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Functional Neuroimaging Using Ultrasonic Blood-brain Barrier Disruption and Manganese-enhanced MRI
Published on: July 12, 2012
MRI and PET studies of manganese-intoxicated monkeys
H Shinotoh1, B J Snow, K A Hewitt
1Neurodegenerative Disorders Centre, University of British Columbia, Vancouver, Canada.
Abstract:
Using MRI and PET, we investigated the consequences of manganese intoxication in a primate model of parkinsonism and dystonia. Three rhesus monkeys were injected intravenously with doses of 10 to 14 mg/kg of MnCl2 on seven occasions, each a week apart. Two animals became hypoactive with abnormal extended posturing in the hind limbs. These motor disturbances did not improve with administration of levodopa. In all three monkeys, T1-weighted MRI demonstrated high signal intensities in the regions of the striatum, globus pallidus, and substantia nigra. No significant changes were found on [18F]6-fluoro-L-dopa, [11C]raclopride, or [18F]fluorodeoxyglucose PET. These results are consistent with the pathologic findings, which were primarily confined to the globus pallidus, and indicate that manganese intoxication is associated with preservation of the nigrostriatal dopaminergic pathway, despite clinical evidence of parkinsonian deficits. Chronic manganese intoxication may cause parkinsonism by damaging output pathways downstream to the nigrostriatal dopaminergic pathway. This is consistent with the demonstrated lack of therapeutic response to levodopa.
Insights
Manganese intoxication in primates caused parkinsonism by damaging downstream pathways, not the nigrostriatal dopaminergic pathway. This explains the lack of response to levodopa treatment.
Area of Science:
- Neuroscience
- Toxicology
- Primate Models
Background:
- Manganese is an essential element, but chronic intoxication can lead to neurological disorders resembling Parkinson's disease.
- The exact mechanisms by which manganese induces parkinsonian symptoms remain unclear.
Purpose of the Study:
- To investigate the neurological consequences of manganese intoxication in a primate model.
- To determine the impact of manganese on the nigrostriatal dopaminergic pathway and related motor functions.
Main Methods:
- Three rhesus monkeys received intravenous manganese chloride (MnCl2) injections over seven weeks.
- Magnetic Resonance Imaging (MRI) and Positron Emission Tomography (PET) scans were used to assess brain changes.
- Clinical motor assessments and levodopa response were evaluated.
Main Results:
- Manganese-intoxicated monkeys exhibited hypoactivity and abnormal posturing, unresponsive to levodopa.
- T1-weighted MRI revealed high signal intensities in the striatum, globus pallidus, and substantia nigra.
- PET scans showed no significant changes in dopaminergic pathways or glucose metabolism.
Conclusions:
- Manganese intoxication in primates causes parkinsonian deficits through damage to pathways downstream of the nigrostriatal dopaminergic system.
- The dopaminergic pathway remains intact, explaining the lack of therapeutic response to levodopa.
- Chronic manganese exposure may induce parkinsonism via extrastriatal mechanisms.
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