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Comparison of the hippocampal vessels enhanced using the MICRO SWI data with cadaver brain data. A) Figure from a cadaver study on hippocampal vascularization using the vascular ink injection technique (Duvernoy et al., 2013) (adapted with permission from Springer Nature, The Human Hippocampus by Henri M. Duvernoy, copyright SpringerVerlag Berlin Heidelberg); B) mIP of the in vivo SWI PGAC data with the overlays of major arteries (red) and major veins (blue); C) the combined 3D rendering of the major arteries, major veins and the intra-hippocampal micro-vasculature (green); and D) the isolated hippocampal micro-vasculature showing agreement with the cadaver brain data in visualizing the fimbrio dentate sulcus (blue arrows) and the subependymal intrahippocampal veins (red arrows). Major arteries: AChA = anterior choroidal artery; PCA = posterior cerebral artery; PmChA = posterior-medial choroidal artery; Major veins: BV = basal vein; IVV = inferior ventricular vein.
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The hippocampus is a small but complex grey matter structure that plays an important role in spatial and episodic memory and can be affected by a wide range of pathologies including vascular abnormalities. In this work, we introduce the use of Ferumoxytol, an ultra-small superparamagnetic iron oxide (USPIO) agent, to induce susceptibility in the ar...
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... mIP of SWI PGAC and the MIP of the segmented intra-hippocampal vessels are separately displayed in Fig. 1C and D, respectively. The hippocampal vasculature on SWI Fe3 , SWI avg,2,3 (the averaged image of SWI Fe2 and SWI Fe3 ) and SWI PGAC data are compared in Figure S3 for four selected subjects. Although the SWI avg,2,3 provides an improvement in SNR over the SWI Fe3 data, the blooming artifact around the larger vessels that can be seen on both SWI Fe3 and SWI avg,2,3 data. ...
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... the SWI avg,2,3 provides an improvement in SNR over the SWI Fe3 data, the blooming artifact around the larger vessels that can be seen on both SWI Fe3 and SWI avg,2,3 data. This vascular blooming was reduced after the adaptive combination (SWI PGAC ) of the dynamically acquired SWI data, which was then used to obtain the MVM, as seen in the bottom row of Figure S3. The SWI avg,2,3 and SWI PGAC data, for all subjects, are shown in supplementary Figures S4A and S4B, respectively. ...
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... better visualize the major vessels penetrating and draining the hippocampus. The entire visible vascular network, including the MVM, that was segmented using the MICRO protocol is displayed in the fourth column, overlayed on the segmented mask of the hippocampus (see also the supplemental Video 1 illustrating the hippocampal vasculature in 3D). Fig. 3 compares the cadaver brain data adapted from Duvernoy et al. (Duvernoy et al., 2013) (Fig. 3A) with our in vivo results in mapping the subvoxel vessels of the hippocampus. The dense vascular layer of the fimbrio dentate sulcus (blue arrows) within the hippocampus, as shown in the cadaver brain data, can be seen on our in vivo results ...
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... vascular network, including the MVM, that was segmented using the MICRO protocol is displayed in the fourth column, overlayed on the segmented mask of the hippocampus (see also the supplemental Video 1 illustrating the hippocampal vasculature in 3D). Fig. 3 compares the cadaver brain data adapted from Duvernoy et al. (Duvernoy et al., 2013) (Fig. 3A) with our in vivo results in mapping the subvoxel vessels of the hippocampus. The dense vascular layer of the fimbrio dentate sulcus (blue arrows) within the hippocampus, as shown in the cadaver brain data, can be seen on our in vivo results with the help of Ferumoxytol and the proposed processing steps. Similarly, the subependymal ...
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... the inclusion of the Fe 2 in the SWI avg,2,3 data to produce the final SWI PGAC results could potentially reduce the contrast for the smaller vessels. The individual SWI Fe2 and SWI Fe3 data possess increased blooming around the larger (even several medium vessels, as shown in Figures S3 and S4), which has overestimated final FVD results (as shown in Fig. 5A and a reduce intercept for SWI PGACderived FVD vs. age correlation in 5B). Nevertheless, the age correlation of the FVDs from all three types of SWI data showed that slopes (|z| < 1.96, Figure S7B), demonstrating the reproducibility of the proposed vessel extraction process. ...
