Age-Related Alterations in Brain Perfusion, Venous Oxygenation, and Oxygen Metabolic Rate of Mice: A 17-Month Longitudinal MRI Study

Wei, Zhiliang; Chen, Lin; Hou, Xirui; Zijl, Peter C.M. van; Xu, Jiadi; Lu, Hanzhang

doi:10.3389/fneur.2020.00559

Cited by 15 publications

(20 citation statements)

References 82 publications

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“…The vasoactive effect of isoflurane on physiological parameters 72 may be one potential confounding factor in animal studies like ours. Therefore, a consistent anesthetic regimen, which has been shown to be helpful in mitigating anesthetic effects over different experimental sessions, 32 was used throughout the current study. With this strategy, while the absolute values of physiological parameters may not be directly comparable with the unanesthetized state, comparisons between groups under a consistent anesthetic regimen are expected to be valid.…”

Section: Discussionmentioning

confidence: 99%

“…The arterial oxygenation (Y a ) is generally characterized by a narrow dynamic range and is close to unity (assumed to be 0.99) 26,27 . Global venous oxygenation (Y v ) was assessed by a TRUST MRI technique, which was first developed on human scanners, 28,29 and was recently optimized and utilized on animal MRI systems 30–32 . Specifically, an axial time‐of‐flight (TOF) sequence was first performed to visualize the confluence of sagittal sinuses, with the following parameters: TR/TE = 20/2.6 ms, field of view (FOV) = 16 × 16 mm 2 , matrix size = 256 × 256, 35 axial slices, slice thickness = 0.5 mm, and scan duration = 2.2 min.…”

Section: Methodsmentioning

confidence: 99%

“…To estimate brain volume, the T 2 ‐weighted images were analyzed manually by delineating the brain boundary on a slice‐by‐slice basis with reference to a mouse brain atlas (https://atlas.brain-map.org/). 32 Voxels inside the masks were summed to yield the total brain volume in mm 3 . The total brain volume was used in the estimation of unit‐mass CBF.…”

Section: Methodsmentioning

confidence: 99%

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Brain metabolism in tau and amyloid mouse models of Alzheimer's disease: An MRI study

Wei

Chen

et al. 2021

NMR in Biomedicine

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Alzheimer's disease (AD) is the leading cause of cognitive impairment and dementia in elderly individuals. According to the current biomarker framework for “unbiased descriptive classification”, biomarkers of neurodegeneration, “N”, constitute a critical component in the tri‐category “A/T/N” system. Current biomarkers of neurodegeneration suffer from potential drawbacks such as requiring invasive lumbar puncture, involving ionizing radiation, or representing a late, irreversible marker. Recent human studies have suggested that reduced brain oxygen metabolism may be a new functional marker of neurodegeneration in AD, but the heterogeneity and the presence of mixed pathology in human patients did not allow a full understanding of the role of oxygen extraction and metabolism in AD. In this report, global brain oxygen metabolism and related physiological parameters were studied in two AD mouse models with relatively pure pathology, using advanced MRI techniques including T2‐relaxation‐under‐spin‐tagging (TRUST) and phase contrast (PC) MRI. Additionally, regional cerebral blood flow (CBF) was determined with pseudocontinuous arterial spin labeling. Reduced global oxygen extraction fraction (by −18.7%, p = 0.008), unit‐mass cerebral metabolic rate of oxygen (CMRO2) (by −17.4%, p = 0.04) and total CMRO2 (by −30.8%, p < 0.001) were observed in Tau4RΔK mice—referred to as the tau AD model—which manifested pronounced neurodegeneration, as measured by diminished brain volume (by −15.2%, p < 0.001). Global and regional CBF in these mice were not different from those of wild‐type mice (p > 0.05), suggesting normal vascular function. By contrast, in B6;SJL‐Tg [APPSWE]2576Kha (APP) mice—referred to as the amyloid AD model—no brain volume reduction, as well as relatively intact brain oxygen extraction and metabolism, were found (p > 0.05). Consistent with the imaging data, behavioral measures of walking distance were impaired in Tau4RΔK mice (p = 0.004), but not in APP mice (p = 0.88). Collectively, these findings support the hypothesis that noninvasive MRI measurement of brain oxygen metabolism may be a promising biomarker of neurodegeneration in AD.

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Section: Discussionmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

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Brain metabolism in tau and amyloid mouse models of Alzheimer's disease: An MRI study

Wei

Chen

et al. 2021

NMR in Biomedicine

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“…First, the wild-type mice in our study were scanned at ~12 months of age in order to age-match the late stage APP swe /PS1 dE9 animals, whereas most previous 17 O-MRI studies were carried out in ~3 month-old animals [ 11 , 12 ]. In mice, there are conflicting reports of either no change [ 26 , 31 ] or even an increase in CMRO 2 [ 32 ] with age. However, these studies were performed using indirect estimates of CMRO 2 .…”

Section: Discussionmentioning

confidence: 99%

Zero Echo Time 17O-MRI Reveals Decreased Cerebral Metabolic Rate of Oxygen Consumption in a Murine Model of Amyloidosis

et al. 2021

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The cerebral metabolic rate of oxygen consumption (CMRO2) is a key metric to investigate the mechanisms involved in neurodegeneration in animal models and evaluate potential new therapies. CMRO2 can be measured by direct 17O magnetic resonance imaging (17O-MRI) of H217O signal changes during inhalation of 17O-labeled oxygen gas. In this study, we built a simple gas distribution system and used 3D zero echo time (ZTE-)MRI at 11.7 T to measure CMRO2 in the APPswe/PS1dE9 mouse model of amyloidosis. We found that CMRO2 was significantly lower in the APPswe/PS1dE9 brain than in wild-type at 12–14 months. We also estimated cerebral blood flow (CBF) from the post-inhalation washout curve and found no difference between groups. These results suggest that the lower CMRO2 observed in APPswe/PS1dE9 is likely due to metabolism impairment rather than to reduced blood flow. Analysis of the 17O-MRI data using different quantification models (linear and 3-phase model) showed that the choice of the model does not affect group comparison results. However, the simplified linear model significantly underestimated the absolute CMRO2 values compared to a 3-phase model. This may become of importance when combining several metabolic fluxes measurements to study neuro-metabolic coupling.

