Microglial activation and dopamine terminal loss in early Parkinson's disease

Abstract

Neuroinflammatory glial response may contribute to degenerative processes in Parkinson's disease (PD). To investigate changes in microglial activity associated with changes in the presynaptic dopamine transporter density in the PD brain in vivo, we studied 10 early-stage drug-naive PD patients twice using positron emission tomography with a radiotracer for activated microglia [(11)C](R)-PK11195 and a dopamine transporter marker [(11)C]CFT. Quantitative levels of binding potentials (BPs) of [(11)C](R)-PK11195 and [(11)C]CFT in the nigrostriatal pathway were estimated by compartment analyses. The levels of [(11)C](R)-PK11195 BP in the midbrain contralateral to the clinically affected side were significantly higher in PD than that in 10 age-matched healthy subjects. The midbrain [(11)C](R)-PK11195 BP levels significantly correlated inversely with [(11)C]CFT BP in the putamen and correlated positively with the motor severity assessed by the Unified Parkinson's Disease Rating Scale in PD. In healthy subjects, the [(11)C](R)-PK11195 BP in the thalamus and midbrain showed an age-dependent increase. In vivo demonstration of parallel changes in microglial activation and corresponding dopaminergic terminal loss in the affected nigrostriatal pathway in early PD supports that neuroinflammatory responses by intrinsic microglia contribute significantly to the progressive degeneration process of the disease and suggests the importance of early therapeutic intervention with neuroprotective drugs.

Meloxicam protects cell damage from 1-methyl-4-phenyl pyridinium toxicity via the phosphatidylinositol 3-kinase/Akt pathway in human dopaminergic neuroblastoma SH-SY5Y cells

“…It has been reported that inflammation is up-regulated in brains of PD patients (McGeer et al, 1988;Whitton, 2007), and parallel changes in microglial activation and corresponding dopaminergic terminal loss are observed in the affected nigrostriatal pathway of early PD (Ouchi et al, 2005). Despite some controversial findings, the beneficial effects of non-aspirin and nonsteroidal antiinflammatory drugs (NSAIDs) on PD progression have been supported by several epidemiological studies (Chen et al, 2003;Hernan et al, 2006;Ton et al, 2006), suggesting that antiinflammatory agents may prevent neuronal death in PD.…”

“…The neuronal protective effect of NSAIDs has been supposedly achieved through the inhibition of cyclooxygenase (COX)-2 that subsequently reduce toxic mediators (such as inflammatory cytokines and oxidants) derived from activated microglia, which have been observed in the affected substantia nigra pars compacta of PD patients (McGeer et al, 1988;Ouchi et al, 2005). However, up-regulation of COX-2 has been found not only in microglia but also in neurons of substantia nigra pars compacta of PD patients and mice intoxicated by 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) (Liberatore et al, 1999;Teismann et al, 2003).…”

Dual effects of TNFα on nerve fiber formation from ventral mesencephalic organotypic tissue cultures

“…TNFα is produced by activated microglia and the number of activated microglial cells are increased in the brains of parkinsonian patients (McGeer and McGeer 1997). Microglia are already activated during the early phase of Parkinson's disease, and the presence of activated microglia is correlated with decrease in dopamine nerve fiber density (Ouchi et al 2005).…”

Evaluation of Reference Tissue Models for the Analysis of [11C](R)-PK11195 Studies

“…Both [ 11 C](R)-PK11195 and [ 11 C]PK11195 have been used as positron emmision tomography (PET) tracers to study activated microglia in various neurologic disorders. It has been used to study stroke (Ramsay et al, 1992;Pappata et al, 2000;Gerhard et al, 2000Gerhard et al, , 2005a), Alzheimer's disease (Groom et al, 1995; Cagnin et al, 2001a;Versijpt et al, 2003), multiple sclerosis (Banati et al, 2000;Debruyne et al, 2002Debruyne et al, , 2003Versijpt et al, 2005) and various other diseases (Pappata et al, 1991; Banati et al, 1999Banati et al, , 2001Goerres et al, 2001;Cagnin et al, 2001bCagnin et al, , 2004Cicchetti et al, 2002;Gerhard et al, 2003Gerhard et al, , 2004Gerhard et al, , 2005bTurner et al, 2004Turner et al, , 2005Venneti et al, 2004;Henkel et al, 2004;Ouchi et al, 2005). Most studies have used a reference tissue approach to quantify binding, either by applying the simplified reference tissue model (SRTM) (Lammertsma and Hume, 1996) or by using uptake normalized to a reference region.…”