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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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Antiparkinsonian Medication Improves Learned Movement Production by Boosting Neuronal Connectivity, Study Finds

Antiparkinsonian Medication

Dopaminergic therapy may ease difficulties with gesturing and using tools in people with Parkinson’s disease by improving brain connectivity between the cognitive and motor regions, a study has found.

The study results, “Dopaminergic modulation of the praxis network in Parkinson’s disease,” were published in NeuroImage: Clinical.

Parkinson’s patients often have trouble performing skilled or learned movements that are crucial for daily living. Praxis is what scientists call this kind of cognitively directed motor action, while apraxia, generally speaking, refers to the difficulty itself, i.e., any disorder of learned movement.

“Although the neuronal basis of praxis functions has been comprehensively investigated in healthy individuals, functional imaging studies targeting these abilities including their impairments in clinical samples are still rare,” the researchers wrote.

Medical University of Vienna researchers studied the functional connectivity of the praxis network in individuals with mild-to-moderate Parkinson’s and at an increased risk for apraxia. They also investigated the influence of dopaminergic therapy on praxis function-related brain network.

For this purpose, a total of 13 Parkinson’s patients (seven men and six women, mean age of 60.23 years) and 13 healthy controls (seven men and 6 women; mean age of 56.77 years) underwent functional magnetic resonance imaging (MRI) and apraxia assessments.

Functional MRI measures the small changes in blood flow that occur with brain activity in response to stimuli or actions.

In the Parkinson’s group, all tests were performed twice: once with individually optimized dopaminergic medication (“on” state) and once without (“off” state).

None of the participants had trouble imitating gestures upon demonstration of object use, and none of the Parkinson’s patients showed apraxia-like symptoms. However, patients in the off period (without optimized symptom control by medication) performed significantly poorer in praxis assessments than controls.

Regarding functioning of the praxis-related brain network, patients in both states (on and off) displayed higher global efficiency than healthy individuals. Further analysis revealed that most of the communication within the network relayed to the bilateral supramarginal gyri, a portion of the brain that is thought to be involved in language perception and processing.

In addition, patients with optimized dopaminergic medication showed higher connectivity between praxis and motor areas, particularly between the supramarginal gyrus and the primary motor cortex, basal ganglia, and frontal areas, in comparison to subjects in the “off” state.

This improved communication “might facilitate the propagation of long-term representations of object-related actions to motor execution areas,” thus enabling the correct execution of the wanted movement.

The praxis network was confined to the left-brain hemisphere in the control sample, while in patients “off” therapy, but not in “on” individuals, the  network expanded to the right hemisphere.

Importantly, antiparkinsonian treatment seemed to normalize patients’ learned movement skills and related network connectivity, suggesting such therapy may support higher-order cognitive motor functions, at least in early stages of this neurodegenerative disorder.

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Brain Changes Might Predict Parkinson’s Mild Cognitive Impairment

Mild cognitive impairment

Early atrophy of a speech-related brain area called temporal lobe and progressive degeneration of a cognitive one (frontal lobe) might be warning signs for Parkinson’s mild cognitive impairment later on, researchers report.

Their study, “Progressive brain atrophy in Parkinson’s disease patients who convert to mild cognitive impairment,” was published in CNS Neuroscience & Therapeutics.

Cognitive impairment is one of the most common non-motor complications of Parkinson’s and is associated with significant disability for patients, worsening their quality of life.

A substantial percentage of Parkinson’s patients will in time develop dementia; this appears to be preceded by mild cognitive impairment. Studies indicate mild cognitive impairment is associated with temporal and frontal cortex atrophy. “However, the consistency between these studies is poor,” the researchers noted.

It is known that the accumulation of harmful proteins and the short supply of the chemical messenger dopamine affect brain structure in Parkinson’s disease, but this exact relationship  remains to be understood, particularly the molecular and structural associations in patients who develop Parkinson’s-related mild cognitive impairment and those that don’t.

A Chinese team of researchers decided to investigate the changes in gray matter volume during cognitive degeneration by comparing Parkinson’s patients who developed mild cognitive impairment, those who did not and healthy subjects. Cognitive impairment has been linked to reduced gray matter volume.

The brain is composed of gray and white matter. The first consists of cell bodies — the control center of neurons — while the latter is made up of nerve cell projections, known as axons or fibers, connecting distinct parts of gray matter.

