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Microglial activation correlates with severity in Huntington disease: a clinical and PET study
1MRC Clinical Sciences Centre and Division of Neuroscience, Faculty of Medicine, Imperial College, Hammersmith Hospital, London, UK.
Background:
Huntington disease (HD) is characterized by the progressive death of medium spiny dopamine receptor bearing striatal GABAergic neurons. In addition, microglial activation in the areas of neuronal loss has recently been described in postmortem studies. Activated microglia are known to release neurotoxic cytokines, and these may contribute to the pathologic process.
Methods:
To evaluate in vivo the involvement of microglia activation in HD, the authors studied patients at different stages of the disease using [(11)C](R)-PK11195 PET, a marker of microglia activation, and [(11)C]raclopride PET, a marker of dopamine D2 receptor binding and hence striatal GABAergic cell function.
Results:
In HD patients, a significant increase in striatal [(11)C](R)-PK11195 binding was observed, which significantly correlated with disease severity as reflected by the striatal reduction in [(11)C]raclopride binding, the Unified Huntington's Disease Rating Scale score, and the patients' CAG index. Also detected were significant increases in microglia activation in cortical regions including prefrontal cortex and anterior cingulate.
Conclusions:
These [(11)C](R)-PK11195 PET findings show that the level of microglial activation correlates with Huntington disease (HD) severity. They lend support to the view that microglia contribute to the ongoing neuronal degeneration in HD and indicate that [(11)C](R)-PK11195 PET provides a valuable marker when monitoring the efficacy of putative neuroprotecting agents in this relentlessly progressive genetic disorder.
Insights
Microglial activation increases with Huntington disease (HD) severity, as shown by [(11)C](R)-PK11195 PET scans. This suggests microglia contribute to neurodegeneration and [(11)C](R)-PK11195 PET can track treatment effectiveness.
Area of Science:
- Neuroscience
- Neurology
- Medical Imaging
Background:
- Huntington disease (HD) involves progressive loss of striatal neurons.
- Microglial activation, releasing neurotoxic cytokines, is observed in affected brain areas.
- The role of microglia in HD pathogenesis requires in vivo investigation.
Purpose of the Study:
- To evaluate in vivo the involvement and extent of microglial activation in Huntington disease (HD).
- To correlate microglial activation levels with HD disease severity and neuronal function.
Main Methods:
- Utilized Positron Emission Tomography (PET) with [(11)C](R)-PK11195 to measure microglia activation.
- Employed [(11)C]raclopride PET to assess dopamine D2 receptor binding, indicating striatal GABAergic neuron function.
- Studied patients across different stages of Huntington disease.
Main Results:
- Significantly increased striatal [(11)C](R)-PK11195 binding (microglia activation) was observed in HD patients.
- Microglia activation levels strongly correlated with disease severity, reduced dopamine D2 receptor binding, and higher CAG repeat index.
- Elevated microglia activation was also noted in cortical regions like the prefrontal cortex.
Conclusions:
- Microglial activation is significantly correlated with Huntington disease severity.
- Findings support the role of microglia in the neurodegenerative process of HD.
- [(11)C](R)-PK11195 PET is a valuable tool for monitoring neuroprotective agent efficacy in HD.
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