Xin Li^{1}, Seymur Gahramanov^{2}, Ramon F Barajas^{3}, and Edward A Neuwelt^{4}

^{1}Advanced Imaging Research Center, Oregon Health & Science University, Portland, OR, United States, ^{2}Department of Neurosurgery, University of New Mexico, Albuquerque, NM, United States, ^{3}Diagnostic Radiology, Oregon Health & Science University, Portland, OR, United States, ^{4}Neurology, Oregon Health & Science University, Portland, OR, United States

### Synopsis

Dynamic
Susceptibility Contrast (DSC) Magnetic Resonance Imaging (MRI) with low
molecular weight Gadolinium based contrast agent (GBCA) is often confounded by
GBCA’s leakage into intersitium space. Thus,
pre-DSC injection of GBCA (preload) is often used to mitigate the
underestimation of relative cerebral blood volume (rCBV) due to the leakage of
GBCA. Here, we present results to demonstrate that preload is generally
effective. However, small dose effect could still be expected in the process.

**Purpose**

Though
widely adopted for brain perfusion measurement, Dynamic Susceptibility Contrast
(DSC) MRI with low molecular weight gadolinium based contrast agent (GBCA) is
often confounded by GBCA’s leakage into interstitium space. An additional
pre-DSC injection of GBCA (preload) is often used to mitigate the underestimation
of relative cerebral blood volume (rCBV) due to GBCA leakage. Here, we use a
linearization approach to uniquely quantify GBCA leakage rate constant and show
that the preload practice is generally effective in mitigating the leakage
effect in DSC with GBCA.**Method**

Eight
female athymic nude rats (weight, 200–240 g) were anesthetized with
intraperitoneal injection of ketamine (60 mg/kg) and diazepam (7.5 mg/kg) for
stereotactic inoculation of U87MG cells. MRIs were performed 13 days after
tumor implantation. DSC images were acquired with a gradient-echo
sequence using the following parameters: TR/TE/FA, 31 ms/5.0 ms/6°; 3.2 x 3.2
cm^{2} field of view, 128 x 128 matrix, and three contiguous
1-mm-thick sections. After an initial 30-second baseline acquisition, 60 μL
bolus of gadodiamide (Omniscan) was injected (3 mL/min) via a tail vein
catheter with an infusion pump, followed by 240 μL saline flush. Three
consecutive DSC MRI acquisitions were performed with ~ 5 minutes between two
adjacent runs. Each previous GBCA injection thus served as a preload for the
subsequent DSC scan. We term the first DSC-MRI without GBCA preload as
“no-preload”, the second DSC as “single-dose preload”, and the third as
“double-dose preload”. Based on the simple assumption that the extravasating
and intravascular GBCA introduced R_{2}^{*} change can be
linearly combined,^{1,2} the pixel ΔR_{2}^{*} time-course
is given in Eq. (1),
$$\triangle R_2^*(t)=K_{1}
\cdot\triangle\overline{R_2^*(t)} -
K_{2}\int_{0}^{t}\triangle\overline{R_2^*(t')} dt'\ (1) $$ where ΔR_{2}^{*} represents
the pixel time-course for R_{2}^{*} change, K_{1} and
K_{2} are proportional constants for intravascular and
extravasating contributions to ΔR_{2}^{*},
respectively. $$$ \triangle\overline{R_2^*}
$$$ approximates relative blood R_{2}^{*} change
by combining signal changes from all non-leaking brain tissue pixels.^{2} Using a method^{3,4} similar to Gjedde-Patlak linearization,^{4,5} we divide Eq. (1) by $$$\triangle\overline{R_2^*(t)}$$$ then graph
the transformed right-hand-side term vs. that associated to the K_{2} term
(see Fig. 2 labels for expressions). If a linear portion exists in the graph,
we can identify a leakage rate constant, K_{L}, as the slope of that
segment. Similar to that of Gjedde-Patlak plot, K_{L} is
only calculated from the linear portion after the transformation.**Results**

Fig. 1a shows the three normalized DSC signal
time-courses for one animal. Only the “no-preload” time-course (red) shows the
apparent leakage effect with a portion of post-GBCA signal increases above
baseline. In 1b,
color-matched ΔR_{2}^{*} time-courses were plotted for
the 1a signals. Only
the no-preload ΔR_{2}^{*} time-course falls
below zero. 1b inset
shows a post-GBCA DSC image. Fig.
2 plots results after the linearization (symbols) of a different
animal, and their respective linear regression lines. The magnitude of the
leakage rate constant (K_{L}) is much larger without preload,
while differences for the ones with preloads are generally much smaller and
closer to zero. Fig. 3. summarizes
the lesion ROI K_{L} values from all animals. The leakage rate is
much greater than zero without preload. On the other hand, neither of the mean K_{L }value for s. d. or d. d. preload is significantly different from zero with p-values of 0.41
and 0.075, respectively. **Discussion**

Using
a linearization approach similar to the Gjedde-Patlak linearization, a unique
pseudo first-order leakage rate constant, K_{L}, is defined for DSC
with GBCA. Therefore, the K_{L} approach can provide a
systematic way in investigating the effectiveness of the preload method in
mitigating the leakage effect in DSC rCBV quantification. The results here show that the mean K_{L} values from eight
animals are not significantly differ from zero, underscoring the generally
effective preload approach. Still, with a p-value from the double dose
preload at only 0.075, it is likely that injection timing and preload dose
still could play a non-negligible role in the overall rCBV quantification. ### Acknowledgements

Grant Support: R01-
NS33618, R01-NS34608, and the Walter S. and Lucienne Driskill Foundation.### References

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