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BACKGROUND: There is an urgent need for better detection and understanding of vascular abnormalities at the micro-level, where critical vascular nourishment and cellular metabolic changes occur. This is especially the case for structures such as the midbrain and hippocampus, where both the feeding and draining vessels are quite small. The hippocamp...
Citations
... Ferumoxytol contrast agent-weighted MRI offers a safe and indirect means to measure relative vascular volume and enhance the visibility of large vessels (Boxerman et al., 1995;Kim et al., 2013;Muehe et al., 2016;Yablonskiy and Haacke, 1994). Compared to gadolinium-based agents, ferumoxytol's longer half-life allows for higher-resolution vascular volume measurements (Buch et al., 2022), albeit these methodologies are hampered by confounding factors such as vessel orientation relative to magnetic field (B0) direction (Ogawa et al., 1993). ...
... EL1a-2a), this analysis revealed an extensive arterio-venous pial vessel network spanning almost the entire cortical surface ( Fig. 2A). We attempted to delineate pial arteries and veins using pre-contrast R2*-values; however, due to the 'blooming' effect of ferumoxytol (Buch et al., 2022) distinguishing adjacent large-caliber vessels was difficult to differentiate with high confidence. Additionally, the continuity of the pial vessel network may also have been influenced by veins crossing the sulci (Duverney et al., 1981). ...
Mapping the vascular organization of the brain is of great importance across various domains of basic neuroimaging research, diagnostic radiology, and neurology. However, the intricate task of precisely mapping vasculature across brain regions and cortical layers presents formidable challenges, resulting in a limited understanding of neurometabolic factors influencing the brain’s microvasculature. Addressing this gap, our study investigates whole-brain vascular volume using ferumoxytol-weighted laminar-resolution multi-echo gradient-echo imaging in macaque monkeys. We validate the results with published data for vascular densities and compare them with cytoarchitecture, neuron and synaptic densities. The ferumoxytol-induced change in transverse relaxation rate (ΔR2*), an indirect proxy measure of cerebral blood volume (CBV), was mapped onto twelve equivolumetric laminar cortical surfaces. Our findings reveal that CBV varies 3-fold across the brain, with the highest vascular volume observed in the inferior colliculus and lowest in the corpus callosum. In the cerebral cortex, CBV is notably high in early primary sensory areas and low in association areas responsible for higher cognitive functions. Classification of CBV into distinct groups unveils extensive replication of translaminar vascular network motifs, suggesting distinct computational energy supply requirements in areas with varying cytoarchitecture types. Regionally, baseline R2* and CBV exhibit positive correlations with neuron density and negative correlations with receptor densities. Adjusting image resolution based on the critical sampling frequency of penetrating cortical vessels, allows us to delineate approximately 30% of the arterial-venous vessels. Collectively, these results mark significant methodological and conceptual advancements, contributing to the refinement of cerebrovascular MRI. Furthermore, our study establishes a linkage between neurometabolic factors and the vascular network architecture in the primate brain.
Highlights
⮚ Cortical layer vascular mapping using ferumoxytol-weighted R2* MRI
⮚ Vascular volume is high in primary sensory areas and low in association areas
⮚ Correlation between R2* and vascular volume with neuron and receptor densities
⮚ Vascularization co-varies with densities of specific interneuron types
... Next year, they were able to display vascular abnormalities and the density of small vessels in multiple sclerosis lesions, providing new insights into disease pathophysiology[76]. In 2022[77], they successfully mapped hippocampal microvasculature, also quantifying tissue fractional vascular density in each of the subfields of the hippocampus; their results suggest that vascular degeneration precede tissue atrophy and are consequently able to measure atrophy and volumetric changes. This data strongly correlated both with ageing and with several neurodegenerative diseases, giving insights into disease etiology. ...
