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

Maier, Florian; Wehrl, Hans F.; Schmid, Andreas M.; Mannheim, Julia G.; Wiehr, Stefan; Lerdkrai, Chommanad; Calaminus, Carsten; Stahlschmidt, Anke; Ye, Lan; Burnet, Michael; Stiller, Detlef; Sabri, Osama; Reischl, Gerald; Staufenbiel, M; Garaschuk, Olga; Jucker, Mathias; Pichler, Bernd J.

doi:10.1038/nm.3734

Cited by 112 publications

(116 citation statements)

References 45 publications

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“…Experiments were performed on female APP23xPS45 double-transgenic mice aged >6 mo overexpressing the human APP with the Swedish mutation (670/671) and the human G384A-mutated PS1 (7,10,11,17,(35)(36)(37). At this age, mice exhibit widespread cerebral Aβ pathology (10,17,36), neuropil dystrophy (10), and astrocytic (17,38) and microglia (39) impairments, as well as learning and memory deficits (10,11,17).…”

Section: Methodsmentioning

confidence: 99%

BACE inhibition-dependent repair of Alzheimer’s pathophysiology

Keskin

Kekuš

Adelsberger

et al. 2017

Proc. Natl. Acad. Sci. U.S.A.

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Amyloid-β (Aβ) is thought to play an essential pathogenic role in Alzheimer´s disease (AD). A key enzyme involved in the generation of Aβ is the β-secretase BACE, for which powerful inhibitors have been developed and are currently in use in human clinical trials. However, although BACE inhibition can reduce cerebral Aβ levels, whether it also can ameliorate neural circuit and memory impairments remains unclear. Using histochemistry, in vivo Ca 2+ imaging, and behavioral analyses in a mouse model of AD, we demonstrate that along with reducing prefibrillary Aβ surrounding plaques, the inhibition of BACE activity can rescue neuronal hyperactivity, impaired long-range circuit function, and memory defects. The functional neuronal impairments reappeared after infusion of soluble Aβ, mechanistically linking Aβ pathology to neuronal and cognitive dysfunction. These data highlight the potential benefits of BACE inhibition for the effective treatment of a wide range of AD-like pathophysiological and cognitive impairments.A lzheimer´s disease (AD) is the most common cause of dementia globally, with an increasing impact on aging societies (1). Therefore, the prevention and treatment of AD is a major unmet medical need. The amyloid hypothesis posits that the abnormal accumulation of amyloid-β (Aβ) peptides in the brain, and their aggregation, is an essential feature of AD (2, 3); however, results from clinical studies using several Aβ-targeting compounds have called into question the existence of a direct link between a reduction in Aβ and improvement of brain function, particularly in more advanced disease stages (4-6). In addition, recent evidence obtained in mouse models carrying genetic mutations that cause AD in humans revealed that immunotherapy with antibodies against Aβ worsened rather than reversed neuronal dysfunction (7). Despite reducing plaque burden, the anti-Aβ antibodies caused a massive increase in cortical hyperactivity and promoted abnormal synchrony of neurons in a subset of the treated mice. In this context, it is noteworthy that another recent mouse study found an increased risk of sudden death after anti-Aβ antibody treatment, which was attributed to enhanced excitatory neuronal activity culminating in fatal convulsive seizures (8).To clarify the causal relationship between Aβ and pathophysiology in vivo, we made use of a novel compound that reduces Aβ by inhibiting the β-secretase BACE, the rate-limiting enzyme for Aβ production (9). This approach allowed us to determine how the inhibition of Aβ production affects neural circuit and memory impairments in APP23xPS45 transgenic mice overexpressing mutant human amyloid precursor protein (APP) and presenilin 1 (PS1). The combination of histochemistry, in vivo Ca 2+ imaging, and behavioral analysis allowed us to directly link the treatment-related changes in brain Aβ levels to changes in neuronal and cognitive functions in individual mice. ResultsIn this study, we used 6-to 8-mo-old APP23xPS45 transgenic mice that exhibit severe cerebral Aβ pathology, neur...

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Section: Methodsmentioning

confidence: 99%

BACE inhibition-dependent repair of Alzheimer’s pathophysiology

Keskin

Kekuš

Adelsberger

et al. 2017

Proc. Natl. Acad. Sci. U.S.A.

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“…For all studies, we used female transgenic (n 5 5) and littermate control (n 5 5) APP23 mice aged 27.5-30 mo; 4 of the littermate control mice were already included in a previous publication (13). APP23 transgenic mice were generated as described previously (5,13).…”

Section: Animalsmentioning

confidence: 99%

“…Thus, the combination of T 2 *-weighted microscopic MR imaging with a second imaging modality providing high sensitivity and specificity appears logical. Recently, we and others have demonstrated the potential of 11 C-PIB PET for selective imaging of amyloid deposits in the brain tissue of transgenic AD mice (11)(12)(13). Taken together, microscopic MR imaging and 11 C-PIB PET potentially provide a powerful combination for the non-invasive quantification and characterization of amyloid deposits at a high spatial resolution and with unmatched sensitivity and specificity.…”

mentioning

confidence: 92%

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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“…For instance, near infrared fluorescence imaging of macrophage presence, angiogenesis, and protease activity in ischemic mouse hearts linked these healing biomarkers to cellular function in the setting of heart failure (56). Translatable PET/MR imaging may enable multispectral imaging, as recently shown in mice with heart failure (57) and Alzheimer's disease (58).…”

Section: Imaging Molecular and Cellular Biomarkersmentioning

confidence: 96%

Advancing biomedical imaging

Weissleder

Nahrendorf

2015

Proc. Natl. Acad. Sci. U.S.A.

135

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Imaging reveals complex structures and dynamic interactive processes, located deep inside the body, that are otherwise difficult to decipher. Numerous imaging modalities harness every last inch of the energy spectrum. Clinical modalities include magnetic resonance imaging (MRI), X-ray computed tomography (CT), ultrasound, and light-based methods [endoscopy and optical coherence tomography (OCT)]. Research modalities include various light microscopy techniques (confocal, multiphoton, total internal reflection, superresolution fluorescence microscopy), electron microscopy, mass spectrometry imaging, fluorescence tomography, bioluminescence, variations of OCT, and optoacoustic imaging, among a few others. Although clinical imaging and research microscopy are often isolated from one another, we argue that their combination and integration is not only informative but also essential to discovering new biology and interpreting clinical datasets in which signals invariably originate from hundreds to thousands of cells per voxel.

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

Cited by 112 publications

References 45 publications

BACE inhibition-dependent repair of Alzheimer’s pathophysiology

BACE inhibition-dependent repair of Alzheimer’s pathophysiology

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

Advancing biomedical imaging

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