Longitudinal assessment of cerebral perfusion and vascular response to hypoventilation in a bigenic mouse model of Alzheimer's disease with amyloid and tau pathology

Govaerts, Kristof; Lechat, Benoit; Struys, Tom; Kremer, Anna; Borghgraef, Peter; Leuven, Fred Van; Himmelreich, Uwe; Dresselaers, Tom

doi:10.1002/nbm.4037

Cited by 12 publications

(22 citation statements)

References 42 publications

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“…We attempted to correlate our angiography data to anatomical images acquired in the same animals (Supplementary data S2), but were unable to find a relation between brain volume and ICA length. Reduced BA radius may indicate reduced cerebral blood flow, which is also commonly reported in AD patients [8] and in mouse models for AD [17], even at the young age of 3 months [18]. This is potentially due to the presence of soluble amyloid, which acts as a vasoconstrictor [19] or due to amyloid accumulations associated with the vasculature [20].…”

Section: Data S1)mentioning

confidence: 88%

Quantitative Assessment of Age-Associated Alterations in Brain Vasculature in Wild-Type Mice and in Bigenic Mice that Model Alzheimer’s Disease

et al. 2019

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Purpose: Vascular disfunction is a major hallmark of Alzheimer's Disease (AD). However, studies that investigated vascular dysfunction in mice modeling AD using magnetic resonance angiography (MRA) are typically limited to qualitative and/or scoring-based paradigms, which are labor-intensive and observer-dependent.Procedures: We developed and validated a semi-automatic MRA processing pipeline and applied this to high-resolution in vivo MRA images acquired on a 9.4T small animal MRI scanner. We assessed vascular morphology at 3, 6 and 12 months in wild-type (WT) and bigenic (APP.V717IxTau.P301L, biAT) mice.Results: Vessel radius or length can increase with age regardless of genotype depending on the respective vessel. We also observed significantly lower internal carotid artery length in biAT mice compared to WT. Conclusions:The results demonstrate that even subtle changes in vessel morphology can be noninvasively quantified. This is of great interest for AD, but also to other models of neurodegenerative diseases involving macrovascular dysfunction.

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Section: Data S1)mentioning

confidence: 88%

Quantitative Assessment of Age-Associated Alterations in Brain Vasculature in Wild-Type Mice and in Bigenic Mice that Model Alzheimer’s Disease

et al. 2019

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“…Assessing changes in cerebral blood flow (CBF) yields important information on the onset and progression of various pathological conditions ( Yonas et al, 2005 , Govaerts et al, 2019 , Struys et al, 2017 ). However, up to date, perfusion MRI in animal models of ALS has not been implemented.…”

Section: Discussionmentioning

confidence: 99%

“…It should be noted that anesthesia has a strong impact on cardiac function, brain function or microvascular hemodynamics, and the combination of all these effects could lead to modifications of CBF ( Hendrich et al, 2001 ). Isoflurane anesthesia tends to increase CBF, which may have masked observations of subtle differences in perfusion values in the groups studied ( Govaerts et al, 2019 ). On the other hand, possible effects of oxygen respiration were controlled by using a control group, assuming there would be no differential response of the disease to this respiratory protocol.…”

Section: Discussionmentioning

confidence: 99%

“…Perfusion maps were recorded from a single 1 mm thick axial forebrain slice covering the motor cortex, striatum and nucleus accumbens using a flow-sensitive alternating inversion recovery (FAIR) approach ( Kim and Tsekos, 1997 ). ASL MR image acquisition was as previously reported ( Oosterlinck et al, 2011 , Govaerts et al, 2019 ). In brief, a rapid acquisition with relaxation enhancement (RARE) readout was used with the following specific parameters: TR = 18 s, TE = 5.2 ms, FOV 2.5 × 2.5 cm, matrix 128 × 128 with partial Fourier acceleration to 128 × 72, 14 inversion times from 20 to 8000 ms, and using an inversion hyperbolic secant pulse of 14 ms with a slab thickness of 1.6 mm.…”

Section: Methodsmentioning

confidence: 99%

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Non-invasive characterization of amyotrophic lateral sclerosis in a hTDP-43A315T mouse model: A PET-MR study

