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Study to Test MRI Technique for Possible Early Parkinson’s Diagnosis

MRI and diagnosis

A clinical study will test the potential of a specific magnetic resonance imaging (MRI) technique to diagnose Parkinson’s disease at early stages.

The 18-month project, supported by a grant from the Center for Clinical and Translational Science in the U.K., will take place at the University of Kentucky’s College of Medicine under the leadership of George Quintero, PhD, and Zain Guduru, MD. It is expected to open this year.

Parkinson’s disease is characterized by progressive loss of coordination and movement, and includes tremors, stiffness and slowing of movement. Currently, a person is diagnosed when those symptoms appear.

However, the brain undergoes alterations that precede symptom onset. Detecting these changes earlier would allow a quicker start of treatments for these symptoms, and possibly to slow disease progression.

Previous research by the same team showed that apomorphine, an FDA-approved Parkinson’s therapy, activates brain areas commonly affected by the disease. Brain activity was measured using a blood oxygenation level dependent (BOLD) magnetic resonance imaging (MRI), an imaging technique that assesses changes in oxygen in the blood.

Apomorphine stimulates the production of dopamine in the brain, a messenger molecule (called a neurotransmitter) that is produced by dopaminergic neurons. Dopaminergic neurons die in Parkinson’s, leading to the characteristic deterioration of motor and cognitive skills observed during this disease’s course.

In this new study, researchers will assess responses in the brain before and after taking apomorphine in Parkinson’s patients and in people with essential tremor, a similar movement disorder. These changes will be measured using BOLD-MRI.

The idea is to test whether this technique can accurately discriminate between the two different patient populations upon apomorphine treatment. Since essential tremor is not caused by inadequate dopamine production, only Parkinson’s patients, in theory, should show specific brain alterations in response to apomorphine.

Should results be favorable, BOLD-MRI could be a way of identifying Parkinson’s early and distinguishing it from similar disorders.

“If apomorphine causes a different brain response in the two groups of patients, it could be a promising method for earlier detection of Parkinson’s,” Quintero said in a press release. “And this leads to earlier interventions that can benefit patients.”

Test results may also inform how the disease progresses, and whether subgroups of Parkinson’s disease patients respond differently to treatment.

“This is truly a translational project. We often want to make that transition between basic science research to human research,” Quintero said. “CCTS provided the opportunity to continue this research.”

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Imaging Analysis Software QyScore Receives FDA Clearance

QyScore software

The U.S. Food and Drug Administration (FDA) has granted 510(k) clearance to Qynapse‘s QyScore, a software that aids in analyzing brain scans taken by magnetic resonance imaging (MRI).

The software, which is compatible with routine imaging workflows, includes an advanced user interface and automatically-generated patient reports. Results are presented in comparison to data on people without known brain disease, giving neurologists and radiologists support in making clinical interpretations and decisions for treatment in a number of conditions, including Parkinson’s disease, multiple sclerosis, and Alzheimer’s disease.

In addition to aiding in diagnostics and monitoring disease progression, the software has been employed in clinical trials to help measure responses to treatment and safety profiles for investigational therapies.

Doing this kind of imaging analysis with a computer program, rather than relying on humans to interpret images, helps cut down on costs and time associated with the analyses. It also reduces variability in interpreting results. This includes both person-to-person variability and variability that can occur for the same person reading images at different times, since the computer is not subject to the same variances that can affect human scorers.

“QyScore makes a difference for the diagnosis of dementias at an early stage of the disease when it remains a challenge,” Bruno Dubois, PhD, said in a press release. Dubois is a professor at Sorbonne University and director of the Memory and Alzheimer’s Disease Institute at Pitié Salpêtrière Hospital in Paris. “The automatic quantification of markers such as brain atrophy, white matter hyperintensities and more, provides highly valuable help to support a timely diagnosis and an efficient monitoring of disease progression,” he said.

QyScore was first commercialized in Europe after receiving CE mark approval in September 2017.

To obtain 510(k) clearance for a new medical device, a company must submit technical, safety, and performance information for that device to the FDA. The FDA then reviews this data and, if appropriate, clears the device for sale in the U.S.

