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

iron accumulation

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.

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New Imaging Technique May Aid Early-Stage Diagnosis of Parkinson’s, Study Says

brain imaging

A new imaging agent can efficiently reach the brain and bind toxic amyloid aggregates during early-stage Parkinson’s and Huntington’s disease, a study has found.

This opens a new approach to diagnose and evaluate the effectiveness of treatments for these neurodegenerative diseases.

The article, “ScFv-conjugated superparamagnetic iron oxide nanoparticles for MRI-based diagnosis in transgenic mouse models of Parkinson’s and Huntington’s diseases,” was published in Brain Research.

It is widely accepted that misfolded amyloidogenic proteins, alpha-synuclein, mutant Huntington protein, and amyloid-beta, are toxic species that play a role in the development of neurodegenerative diseases including Parkinson’s, Huntington’s, and Alzheimer’s diseases.

However, there are currently no conclusive diagnoses for the early stages of these neurodegenerative diseases.

Despite the differences in the makeup of amyloidogenic proteins and their associated diseases, these misfolded aggregates assembled from distinct amyloid proteins share general common structural features and mechanisms of toxicity. Therefore, antibodies targeting each specific misfolded amyloidogenic protein can be powerful tools for early diagnosis and treatment of several neurodegenerative diseases.

Over the past decade, molecular imaging — the visualization, characterization, and measurement of biological processes at the level of cells and molecules in humans and other living systems — has become a thriving field and offers potential tools for disease diagnosis.

Magnetic resonance imaging (MRI) techniques represent one of the best non-invasive molecular imaging methods and hold great promise for studying the brain.

The use of nanoparticles — tiny molecules — also is attracting increased attention due to their unique capacity to facilitate diagnostics and therapeutics. Among all types of nanoparticles, biocompatible superparamagnetic iron oxide nanoparticles (SPIONs) have attracted a great deal of attention for therapeutic delivery applications.

SPIONs consist of magnetic cores made of iron oxides coated with a biocompatible polymer that can be targeted to the required area through external magnets. The coating acts to shield the magnetic particle from the surrounding environment and also can be used to attach different types of molecules to increase their targeting capacity. These molecules then act as attachment points for the coupling of therapeutic molecules or antibodies to be delivered to the organ of interest.

SPIONs have been shown to penetrate the blood-brain barrier — a lining of cells that protect the brain from circulating molecules capable of damaging and disrupting neural function. When joined with an antibody that recognized amyloid-beta, SPIONs were successfully used to diagnose Alzheimer’s using MRI.

Although recent advances in molecular imaging techniques have improved the ability to diagnose other neurodegenerative diseases, Parkinson’s is still diagnosed mainly by a doctor’s observation based on motor symptoms including slowness of movement (i.e., bradykinesia), resting tremors, and muscular rigidity. For these reasons, researchers wanted to investigate whether SPIONs could be used to target amyloidogenic proteins in Parkinson’s disease and Huntington’s disease.

The team developed an amyloidogenic-targeted molecular MRI probe called W20-SPIONs. This imaging probe consists of an amyloidogenic-specific antibody known as W20 joined to SPIONs.

The researchers showed that these W20-SPIONs were stable, non-toxic, and specifically recognized alpha-synuclein oligomers in human cells and mice. Oligomers consist of a few units (or monomers) and are suggested to be the most toxic form of amyloid.

When applied to mouse models of Parkinson’s and Huntington’s, W20-SPIONs crossed the blood-brain barrier and specifically bound to the brain regions with amyloidogenic proteins, giving an MRI signal and distinguishing between mice with neurodegenerative disease from healthy controls.

These results indicate that W20-SPIONs have potential in early-stage diagnosis of Parkinson’s and Huntington’s disease and open a new strategy for assessing the effectiveness of new treatments for neurodegenerative diseases.

“In our study, W20-SPIONs showed sufficient signal sensitivity, good biostability, and no potential toxicity in vitro and in vivo, which also had the capacity of specially targeting oligomers in the brain,” researchers wrote.

“This evidence supports that W20-SPIONs were a successful oligomer-targeted MRI probe for early diagnostics of Parkinson’s and Huntington’s disease. Identification of reliable biomarkers of disease progression will play a key role in the diagnosis of neurodegenerative diseases, and also be important for the development and assessment of disease-modifying treatments,” they added.

Future studies will be required to show the safety and effectiveness of W20-SPIONs in the early-stage diagnosis of Parkinson’s disease and other neurodegenerative diseases in human patients.

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New Scanner Worn as Helmet Allows Brain Imaging in Parkinson’s Patients

brain imaging

A new brain scanner that can be worn as a helmet could potentially revolutionize the world of human brain imaging, allowing patients with Parkinson’s disease to undergo brain scanning — a task previous traditional scanners failed.

Brain cells use electrical impulses to communicate and, in doing so, form small magnetic fields that can be detected outside the head. Human brain function can be imaged by capturing these magnetic fields through a technique called magnetoencephalography (MEG).

With current scanners, patients have to remain perfectly still while being scanned, as even a tiny movement could render the images unusable. This means it is very difficult to scan people who find it hard to remain still, such as patients with movement disorders.

Researchers at the Sir Peter Mansfield Imaging Centre, University of Nottingham UK have tackled this issue by developing a new MEG system that’s worn as a helmet, allowing subjects to move around freely and naturally during scanning.

The new scanner is more sensitive than current systems, giving a detailed, millisecond-by-millisecond picture of the brain while subjects perform different tasks, such as speaking or moving.

It was recently described in the study, “Moving magnetoencephalography towards real-world applications with a wearable system,” published in the journal Nature.

“This new technology raises exciting new opportunities for a new generation of functional brain imaging. Being able to scan individuals whilst they move around offers new possibilities, for example to measure brain function during real world tasks, or genuine social interactions. This has significant potential for impact on our understanding of not only healthy brain function but also on a range of neurological, neurodegenerative and mental health conditions,” Matt Brookes, PhD, the study’s co-lead author, said in a press release.

Traditional scanners are extremely heavy, weighing about half a ton, because their sensors require extremely low temperatures (-269 degrees Celsius, equivalent to -452 degrees Fahrenheit), which means the machine must contain built-in cooling technology.

The new scanner has scaled-down technology that takes advantage of “quantum” sensors incorporated in a 3-D printed prototype helmet. The new sensors are extremely lightweight and can work at room temperature, allowing them to be placed directly onto the patient’s head. This positioning also means the sensors are closer to the brain, increasing the amount of signal they can pick up.

To allow patients to move their heads during scanning, researchers had to adjust the helmet’s electromagnetic potential and build special electromagnetic coils.

After designing a successful prototype, researchers are now developing new types of helmets to fit babies and children, as well as adults. They predict this new type of scanner will increase the sensitivity of brain imaging fourfold in adults, and up to 15 or 20 times in children.

“This has the potential to revolutionize the brain imaging field, and transform the scientific and clinical questions that can be addressed with human brain imaging. Our scanner can be worn on the head like a helmet, meaning people can undertake tasks whilst moving freely. Importantly, we will now be able to study brain function in many people who, up until now, have been extremely difficult to scan — including young children and patients with movement disorders. This will help us better understand healthy brain development in children, as well as the management of neurological and mental health disorders,” said Gareth Barnes, PhD, a professor and the leader of the project at Wellcome Centre for Human Neuroimaging at University College London.

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Source: Parkinson's News Today