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“…In ageing rodents, resting CBF is less frequently quantified. There have been mixed findings between studies of ageing mice: one longitudinal and one crosssectional study have found no effect of age on regional CBF (Maier et al, 2014;Hirschler et al, 2018), while another longitudinal study reported an increase (Wei et al, 2020). Meanwhile, studies in rats have only calculated the relative change of CBF in response to stimuli rather than quantifying resting perfusion rate.…”

Section: Rationalementioning

confidence: 99%

Longitudinal Characterisation of Healthy Ageing in Rats using Multimodal Magnetic Resonance Imaging

MacNicol¹

2021

Preprint

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Ageing is a universally heterogeneous process which is associated with a decline in certain cognitive functions and changes to brain structure, but a given individual’s ageing phenotype is complex and difficult to predict. Ageing trajectories are non-linear and influenced throughout the lifespan by a multitude of factors, including diet and lifestyle. Non-invasive neuroimaging, such as magnetic resonance imaging, facilitates the in vivo characterisation of brain structure and function and is widely used in the endeavour of identifying individual trajectories of the ageing brain.However, it is unknown how ageing, brain structure, and cognitive function are related, which exaggerates the difficulties in predicting whether an individual is likely to be susceptible to cognitive decline and to what extent. In fact, ageing studies, which are typically cross-sectional, are often not designed to achieve this end; longitudinal studies, which are the most pertinent design to account for the considerable degree of individual variability observed, are less common due to the cost and time restraints. Thus, animal models of healthy ageing are valuable because they develop analogous phenotypes within a shorter lifespan, which reduces the time necessary to complete a longitudinal study. Moreover, there is greater control of environmental and genetic factors in preclinical studies, which can be difficult to account for in human studies.The Resilient study followed a cohort of 48 male Sprague-Dawley rats who were behaviourally tested and underwent an extensive MRI protocol up to four times, to characterise changes in brain structure and function across the adult lifespan. Half of the rats were also subjected to an environmental enrichment protocol, which involves weekly rotation of toys in the home cage, and a caloric restriction in the form of intermittent fasting. Combined, both interventions are intended to mimic the beneficial lifestyle choices believed to promote healthy ageing. A clinical frailty battery, and behaviour tests, including novel object recognition and attentional set-shifting, were employed to characterise individual ageing trajectories.Brain structure was assessed with a variety of metrics including a comparison of brain volumes, and mass univariate voxelwise comparisons using voxel-based morphometry, tensor-based morphometry, relaxometry, and diffusion metrics. As structurally similar regions are more likely to be physically connected, this was complemented with the construction of structural connectome graphs, derived from morphometric similarity networks using the multi-modal metrics to characterise 154 brain regions. Changes in brain structure between the groups were most frequently observed at the 5-month time point, which was likely a consequence of the difference in tissue growth.Brain function was assessed by graph-theoretical analyses of adjacency matrices derived from the regional BOLD signal fluctuations, as measured by multi-echo resting-state fMRI, and regional comparisons of cerebral blood flow maps. Differences were observed between the groups’ overall functional connectivity and modularity, particularly at 5 months old. Although the groups did not differ in their overall functional connectivity of the default mode network, the previously observed result of declining connectivity within the default mode network with increasing age was replicated, with the EEDR group deferring their largest decline in DMN covariance later than the decline observed in the control group. Finally, an age-related increase in cerebral blood flow was observed, and variance was observed in the regional trajectories, indicating that the change of perfusion rate is not uniform across the brain.As there were fewer group differences than hypothesised a priori, post-hoc analyses explored the functional and structural changes using physiological and behavioural outcomes instead of experimental grouping. However, the metrics explored did not explain more of the individual variability than the original groups. Consequently, post-hoc exploratory analyses used weight, experimental group, and age to predict the observed age-related changes in brain structure and function, revealing substantial residual variance despite controlling for factors controlled by genetics, shared environment, and age. The effect of body weight on brain tissue volume and defaultmode network overall connectivity changed with age and is possibly reflective of the changes in metabolic processes that underpin brain growth and remodelling.Future directions for this work include larger replications, without restrictive timelines, which would better characterise the life outcomes of the subjects. Moreover, future work should measure both cerebral metabolic rate of oxygen and glucose, to measure the relative contributions of metabolic substrates that may underpin the observed differences in brain structure and function in healthy ageing.

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Age-Related Alterations in Brain Perfusion, Venous Oxygenation, and Oxygen Metabolic Rate of Mice: A 17-Month Longitudinal MRI Study

Cited by 15 publications

References 82 publications

Brain metabolism in tau and amyloid mouse models of Alzheimer's disease: An MRI study

Brain metabolism in tau and amyloid mouse models of Alzheimer's disease: An MRI study

Zero Echo Time 17O-MRI Reveals Decreased Cerebral Metabolic Rate of Oxygen Consumption in a Murine Model of Amyloidosis

Longitudinal Characterisation of Healthy Ageing in Rats using Multimodal Magnetic Resonance Imaging

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