Diffusion-derived vessel density (DDVD) for penumbra delineation in brain acute ischemic stroke: initial proof-of-concept results using single NEX DWI

Introduction

Stroke is a major cause of death and a leading cause of disability globally. Neuroimaging, including non-contrast computed tomography (CT), magnetic resonance imaging (MRI), vascular and perfusion imaging, is a cornerstone in the diagnosis and treatment decision-making. A rapid and accurate diagnosis is the key, specifically for time-critical reperfusion therapies. Identification of medium-large vessel occlusions by CT or MR angiography with additional perfusion imaging helps identify salvageable brain tissue (the ‘penumbra’) in patients who are likely to benefit from reperfusion therapies. Successful reperfusion of salvageable penumbra is expected to reduce the extent of ischemic stroke and thus improve clinical outcomes, whereas reperfusion of irreversibly affected brain tissue is thought to be futile and may result in harm due to the risk of hemorrhagic transformation (1,2). For neuroimaging work-up of acute stroke, CT is more commonly applied than MRI, due to the wider availability in emergency settings. However, CT is associated with administration of iodinated contrast agent and involves variable dosages of local ionizing radiation. Moreover, the CT perfusion readout threshold to define the infarct area remains controversial (3-5). On the other hand, MRI has the overall advantage of better tissue contrast, and the capability to acquire diffusion-weighted imaging (DWI) which remains the best imaging modality to define the infarct area (2,6,7). MRI diffusion imaging provides a reference standard for the presence of ischemia, core size, and penumbral tissue estimation. MRI also offers an added advantage of identification of smaller ischemic areas that may escape detection in early CT or CT perfusion, while ischemic core estimates using CT perfusion sometimes do not include the full extent of MR diffusion restriction (2).

Our exploration of DWI in liver fibrosis evaluation revealed that diffusion-derived vessel density (DDVD) could potentially reflect microvascular changes. This finding inspired us to investigate DDVD’s application in brain acute ischemic stroke, particularly in the delineation of the penumbra area, where timely intervention is critical. We noted that for spin-echo type echo-planar sequence (EPI) we can take the assumption that the second motion probing gradient after the 180-degree RF pulse cannot fully re-focus the flowing spins in vessel and micro-vessels after being de-phased by the first motion probing gradient before the 180-degree RF pulse (Figure S1). Therefore, liver blood vessels show high signal when there is no motion probing gradient (b=0 s/mm²) and low signal when even very low b-values (such as b=1, b=2) are applied (Figure 1) (9). Thus, the signal difference between images when the motion probing gradient is ‘off’ and ‘on’ reflects the extent of tissue vessel density, and we term this as DDVD (diffusion derived vessel density). DDVD is derived from the Eq. [1] (9):

DDVD(b0b2)=Sb0/ROIarea2[unit:arbitrary unit(au)/pixel][1]

Figure 1 1.5 T liver diffusion weighted images with b-value of 0, 1, 2, 15 s/mm². The signal difference between b=0 s/mm² image and b=1 or 2 s/mm² images is dramatic, particularly the vessels show high signal when without diffusion gradient while showing dark signal when the diffusion gradient is on even at b=1 s/mm². [Reproduced with permission from (8)].

where ROIarea0 and ROIarea2 refer to the number of pixels in the selected region-of-interest (ROI) on b=0 and b=2 DWI, respectively. Sb0 refers to the measured total signal intensity within the ROI when b=0, and Sb2 refers to the measured total signal intensity within the ROI when b=2, thus Sb/ROIarea equates to the mean signal intensity within the ROI. Sb2 and ROIarea2 can also be approximated by other low b-values (such as b=10) DWI. If we consider a pixel is an individual ROI, DDVD pixelwise map (DDVDm) can be constructed pixel-by-pixel with this same principle (10). In our initial testing, with 20 healthy livers, 11 stage-1 fibrotic livers, and 5 stage-4 fibrotic livers, DDVD (arbitrary unit/pixel) was 26.5 for healthy livers, 21.8 for stage-1 fibrotic livers, and 12.1 for stage-4 fibrotic livers (9).

