Microglia, amyloid, and glucose metabolism in Parkinson's disease with and without dementia

Abstract

[(11)C](R)PK11195-PET measures upregulation of translocator protein, which is associated with microglial activation, [(11)C]PIB-PET is a marker of amyloid, while [(18)F]FDG-PET measures cerebral glucose metabolism (rCMRGlc). We hypothesize that microglial activation is an early event in the Parkinson's disease (PD) spectrum and is independent of the amyloid pathology. The aim of this study is to evaluate in vivo the relationship between microglial activation, amyloid deposition, and glucose metabolism in Parkinson's disease dementia (PDD) and PD subjects without dementia. Here, we evaluated 11 PDD subjects, 8 PD subjects without dementia, and 24 control subjects. Subjects underwent T1 and T2 MRI, [(11)C](R)PK11195, [(18)F]FDG, and [(11)C]PIB PET scans. Parametric maps of [(11)C](R)PK11195 binding potential, rCMRGlc, and [(11)C]PIB uptake were interrogated using region of interest and SPM (statistical parametric mapping) analysis. The PDD patients showed a significant increase of microglial activation in anterior and posterior cingulate, striatum, frontal, temporal, parietal, and occipital cortical regions compared with the controls. The PD subjects also showed a statistically significant increase in microglial activation in temporal, parietal, and occipital regions. [(11)C]PIB uptake was marginally increased in PDD and PD. There was a significant reduction in glucose metabolism in PDD and PD. We have also demonstrated pixel-by-pixel correlation between mini-mental state examination (MMSE) score and microglial activation, and MMSE score and rCMRGlc. In conclusion, we have demonstrated that cortical microglial activation and reduced glucose metabolism can be detected early on in this disease spectrum. Significant microglial activation may be a factor in driving the disease process in PDD. Given this, agents that affect microglial activation could have an influence on disease progression.

Figure 1

[¹¹C](R)PK11195 uptake in PDD and PD subjects compared with controls. (a) [¹¹C](R)PK11195 uptake in 11 PDD subjects compared with 10 control subjects showing significant increase in microglial activity in frontal, temporo-parietal, and occipital cortical regions at a P<0.005 and extent threshold of 50 voxels. (b) [¹¹C](R)PK11195 uptake in eight PD subjects compared with 10 control subjects showing significant increase in microglial activity in temporo-parietal and occipital cortical regions at a P<0.005 and extent threshold of 50 voxels.

Figure 2

Statistical parametric mapping (SPM) analysis of [¹¹C](R)PK11195 BP and rCMRGlc between PDD and PD subjects. (a) SPM analysis of [¹¹C](R)PK11195 BP between PDD and PD subjects. Shows minimally increased microglial activity in PDD compared with PD using [¹¹C](R)PK11195 in11 PDD subjects compared with 8 PD subjects at voxel threshold of P<0.05 and extent threshold of 50 voxels. (b) SPM analysis of rCMRGlc between PDD and PD subjects. Shows significantly reduced glucose metabolism in PDD compared with PD using [¹⁸F]FDG PET in11 PDD subjects compared with 6 PD subjects at voxel threshold of P<0.05 and extent threshold of 50 voxels.

Figure 3

Statistical parametric mapping (SPM) analysis of rCMRGlc in PDD and PD subjects compared with the controls. (a) Reduction in rCMRGlc in 11 PDD subjects compared with eight control subjects showing significant reduction in frontal, temporo-parietal, and occipital region at voxel threshold of P<0.005 and extent threshold of 50 voxels. (b) Reduction in rCMRGlc in eight PD subjects compared with eight control subjects showing significant reduction in frontal, temporo-parietal, and occipital region at voxel threshold of P<0.05 and extent threshold of 50 voxels.

Figure 4

Single subject SPM analysis of microglial activation and glucose metabolism in PDD and PD subjects against controls. (a, b) Increased microglial activation and reduced glucose metabolism, respectively, in a PDD. (c and d) Increased microglial activation and reduction in glucose metabolism in PD subject.

Figure 5

Pixel-by-pixel correlation between microglial activation, glucose metabolism, and MMSE scores in PDD subjects. (a) Significant clusters using regression analysis of [¹¹C](R)PK11195 BP against MMSE score in 11 PDD subjects at a cluster threshold of P<0.00005 with extent threshold of 200 voxels. Cortical microglial activation was correlated with MMSE in PDD subjects. (b) Significant clusters using regression analysis of rCMRGlc against MMSE score in 11 PDD subjects at a cluster threshold of P<0.00005 with extent threshold of 200 voxels. Cortical rCMRGlc was correlated with the MMSE scores.

Figure 6

Semi-quantitative figure showing microglial activation vs hypometabolism overlaid on SPM templates. (a) [¹¹C](R)PK11195 BP map overlaid on rCMRGlc map in PDD, (b) the same in a PD subject. Microglial activation is represented in red, rCMRglc in blue, while purple demonstrates the overlap.