Microglial activation in normal-appearing brain regions of patients with cerebral glioma: a cross-sectional study

Background

Translocator protein (TSPO) is overexpressed mainly in activated microglia under disease conditions. [¹¹C]-(R)PK11195 is a radioligand for TSPO widely applied in PET studies. Previously we have found upregulated TSPO in neoplastic cells and its correlation with malignant transformation in human gliomas using [¹¹C]-(R)PK11195 PET and neuropathological assessment. We aimed to investigate TSPO expression and microglial activation in normal-appearing brain regions of patients with glioma.

Methods

14 patients with low-grade glioma (before tumour biopsy or debulking) and ten healthy controls underwent MRI and PET scans. Epilepsy history was reviewed. Binding potential (BP_ND) of [¹¹C]-(R)PK11195 was calculated by the simplified reference tissue model. BP_ND of normal-appearing brain regions was compared with that in controls. Post-mortem brains with treatment-naive low-grade glioma were assessed for TSPO and microglia by immunohistochemistry.

Findings

BP_ND of [¹¹C]-(R)PK11195 in low-grade gliomas was lower than in normal-appearing cerebral regions in the contralateral hemisphere (mean ?0·108 [SD 0·148] vs 0·047 [0·101], p=0·0006). Compared with controls, BP_ND in patients' normal-appearing brain regions was increased (0·065 [0·062] vs 0·002 [0·024], p=0·001), being more prominent in the tumour-bearing hemisphere than in the tumour-free hemisphere (0·081 [0·064] vs 0·057 [0·063], p=0·002). The extratumoral BP_ND correlated with the length of epilepsy history (Spearman rank correlation coefficient r=0·5, p=0·016). An ipsilateral pattern of increased extratumoral BP_ND was seen in patients with partial seizures, whereas a bilateral pattern of increase was seen in those with generalised seizures. Post-mortem brain tissue showed a 10-fold increase in microglia and elevation in TSPO-expressing microglia in the gyri adjacent to the tumour and in the contralateral tissue compared with normal brains.

Interpretation

[¹¹C](R)PK11195 PET and neuropathological assessment revealed widespread microglial activation in normal-appearing brain regions of patients with glioma. That the magnitude of activation was associated with length of epilepsy history and seizure type suggests that modulation of microglial activation could be a novel target for seizure control in these patients. TSPO PET provides an in-vivo demonstration of this inflammatory response, which is undetectable by structural MRI.

Funding

European Union's Seventh Framework Programme (FP7/2007-2013) under grant agreement INMiND (HEALTH-F2-2011-278850), Engineering and Physical Science Research Council grant MIMIT (EP/G041733/1), Astro Brain Tumour Fund (1133561).