Microglial Activation Is Increased in Glucocerebrosidase (GBA1) Mutation Carriers: A Cross-Sectional PET Study

Abstract

Background: Glucocerebrosidase mutations (GBA1) are the most common genetic risk factor for Parkinson disease (PD). Five-15% of PD patients and 1% of the general population carry a GBA1 mutation, however only 10-30% will develop PD. Mechanisms to predict PD conversion are required for targeting of future neuroprotective compounds. GBA1 mutation carriers represent an ideal group to study such early brain changes. \n \nMethods: We carried out positron emission tomography (PET) scans on 9 GBA1 carriers unaffected by PD and 29 controls, using 11C-(R)-PK11195BPND to detect glial activation and 18F-DOPA to measure dopaminergic integrity. GBA1 carriers were screened for prodromal clinical features of PD. \n \nFindings: Region of interest analysis of nigrostriatal structures showed that 11C-(R)-PK11195BPND was increased in the substantia nigra of our GBA1 carriers (Student s t test, right t=-3.4 p=0.0022, left t=-4.5, 3p=0.0001). However, they had a similar mean striatal 18F-DOPA uptake as healthy controls. There was no correlation between 18F-DOPA uptake and 11C-(R)-PK11195BPND. The degree of hyposmia measured with the UPSIT test correlated with nigral 11C-(R)-PK11195BPND (Spearman s rank, right, p=0.031, left p=0.006). Statistical Parametric Mapping localised further areas of significantly increased 11C-(R)-PK11195BPND in the occipital and temporal lobes, cerebellum, hippocampus, and the mesencephalon of GBA1 carriers compared to controls. \n \nInterpretation: In vivo 11C-(R)-PK11195BPND PET imaging detects the presence of neuroinflammation (microglial activation) in brain regions susceptible to Lewy body pathology in GBA1 carriers. Levels of microglial activation in the substantia nigra correlate with hyposmia severity in GBA1 carriers and precede the loss of striatal dopaminergic terminal function measured with 18F-DOPA PET. These findings have implications for the sequence of pathogenesis in GBA1-related PD and suggest 11C-(R)-PK11195BPND PET may be a pre-clinical marker for PD-GBA1. \n \nFunding: MRC (UK), Independent Research Fund Denmark, Lundbeck Foundation, Kattan Trust, Joint Programme Neurodegenerative Disease Research, Leonard Wolfson Experimental Neurology Centre, NIHR(UK). \n \nDeclaration of Interest: SM has received honoraria and travel support for speaking at meetings supported by Shire pharmaceuticals and honoraria for consulting for Huron. AHVS has received honorarium for consultancy to Sanofi and Lundbeck. \n \nEthical Approval: Ethical approval was obtained from The London (Hampstead) Research ethics committee, UK (10/H0720/21) and the Ethics Committee Region Midtjylland, Denmark (M-2014-397-14)