The nexus of advanced technology and medical therapeutics has ushered in a transformative epoch in contemporary medicine. Within this arena, Magnetic Resonance Imaging (MRI) emerges as a paramount tool, intertwining the advancements of technology with the art of healing. MRI's pivotal role is evident in its broad applicability, spanning from neurological diseases, soft-tissue and tumour characterization, to many more applications. Though already foundational, aspirations remain to further enhance MRI's capabilities. A significant avenue under exploration is the incorporation of innovative nanotechnological contrast agents. Forefront among these are Superparamagnetic Iron Oxide Nanoparticles (SPIONs), recognized for their adaptability and safety profile. SPION's intrinsic malleability allows them to be tailored for improved biocompatibility, while their functionality is further broadened when equipped with specific targeting molecules. Yet, the path to optimization is not devoid of challenges, from renal clearance concerns to potential side effects stemming from iron overload. This review endeavors to map the intricate journey of SPIONs as MRI contrast agents, offering a chronological perspective of their evolution and deployment. We provide an in-depth current outline of the most representative and impactful pre-clinical and clinical studies centered on the integration of SPIONs in MRI, tracing their trajectory from foundational research to contemporary applications.
... 13 of Frangi et al. (Frangi et al., 1998). Binary masks were obtained using a thresholding method described by Buch et al. (Buch et al., 2022). IVV and BVR were separated from small vessels with lower susceptibility values using a thresholding method (Δχ vein > 100 ppb) along with a multiple-scale Frangi filter on the QSM data. ...
... However, current clinical scanners at 1.5T and 3T have limitations in visualizing microvasculature, particularly in the hippocampus with venous network at micro-level compared to small veins in periventricular regions. Ferumoxytol-enhanced SWI has been used to depict detailed microvasculature at mid-brain (Buch et al., 2020) and hippocampus (Buch et al., 2022) regions, but the Ferumoxytol confounds venous oxygenation levels and leads to signal and contrast changes due to the strong blooming effect (Kuppusamy et al., 1996). Another approach to increase sensitivity in detecting small veins on SWI is performing high resolution scans at ultrahigh field strength (e.g., 7T) without contrast injection, which provides higher phase sensitivity and enables detailed delineation of microvasculature while preserving original venous oxygenation levels (Deistung et al., 2008;Rutland et al., 2020). ...
... Our high-resolution SWI at 7T (Fig. 1 and 3) revealed intricate details of the venous vasculature of hippocampus without the use of contrast agents. Interestingly, the venous system observed at 7T without contrast exhibited similar structures to those reported by Buch et al. using Ferumoxytol at 3T with similar imaging parameters (Buch et al., 2022). Our findings provide additional evidence supporting the presence of venous arches instead of arterial structures in the hippocampus. ...
Mapping the small venous vasculature of the hippocampus in vivo is crucial for understanding how functional changes of hippocampus evolve with age. Oxygen utilization in the hippocampus could serve as a sensitive biomarker for early degenerative changes, surpassing hippocampal tissue atrophy as the main source of information regarding tissue degeneration. Using an ultrahigh field (7T) susceptibility-weighted imaging (SWI) sequence, it is possible to capture oxygen-level dependent contrast of submillimeter-sized vessels. Moreover, the quantitative susceptibility mapping (QSM) results derived from SWI data allow for the simultaneous estimation of venous oxygenation levels, thereby enhancing the understanding of hippocampal function. In this study, we proposed two potential imaging markers in a cohort of 19 healthy volunteers aged between 20 and 74 years. These markers were: 1) hippocampal venous density on SWI images and 2) venous susceptibility (Δχvein) in the hippocampus-associated draining veins (the inferior ventricular veins (IVV) and the basal veins of Rosenthal (BVR) using QSM images). They were chosen specifically to help characterize the oxygen utilization of the human hippocampus and medial temporal lobe (MTL). As part of the analysis, we demonstrated the feasibility of measuring hippocampal venous density and Δχvein in the IVV and BVR at 7T with high spatial resolution (0.25 × 0.25 × 1 mm³). Our results demonstrated the in vivo reconstruction of the hippocampal venous system, providing initial evidence regarding the presence of the venous arch structure within the hippocampus. Furthermore, we evaluated the age effect of the two quantitative estimates and observed a significant increase in Δχvein for the IVV with age (p = 0.006, r² = 0.369). This may suggest the potential application of Δχvein in IVV as a marker for assessing changes in atrophy-related hippocampal oxygen utilization in normal aging and neurodegenerative diseases such as AD and dementia.
