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Vascular Mapping of the Human Hippocampus Using USPIO
Sagar Buch1, Yongsheng Chen2, Pavan Jella3, Yulin Ge4, and Ewart Mark Haacke1
1Radiology, Wayne State University, Detroit, MI, United States, 2Neurology, Wayne State University, Detroit, MI, United States, 3Wayne State University, Detroit, MI, United States, 4Radiology, New York University School of Medicine, New York, NY, United States

Synopsis

In this work, we introduce the use of Ferumoxytol, an ultra-small superparamagnetic iron oxides (USPIO) agent, to increase the susceptibility in the veins and arteries to map the hippocampal microvasculature and to evaluate the fractional vascular density (FVD) in each of its subfields. We found that the hippocampal fissure, along with the fimbria, granular cell layer of the dentate gyrus and cornu ammonis layers (except for CA1), showed higher microvascular FVD than other parts of the hippocampus.

INTRODUCTION

The hippocampus is a complex grey matter structure that plays an important role in spatial and episodic memory. It can be affected by a wide range of pathologies including vascular abnormalities. We recently introduced the concept of MICRO (Microvascular In-vivo Contrast Revealed Origins) protocol to image micro-cerebral vessels.1 MICRO uses Ferumoxytol, an ultra-small superparamagnetic iron oxides (USPIO) agent, to induce susceptibility in the arteries and veins. In this work, we use MICRO imaging to map the hippocampal microvasculature, and evaluate the change in fractional vascular density (FVD) in each of its subfields.

METHODS

A total of 39 healthy volunteers (aged 36.7±14.2 years, from 21 to 81 years old, women = 21) were scanned on a 3T Siemens VERIO scanner with a high-resolution SWI sequence at four time points during a gradual increase in Ferumoxytol dose (final dose = 4 mg/kg). The imaging parameters were: TE1/TE2/TR=7.5/15/27 ms, bandwidth=180 Hz/pixel; with a voxel size = 0.22×0.44×1 mm3 (interpolated to 0.22×0.22×1 mm3). Dynamically acquired SWI data were co-registered and combined (phase gradient-based adaptive combination or SWIPGAC) to reduce the blooming artifacts from large vessels, preserving the small-vessel contrast1. The hippocampal subfields were automatically segmented from the registered pre-contrast T1 MPRAGE data with the hippocampus segmentation tool in Freesurfer (version 6.0.0).2 The Frangi vesselness filter was used on the resultant SWI data to segment the microvasculature and the FVD [(volume occupied by vessels)/(total volume)] of the subfields was measured.3

RESULTS

The presence of Ferumoxytol helped to enhance the hippocampal microvasculature, something that has previously only been demonstrated in cadaver brain studies (Figure 1). Figure 2 shows the difference between the pre-contrast SWI and SWIPGAC data in visualizing the micro-vasculature across four selected subjects. The intra-hippocampal and superficial major arteries (MRA, obtained through a non-linear subtraction method4) and veins (MRV, obtained by averaging the T1-shortening map, pre-contrast QSM and pre-contrast R2* maps) are used as an overlay in the third column to better visualize the major vessels penetrating and draining the hippocampus. Figure 3 compares the cadaver brain data adapted from Duvernoy et al.5 (Figure 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. The hippocampal fissure, along with the fimbria, granular cell layer of the dentate gyrus and cornu ammonis layers (except for CA1), showed higher microvascular FVD than other parts of the hippocampus (Figure 4A). On the other hand, the FVD of major arteries (Figure 4B) and major veins (Figure 4C) was higher in the hippocampal fissure and CA2/3 composite regions, suggesting a stronger probability that these regions serve as the entry/exit area for the penetrating arteries and draining veins.

DISCUSSION

By administering Ferumoxytol, the small vessels in the brain can be enhanced. The lower FVD in the CA1 can be partly explained through the recent work that studied the distance of major arteries from the different hippocampal subfields, which showed that the distance was highest from CA1 than other layers of the cornu ammonis.6 The earlier cadaver brain work with vascular ink injection also showed that the CA1 is poorly vascularized compared to the other layers of the cornu ammonis (i.e., CA2 and CA3)5, which helps validate our results. Mapping the vasculature of the brain and hippocampus in particular has immediate implications for understanding the etiology of many neurovascular and neurodegenerative diseases. With a larger subject population, the change in FVDs, measured across all the subfields, can be accessed as a function of age and compared with tissue volume changes as a function of age to determine whether the vascular atrophy is a precursor to tissue atrophy in the hippocampus due to normal aging or caused by disease.

