Abnormal pattern of brain glucose metabolism in Parkinson's disease: replication in three European cohorts

Abstract

Rationale: In Parkinson's disease (PD), spatial covariance analysis of ¹⁸F-FDG PET data has consistently revealed a characteristic PD-related brain pattern (PDRP). By quantifying PDRP expression on a scan-by-scan basis, this technique allows objective assessment of disease activity in individual subjects. We provide a further validation of the PDRP by applying spatial covariance analysis to PD cohorts from the Netherlands (NL), Italy (IT), and Spain (SP).

Methods: The PDRP_NL was previously identified (17 controls, 19 PD) and its expression was determined in 19 healthy controls and 20 PD patients from the Netherlands. The PDRP_IT was identified in 20 controls and 20 "de-novo" PD patients from an Italian cohort. A further 24 controls and 18 "de-novo" Italian patients were used for validation. The PDRP_SP was identified in 19 controls and 19 PD patients from a Spanish cohort with late-stage PD. Thirty Spanish PD patients were used for validation. Patterns of the three centers were visually compared and then cross-validated. Furthermore, PDRP expression was determined in 8 patients with multiple system atrophy.

Results: A PDRP could be identified in each cohort. Each PDRP was characterized by relative hypermetabolism in the thalamus, putamen/pallidum, pons, cerebellum, and motor cortex. These changes co-varied with variable degrees of hypometabolism in posterior parietal, occipital, and frontal cortices. Frontal hypometabolism was less pronounced in "de-novo" PD subjects (Italian cohort). Occipital hypometabolism was more pronounced in late-stage PD subjects (Spanish cohort). PDRP_IT, PDRP_NL, and PDRP_SP were significantly expressed in PD patients compared with controls in validation cohorts from the same center (P < 0.0001), and maintained significance on cross-validation (P < 0.005). PDRP expression was absent in MSA.

Conclusion: The PDRP is a reproducible disease characteristic across PD populations and scanning platforms globally. Further study is needed to identify the topography of specific PD subtypes, and to identify and correct for center-specific effects.

Keywords: 18F-FDG PET; Metabolic pattern; Networks; Parkinson’s disease.

Fig. 1

Display of PDRP_NL (a), PDRP_IT (b), and PDRP_SP (c). All voxel values of each PDRP are overlaid on a T1 MRI template. Red indicates positive voxel weights (relative hypermetabolism) and blue indicates negative voxel weights (relative hypometabolism).L=left. Coordinates in the axial (Z) and sagittal (X) planes are in Montreal Neurological Institute (MNI) standard space.

Fig. 2

Display of stable voxels of each PDRP, determined after bootstrap resampling (90% confidence interval not straddling zero). Overlay on a T1 MRI template. Positive voxel weights are color-coded red (relative hypermetabolism), and negative voxel weights are color-coded blue (relative hypometabolism). L, left. Coordinates in the axial (Z) and sagittal (X) planes are in Montreal Neurological Institute (MNI) standard space.

Fig. 3

Subject scores for each PDRP in their respective derivation and validation cohorts. a PDRP_NL was identified in 17 HC and 19 PD (NL1) and validated in 19 HC and 20 PD (NL2). Because reconstruction parameters were different for cohort NL1 and NL2, PDRP subject scores were z-transformed to corresponding healthy controls. b PDRP_IT was identified in 20 HC and 20 PD, and validated in 24 HC and 18 PD. All subject scores were z-transformed to the 20 HC from the derivation sample. c PDRP_SP was identified in 19 HC and 19 PD, and validated in 30 PD. Additional HC for validation were not available. All subject scores were z-transformed to the 19 HC from the derivation sample. Subject z-scores are compared between groups with a Student’s t test. Bars indicate mean and standard deviation

Fig. 4

Subject scores for each PDRP in the other cohorts (cross-validation). a PDRP_NL subject scores are plotted for the Italian (IT) and Spanish (SP) data. b PDRP_IT subject scores are plotted for the two Dutch samples (NL1 and NL2) and in SP data. c PDRP_SP subject scores are plotted for NL1, NL2, and IT data. Subject scores are z-transformed to healthy control values from the same camera, and compared between groups with a Student’s t test. Bars indicate mean and standard deviation

Fig. 5

Subject z-scores for the reference pattern PDRP_USA [11] in each of the datasets. Subject scores are z-transformed to healthy control values from the same camera, and compared between groups with a Student’s t test. Bars indicate mean and standard deviation

Fig. 6

Subject scores for each PDRP in eight cases of MSA-p. Subject scores are z-transformed to NL2 controls and compared between groups with a Student’s t test. Bars indicate mean and standard deviation