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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Simple Genetic System Controls Posture-Related Behavior, Insect Study Suggests

posture-related behavior

A small molecule that regulates the expression of genes, called microRNA, controls nerve cells involved in postural control by affecting a gene within motor neurons, according to a recent fruit fly study.

The research, “A Single MicroRNA-Hox Gene Module Controls Equivalent Movements in Biomechanically Distinct Forms of Drosophila” was published in Current Biology.

Parkinson’s disease is a multi-system neurodegenerative disorder with motor and nonmotor features. Among motor symptoms and signs are resting tremor, slowness of movement (bradykinesia), rigidity, impairment of posture, balance, and gait.

“Given that the circuit components of behavior are built under the influence of genes, the question arises as to what extent the genetic make-up of the organism affects the control of its movements,” the researchers wrote.

Scientists at the University of Sussex in Brighton, England, and the Champalimaud Centre for the Unknown in Lisbon, Portugal, looked at distinct developmental stages of the fruit fly — an animal model commonly used in the lab — and how they were affected by a genetic system composed of a microRNA, called miR-iab4 molecule, and a particular Hox gene, called Ultrabithorax. This microRNA has been linked to motor control in fruit flies.

Of note, miRNAs are small, highly conserved non-coding RNA molecules involved in the regulation of gene expression (the process by which information in a gene is synthesized to create a working product, like a protein). Hox genes are a family of genes that act as major regulators of animal development.

By using fruit flies, scientists can isolate genes with associated roles in movement control, such as the Hox genes, which specify body segments during embryonic development — i.e., whether a segment of the embryo will form part of the head, thorax, or abdomen.

These genes have been thought to be involved only in the formation of body structures and the brain. But researchers now have found that microRNAs control the function, rather than the morphology, of motor neurons, and that post-developmental changes in the expression of Hox genes can modulate behavior in the adult fruit fly.

The team studied the animals’ self-righting behavior, an important motor milestone in invertebrate development. Self-righting refers to an innate response that allows a change in the posture (position) of an organism in respect to the ground. For instance, in fruit fly larva it enables the insect to rectify its orientation if turned upside down.

The miR-iab4 miRNA was found to be essential for normal self-righting behavior across fruit fly developmental stages — embryo, larva and adult —  which all are associated with different morphology, neural constitution, and biomechanics.

Researchers also found that this microRNA molecule inhibited the Ultrabithorax gene in a specific subset of adult motor neurons, and that such inhibition elicited the self-righting behavior, indicating changes in Hox gene function can modulate motor control in the adult insect.

How does this apply to humans? After birth, newborns reach several milestones, including motor ones, which doctors use to monitor infants’ development. One of those milestones is rolling over, an equivalent to the fruit fly’s self-righting behavior.

These fruit fly findings hold the potential to unravel the molecular basis of movement-related neurodegenerative disease, such as Parkinson’s.

“Although our work is focused on deducing fundamental biological principles — what you may call “basic science” — there are several possible biomedical projections of this study,” Claudio Alonso, PhD, said in a press release. Professor Alonso is Subject Chair for Neuroscience at the School of Life Sciences, a member of the research center of Sussex Neuroscience, and senior author of the study.

“For example, aging, as well as various forms of neural disease including motor neurone disease, Parkinson’s and Huntingdon’s disease, can degrade posture and motor control, leading to a deterioration of health and quality of life. In order to understand more about these conditions and to be able to map the anomalies caused by disease or advanced age, we need a deeper understanding of the genetic and physiological factors that underlie normal posture control and movement,” Alonso said.

According to Alonso, this is the first study to report Hox-dependent roles in neurophysiological and behavioral control in the fully formed organisms (once development has concluded).

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Coupling of Brain Electrical Signals May Be Parkinson’s Biomarker, Way to Improve Deep Brain Stimulation, Study Suggests

cross-frequency coupling electrical signals

The coupling of electrical signals in the brain — as it responds to levodopa and is associated with motor improvements — may provide ways to better assess the clinical state of people with Parkinson’s disease, and improve the efficacy of deep brain stimulation (DBS), according to new research.