Ninety-four Parkinson’s patients without cognitive problems at the time of recruitment and 32 healthy subjects were included in this study. Participants underwent magnetic resonance imaging (MRI) and neuropsychological assessment at the study’s beginning and 28 months later.

Of the Parkinson’s sample, 24 subjects (16 men and eight women; mean age 63.1 years) developed disease-related mild cognitive impairment (converters) after 28 months of follow-up, while 70 individuals (43 men and 27 women; mean age 62.3 years) did not develop cognitive problems (non-converters).

Converters had significant right temporal atrophy at the beginning of the study and extensive temporal lobe degeneration 28 months later. Nonetheless, biochemical analysis showed no association between right temporal atrophy and Parkinson’s-related protein levels in cerebrospinal fluid. Sitting behind the ears, the temporal lobe is the region where sound is processed and where auditory language and speech comprehension systems are located.

Those who developed mild cognitive impairment also had progressive bilateral frontal lobe atrophy. Located directly behind the forehead, the frontal lobe carries out higher mental processes such as thinking, decision making, and planning.

Using DaT scan — an imaging technique that allows scientists to visualize the functioning of dopaminergic nerve cells — the team reported that loss of dopamine-producing neurons in the striatum (a brain region involved in motor control) of patients who progressed to mild cognitive impairment was correlated with right temporal atrophy.

The findings suggest that structural changes in the temporal and frontal lobes of Parkinson’s patients might be a biomarker for cognitive decline in the long term.

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Voyager’s Gene Therapy Shows Positive Interim Results in Phase 1b Trial

Gene therapy

An investigational gene therapy being developed for the treatment of Parkinson’s disease was well-  tolerated and eased patients’ motor fluctuations in a dose-dependent manner after a one-time administration, according to interim results.

The study, “Magnetic Resonance Imaging-Guided Phase 1 Trial of Putaminal AADC Gene Therapy for Parkinson’s Disease,” was published in Annals of Neurology.

VY-AADC01 is a gene therapy being developed by Neurocrine Biosciences and Voyager Therapeutics. It uses a viral vector (AAV) to deliver the AADC gene — which codes for an enzyme called L-amino acid decarboxylase (AADC) and mediates the conversion of levodopa into dopamine — directly into a specific brain area called the putamen, a large structure filled with dopamine receptors.

Death of dopaminergic neurons and a reduction in AADC enzyme levels are two fundamental mechanisms underlying Parkinson’s disease. By delivering the AADC enzyme into brain cells, researchers aim to restore the conversion of levodopa and increase dopamine production.

The open-label, Phase 1b study (NCT01973543) enrolled 15 people (13 men and two women, mean age 57.7 years) with moderately advanced Parkinson’s disease and fluctuating responses to levodopa. Subjects were divided into three groups and treated with ascending doses of VY-AADC01 (7.5 × 1011vector genomes (vg); 1.5 × 1012vg; 4.7 × 1012vg).

The therapy was administered in a single-dose infusion using magnetic resonance imaging (MRI) to guide its delivery. Group 1 (lower dose) was followed for up to three years, group 2 through two years, and group 3 (higher dose) for up to 1.5 years. During the study, patients kept taking their antiparkinsonian medications, including levodopa.

The trial’s primary goals were the safety, tolerability, and distribution of ascending doses of VY-AADC01. Secondary objectives included AADC activity changes in response to levodopa, clinical outcomes over a year, and the durability of those changes after 12 months.

Results showed that large-volume administrations of VY-AADC01 were well-tolerated. At six months post-treatment, the MRI-guided delivery approach increased the coverage area reached by the gene therapy: coverage of 21% in group 1, 34% in group 2 and 42% in group 3. This was found to be closely correlated with increases in AADC activity: 13%, 56%, and 79%, respectively. The increase in putaminal coverage was also related to reductions in the patients’ medication regimen: 15% less in group 1, 33% less in group 2 and 42% less in group 3.

A year after treatment, investigators observed VY‐AADC01 dose-dependent improvements in motor fluctuations, motor scores on the Unified Parkinson’s Disease Rating Scale (UPDRS part III) and patients’ quality of life, despite reductions in antiparkinsonian medications.

