Iron Accumulation in Brain Detected With High-Resolution MRI Technique, Animal Study Shows

An experimental model of Parkinson’s in non-human primates leads to the accumulation of iron — known to contribute to the underlying causes of the disease — in a brain area linked to motor control. This metal accumulation can be detected using a neuroimaging technique called susceptibility-weighted imaging, according to recent research.

The study, titled “The role of iron in Parkinson’s disease monkeys assessed by susceptibility weighted imaging and inductively coupled plasma mass spectrometry,” was published in Life Sciences.

Higher-than-usual iron levels have been found in a brain region — called the substantia nigra — in Parkinson’s patients. This brain area, which plays a key role in motor control, is particularly affected during the course of the neurodegenerative disease.

In non-human primates, scientists have observed that this iron accumulation is accompanied by the loss of neurons that produce the neurotransmitter dopamine. That chemical messenger is in short supply in Parkinson’s. Such high levels of iron also are thought to be correlated with an increased severity in motor deficits.

Various imaging techniques have been used to study Parkinson’s disease in distinct animal models and have been found to produce consistent results. However, such methods are rarely validated.

Now, using cynomolgus monkeys, or crab-eating macaques, researchers investigated the role of metal accumulation in the striatum and midbrain (both motor control areas) in Parkinson’s. The researchers evaluated the use of susceptibility-weighted imaging (SWI) to measure iron deposits in the brains of Parkinson’s monkeys.

SWI is a high-resolution magnetic resonance imaging (MRI) technique that is sensitive to the magnetic properties of blood, iron, and calcifications, or calcium build-up in the body. These substances disturb magnetic fields, producing a not-so-clear image in a standard MRI scenario. SWI provides a unique contrast, generating 3D high-spatial-resolution images.

The animals received a left-side carotid artery injection of MPTP, a neurotoxin that induces the death of dopamine-producing neurons and mimics Parkinson’s symptoms. The carotid artery is one of the arteries that supplies the brain with blood.

An SWI-MRI was performed before and after the monkeys had received the MPTP injections.

Around 4-to-6 days after the injection, the monkeys exhibited limb muscle stiffness and limb postural tremor, and lost the ability to move their muscles freely (called akinesia). Importantly, these effects were only observed on the body side opposite, or contralateral, to the injection’s site.

The MRI results indicated there were higher-than-usual iron deposits in the MPTP-lesion side of the substantia nigra compared with the opposite side in the same animal. Similar results were found when these animals were compared with the control group of monkeys, which had been injected with a saline solution. Despite this indication, statistical significance was not attained.

Nevertheless, “MPTP did not affect the iron levels in other brain regions of monkeys,” the researchers said.

Post-mortem analysis of brain samples revealed that MPTP treatment provoked the loss of dopamine-producing neurons in the substantia nigra. The scientists reported that approximately 67.4% of dopaminergic nerve cells were lost in the substantia nigra on the injection side, while 30.0% were lost in the contralateral (opposite) side.

Neuronal loss in the substantia nigra on the injection’s side was correlated with worse behavioral performance and with motor impairment.

Biochemical analysis showed that MPTP increased iron levels in the injection’s side of the animals’ midbrain, but not in the striatum. However, calcium and manganese levels, which have been previously linked to Parkinson’s molecular mechanism, were unaffected by MPTP treatment.

“Taken together, the results confirm the involvement of [substantia nigra] iron accumulations in the MPTP-treated monkey models for [Parkinson’s disease], and indirectly verify the usability of SWI for the measurement of iron deposition in the cerebral nuclei of [Parkinson’s disease],” the researchers concluded.