Spatial covariance pattern of α4β2 nicotinic cholinergic receptors ([18F]flubatine) in Parkinson disease

Objectives In vivo brain PET shows widespread reduction of α4β2 nicotinic cholinergic receptor (nAChR) expression in Parkinson disease (PD). However, less is known about changes in functional and structural connections of α4β2 nAChRs expression in PD. We used spatial covariance analysis (SCA) to explore the cerebral change in the spatial covariance pattern of [18F]flubatine PET, a high affinity and specificity α4β2 nAChR ligand, relative to normal controls (NC).

Methods Cross-sectional study. 27 (20 PD; 7 NC) subjects underwent [18F]flubatine brain PET. Images were spatially normalized to a PET template. Multivariate spatial covariance analysis based on the scaled subprofile model was performed simultaneously on all images using the generalized covariance analysis software suit (http://www.nitrc.org/projects/gcva_pca/) in order to identify between-group variations as a spatial covariance pattern (SCP). The MDS-UPDRS, a PD disease symptom severity neurological assessment scale, was performed in the dopaminergic “off” state.

Results SCP analysis showed a strong pattern of negative weights in the cerebellum. The mean subject scaling factor (SSF) score, representing the extent to which each subject expressed the SCP, was significantly higher in PD than in NC (13.0 ± 11.7 vs.-2.4 ± 9.6; t=-3.1, p=0.004). For PD patients, SSF did not correlate with age, disease duration, or disease symptom severity; however, it did correlate with absolute [18F]flubatine binding in the cerebellum (r=-0.677, p=0.001) and the pons (r=-0.574, p=0.008).

Conclusions The multivariate SCA approach identified a SCP with the cerebellum as a region of concomitant down-regulation of α4β2 nAChRs in PD patients. However, the strength of this effect for individual PD patients (SSF) was not related to PD disease characteristics. The lack of significant clinical correlation of this downregulation may represent a PD-specific mechanism that will need to be further explored in longitudinal studies.