Evidence for inflammation in normal-appearing brain regions in patients with growing sporadic vestibular schwannoma: A PET study

Abstract

Background: Nonauditory symptoms can be a prominent feature in patients with sporadic vestibular schwannoma (VS), but the cause of these symptoms is unknown. Inflammation is hypothesized to play a key role in the growth and symptomatic presentation of sporadic VS, and in this study, we investigated through translocator protein (TSPO) positron emission tomography (PET) whether inflammation occurred within the "normal appearing" brain of such patients and its association with tumor growth.

Methods: Dynamic PET datasets from 15 patients with sporadic VS (8 static and 7 growing) who had been previously imaged using the TSPO tracer [¹¹C](R)-PK11195 were included. Parametric images of [¹¹C](R)-PK11195 binding potential (BP_ND) and the distribution volume ratio (DVR) were derived and compared across VS growth groups within both contralateral and ipsilateral gray (GM) and white matter (WM) regions. Voxel-wise cluster analysis was additionally performed to identify anatomical regions of increased [¹¹C](R)-PK11195 binding.

Results: Compared with static tumors, growing VS demonstrated significantly higher cortical (GM, 1.070 vs. 1.031, P = .03) and whole brain (GM & WM, 1.045 vs. 1.006, P = .03) [¹¹C](R)-PK11195 DVR values. The voxel-wise analysis supported the region-based analysis and revealed clusters of high TSPO binding within the precentral, postcentral, and prefrontal cortex in patients with growing VS.

Conclusions: We present the first in vivo evidence of increased TSPO expression and inflammation within the brains of patients with growing sporadic VS. These results provide a potential mechanistic insight into the development of nonauditory symptoms in these patients and highlight the need for further studies interrogating the role of neuroinflammation in driving VS symptomatology.

Keywords: PET; TSPO; inflammation; microglia; vestibular schwannoma.

Figure 1.

[¹¹C](R)PK11195 DVR in normal-appearing brain. (A) Dot plot demonstrating [¹¹C](R)PK11195 DVR values in global brain cortex (GM) and whole brain (GM & WM). Red circles (first column) represent growing VS; blue (second column) represents static VS. Horizontal black lines represent the mean ± 1 SD. Asterisk (*) indicates P < .05; unpaired 2-sample t-test. (B) Dot plot demonstrating breakdown of [¹¹C](R)PK11195 DVR values in ipsilesional and contralesional brain cortex (GM) and whole brain (GM & WM). (C) Summed [¹¹C](R)-PK11195 DVR image combining DVR values from the growing (top row) and static VS (bottom row). Summed [¹¹C](R)PK11195 DVR image shown overlaid on average T1W image. In all patients, the hemisphere ipsilateral to the tumor (ipsilesional) is shown on the right side with contralateral brain (contralesional) shown on the left. Note in patients with growing VS the increased [¹¹C](R)PK11195 DVR within supratentorial GM and WM, and the increased [¹¹C](R)PK11195 DVR within contralesional vs. ipsilesional brain areas.

Figure 2.

Correlation of brain TSPO expression with tumor size and tumor [¹¹C](R)PK11195 DVR. Correlation results of [¹¹C](R)-PK11195 DVR in global brain cortex (GM) and global whole brain (GM & WM) against mean tumoral [¹¹C](R)PK11195 DVR and tumor volume (cm³). Red circles represent growing VS; blue represent static VS. Pearson’s product–moment correlation coefficient (r) and adjusted r² estimates reported.

Figure 3.

Brain TSPO expression and intratumoral inflammation. (A) Representative [¹¹C](R)PK11195 DVR images (overlaid on T1W images) from a patient with a growing and static VS, respectively. Bottom row: Axial image through cerebellopontine angle shows increased [¹¹C](R)PK11195 DVR within growing VS relative to static tumor (arrow). Top row: Axial image through supratentorial brain regions shows increased [¹¹C](R)PK11195 DVR within contralesional GM and WM in the patient with a growing VS. (B) Representative tumor tissue immunostains (Iba1 = red) from the growing and static VS shown in panel B. Note the high abundance of Iba1⁺ macrophages within the growing VS relative to the static tumor (immunoperoxidase, ×20 HPF). C: Double immunostained (Iba1 = red /TSPO = brown) image sections from the growing VS shown in panel A and B demonstrating colocalization of TSPO expression within the cytoplasm of Iba1⁺ macrophages and demonstrating macrophages as the principal source of TSPO binding (immunoperoxidase, ×40 HPF).

Figure 4.

Voxel-wise SPM analysis of [¹¹C](R)PK11195 DVR. The location of significant clusters (FWE P < .05) with voxel-wise differences between static and growing VS are shown. The color bar values indicate the value of the T-statistic. Clusters shown overlaid on coronal template T1W images in MNI space (panel A). 3D brain renders also shown with significant clusters shown in red (panel B). In patients with a left-sided tumor, the individual structural T1-weighted MRI and parametric [¹¹C](R)PK11195 DVR images were first left-right flipped. In all patients, the hemisphere ipsilateral to the tumor (ipsilesional) is therefore shown on the right side. Clusters of increased [¹¹C](R)PK11195 binding were observed in the ipsilesional postcentral gyrus, ipsilesional prefrontal cortex, contralesional precentral gyrus, and contralesional prefrontal cortex in patients with growing VS compared to patients with static tumors. Parametric [¹¹C](R)PK11195 DVR images were smoothed using a 3-dimensional 6-mm FWHM Gaussian filter before statistical analysis and the threshold of P < .05 under FWE corrected statistics at the cluster level (FWEc) was applied.