloid plaques to show the regional differences between WT and AD mice in the cerebral cortex and the hippocampus on D+1 and D+3 and to evaluate the effects of therapeutic drugs by comparing AD and drug-treated AD mice.…”

Section: Discussionmentioning

confidence: 99%

Magnetic resonance imaging for monitoring therapeutic response in a transgenic mouse model of Alzheimer’s disease using voxel-based analysis of amyloid plaques

Kim¹,

et al. 2014

NeuroReport

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In this study, we have shown the potential of a voxel-based analysis for imaging amyloid plaques and its utility in monitoring therapeutic response in Alzheimer’s disease (AD) mice using manganese oxide nanoparticles conjugated with an antibody of Aβ1-40 peptide (HMON-abAβ40). T1-weighted MR brain images of a drug-treated AD group (n=7), a nontreated AD group (n=7), and a wild-type group (n=7) were acquired using a 7.0 T MRI system before (D−1), 24-h (D+1) after, and 72-h (D+3) after injection with an HMON-abAβ40 contrast agent. For the treatment of AD mice, DAPT was injected intramuscularly into AD transgenic mice (50 mg/kg of body weight). For voxel-based analysis, the skull-stripped mouse brain images were spatially normalized, and these voxels’ intensities were corrected to reduce voxel intensity differences across scans in different mice. Statistical analysis showed higher normalized MR signal intensity in the frontal cortex and hippocampus of AD mice over wild-type mice on D+1 and D+3 (P<0.01, uncorrected for multiple comparisons). After the treatment of AD mice, the normalized MR signal intensity in the frontal cortex and hippocampus decreased significantly in comparison with nontreated AD mice on D+1 and D+3 (P<0.01, uncorrected for multiple comparisons). These results were confirmed by histological analysis using a thioflavin staining. This unique strategy allows us to detect brain regions that are subjected to amyloid plaque deposition and has the potential for human applications in monitoring therapeutic response for drug development in AD.

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Voxel-Based Analysis of Amyloid-Burden Measured with [11C]PiB PET in a Double Transgenic Mouse Model of Alzheimer’s Disease

Cited by 16 publications

References 33 publications

Longitudinal PET-MRI reveals β-amyloid deposition and rCBF dynamics and connects vascular amyloidosis to quantitative loss of perfusion

Longitudinal PET-MRI reveals β-amyloid deposition and rCBF dynamics and connects vascular amyloidosis to quantitative loss of perfusion

Quantification of β-Amyloidosis and rCBF with Dedicated PET, 7 T MR Imaging, and High-Resolution Microscopic MR Imaging at 16.4 T in APP23 Mice

Magnetic resonance imaging for monitoring therapeutic response in a transgenic mouse model of Alzheimer’s disease using voxel-based analysis of amyloid plaques

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