Acknowledgements

The authors would like to thank our MRI technicians, Zahid Latif and Yang Xuan, for their efforts in collecting and organizing the data. The authors would also like to thank the participants that volunteered for this study. This work was supported in part by the sub-organizations of National Institutes of Health (NIH): National Institute on Aging (grant numbers: R56-AG060822, R13-AG067684), National Institute of Neurological Disorders and Stroke (grant numbers: R01-NS108491, RF1-NS110041), Eunice Kennedy Shriver National Institute of Child Health and Human Development (grant number: R21-HD094424) and National Heart, Lung, And Blood Institute (grant number: R44-HL145826). The content of this paper is the sole responsibility of the authors and does not necessarily represent the official views of the NIH. This work was also supported, in part, by the Silverman Endowment Fund at Wayne State University and by the Office of the Vice President for Research at Wayne State University for their support of the MR Research Facility.

References

[1] Buch S, Wang Y, Park MG, Jella PK, Hu J, Chen Y, Shah K, Ge Y, Haacke EM. Subvoxel vascular imaging of the midbrain using USPIO-Enhanced MRI. Neuroimage. 2020 Oct 15;220:117106. doi: 10.1016/j.neuroimage.2020.117106.

[2] Iglesias JE, Augustinack JC, Nguyen K, Player CM, Player A, Wright M, Roy N, Frosch MP, McKee AC, Wald LL, Fischl B, Van Leemput K; Alzheimer's Disease Neuroimaging Initiative. A computational atlas of the hippocampal formation using ex vivo, ultra-high resolution MRI: Application to adaptive segmentation of in vivo MRI. Neuroimage. 2015 Jul 15;115:117-37. doi: 10.1016/j.neuroimage.2015.04.042.

[3] Frangi AF, Niessen WJ, Vincken KL, Viergever MA (1998) Multiscale vessel enhancement filtering. In: Wells W.M., Colchester A., Delp S. (eds) Medical Image Computing and Computer-Assisted Intervention — MICCAI’98. MICCAI 1998. Lecture Notes in Computer Science, vol 1496. Springer, Berlin, Heidelberg. https://doi.org/10.1007/BFb0056195.

[4] Ye Y, Hu J, Wu D, Haacke EM. Noncontrast-enhanced magnetic resonance angiography and venography imaging with enhanced angiography. J Magn Reson Imaging. 2013 Dec;38(6):1539-48. doi: 10.1002/jmri.24128.

[5] Duvernoy, HM, Cattin F, Risold PY. The Human Hippocampus: Functional Anatomy, Vascularization and Serial Sections with MRI. (Springer-Verlag, 2013). doi:10.1007/978-3-642-33603-4.

[6] Haast RAM. et al. Delineating perfusion and the effects of vascularisation patterns across the hippocampal subfields at 7T. in Proceedings of the 20th Annual Meeting of ISMRM (2021).

Figures

Figure 1. A) Whole brain vasculature (red color) that was enhanced after the administration of Ferumoxytol and then extracted using the proposed vesselness filtering steps to obtain the microvascular map, and with the maximum intensity projection (MIP) over all the transverse slices covering the hippocampus (white color). The minimum intensity projection (mIP) of SWIPGAC and the MIP of the segmented intra-hippocampal vessels are separately displayed in (B) and (C), respectively.

Figure 2. Revealing the microvasculature of the hippocampus using USPIO. Pre- and post-contrast SWI data, for four healthy controls (each in one row), are displayed with the overlays of major arteries (red), major veins (blue) and intra-hippocampal microvasculature (green). Although the pre-contrast SWI was able to highlight the presence of major veins due to the presence of deoxyhemoglobin, the vascular contrast from both arteries and veins was improved significantly on the post-contrast SWI data.

Figure 3. A) Figure adapted from a cadaver study on hippocampal vascularization5; B) mIP of the in vivo SWIPGAC data with overlays of major arteries (red) and veins (blue); C) the combined 3D rendering with the micro-vasculature (green); and D) the isolated micro-vasculature showing agreement with the cadaver brain data in visualizing fimbrio dentate sulcus (blue arrows) and subependymal veins (red arrows). AChA=anterior choroidal artery; PCA=posterior cerebral artery; PmChA=posterior-medial choroidal artery; BV=basal vein; IVV=inferior ventricular vein.

Figure 4. Boxplots of fractional vessel density (FVD) measures for the intra-hippocampal (A) micro-vasculature, (B) major arteries and (C) major veins for each of the subfields. Boxplots provide the median values in form of red lines, boxes across the interquartile range, and dotted bars across the 95% confidence interval . The values outside of this window are deemed as outliers. CA1, CA2/3, CA4 = Cornu Ammonis layers, GC-DG = Granule cell layer of the dentate gyrus, MolLayer = Molecular layer of hippocampus, HCfissure = hippocampal fissure, HCtail = hippocampal tail.

Proc. Intl. Soc. Mag. Reson. Med. 30 (2022)
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DOI: https://doi.org/10.58530/2022/3929