Hybrid PET/MRI enables high-spatial resolution, quantitative imaging of amyloid plaques in an Alzheimer’s disease mouse model

Frost, Georgia; Longo, Valerie A.; Li, Thomas; Jonas, Lauren A.; Judenhofer, Martin S.; Cherry, Simon R.; Koutcher, Jason A.; Lekaye, Carl; Zanzonico, Pat; Li, Yue Ming

doi:10.1038/s41598-020-67284-z

Cited by 16 publications

(7 citation statements)

References 42 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…We found Aβ deposition in various regions of the thalamus of 5xFAD mice. Deposition of Aβ in thalamus was also reported in post-mortem human AD brain tissues and in AD models by positron emission tomography ( Alderson et al, 2017 ; Frost et al, 2020 ). The thalamus is connected to the hippocampus to regulate spatial memory, spatial sensory information, and human episodic memory ( Burgess et al, 2002 ; Aggleton et al, 2010 ; Chan et al, 2017 ).…”

Section: Discussionmentioning

confidence: 79%

See 1 more Smart Citation

Distribution and inter-regional relationship of amyloid-beta plaque deposition in a 5xFAD mouse model of Alzheimer’s disease

Tsui

Roy

Chau

et al. 2022

Front. Aging Neurosci.

View full text Add to dashboard Cite

Alzheimer’s disease (AD) is the most common form of dementia. Although previous studies have selectively investigated the localization of amyloid-beta (Aβ) deposition in certain brain regions, a comprehensive characterization of the rostro-caudal distribution of Aβ plaques in the brain and their inter-regional correlation remain unexplored. Our results demonstrated remarkable working and spatial memory deficits in 9-month-old 5xFAD mice compared to wildtype mice. High Aβ plaque load was detected in the somatosensory cortex, piriform cortex, thalamus, and dorsal/ventral hippocampus; moderate levels of Aβ plaques were observed in the motor cortex, orbital cortex, visual cortex, and retrosplenial dysgranular cortex; and low levels of Aβ plaques were located in the amygdala, and the cerebellum; but no Aβ plaques were found in the hypothalamus, raphe nuclei, vestibular nucleus, and cuneate nucleus. Interestingly, the deposition of Aβ plaques was positively associated with brain inter-regions including the prefrontal cortex, somatosensory cortex, medial amygdala, thalamus, and the hippocampus. In conclusion, this study provides a comprehensive morphological profile of Aβ deposition in the brain and its inter-regional correlation. This suggests an association between Aβ plaque deposition and specific brain regions in AD pathogenesis.

show abstract

Section: Discussionmentioning

confidence: 79%

“…The thalamus is connected to the hippocampus to regulate spatial memory, spatial sensory information, and human episodic memory ( Burgess et al, 2002 ; Aggleton et al, 2010 ; Chan et al, 2017 ). Therefore, Aβ deposition in the thalamus might contribute to the cognitive impairment in AD ( Alderson et al, 2017 ; Frost et al, 2020 ).…”

Section: Discussionmentioning

confidence: 99%

Distribution and inter-regional relationship of amyloid-beta plaque deposition in a 5xFAD mouse model of Alzheimer’s disease

Tsui

Roy

Chau

et al. 2022

Front. Aging Neurosci.

View full text Add to dashboard Cite

show abstract

“…An age-dependent increase in 64 Cu- 9 uptake (0,236 ± 0,007 vs. 0,310 ± 0,008 %ID/g) was detected in the areas of the thalamus and hippocampus with preference for the former, which has often been overlooked in AD studies ( Fig. 5 ) ( 68 , 70 , 71 ). No accumulation of 64 Cu- 9 was detected in the cortex of 44-d-old 5xFAD mice; instead, intense PET signal was observed in the pons and medulla (brainstem) of 72-d-old mice, suggesting that Aβ oligomers may spread from the thalamus to other parts of the brain ( 72 ).…”

Section: Resultsmentioning

confidence: 96%

“…The relevance of significant quantity of Aβ oligomer in the thalamus was imaged in young, presymptomatic 5xFAD mice and shown to increase with age, as validated subsequently by immunohistochemistry. Fibrillar Aβ have been imaged in the thalamus of relatively old 5xFAD mice (5.5–14-mo-old) using the 18 F-PET tracers 18 F-FC119S, 18 F-Florbetapir, and 18 F-Florbetaben ( 69 , 71 , 87 ). In contrast, the PET imaging and immunohistochemistry with oligomer-specific A11 antibody demonstrated that 64 Cu- 9 gave earlier detection of Aβ oligomers with superior contrast than 11 C-PIB standard, which imaged only late forming plaque in the cortex.…”