... of microvascular density (25). Nonetheless, it has remained unclear how these macro-and microvascularization patterns translate to variability in the amount of blood (in mL/100 g/min) perfused in the hippocampal tissue. ...
... We demonstrate that there are clear, measurable differences between subfields. Most strikingly, CA1 appears to be characterized by the lowest perfusion among hippocampal subfields, which is in line with previous in vivo and ex vivo indices of microvascular density in animals (46) and humans (25,47). While characterized by a lower microvascular density and blood flow, CA1 is not necessarily characterized by a difference in activity due to the prominent role of its (mostly pyramidal) neurons in hippocampal structure and function (48). ...
We present a comprehensive study on the non-invasive measurement of hippocampal perfusion. Using high-resolution 7 tesla arterial spin labeling (ASL) data, we generated robust perfusion maps and observed significant variations in perfusion among hippocampal subfields, with CA1 exhibiting the lowest perfusion levels. Notably, these perfusion differences were robust and already detectable with 50 perfusion-weighted images per subject, acquired in 5 min. To understand the underlying factors, we examined the influence of image quality metrics, various tissue microstructure and morphometric properties, macrovasculature, and cytoarchitecture. We observed higher perfusion in regions located closer to arteries, demonstrating the influence of vascular proximity on hippocampal perfusion. Moreover, ex vivo cytoarchitectonic features based on neuronal density differences appeared to correlate stronger with hippocampal perfusion than morphometric measures like gray matter thickness. These findings emphasize the interplay between microvasculature, macrovasculature, and metabolic demand in shaping hippocampal perfusion. Our study expands the current understanding of hippocampal physiology and its relevance to neurological disorders. By providing in vivo evidence of perfusion differences between hippocampal subfields, our findings have implications for diagnosis and potential therapeutic interventions. In conclusion, our study provides a valuable resource for extensively characterizing hippocampal perfusion.
... This structure is functionally segregated along its longitudinal axis, and this is similar across rodents, monkeys, and humans [6] with highly specific ventral (anterior in humans) hippocampal networks [7,8] with dissociable roles in learning, memory, stress and emotional processing [8]. It has a complex vascularization system which is particularly vulnerable to vascular risk factors [9]. This vulnerability is corroborated by studies that have identified reduced grey matter volume (GMv) in this region in T2D [10,11]. ...
Type 2 diabetes (T2D) often impairs memory functions, suggesting specific vulnerability of the hippocampus. In vivo neuroimaging studies relating encoding and retrieval of memory information with endogenous neuroprotection are lacking. The neuroprotector glucagon-like peptide (GLP-1) has a high receptor density in anterior/ventral hippocampus, as shown by animal models. Using an innovative event-related fMRI design in 34 participants we investigated patterns of hippocampal activity in T2D (n = 17) without mild cognitive impairment (MCI) versus healthy controls (n = 17) during an episodic memory task. We directly measured neurovascular coupling by estimating the hemodynamic response function using event-related analysis related to encoding and retrieval of episodic information in the hippocampus. We applied a mixed-effects general linear model analysis and a two-factor ANOVA to test for group differences. Significant between-group differences were found for memory encoding, showing evidence for functional reorganization: T2D patients showed an augmented activation in the posterior hippocampus while anterior activation was reduced. The latter was negatively correlated with both GLP-1 pre- and post-breakfast levels, in the absence of grey matter changes. These results suggest that patients with T2D without MCI have pre-symptomatic functional reorganization in brain regions underlying episodic memory, as a function of the concentration of the neuroprotective neuropeptide GLP-1.
... Notably, our findings revealed a significant association between higher BMI and larger hippocampal fissure volumes in non-demented older females. The hippocampal fissure possesses a higher fractional vascular density compared to other subfields of the hippocampus [65], and it is a susceptible subregion for Alzheimer's disease pathology [66,67]. Enlargement of the hippocampal fissure is indicative of early gray matter atrophy within the hippocampal formation [68,69]. ...