The analysis of DDVD requires only two b-values (with one being b=0 s/mm² and the other being non-zero low b-value), with a significantly shorter scanning time than contrast enhanced CT/MRI while without the need of a contrast agent injection. DDVD is conceptually as simple as apparent diffusion coefficient (ADC). DDVD measure based on this simple principle appears to be useful as a straightforward imaging biomarker in diverse clinical scenarios. Huang et al. (11) showed that DDVD analysis demonstrates liver parenchyma has an age-dependent decrease of micro-perfusion in healthy women. This agrees with the known physiological age-dependent reduction in liver blood flow which has been well documented using a variety of technical methods including histology, dye dilution, indicator clearance. DDVD is a useful parameter for distinguishing of livers with and without fibrosis, and livers with severer fibrosis tend to have even lower DDVD measurements than those with milder liver fibrosis (9,12,13). With DDVD analysis, Zheng et al. (14) demonstrated that per unit micro-circulation of spleen is decreased in viral hepatitis-b liver fibrosis patients. This is consistent with, for example, the report of Gitlin et al. (15) with analysis of the washout curves of Xenon 133 injected in the splenic artery in patients with liver cirrhosis and portal hypertension. Among the patients, splenic blood flow, expressed as ml per 100 g of splenic tissue, was decreased. On the contrary, total splenic blood flow, calculated by multiplying specific splenic flow by spleen volume, was increased (15). He et al. (16) reported that placenta DDVD as a perfusion biomarker allows excellent separation of normal and early preeclampsia pregnancies. Lu et al. (17) reported that placenta regional DDVD is significantly higher in pregnant women with placenta accreta spectrum disorders than women with normal placenta, and especially higher in patients with placenta increta and percreta. Hu et al. (18) described that liver hemangiomas can be mostly differentiated from liver mass-forming lesions (hepatocellular carcinomas and focal nodular hyperplasia) solely based on DDVDm.

As absolute MR signal intensity is influenced by various factors, including B0/B1 spatial inhomogeneity, coil loading, receiver gain, etc., we use the ratio of a lesion to its adjacent native tissue [such as the ratio of hepatocellular carcinoma (HCC)’s DDVD to liver DDVD] to minimize these scaling factors. Li et al. (19) applied DDVD to assess the perfusion of HCC. DDVD results (ratio of HCC DDVD to background liver DDVD equals around 3.0) approximately agree with other dynamic contrast enhanced CT/MRI literature data. Lu et al. (20) reported earlier clinical grades rectal carcinoma had a higher DDVD ratio (DDVDr) (tumor to tumor-free rectal wall) than those of the advanced clinical grades (2.245 for grade 0&I, 1.460 for grade II, 1.430 for grade III, 1.130 for grade IV). These parameters are all consistent with the biological behaviors of HCC and rectal carcinoma. In an unpublished study, we used DDVDr to evaluate 24 pleomorphic adenomas (PA), 14 malignant tumors, and 16 Warthin’s tumors. DDVDr was DDVD of the tumor divided by DDVD of tumor free parotid gland tissue. A systematic literature search was conducted for parotid gland tumor perfusion imaging and histology microvessel density studies (21-36). Perfusion parameters of PAs, malignant tumors, and Warthin’s tumors were further normalized by PA’ measure (thus the normalized measure for PA is 1). The ratio results of malignant tumor DDVD and Warthin’s tumors DDVD were compared with literature results. It was noted that DDVDr ratios of both malignant tumor to PA (1.56) and Warthin’s tumor to PA (2.47) were very similar to the mean ratio of CT measured blood volume of these tumors (1.54 for malignant tumor to PA, and 2.51 for Warthin’s tumor to PA) (21-23). DDVDr ratio of malignant tumor to PA was also approximately close to the histology microvessel density ratio (1.29) reported by Zhao et al. (24), and DDVDr ratio of Warthin’s tumor to PA was close to the medium value of histology microvessel density ratio (2.41) of three reports (24-26). In these cases of this parotid gland tumors study, DDVD appears to offer more consistent and comparable results (comparable to CT and histology microvessel density results) than arterial spin labeling (25,27-31) and IVIM (30,32,33). IVIM-PF (intervoxel incoherent -perfusion fraction) is known to be affected by tissue’s T2 time, with longer T2 time leading to a ‘depressed’ perfusion fraction measure (19,37).