Patients reported increases in their “on” periods (when medication does not wear off and motor symptoms are controlled) without experiencing troublesome abnormal involuntary movements (dyskinesia).

“The interim results from this Phase 1b trial demonstrated that administration of [VY-AADC01] to the putamen using a novel technique, which included intraoperative monitoring with magnetic resonance imaging guidance, facilitated targeted delivery of the investigational gene therapy,” Chad Christine, MD, professor of neurology, University of California, San Francisco and investigator in this trial, said in a news release.

“Additionally, administration of [VY-AADC01] resulted in dose-dependent increases in AADC enzyme expression and improvements in clinical measures and has been well-tolerated to date,” he said.

Based on these open-label results, researchers have initiated the RESTORE-1 Phase 2 trial (NCT03562494) to evaluate the safety and efficacy of VY-AADC01 and understand “its efficacy relative to optimal medical management alone,” they said.

The trial, which is recruiting, will randomize patients with advanced Parkinson’s disease who have not responded adequately to oral therapy to either optimized medical management plus VY-AADC01 or continued optimized medical management — including levodopa — plus placebo-surgery. Researchers plan to enroll 42 participants.

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Genetic Variant Predetermines Risk of Cognitive Decline in Parkinson’s, Research Suggests

genetic variant

Researchers have found that Parkinson’s patients whose cognitive ability is intact, but who have a specific genetic variant, have significantly less gray matter in the regions of their brain that are related to dementia.

The study with that finding, “Reduced gray matter volume in cognitively preserved COMT 158Val/Val Parkinson’s disease patients and its association with cognitive decline,” was published in Brain Imaging and Behavior.

Several mutations in the COMT gene have been associated with the risk of developing Parkinson’s disease. This gene provides instructions for making catechol-O-methyltransferase (COMT), an enzyme that helps break down certain chemical messengers like dopamine.

The most common alteration in the DNA sequence that makes up the COMT gene is the Val158Met mutation in which a valine (Val) is replaced by a methionine (Met) at position 158. Val and Met are both amino acids, also known as the protein’s building blocks.

Every individual has two copies of each gene, one inherited from each parent. Therefore, a person can have two Val’s in the same position at both COMT gene copies (also known as the Val/Val genotype), a Val in one gene and a Met in the other (Val/Met genotype), or two Met’s (Met/Met genotype). Scientists use the word “genotype” to describe a person’s genetic constitution.

Changes in COMT’s molecular structure, lead to high (Val/Val), intermediate (Val/Met) and low (Met/Met) enzymatic activity.

The Val158Met mutation in the COMT gene has been associated with an increased risk of cognitive decline in Parkinson’s disease, particularly in people with greater COMT activity. When this happens, there is too much neurotransmitter degradation, thus leading to reduced levels of dopamine and affecting basic brain functions such as motor coordination and memory.

Evidence suggests a correlation between cognitive impairment, one of Parkinson’s non-motor features, and reduced gray matter volume.

The brain is composed of gray and white matter. The first consists of cell bodies — the control center of neurons — while the latter is made up of nerve cell projections, known as axons or fibers, connecting distinct parts of gray matter.

A Spanish team of researchers used magnetic resonance imaging (MRI), a non-invasive imaging technology, to investigate a possible structural brain compromise in Parkinson’s patients with highly active COMT activity that could explain their increased risk for subsequent cognitive impairment.

The study included 120 newly diagnosed Parkinson’s patients with normal cognition (who were not previously treated for the disease) and 48 healthy controls from the Parkinson’s Progression Markers Initiative database.

Results showed that there was a widespread, significant reduction in cerebral gray matter volume in patients with the Val/Val genotype. They observed alterations in the fronto-subcortical and posterior-cortical brain regions, where motor and cognitive functions originate.

Gray matter volume at some of the identified regions was associated with cognitive decline in a four-year follow-up period, suggesting that gray matter volume reduction during the early stages of disease predisposes Val/Val patients to cognitive impairment.

Nonetheless, gray matter volume analysis at one-year follow-up was not increased in Val/Val subjects, in comparison to Val/Met and Met/Met participants, indicating a somewhat stable atrophy in the Val/Val subset and that those brain changes might already be present prior to diagnosis.

The team believes their research “sparks the need to further characterize the association between a modified COMT enzymatic effect and a structural brain compromise in the early stages of [Parkinson’s disease].”

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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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