The researchers say coupling patterns may enable broader insight into Parkinson’s, and have potential use as a biomarker.

The study, “Distinct subthalamic coupling in the ON state describes motor performance in Parkinson’s disease,” appeared in the journal Movement Disorders.

The human brain displays repetitive patterns of neural activity, or electrical pulses, due to the communication between brain nerve cells (neurons). These are called brainwaves.

Measuring a type of electrical pulses called local field potentials (LFPs) from the subthalamic nucleus (STN) — a brain region hyperactive in Parkinson’s patients — has shown the existence of frequency bands, or wave oscillations, that correlate with motor impairment and respond to medication.

The interactions between high- and low-frequency brain waves — cross-frequency coupling — also has been increasingly studied. This is particularly evident in unmedicated patients. Yet, what these interactions mean is still scarcely understood.

A team at the University of Houston addressed how these bands are changed by medication, as well as their coupling, via a 24-hour monitoring period that included three trials. Those trials involved nine people (seven men, ages 39-70 years) with idiopathic Parkinson’s, meaning the disease with no known cause. The participants underwent local field potential recording three weeks after deep brain stimulation of the subthalamic nucleus. The recordings were then correlated with motor improvements over three treatment cycles.

Clinical and behavioral assessments were made within 30 minutes prior to taking levodopa, which controls Parkinson’s symptoms. Similar evaluations were then done within 30 minutes after the participants said they felt the medication kicking in, in terms of motor function (verbal on state).

Specifically, the clinicians used the Unified Parkinson’s Disease Rating Scale to assess numerous symptoms: hand and foot tremors (item 20); upper and lower extremity rigidity (item 22); and finger tapping, hand open and close, hand pronation and supination — which means flipping the palm face up or face down — and leg agility (items 23–26).

A computer-based task also was used, with a keyboard. Participants had to press the left and right arrow keys sequentially and as fast as possible, for 30 seconds, using the index and middle fingers. The total number of keypresses was then analyzed.

The results showed that bradykinesia — slowness of movement — and keyboard scores differed between “off” and “on” states, meaning the periods before and after taking levodopa and regaining motor control. However, these responses did not correlate in all patients. Two patients showed eased bradykinesia yet minimal-to-no improvement in the performance of the keyboard task.

The data also showed distinct peaks across different bands. In the off state, the activity of low-beta (13-22Hz) and high-frequency oscillations (200-300Hz) was higher than normal. It was either suppressed, or shifted to a different frequency, after taking levodopa. Among other findings, six patients also showed a peak in the gamma range (50–200 Hz).

The investigators also found that, in the off state, the amplitude or signal strength of high-frequency oscillations was coupled with a specific parameter — called phase — of low-beta bands in all participants.

After the transition to the on state, this coupling shifted to a different subset of beta bands (22-30Hz) and high-frequency oscillations (300-400Hz). It also was linked with more pronounced improvements in the keyboard task scores. Only two patients failed to show this coupling after taking levodopa. That could be due to suboptimal dose, the team said.

Overall, the findings show that cross frequency coupling also exists in treated patients. “So in effect we have ‘cleared coupling’s name’ and showed the frequencies involved in coupling impacts whether its effects are negative or positive,” Musa Ozturk, the study’s lead author, said in a press release.

“Together with the differences in the ON-state coupling according to the degree of motor improvement, our observations suggest that [cross-frequency coupling] patterns provide a broader insight into [Parkinson’s], and have potential utility as a biomarker for the clinical state of patients,” the researchers said.

One potential application is deep brain stimulation.

“We can now make the closed-loop stimulator adaptive to sense a patient’s symptoms, so it can make the adjustments to the fluctuations in real time, and the patient no longer has to wait for weeks or months until the doctor can adjust the device,” said Nuri Ince, PhD, the study’s senior author.

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Specific Form of Alpha-Synuclein Linked to More Severe Parkinson’s Symptoms in Early Study

alpha-synuclein study

Small amounts of a particular form of alpha-synuclein, known as beta-sheet, may cause a significant loss of dopamine-releasing neurons by recruiting more alpha-synuclein molecules, leading to Parkinson’s-like symptoms and disease progression, according to a recent lab study.