Case presentations

In this article, we suggest that DDVD can contribute to acute ischemic stroke assessment by providing insight into brain microvascular perfusion. DDVD, by requiring only two b-values, offers a faster alternative with no need for contrast agents. Hereby we describe our initial promising results of three brain acute ischemic stroke cases. Patient data were collected at Hainan Medical University Hospital, Haikou, China. The study was conducted in accordance with the Declaration of Helsinki (as revised in 2013). Institutional ethical approval was granted for this study, and verbal informed consent was obtained and recorded for this study. DWI data were acquired with a 3.0-T MRI scanner (Discovery MR750w, GE medical system, Milwaukee, USA) and a 16-channel head coil. DWI was performed using a single-shot spin-echo EPI, and the scan parameters included: repetition time (TR) =4,500 ms, echo time (TE) =78 ms, slice thickness =5 mm and inter-slice gap =1 mm, acquisition matrix = 120×120, field of view =240 mm × 240 mm, in plane resolution =2 mm. Number of excitation (NEX) =1. It is important to note that, the DDVDm in the current study appears low signal-to-noise ratio, as the DWI data acquisition used one NEX only. In further studies, we will improve the signal-to-noise ratio with higher NEX and explore de-noise techniques to improve the image quality. The figure contrast may be enhanced when cerebrospinal fluid high signal and noises are suppressed by applying masking and smoothing algorithms.

Case 1 was an 89-year-old woman admitted to the emergency department with a sudden onset of left limb weakness 12 hours earlier. Neurological examination showed a National Institutes of Health Stroke Scale (NIHSS) score of 10. CT angiogram showed occlusion at the right common carotid artery and extracranial internal carotid artery (Figure 2). The DDVDm, DWI, and CT perfusion source image of Case 1 are shown in Figure 3. The results show good agreement between DDVD perfusion deficit area and CT perfusion deficit.

Figure 2 CT angiogram of Case 1. Right CCA and extracranial ICA show occlusion. Right MCA shows smaller diameter than the left MCA. R, right; MCA, middle cerebral artery; L, left; a., artery; ICA, internal carotid artery; CCA, common carotid artery; CT, computed tomography.

Figure 3 DDVDm shows a perfusion deficit in frontal and parietal lobes (red arrows) consistent with CT perfusion deficit (blue arrows). (A) CE-CT source image; (B) DDVDm, (C) DWI with b=1,000 s/mm². CE-CT was acquired one month before the DWI exam. Note that CSF may show DDVD artificial high signal which can be easily identified on b=1,000 s/mm² DWI (10,18). CE-CT, contrast enhanced-computed tomography; DDVD, diffusion derived vessel density; DWI, diffusion weighted imaging; DDVDm, diffusion derived vessel density pixelwise map; CSF, cerebrospinal fluid.

Case 2 was a 56-year-old man admitted to the emergency department, with a onset of left limb weakness 12 hours earlier. Neurological examination showed a NIHSS score of 5. Severe stenosis at the C7 segment of the right internal carotid artery was found on CT angiogram (Figure 4). The DDVDm, DWI, and CT perfusion cerebral blood volume (CBV) map, and mean transit time (MTT) map, time to maximum enhancement (Tmax) map of Case 2 are shown in Figure 5. The DDVD perfusion deficit area is slightly larger than the infarct area shown on DWI. Perfusion CT was performed 7 days after MRI. DDVD perfusion deficit area appears to agree with the Tmax perfusion deficit area.

Figure 4 CT angiogram of Case 2. (A) Right ICA intracranial seg. C7 shows severe stenosis. This might be the main cause of the ischemic infarction. Left ICA intracranial seg shows mild stenosis. (B) Right parietal lobe shows paucity in vessel supply. It was also possible these small vessels had occlusion and contributed to the ischemic infarction. R, right; ICA, internal carotid artery; L, left; seg., segment; ve., vessel; CT, computed tomography.

Figure 5 DDVDm shows the right occipital lobe perfusion deficit consistent with CBV map, MTT map and Tmax map. 1: DDVDm, 2: DWI with b=1,000 s/mm²; 3: perfusion CT CBV map; 4: perfusion CT MTT map; 5: perfusion CT Tmax map. The DDVD perfusion deficit area is slightly larger than the infarct area shown on DWI. Note that CSF may show DDVD artificial high signal which can be easily identified on b=1,000 s/mm² DWI (10,18). DDVD, diffusion derived vessel density; DWI, diffusion weighted imaging; CBV, cerebral blood volume; MTT, mean transit time; Tmax, time to maximum enhancement; DDVDm, diffusion derived vessel density pixelwise map; CT, computed tomography; CSF, cerebrospinal fluid.