Section: Discussionmentioning

confidence: 99%

Early diagnosis and treatment of Alzheimer’s disease by targeting toxic soluble Aβ oligomers

Habashi

Vutla

Tripathi

et al. 2022

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

View full text Add to dashboard Cite

Transient soluble oligomers of amyloid-β (Aβ) are toxic and accumulate early prior to insoluble plaque formation and cognitive impairment in Alzheimer’s disease (AD). Synthetic cyclic D,L-α-peptides (e.g., 1 ) self-assemble into cross β-sheet nanotubes, react with early Aβ species (1-3 mers), and inhibit Aβ aggregation and toxicity in stoichiometric concentrations, in vitro. Employing a semicarbazide as an aza-glycine residue with an extra hydrogen-bond donor to tune nanotube assembly and amyloid engagement, [azaGly 6 ]- 1 inhibited Aβ aggregation and toxicity at substoichiometric concentrations. High-resolution NMR studies revealed dynamic interactions between [azaGly 6 ]- 1 and Aβ42 residues F19 and F20, which are pivotal for early dimerization and aggregation. In an AD mouse model, brain positron emission tomography (PET) imaging using stable 64 Cu-labeled (aza)peptide tracers gave unprecedented early amyloid detection in 44-d presymptomatic animals. No tracer accumulation was detected in the cortex and hippocampus of 44-d-old 5xFAD mice; instead, intense PET signal was observed in the thalamus, from where Aβ oligomers may spread to other brain parts with disease progression. Compared with standard 11 C-labeled Pittsburgh compound-B ( 11 C-PIB), which binds specifically fibrillar Aβ plaques, 64 Cu-labeled (aza)peptide gave superior contrast and uptake in young mouse brain correlating with Aβ oligomer levels. Effectively crossing the blood–brain barrier (BBB), peptide 1 and [azaGly 6 ]- 1 reduced Aβ oligomer levels, prolonged lifespan of AD transgenic Caenorhabditis elegans , and abated memory and behavioral deficits in nematode and murine AD models. Cyclic (aza)peptides offer novel promise for early AD diagnosis and therapy.

show abstract

“…The rapid onset of amyloidosis in the 5xFAD model makes it attractive in assaying new PET tracers and new PET hardware. Frost and colleagues developed a small-animal PET/MRI hybrid system to assess amyloid deposition [82]. Using 14-month-old 5xFAD mice, they were able to detect an increased uptake of 18 F-Florbetapir in the cortex, hippocampus, and thalamus relative to WT.…”

Section: Pet: Fluorodeoxyglucosementioning

confidence: 99%

Neuroimaging of Mouse Models of Alzheimer’s Disease

2022

View full text Add to dashboard Cite

Magnetic resonance imaging (MRI) and positron emission tomography (PET) have made great strides in the diagnosis and our understanding of Alzheimer’s Disease (AD). Despite the knowledge gained from human studies, mouse models have and continue to play an important role in deciphering the cellular and molecular evolution of AD. MRI and PET are now being increasingly used to investigate neuroimaging features in mouse models and provide the basis for rapid translation to the clinical setting. Here, we provide an overview of the human MRI and PET imaging landscape as a prelude to an in-depth review of preclinical imaging in mice. A broad range of mouse models recapitulate certain aspects of the human AD, but no single model simulates the human disease spectrum. We focused on the two of the most popular mouse models, the 3xTg-AD and the 5xFAD models, and we summarized all known published MRI and PET imaging data, including contrasting findings. The goal of this review is to provide the reader with broad framework to guide future studies in existing and future mouse models of AD. We also highlight aspects of MRI and PET imaging that could be improved to increase rigor and reproducibility in future imaging studies.

show abstract

Hybrid PET/MRI enables high-spatial resolution, quantitative imaging of amyloid plaques in an Alzheimer’s disease mouse model

Cited by 16 publications

References 42 publications

Distribution and inter-regional relationship of amyloid-beta plaque deposition in a 5xFAD mouse model of Alzheimer’s disease

Distribution and inter-regional relationship of amyloid-beta plaque deposition in a 5xFAD mouse model of Alzheimer’s disease

Early diagnosis and treatment of Alzheimer’s disease by targeting toxic soluble Aβ oligomers

Neuroimaging of Mouse Models of Alzheimer’s Disease

Contact Info

Product

Resources

About