The study, “Defining α-synuclein species responsible for Parkinson disease phenotypes in mice,” was published in the Journal of Biological Chemistry.

In Parkinson’s, a particular form of the protein alpha-synuclein originates in insoluble fibrils (i.e. “small fibers”) that clump together, and those fibers accumulate inside nerve cells (neurons). These aggregates, also known as Lewy bodies, are harmful to cells and eventually kill them, which, in turn, contributes to the onset of disease-related symptoms.

Besides fibrils, alpha-synuclein exists in other structural forms, including an orderly stacked form called beta-sheet. To date, not much is known about which of alpha-synuclein’s structural arrangements contribute more strongly to disease mechanisms and Parkinson’s manifestations.

Researchers at the University of Alabama at Birmingham (UAB) studied three distinct structural forms of alpha-synuclein (long fibrils, a mix of fragmented fibrils, and short fragmented fibrils; all with beta-sheet in them) to determine which was most responsible for Parkinson’s-related damage.

Investigators injected one of the three alpha-synuclein forms, as well as small (insoluble) alpha-synuclein fibers, into the striatum — a crucial brain region involved in motor control that’s extensively damaged in Parkinson’s — of healthy mice to establish the ability of each protein arrangement to induce Parkinson’s-like symptoms.

Three months after injection of small alpha-synuclein molecules (that have a lesser amount of beta-sheet in them) there was a slight but significant loss of dopamine-producing neurons in the substantia nigra – a brain area deeply connected with the striatum. But it did not induce Lewy body formation or lead to evidence of motor impairment.

In contrast, those animals injected with short beta-sheet fibril fragments showed fewer striatal dopamine terminals (meaning “neuronal sites where dopamine is released to communicate with nearby neurons”), a loss of dopaminergic neurons within the substantia nigra, and Parkinson’s-like motor behavior defects.

“Our findings indicate that the form most toxic to neurons was a structure referred to as beta-sheet fibrillar fragments,” Laura Volpicelli-Daley, PhD, assistant professor at UAB’s Department of Neurology, and the study’s lead author, said in a press release.

“This is a form of alpha-synuclein that makes overlapping sheets of the protein, which subsequently develop into long filaments. The filaments can then break into smaller fragmented pieces. We hypothesize that the smaller fibrillar fragments are the most toxic to neurons because they are able to attract and corrupt normal alpha-synuclein, causing it to form aggregates that spread throughout the neuron, causing damage to the brain,” Volpicelli-Daley added.

“Our results suggest that inhibiting the accumulation of small fibrillar [alpha]-synuclein fragments generated either during the process of protein aggregation or by the fragmentation or disaggregation of longer fibrils, have the potential to be a therapeutic strategy against [Parkinson’s disease] progression,” the researchers concluded.

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#AAN2018 — Vercise Deep Brain Stimulation Improves Motor Control in Parkinson’s Patients, Trial Shows

Parkinson's DBS

People with Parkinson’s disease show better motor control, longer “on” periods, and an improved quality of life when treated with a recently approved deep brain stimulation system, one-year results from a clinical trial show.

The research, “INTREPID: A Prospective, Double Blinded, Multicenter Randomized Controlled Trial Evaluating Deep Brain Stimulation with a New Multiple Source, Constant Current Rechargable System in Parkinson’s Disease,” was presented Tuesday at the 2018 American Academy of Neurology (AAN) Annual Meeting, taking place through April 27 in Los Angeles.

Deep brain stimulation, or DBS, is a surgical procedure to treat disabling neurological symptoms in Parkinson’s, such as tremors, rigidity, stiffness, slowed movement, and walking problems. It uses a small, pacemaker-like device called a neurostimulator to deliver electrical stimulation to electrodes surgically placed in specific areas of the brain.

Although diverse clinical trials have shown DBS to be an effective adjunct Parkinson’s therapy, the degree of improvement is variable.

The INTREPID study (NCT01839396), for this reason, is specifically evaluating the safety and effectiveness of Boston Scientific‘s Vercise DBS system in people with advanced but levodopa-responsive Parkinson’s, whose symptoms are not adequately controlled by the medication. Full study results are expected after it concludes in 2021.