Case 3 was a 56-year-old man admitted to the hospital with a complaint of dysphasia for three days. Neurological examination showed a NIHSS score of 4. CT angiogram showed right internal carotid artery proximal segment stenosis and its intracranial segment severe stenosis (Figure 6). The DDVDm, DWI, and CT perfusion CBV map, and MTT map, Tmax map of Case 3 are shown in Figure 7. DDVD perfusion deficit area appears to agree with those of MTT and Tmax perfusion deficit area. CBV does not show an apparent infarct area, while DWI shows a high signal infarct region. The mismatch between DDVDm and DWI suggests a large at-risk penumbra area.

Figure 6 CT angiogram of Case 3. Right ICA intracranial seg. shows severe stenosis. The proximal segment of the right ICA also shows stenosis. R, right; ICA, internal carotid artery; seg., segment; L, left; a., artery; CT, computed tomography.

Figure 7 DDVDm shows perfusion deficit in right temporal lobe/occipital lobe consistent with MTT map and Tmax map. 1: DDVDm, 2: DWI with b=1,000 s/mm²; 3: perfusion CT CBV map; 4: perfusion CT MTT map; 5: perfusion CT Tmax map. (A1) Arrows indicate the perfusion deficit area. (B1) Compared with the left side, the right-side region inside the dotted oval circle shows lower DDVD intensity. (C1) Compared with the left side, arrows indicate slightly lower DDVD intensity. In (B1) and (C1), the region inside the red circle shows even lower DDVD signal which is consistent with the infarct area shown on DWI. No apparent regional perfusion deficit is noted on CBV map (thus the CBV map misses the infarct area). Note that CSF shows DDVD high signal which can be easily differentiated with b=1,000 DWI. Perfusion CT was performed 3 days after MRI. DDVD, diffusion derived vessel density; DWI, diffusion weighted imaging; CBV, cerebral blood volume; MTT, mean transit time; Tmax, time to maximum enhancement; DDVDm, diffusion derived vessel density pixelwise map; CT, computed tomography; CSF, cerebrospinal fluid.

The principle of DDVD DWI protocol also allows for the generation of angiographic images, though currently more mature approaches for MRI-based cerebral artery angiography are already available. As a proof-of-principle example, a case of DDVD angiography of the pelvis region is shown in Figure 8 (10). Better data acquisition and image post-processing techniques are needed to make DDVD angiography clinically useable. Another interesting development is the availability of portable MRI scanners in recent years. Acquisition of MR images using lower field magnets has been made possible, with a significant decrease in the size and costs of such machines (38-41). These smaller machines are shown to provide portability with reasonable accuracy in acute stroke imaging in pilot studies (40,41). Portable MRI scanner and time-efficient assessment of brain perfusion with DDVD protocol may both make MRI more accessible in community emergency settings.

Figure 8 An example of DDVD angiography (10). (A) A DDVDm at the pelvis level. DDVDm is computed from b=0 and b=5 s/mm² DWI. The voxel size of the original DWI for (A) is 2.73×2.73×6.0 mm³. (B) 3D surface-rendering of DDVDms of the pelvis. The patient was scanned with the rectum extended with fluid. [Modified with permission from (10)]. DDVD, diffusion derived vessel density; DDVDm, diffusion derived vessel density pixelwise map; DWI, diffusion weighted imaging; 3D, three-dimensional.

Conclusions

In conclusion, this study provides initial proof-of-concept results that DDVD may offer valuable information about the existence and size of penumbra area in acute ischemic stroke, potentially guiding clinical interventions. While promising, further research is needed to refine the technique, improve image quality, and validate its use in larger patient cohorts.

Acknowledgments

Funding: This work was supported by a Hong Kong General Research Fund project (No. 14112521) and a Hong Kong Research Grants Council Research Impact Fund project (No. R4015-21).

Footnote

Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://qims.amegroups.com/article/view/10.21037/qims-24-2139/coif). Y.X.J.W. serves as the Editor-in-Chief of Quantitative Imaging in Medicine and Surgery. Y.X.J.W. is the founder of Yingran Medicals Ltd., which develops medical image-based diagnostics software. The other authors have no conflicts of interest to declare.

Ethical Statement: The authors are accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved. The study was conducted in accordance with the Declaration of Helsinki (as revised in 2013). Institutional ethical approval was granted for this study, and verbal informed consent was obtained and recorded for this study.

Open Access Statement: This is an Open Access article distributed in accordance with the Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International License (CC BY-NC-ND 4.0), which permits the non-commercial replication and distribution of the article with the strict proviso that no changes or edits are made and the original work is properly cited (including links to both the formal publication through the relevant DOI and the license). See: https://creativecommons.org/licenses/by-nc-nd/4.0/.

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