Recent research suggests a possible association between midlife obesity and an increased risk of dementia in later life. However, the underlying mechanisms remain unclear. Little is known about the relationship between body mass index (BMI) and hippocampal subfield atrophy. In this study, we aimed to explore the associations between BMI and hippocampal subfield volumes and cognitive function in non-demented Chinese older adults. Hippocampal volumes were assessed using structural magnetic resonance imaging. Cognitive function was evaluated using the Repeatable Battery for the Assessment of Neuropsychological Status (RBANS). A total of 66 participants were included in the final analysis, with 35 females and 31 males. We observed a significant correlation between BMI and the hippocampal fissure volume in older females. In addition, there was a negative association between BMI and the RBANS total scale score, the coding score, and the story recall score, whereas no significant correlations were observed in older males. In conclusion, our findings revealed sex-specific associations between BMI and hippocampal subfield volumes and cognitive performance, providing valuable insights into the development of effective interventions for the early prevention of cognitive decline.
... Laser scanning confocal 3D immunofluorescent microscopy of young and aging vascular beds in multiple mice and human organs, including brain tissue, has also demonstrated an age-dependent decline in vessel density . To the best of our knowledge, this is one of the first in vivo studies on aging effects on cerebral small vessel density using MRI (Buch et al., 2022;Huang et al., 2023). The regional patterns of vessel density changes mapped by our method are consistent with previous findings of cerebral blood flow (CBF) decreases in aging brains (Chen et al., 2011). ...
Small cerebral blood vessels are largely inaccessible to existing clinical in vivo imaging technologies. This study aims to present a novel analysis pipeline for vessel density mapping of small cerebral blood vessels from high-resolution 3D black-blood MRI at 3T. Twenty-eight subjects (10 under 35 years old, 18 over 60 years old) were imaged with the T1-weighted turbo spin-echo with variable flip angles (T1w TSE-VFA) sequence optimized for black-blood small vessel imaging with iso-0.5 mm spatial resolution (interpolated from 0.51×0.51×0.64 mm³) at 3T. Hessian-based vessel segmentation methods (Jerman, Frangi and Sato filter) were evaluated by vessel landmarks and manual annotation of lenticulostriate arteries (LSAs). Using optimized vessel segmentation, large vessel pruning and non-linear registration, a semiautomatic pipeline was proposed for quantification of small vessel density across brain regions and further for localized detection of small vessel changes across populations. Voxel-level statistics was performed to compare vessel density between two age groups. Additionally, local vessel density of aged subjects was correlated with their corresponding gross cognitive and executive function (EF) scores using Montreal Cognitive Assessment (MoCA) and EF composite scores compiled with Item Response Theory (IRT). Jerman filter showed better performance for vessel segmentation than Frangi and Sato filter which was employed in our pipeline. Small cerebral blood vessels including small artery, arterioles, small veins, and venules on the order of a few hundred microns can be delineated using the proposed analysis pipeline on 3D black-blood MRI at 3T. The mean vessel density across brain regions was significantly higher in young subjects compared to aged subjects. In the aged subjects, localized vessel density was positively correlated with MoCA and IRT EF scores. The proposed pipeline is able to segment, quantify, and detect localized differences in vessel density of small cerebral blood vessels based on 3D high-resolution black-blood MRI. This framework may serve as a tool for localized detection of small vessel density changes in normal aging and cerebral small vessel disease.
... 30,31 A higher vascular density may provide resilience against aging and vascular risk factors. 32 Some small arteries, such as the LSAs and anterior choroidal artery, are crucial for maintaining basic brain functions. Early detection of stenosis and abnormal dilation in these arteries can help make preventive treatment plans. ...
... A follow-up study used MICRO to investigate the degenerating processing of hippocampal vasculature during aging. 32 The authors showed that CA1, subiculum, and hippocampal tail exhibited lower vascular density than the other subfields. Furthermore, vascular density in the CA1 region showed a significant association with both age and CA1 volume changes. ...
... Furthermore, vascular density in the CA1 region showed a significant association with both age and CA1 volume changes. 32 The MICRO protocol has great potential for both neuroscience research and clinical applications. Many imaging studies have already used Ferumoxytol, a USPIO drug initially approved for the treatment of iron deficiency anemia, for diagnostic imaging of vascular disease, tumors, etc. ...