The Vercise DBS system, which targets the subthalamic nucleus (STN) part of the brain that is hyperactive in patients,  was approved to treat motor symptoms by the U.S. Food and Drug Administration in late 2017. It works using implanted leads with eight electrodes, and allows a doctor to vary the amount of current delivered by each electrode.

Reported results from this multicenter, double-blinded study involved 292 patients at 23 U.S. medical centers. All used the STN-implanted Vercise system for 12 weeks, and were randomly assigned to either an active (medium and continuous dose) or control (low and intermittent dose) treatment group.

INTREPID’s primarily goal was changes in the duration of “on” periods, characterized by improved motor control following levodopa treatment.

Improvements in motor function and quality of life were evaluated using a Parkinson’s diary, the Unified Parkinson’s Disease Rating Scale (UPDRS), the 39-item Parkinson’s Disease Questionnaire (PDQ-39), and neuropsychological assessments. Safety was measured through reported adverse events.

Results showed that 12 weeks of treatment increased the duration of “on” periods by a mean 3.03 hours in active patients compared with those in the control group. Secondary outcomes included a 49.2% improvement in motor symptoms in UPDRS scores, and a sustained and better life quality through the patient questionnaire, Boston Scientific also reported in a company press release.

Safety data showed low rates of infection and brain hemorrhage during the implant surgery.

Overall, these findings show the “DBS system is safe and effective in the treatment of Parkinson’s disease symptoms,” the researchers wrote.

“This study meets a new level of rigor in evaluating the effectiveness of a DBS system,” Jerrold Vitek, MD, PhD, chair of neurology at the University of Minnesota Medical School and the coordinating principal investigator for  INTREPID, said in the release. “The double-blind design gives us confidence that the improvements in patients on time with good symptom control, as evaluated by the diary data, are an objective measure of the outcomes and suggests patients will benefit from the Vercise System.”

The Vercise DBS system is also approved to treat Parkinson’s patients in Europe and Australia.

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Source: Parkinson's News Today

New Tremor Suppression Glove May Help Parkinson’s Patients Regain Motor Control


Researchers at Western University in Canada have developed a prototype of a new tremor suppression glove that may help people cope with the tremors associated with Parkinson’s disease.

The gloves not only prevent tremors from happening but also improve motor control.

tremor is an unintentional, uncontrollable, somewhat rhythmic, muscle contraction, which manifests as trembling of one or more body parts, most commonly the hands. It can happen when muscles are relaxed and still, called resting tremors, or during voluntary movements, called action tremors.

About 70 percent of Parkinson’s patients experience tremors in the early stages of the disease, and more than 25 percent have action tremors, most often in the hands, restricting them from performing everyday activities.

Previous studies by the Western research team showed that most tremor suppression devices targeting the wrists and elbows worsen tremors in the fingers, making things even harder for Parkinson’s patients. They also often end up suppressing all movements, even voluntary ones.

But the new gloves, using a series of motors and sensors, are actually able to track voluntary movements and distinguish them from involuntary ones. So if a person is trying to complete a specific task, the gloves will allow the movement while minimizing involuntary tremors.

Real data from participants with Parkinson’s was used to help develop the software that controls the glove.

To maximize the benefits of the new gloves, they can be custom-designed for each patient’s hand. The team’s prototype was designed specifically for the left hand of doctoral student Yue Zhou, who also 3-D printed the key components of the glove.

The team believes the new gloves will bring real change to the lives of Parkinson’s patients, allowing them to do more daily activities on their own and live more normal lives.

“By creating a glove that allows people to perform these actions while suppressing the tremors, I think they could go back to being much more independent in their own homes for a far longer period of time,” Ana Luisa Trejos, the lead investigator at the Wearable Biomechatronics Laboratory Group, said in a press release.

Researchers are now waiting on ethics approval to test the gloves on Parkinson’s patients.

Trejos and her team developed the project with the support of the Peter C. Maurice Fellowship in Biomedical Engineering.

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Source: Parkinson's News Today