Weerasekera

Crabbé

Tomé

et al. 2020

NeuroImage: Clinical

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Currently TAR DNA binding protein 43 (TDP-43) pathology, underlying Amyotrophic Lateral Sclerosis (ALS), remains poorly understood which hinders both clinical diagnosis and drug discovery efforts. To better comprehend the disease pathophysiology, positron emission tomography (PET) and multi-parametric magnetic resonance imaging (mp-MRI) provide a non-invasive mode to investigate molecular, structural, and neurochemical abnormalities in vivo . For the first time, we report the findings of a longitudinal PET-MR study in the TDP-43 A315T ALS mouse model, investigating disease-related changes in the mouse brain. 2-deoxy-2-[ 18 F]fluoro-D-glucose [ 18 F]FDG PET showed significantly lowered glucose metabolism in the motor and somatosensory cortices of TDP-43 A315T mice whereas metabolism was elevated in the region covering the bilateral substantia nigra, reticular and amygdaloid nucleus between 3 and 7 months of age, as compared to non-transgenic controls. MR spectroscopy data showed significant changes in glutamate + glutamine (Glx) and choline levels in the motor cortex and hindbrain of TDP-43 A315T mice compared to controls. Cerebral blood flow (CBF) measurements, using an arterial spin labelling approach, showed no significant age- or group-dependent changes in brain perfusion. Diffusion MRI indices demonstrated transient changes in different motor areas of the brain in TDP-43 A315T mice around 14 months of age. Cytoplasmic TDP-43 proteinaceous inclusions were observed in the brains of symptomatic, 18-month-old mice, but not in non-symptomatic transgenic or wild-type mice. Our results reveal that disease- and age-related functional and neurochemical alterations, together with limited structural changes, occur in specific brain regions of transgenic TDP-43 A315T mice, as compared to their healthy counterparts. Altogether these findings shed new light on TDP-43 A315T disease pathogenesis and may prove useful for clinical management of ALS.

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“…Nevertheless, ASL is increasingly used in pre-clinical research, in particular in models of neurological and neurodegenerative diseases [ 110 , 111 , 112 , 113 ]. In contrast to exogenous-perfusion-weighted imaging methods, ASL can be used to measure relatively rapid changes in CBF, for example, in response to changed physiological parameters such as pCO 2 or pH.…”

Section: Cerebral Perfusion Mri Techniquesmentioning

confidence: 99%

Non-Invasive Evaluation of Cerebral Microvasculature Using Pre-Clinical MRI: Principles, Advantages and Limitations

2021

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Alterations to the cerebral microcirculation have been recognized to play a crucial role in the development of neurodegenerative disorders. However, the exact role of the microvascular alterations in the pathophysiological mechanisms often remains poorly understood. The early detection of changes in microcirculation and cerebral blood flow (CBF) can be used to get a better understanding of underlying disease mechanisms. This could be an important step towards the development of new treatment approaches. Animal models allow for the study of the disease mechanism at several stages of development, before the onset of clinical symptoms, and the verification with invasive imaging techniques. Specifically, pre-clinical magnetic resonance imaging (MRI) is an important tool for the development and validation of MRI sequences under clinically relevant conditions. This article reviews MRI strategies providing indirect non-invasive measurements of microvascular changes in the rodent brain that can be used for early detection and characterization of neurodegenerative disorders. The perfusion MRI techniques: Dynamic Contrast Enhanced (DCE), Dynamic Susceptibility Contrast Enhanced (DSC) and Arterial Spin Labeling (ASL), will be discussed, followed by less established imaging strategies used to analyze the cerebral microcirculation: Intravoxel Incoherent Motion (IVIM), Vascular Space Occupancy (VASO), Steady-State Susceptibility Contrast (SSC), Vessel size imaging, SAGE-based DSC, Phase Contrast Flow (PC) Quantitative Susceptibility Mapping (QSM) and quantitative Blood-Oxygenation-Level-Dependent (qBOLD). We will emphasize the advantages and limitations of each strategy, in particular on applications for high-field MRI in the rodent’s brain.

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Longitudinal assessment of cerebral perfusion and vascular response to hypoventilation in a bigenic mouse model of Alzheimer's disease with amyloid and tau pathology

Cited by 12 publications

References 42 publications

Quantitative Assessment of Age-Associated Alterations in Brain Vasculature in Wild-Type Mice and in Bigenic Mice that Model Alzheimer’s Disease

Quantitative Assessment of Age-Associated Alterations in Brain Vasculature in Wild-Type Mice and in Bigenic Mice that Model Alzheimer’s Disease

Non-invasive characterization of amyotrophic lateral sclerosis in a hTDP-43A315T mouse model: A PET-MR study

Non-Invasive Evaluation of Cerebral Microvasculature Using Pre-Clinical MRI: Principles, Advantages and Limitations

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