Cerebral small vessel disease is a major contributor to brain disorders in older adults. It is associated with a much higher risk of stroke and dementia. Due to a lack of clinical and fluid biomarkers, diagnosing and grading small vessel disease are highly dependent on magnetic resonance imaging. In the past, researchers mostly used brain parenchymal imaging markers to represent small vessel damage, but the relationships between these surrogate markers and small vessel pathologies are complex. Recent progress in high‐resolution magnetic resonance imaging methods, including time‐of‐flight MR angiography, phase‐contrast MR angiography, black blood vessel wall imaging, susceptibility‐weighted imaging, and contrast‐enhanced methods, allow for direct visualization of cerebral small vessel structures. They could be powerful tools for understanding aging‐related small vessel degeneration and improving disease diagnosis and treatment. This article will review progress in these imaging techniques and their application in aging and disease studies. Some challenges and future directions are also discussed.
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... Our results showed improved visualization of the micro venous system in the hippocampus using high-resolution 7 T SWI data without the contrast agent. 5 In summary, the characterization of venous QSM in major tributaries related to the hippocampus offers a novel perspective on oxygen utilization in the hippocampus, which may be useful for studying age-related dementia. We delineated the hierarchical network of the hippocampus venous system using SWI/QSM at 7 T and extract the venous density and venous susceptibility value in hippocampus-related small veins and major venous tributaries, as an overall measure for venous oxygenation level related to the hippocampus, which may be used as an early marker for hippocampal atrophy in Alzheimer's disease. ...
Background: The current understanding of the venous system in the hippocampus is mostly based on histological and autopsy studies.1 However, the main disadvantage is that it only reveals the anatomy of the vascular system at the post-mortem stage and lacks physiological aspects associated with neuronal metabolism. In vivo characterization of the venous system using susceptibility weighted imaging (SWI) at 7 T could provide valuable information on both venous anatomy and blood oxygen saturation, through high-resolution SWI venography2 and quantitative susceptibility mapping (QSM).3 In this study, we aim to elucidate the hierarchical network of the hippocampal venous system and then test the feasibility of using venous susceptibility to characterize venous oxygenation level changes related to neurodegeneration.
Methods: Seven healthy volunteers were recruited for this study. We used high in-plane resolution of flow-compensated dual-echo gradient echo sequence (TE1/TE2/TR=7.5/15/22 ms, voxel size: 0.25*0.25*1 mm). SWI and QSM were then reconstructed using the iterative SWI and mapping (iterative SWIM) algorithm,3 as shown in Figure 1. Hippocampus masks were extracted from the T1-MPRAGE image, which was transformed to SWI space afterwards. To reduce the partial volume effect from the tissue-vessel boundary, we extract the venous susceptibility value from each voxel along the centerline of the vessels.
Results: High-resolution in vivo mapping of hippocampal venous vasculature exhibits a high analogy to Duvernoy’s reference4 for hippocampal vascularization. As shown in Figure 1, there is a shape of venous arch near the fimbria of the hippocampus, and small veins extending through the arch are possibly the intrahippocampal veins. The intrahippocampal veins will eventually reach the inferior ventricular vein (IVV) (anteriorly) and medial atrial vein (MAV) (posteriorly), before joining the basal vein of Rosenthal (BVR). For venous susceptibility quantification, Figure 1 shows the representative color-coded QSM for centerline extraction on BVR.
Conclusions: Our results showed improved visualization of the micro venous system in the hippocampus using high-resolution 7 T SWI data without the contrast agent.5 In summary, the characterization of venous QSM in major tributaries related to the hippocampus offers a novel perspective on oxygen utilization in the hippocampus, which may be useful for studying age-related dementia. We delineated the hierarchical network of the hippocampus venous system using SWI/QSM at 7 T and extract the venous density and venous susceptibility value in hippocampus-related small veins and major venous tributaries, as an overall measure for venous oxygenation level related to the hippocampus, which may be used as an early marker for hippocampal atrophy in Alzheimer’s disease.
