Hemodynamic response imaging: a potential tool for the assessment of angiogenesis in brain tumors.

Blood oxygenation level dependence (BOLD) imaging under either hypercapnia or hyperoxia has been used to study neuronal activation and for assessment of various brain pathologies. We evaluated the benefit of a combined protocol of BOLD imaging during both hyperoxic and hypercapnic challenges (termed hemodynamic response imaging (HRI)). Nineteen healthy controls and seven patients with primary brain tumors were included: six with glioblastoma (two newly diagnosed and four with recurrent tumors) and one with atypical-meningioma. Maps of percent signal intensity changes (ΔS) during hyperoxia (carbogen; 95%O2+5%CO2) and hypercapnia (95%air+5%CO2) challenges and vascular reactivity mismatch maps (VRM; voxels that responded to carbogen with reduced/absent response to CO2) were calculated. VRM values were measured in white matter (WM) and gray matter (GM) areas of healthy subjects and used as threshold values in patients. Significantly higher response to carbogen was detected in healthy subjects, compared to hypercapnia, with a GM/WM ratio of 3.8 during both challenges. In patients with newly diagnosed/treatment-naive tumors (n = 3), increased response to carbogen was detected with substantially increased VRM response (compared to threshold values) within and around the tumors. In patients with recurrent tumors, reduced/absent response during both challenges was demonstrated. An additional finding in 2 of 4 patients with recurrent glioblastoma was a negative response during carbogen, distant from tumor location, which may indicate steal effect. In conclusion, the HRI method enables the assessment of blood vessel functionality and reactivity. Reference values from healthy subjects are presented and preliminary results demonstrate the potential of this method to complement perfusion imaging for the detection and follow up of angiogenesis in patients with brain tumors

Means and standard deviations of HRI values calculated from all healthy subjects.

<p>ΔS = percent signal intensity changes; GM = gray matter; WM = white matter; VRM = vascular reactivity mismatch.</p

Hemodynamic Response Imaging in the healthy brain.

<p>Representative HRI results obtained from a 29 year old healthy subject. (A) ΔS-O₂ map; (B) ΔS-CO₂ map; (C) the corresponding T₁-weighted (anatomical) image; (D) the gray and white matter masks (GM and WM, respectively); the mean time courses of the signal intensity change (%) during hyperoxic challenge (E) and hypecapnic (F) challenges, calculated from the GM VOI of this subject.</p

Patients' clinical information.

<p>y = years; M/F = male/female; RT = radiation therapy; Chemo = chemotherapy;</p

Hemodynamic Response Imaging and pathological findings.

<p>Results obtained from a newly diagnosed patient with GB (patient number 2). Representative sagital (left), axial (center) and coronal (right) orientations taken through the tumor center of (A) T₁-weighted images; (B) ΔS-O₂ maps; (C) ΔS-CO₂ maps; (D) VRM maps (of the tumor area marked by white rectangle on <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0049416#pone-0049416-g003" target="_blank">figure 3B,C</a>) and (E) rCBV maps. The maps are superimposed on the anatomical images; color scales for all maps are located on the right side. Immunohistochemical staining of samples from the same tumor with: (F) Ki67 antibody for proliferation; (G) CD31 antibody for endothelial cells indicating vascularity and (H) SMA antibody for smooth muscle cells indicating vascular maturation.</p

Hemodynamic Response Imaging in patients.

<p>HRI results obtained from a patient with atypical meningioma (Left; patient number 1) and from a patient with newly diagnosed glioblastoma (Right; patient number 3); For both patients a representative coronal slice through the tumor center of (A) ΔS-O₂ maps, (B) ΔS-CO₂ maps, (C) VRM maps (of the tumors area which are marked by white rectangle on figures A and B) and (D) rCBV maps. All the maps are superimposed on the anatomical images. Color scales for all maps are located on the right side. PSC- percent signal change; SD- standard deviation.</p

HRI and rCBV values calculated at the lesion and contra lateral side VOIs.

<p>ΔS = percent signal intensity changes; rCBV = relative cerebral blood volume; CLS = contralateral side.</p>1<p>Vascular reactivity index, number of voxels (in percentages) above the defined VRM threshold.</p>2<p>Lesion crosses brain midline, thus contralateral side VOI could not be defined.</p>3<p>DSC perfusion was not performed.</p

Negative

<p>Δ<b>S-O2 response.</b> Representative results obtained from a patient with recurrent GB (patient number 4), showing negative ΔS-O2 response during hyperoxic challenge observed distant from the tumor area. (A) ΔS-O₂ map; (B) T₁WI post contrast agent injection and (C) fluid attenuation inversion recovery (FLAIR) image. (D) The mean time courses of the signal intensity change (%) during hyperoxic challenge obtained from the area with negative response (VOI is marked by red rectangle on <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0049416#pone-0049416-g004" target="_blank">Figure 4A</a>).</p