Simultaneously Trace Blood Perfusion and Glymphatic Passage by Analyzing Deuterium Oxide Perfusion Imaging with a Two-Compartment Parallel Model
Cheng-He Li1, Zi-Min Lei1, Sheng-Min Huang1, Chin-Tien Lu1, Kung-Chu Ho2, and Fu-Nien Wang1

1Biomedical Engineering and Environmental Sciences, National Tsing Hua University, Hsinchu, Taiwan, 2Nuclear Medicine, Chang Gung Memorial Hospital, Linkou, Taoyuan, Taiwan

Synopsis

This study tried to simultaneously trace blood perfusion and glymphatic passage by applying two-compartment parallel model (2CPM) on D2O perfusion using the new imaging strategy. Six rats were injected with D2O, and both F1 and F2 were quantified from 2CPM. The results show that F1 is highly coordinated with cerebral blood flow, while F2 is much irrelevant. Only regions near several arteries show significant F2 values, which is speculated as the paravascular pathway of CSF regulated by glymphatic system. Therefore, using 2CPM for tracing D2O might noninvasively reveal the information of both blood and CSF dynamics.

Introduction

Glymphatic system has been demonstrated as a lymphatic-like circulating system in brain tissue and was predicted existing in paravascular pathway. A recent study has confirmed this hypothesis by injecting fluorescent tracers into the cisterna magna and thus located their distribution in murine 1. As a freely diffusible tracer, deuterium oxide (D2O) may be an alternative in discovering glymphatic system through non-invasive tail-vein injection method. In addition to the quantification of hemodynamics 2, D2O may also trace the water passage in glymphatic system because of its water-close characteristic. Wang et al. have used D2O as a negative contrast agent by 1H-MRI imaging and showed improved signal-to-noise ratio comparing to direct measurement of D2O 3. Therefore, we used this new strategy to acquire D­2O perfusion images in this study, and extracted both blood and glymphatic dynamics simultaneously by applying two-compartment parallel model (2CPM). The traditional one-compartment Tofts model (1CTM) was also applied to quantify cerebral blood flow (CBF) for comparison 4.

Materials and Methods

Six adult male Spaugue-Dawley rats were anesthetized by 1.5 % isoflurane and injected with D2O (2ml/100g) via tail vein at 7T Bruker Clinscan MRI scanner. 80 measurements were acquired by the following parameters: turbo-spin-echo (TSE) with TR/TE = 2000/14ms, matrix size = 128x256, FOV = 35mm, turbo factor = 3, slice number = 3, slice thickness = 1.5mm, distant factor = 40%, sampling interval = 34s. Then, the relative concentration-time curves were estimated by calculating signal change from the pre-injection baseline level. The arterial input function (AIF) was extracted by averaging three to six selected voxels in the area of cerebral artery and reconstructed by a0*t for wash-in phase and a1*exp(-b*t)+c for wash-out. The two pharmacokinetic models, 1CTM and 2CPM, were utilized as the following equation (1) and (2), respectively.

(1) $$$C_{t}(t)=AIF(t)\otimes[F_{0}\exp(-F_{0}t/v_{0})]$$$

(2) $$$C_{t}(t)=AIF(t)\otimes[F_{1}\exp(-F_{1}t/v_{1})+F_{2}\exp(-F_{2}t/v_{2})]$$$

where Ct: concentration-time curve, Fi: flow, vi: distributed volume, where i=0,1,2. Parameter constraint: v0<1, F1≥F2, v1+v2=1. Then we quantified Fi as flow with a unit of ml/min/100g.

Results

Figure 1 shows the spatial maps of F0 quantified from 1CTM (1a) and F1 from 2CPM (1b) of six rats (R1-6), respectively. These two maps both show nice contrast of brain tissues and appear to be very similar to each other. The F2 maps from 2CPM are presented in Figure 2. Only regions at some specific structures show significant flow values. In Figure 3, the F2 values of Rat 5 higher than an empirical threshold (in this case, F2 > 3 ml/min/100g) are included in the regions of interest (ROIs), and superimposed on the anatomical images. These locations of ROIs are near several arteries, including (I) middle cerebral artery, (II) azygos pericallosal artery, (III) supracollicular arterial network, and (IV) posterior communicating artery. Some regions surrounding on the cortical surface of brain might be surface and penetrating arteries. Figure 4 demonstrates the averaged concentration-time curves of whole brain and ROIs in Rat 5 with a curve of the corresponding AIF for reference. Comparing to the whole-brain concentration-time curve, the ROIs curve shows a higher magnitude at first-bolus arrival and slower clearance rate at the end of dynamic scans. Figure 5 summarizes flow values of all rats and their coefficients of determination, where R12 is F0 versus F1 and R22 is F0 versus F2, respectively.

Discussion and Conclusion

This study demonstrated that the multi-compartment analyses on D2O perfusion by using the new imaging strategy could be useful to quantify the water dynamics with adequate spatial and temporal information. F1 was highly coordinated with F0 despite of an insignificant augment, thus F1 could be speculated as the CBF. On the other hand, the F2 value of a parallel flow was much irrelevant with the blood flow, and the spatial distributions of the parallel flow were adjacent to the location of cerebral arteries, which matched with the recent report of the paravascular pathway of cerebral-spinal fluid (CSF) 1. Therefore, according to the blood irrelevant flow values and the spatial matched mapping, we have demonstrated that using 2CPM for tracing D2O might noninvasively reveal the information of CSF-dynamics which is regulated by glymphatic system. Further investigations and applications should be conducted to connect D2O tracer analysis of 2CPM with the comprehensive water passage in rat brain.

Acknowledgements

The Ministry of Science and Technology provided the grant support of this work. (MOST 103-2221-E-007-008-, 104-2221-E-007-063-)

References

1. lliff JJ, Wang M, Liao Y, Plogg BA, Peng W, Gundersen GA, Benveniste H, Vates GE, Deane R, Goldman SA, Nagelhus EA, Nedergaard M. A paravascular pathway facilitates CSF flow through the brain parenchyma and the clearance of interstitial solutes, including amyloid β. Sci Transl Med. 2012;4(147):147ra111

2. Kim SG, Ackerman JJ. Multicompartment analysis of blood flow and tissue perfusion employing D2O as a freely diffusible tracer: a novel deuterium NMR technique demonstrated via application with murine RIF-1 tumors. Magn Reson Med. 1988;8(4):410-426

3. Wang FN, Peng SL, Lu CT, Peng HH, Yeh TC. Water signal attenuation by D2O infusion as a novel contrast mechanism for 1H perfusion MRI. NMR Biomed. 2013;26(6):692-698

4. Tofts PS, Brix G, Buckley DL, Evelhoch JL, Henderson E, Knopp MV, Larsson HB, Lee TY, Mayr NA, Parker GJ, Port RE, Taylor J, Weisskoff RM. J Magn Reson Imaging. 1999;10(3):223-232

Figures

The spatially distributed maps of all 6 rats. (a) F0 from 1CTM (b) F1 from 2CPM.

F2 maps from 2CPM of all 6 rats.

Superimposing the ROI whose F2 value is greater than 3 ml/min/100g on the anatomical images of Rat 5. The locations of yellow arrows are indicated in the text.

Relative concentration-time curves of reconstructed AIF (red), averaged whole brain (black) and ROI (blue).

Mean and standard deviation (SD) of flow (Fi, i=0,1,2) and coefficient of determination (R12: F0 vs. F1, R22: F0 vs. F2) from 6 rats.



Proc. Intl. Soc. Mag. Reson. Med. 24 (2016)
3695