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]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.

Imaging in Parkinson's Disease

“…PDD patients have higher incidence of cortical Aβ-amyloid deposition compared to healthy subjects, PD and PD-MCI, ranging from 0% to 80% (Edison et al, 2013(Edison et al, , 2008Foster et al, 2010;Gomperts et al, 2012Gomperts et al, , 2008Jokinen et al, 2010;Maetzler et al, 2009Maetzler et al, , 2008. Amyloid burden in PDD patients is heterogeneous with cases of PDD, where amyloid deposition overlaps with the levels observed in healthy subjects and in PD patients (Edison et al, 2013(Edison et al, , 2008Foster et al, 2010;Gomperts et al, 2012Gomperts et al, , 2008Jokinen et al, 2010;Maetzler et al, 2009Maetzler et al, , 2008 and other cases of PDD showing elevated cortical amyloid deposition in the Alzheimer's disease (AD) range (Edison et al, 2013(Edison et al, , 2008Foster et al, 2010;Gomperts et al, 2012;Jokinen et al, 2010;Maetzler et al, 2009Maetzler et al, , 2008Shimada et al, 2013). In contrast, amyloid burden is usually elevated in DLB patients compared to healthy subjects and PD patients and the incidence ranges between 33% and 100% (Burke et al, 2011;Claassen, Lowe, Peller, Petersen, & Josephs, 2011;Edison et al, 2008;Foster et al, 2010;Gomperts et al, 2012Gomperts et al, , 2008Graff-Radford et al, 2012;Kantarci et al, 2012;Maetzler et al, 2009Maetzler et al, , 2008Rowe et al, 2007;<...>…”

“…Moreover, the levels of microglial activation remained stable over a period of 2 years (Gerhard et al, 2006). [ 11 C]PK11195 binding was also increased in the anterior and posterior cingulate, striatum, frontal, temporal, parietal, and occipital cortical regions in PDD patients (Edison et al, 2013) and in the substantia nigra, putamen, and several associative cortices of DLB patients (Iannaccone et al, 2013).…”

“…However, extracellular Aβ-amyloid plaques and intracellular tau neurofibrillary tangle are also observed at autopsy in PD, PDD, and DLB patients (Horvath, Herrmann, Burkhard, Bouras, & K€ ovari, 2013;Jellinger & Attems, 2008;Jellinger, Seppi, Wenning, & Poewe, 2002 of amyloid deposition in PD, PDD, and DLB. Overall these studies found that amyloid deposition tends to be modest in PD with normal cognition occurring in about 0%-13% of PD patients (Edison et al, 2013(Edison et al, , 2008Foster et al, 2010;Gomperts et al, 2012Gomperts et al, , 2008Johansson et al, 2008;Jokinen et al, 2010;Maetzler et al, 2009;Siderowf et al, 2014;Villemagne et al, 2011). Amyloid burden is generally low in PD subjects with mild cognitive impairment (MCI), and does not distinguish cognitively normal PD patients from PD-MCI (Foster et al, 2010;Gomperts et al, 2012Gomperts et al, , 2013Petrou et al, 2012).…”

“…Amyloid burden is generally low in PD subjects with mild cognitive impairment (MCI), and does not distinguish cognitively normal PD patients from PD-MCI (Foster et al, 2010;Gomperts et al, 2012Gomperts et al, , 2013Petrou et al, 2012). PDD patients have higher incidence of cortical Aβ-amyloid deposition compared to healthy subjects, PD and PD-MCI, ranging from 0% to 80% (Edison et al, 2013(Edison et al, , 2008Foster et al, 2010;Gomperts et al, 2012Gomperts et al, , 2008Jokinen et al, 2010;Maetzler et al, 2009Maetzler et al, , 2008. Amyloid burden in PDD patients is heterogeneous with cases of PDD, where amyloid deposition overlaps with the levels observed in healthy subjects and in PD patients (Edison et al, 2013(Edison et al, , 2008Foster et al, 2010;Gomperts et al, 2012Gomperts et al, , 2008Jokinen et al, 2010;Maetzler et al, 2009Maetzler et al, , 2008 and other cases of PDD showing elevated cortical amyloid deposition in the Alzheimer's disease (AD) range (Edison et al, 2013(Edison et al, , 2008Foster et al, 2010;Gomperts et al, 2012;Jokinen et al, 2010;Maetzler et al, 2009Maetzler et al, , 2008Shimada et al, 2013).…”

Commentary on interactions between neurotropic pathogens, neuroinflammatory pathways, and autophagic neural cell death

“…In a rat brain AD model elevated TSPO levels were found in tau-rich hippocampus and entorhinal cortex region of the brain and there was a constant increase of tracer uptake in the brain region with the progression of AD [34] . In PD patients, microglia activation could be detected via TPSO PET at the early phase of the disease, and its activity is correlated with the development of dementia in PD [35] .…”