Neurovascular imaging with QUTE-CE MRI in APOE4 rats reveals early vascular abnormalities

Leaston, Joshua; Ferris, Craig F.; Kulkarni, Praveen; Dhasarathan, Chandramohan; Ven, Anne L. van de; Qiao, Junfei; Timms, Liam; Sepulcre, Jorge; Fakhri, Georges El; Ma, Chao; Normandin, Marc D.; Gharagouzloo, Codi

doi:10.1371/journal.pone.0256749

Cited by 8 publications

(10 citation statements)

References 52 publications

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“…and in pericytes E4-lower genes were enriched in cell migration regulation, transport across BBB (ATP1A2, SLC6A13, SLC19A1, SLC6A1), and cell-cell junction maintenance (CSF1R, TJP1) ( Fig. 6b ), in agreement with reports of ApoE ε4 individuals showing reduced cerebral blood flow 112 , and cerebrovascular abnormalities 113 . APOE4-higher genes were significantly enriched for cytokine response in both capillary endothelial cells and pericytes, negative regulation of cell migration in capillary endothelial cells, and apoptotic process and positive regulation of endocytosis in pericytes ( Fig.…”

Section: Resultssupporting

confidence: 88%

Single-cell multi-region dissection of brain vasculature in Alzheimer’s Disease

Sun

Akay

Murdock

et al. 2022

Preprint

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Cerebrovascular breakdown occurs early in Alzheimer′s Disease (AD), but its cell-type-specific molecular basis remains uncharacterized. Here, we characterize single-cell transcriptomic differences in human cerebrovasculature across 220 AD and 208 control individuals and across 6 brain regions. We annotate 22,514 cerebrovascular cells in 11 subtypes of endothelial, pericyte, smooth muscle, perivascular fibroblast, and ependymal cells, and how they differ between brain regions. We identify 2,676 AD-differential genes, including lower expression of PDGFRB in pericytes, and ABCB1 and ATP10A in endothelial cells. These AD-differential genes reveal common upstream regulators, including MECOM, EP300, and KLF4, whose targeting may help restore vasculature function. We find coordinated vasculature-glial-neuronal co-expressed gene modules supported by ligand-receptor pairs, involved in axon growth/degeneration and neurogenesis, suggesting mechanistic mediators of neurovascular unit dysregulation in AD. Integration with AD genetics reveals 125 AD-differential genes directly linked to AD-associated genetic variants (through vasculature-specific eQTLs, Hi-C, and correlation-based evidence), 559 targeted by AD-associated regulators, and 661 targeted by AD-associated ligand-receptor signaling. Lastly, we show that APOE4-genotype associated differences are significantly enriched among AD-associated genes in capillary and venule endothelial cells, and subsets of pericytes and fibroblasts, which underlie the vascular dysregulation in APOE4-associated cognitive decline. Overall, our multi-region molecular atlas of differential human cerebrovasculature genes and pathways in AD can help guide early-stage AD therapeutics.

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Section: Resultssupporting

confidence: 88%

Single-cell multi-region dissection of brain vasculature in Alzheimer’s Disease

Sun

Akay

Murdock

et al. 2022

Preprint

View full text Add to dashboard Cite

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“…Other preclinical technologies for visualizing BBB disruption are also being actively investigated, but have not yet been tested in human patients. Some of these technologies include dual-wavelength high-resolution photoacoustic microscopy (Wang et al, 2022), PET-MRI nanoparticles (Debatisse et al, 2020), and quantitative ultra-short time-to-echo contrast-enhanced MRI (Leaston et al, 2021); however, more research is necessary to assess their diagnostic potential.…”

Section: Discussionmentioning

confidence: 99%

Imaging blood–brain barrier disruption in neuroinflammation and Alzheimer’s disease

Lee

Funk

2023

Front. Aging Neurosci.

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The blood–brain barrier (BBB) is the neurovascular structure that regulates the passage of cells and molecules to and from the central nervous system (CNS). Alzheimer’s disease (AD) is a neurodegenerative disorder that is associated with gradual breakdown of the BBB, permitting entry of plasma-derived neurotoxins, inflammatory cells, and microbial pathogens into the CNS. BBB permeability can be visualized directly in AD patients using imaging technologies including dynamic contrast-enhanced and arterial spin labeling magnetic resonance imaging, and recent studies employing these techniques have shown that subtle changes in BBB stability occur prior to deposition of the pathological hallmarks of AD, senile plaques, and neurofibrillary tangles. These studies suggest that BBB disruption may be useful as an early diagnostic marker; however, AD is also accompanied by neuroinflammation, which can complicate these analyses. This review will outline the structural and functional changes to the BBB that occur during AD pathogenesis and highlight current imaging technologies that can detect these subtle changes. Advancing these technologies will improve both the diagnosis and treatment of AD and other neurodegenerative diseases.

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“…Chang et al reported using diffusion-weighted imaging assisted with monocrystalline iron oxide nanoparticle for assessing the abnormalities in the vessel size index, diameter, density, mean vessel-weighted image, and blood volume fraction in 5 × FAD mice compared to wild-type mice [ 203 ]. Leaston et al showed early vascular abnormalities in APOE4 knock-in rats compared to wild-type rats by using quantitative ultra-short time-to-echo (QUTE) CE-MRI [ 202 ]. MR elastography has been used to detect the impaired cerebral viscoelastic properties in 5 × FAD, APP/PS1, and APP23 mice [ 206 , 207 , 208 ].…”

Section: Cerebrovascular Imagingmentioning

confidence: 99%

Magnetic Resonance Imaging in Animal Models of Alzheimer’s Disease Amyloidosis

2021

IJMS

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Amyloid-beta (Aβ) plays an important role in the pathogenesis of Alzheimer’s disease. Aberrant Aβ accumulation induces neuroinflammation, cerebrovascular alterations, and synaptic deficits, leading to cognitive impairment. Animal models recapitulating the Aβ pathology, such as transgenic, knock-in mouse and rat models, have facilitated the understanding of disease mechanisms and the development of therapeutics targeting Aβ. There is a rapid advance in high-field MRI in small animals. Versatile high-field magnetic resonance imaging (MRI) sequences, such as diffusion tensor imaging, arterial spin labeling, resting-state functional MRI, anatomical MRI, and MR spectroscopy, as well as contrast agents, have been developed for preclinical imaging in animal models. These tools have enabled high-resolution in vivo structural, functional, and molecular readouts with a whole-brain field of view. MRI has been used to visualize non-invasively the Aβ deposits, synaptic deficits, regional brain atrophy, impairment in white matter integrity, functional connectivity, and cerebrovascular and glymphatic system in animal models of Alzheimer’s disease amyloidosis. Many of the readouts are translational toward clinical MRI applications in patients with Alzheimer’s disease. In this review, we summarize the recent advances in MRI for visualizing the pathophysiology in amyloidosis animal models. We discuss the outstanding challenges in brain imaging using MRI in small animals and propose future outlook in visualizing Aβ-related alterations in the brains of animal models.

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Neurovascular imaging with QUTE-CE MRI in APOE4 rats reveals early vascular abnormalities

Cited by 8 publications

References 52 publications

Single-cell multi-region dissection of brain vasculature in Alzheimer’s Disease

Single-cell multi-region dissection of brain vasculature in Alzheimer’s Disease

Imaging blood–brain barrier disruption in neuroinflammation and Alzheimer’s disease

Magnetic Resonance Imaging in Animal Models of Alzheimer’s Disease Amyloidosis

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