Imaging microglial activation in Huntington's disease

https://doi.org/10.1016/j.brainresbull.2006.10.029Get rights and content

Abstract

Activated microglia have been proposed to play a major role in the pathogenesis of Huntington's Disease (HD). PK11195 is a ligand which binds selectively to peripheral benzodiazepine binding sites, a type of receptor selectively expressed by activated microglia in the central nervous system. Using 11C-(R)-PK11195 positron emission tomography (PET), we have recently shown in vivo evidence of increased microglial activation in both symptomatic and presymptomatic HD gene carriers and that the degree of microglial activation in the striatum correlates with the severity of striatal dopamine D2 receptor dysfunction measured with 11C-raclopride PET. Our findings indicate that microglial activation is an early process in the HD pathology, occurring before the onset of symptoms. The close spatial and temporal relationship between microglial activation and neuronal dysfunction lends further support to the pathogenic link between the two processes in HD. Further longitudinal studies are needed to fully elucidate this link.

Introduction

Huntington's disease (HD) is an autosomal dominantly inherited neurodegenerative disease. The underlying genetic mutation has been identified as a CAG-repeat expansion in the IT15 gene of chromosome 4. This leads to the formation of a mutant huntingtin protein with an elongated N-terminal polyglutamine chain [19]. The exact mechanisms linking the formation of the mutant huntingtin to neuronal cell death, particularly in the striatum, are as yet unclear but fibril formation leading to excitotoxicity, caspase activation and apoptosis, mitochondrial dysfunction, and RNA dysregulation have all been implicated [11]. Recent evidence suggests that microglial activation is also an integral part of HD pathogenesis.

Section snippets

Activated microglia

Microglia are the major intrinsic immunocompetent phagocytic cells in the central nervous system. They comprise 10–20% of the white cell population and are normally found in a quiescent state with spidery processes. Upon exposure of the brain to any form of insult, such as trauma, infection or ischaemia, the microglia rapidly become activated. They proliferate and surround the site of injury, stripping and remodelling synapses. In the case of HD, the insult could be the presence of dying

In vivo imaging of microglial activation using 11C-(R)-PK11195 PET

When microglia become activated, they express peripheral benzodiazepine binding sites (PBBS) on their mitochondrial membrane. PBBS are functionally and structurally distinct from central benzodiazepine receptors associated with γ-aminobutyric acid (GABA)-regulated chloride channels. PBBS are found in abundance in peripheral organs (liver and adrenals) and haematogenous cells, but are present at only very low levels in the normal central nervous system [1]. PK11195, an isoquinoline, binds

Clinical implications

Despite the inconsistent animal data on the efficacy of minocycline [5], [6], [17] and some evidence suggesting beneficial effects of microglial activation [9], several studies investigating the safety and efficacy of minocycline in human HD patients are currently underway [3], [8], [20]. Our finding of significant association between microglial activation and striatal neuronal pathology in HD provides further support for the rationale of these trials. Should the trials in symptomatic HD

Conclusion

11C-(R)-PK11195 PET provides an important in vivo marker of microglial activation in HD. Using this technique, we have shown significant microglial activation in HD patients and asymptomatic carriers, and the close association between microglial activation and striatal neuronal dysfunction. Although both detrimental and beneficial roles of activated microglia in neurodegenerative diseases have been reported, the weight of evidence in the literature supports the former. Longitudinal clinical

Acknowledgements

Y. F. Tai was funded by the Wellcome Trust. The study was funded by the Medical Research Council, UK.

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