“FDA clearance is a major milestone to expand the commercialization of the software within the U.S.,” said Olivier Courrèges, CEO of Qynapse. “Qynapse will accelerate collaboration with experts and healthcare providers in the U.S. to pursue its journey for better patient care in neurology.”

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Glassy Carbon Electrodes Safer Than Metal in MRIs, Study Suggests

glassy carbon electrodes

Implantable electrodes made of glassy carbon may be safer for use in MRI scans than traditional electrodes made of metal for people who undergo deep brain stimulation, a new study shows.

The study, “Glassy carbon microelectrodes minimize induced voltages, mechanical vibrations, and artifacts in magnetic resonance imaging,” was published in Microsystems & Nanoengineering.

In cases where Parkinson’s patients are not responding well to medication, deep brain stimulation (DBS) can be used to treat motor symptoms associated with this neurodegenerative disease. The treatment involves surgically implanting an electrode directly in the brain, then using that electrode to electrically stimulate specific brain regions.

Traditionally, electrodes used for DBS have been made of metal, most typically platinum. But metal electrodes pose a problem when a person needs to undergo an MRI scan. Such scans can be used to image the brain using powerful magnets, but those magnets can interact badly with metal electrodes.

Specifically, the electrodes can lead to large “white spots” on the MRI images themselves, which can limit the utility of the images. Plus, the magnetic fields generated in MRI can cause electrodes to vibrate, or they can generate electrical currents that make the electrode heat up. These circumstances run the risk of causing damage or irritation in the brain.

In the new study, researchers wondered if electrodes made of glassy carbon, instead of metal, would be resistant to these issues. Glassy carbon (GC) is basically a bunch of very thin layers of carbon pressed together.

The researchers previously had created GC-based electrodes designed for DBS, and in a previous study, they showed that these electrodes were more durable than traditional platinum ones.

“Inherently, the carbon thin-film material is homogenous—or one continuous material—so it has very few defective surfaces. Platinum has grains of metal which become the weak spots vulnerable to corrosion,” Sam Kassegne, PhD, a professor at San Diego State University (SDSU) and co-author of both studies, said in a press release.

The researchers tested their GC electrodes in an MRI; but, rather than using actual human brains, they implanted the electrodes in a substance sort of like Jell-O. The researchers demonstrated that, while the metal electrode created a bright white patch on the MRI images themselves, the CG was nearly invisible — suggesting that, in an actual brain, this type of electrode would interfere with imaging far less.

They measured the currents generated in these electrodes during an MRI scan, as well as how much they vibrated, and compared these measurements to similar measurements obtained using traditional metal probes.

They found that the current generated in the GC electrodes was about 10 times lower than that in the metal probes. Similarly, vibrations in the GC electrode were about 40 times weaker than those in the metal ones, Researchers noted, however, that “for both types of microelectrodes, the measurable forces were below the detection limit” — that is, the vibrations were very small for both, even if they were smaller for the GC electrode.

“Our lab testing shows that unlike the metal electrode, the glassy carbon electrode does not get magnetized by the MRI, so it won’t irritate the patient’s brain,” said Surabhi Nimbalkar, study co-author and doctoral candidate at SDSU.

Although the researchers noted that they did not directly assess heating of the electrodes, which may be an avenue for further study, they nonetheless concluded that “GC microelectrodes demonstrate superior behavior with respect to MR safety compared to [platinum]-based electrodes.”

“Since GC has recently been demonstrated to have a compelling advantage over other materials for neural stimulation (…), this MRI compatibility validated in this study offers an additional advantage for long-term in vivo use in clinical settings,” they wrote.

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New MRI Technique Can Visualize Brain Molecular Composition, Study Shows

MRI molecular composition

A new magnetic resonance imaging (MRI) technique allows for the visualization of molecular changes in the brain, a study reports.

This technique will allow researchers to further understand how the brain works and how it changes with ageing or during the onset of neurodegenerative diseases like Parkinson’s.

Moreover, in the future, clinicians may use the brain’s “molecular signature” for early diagnoses — allowing patients to get access to treatment at early stages of disease and increasing their likelihood for better outcomes.

The study, “Disentangling molecular alterations from water-content changes in the aging human brain using quantitative MRI,” was published in the journal Nature Communications.

An MRI scan is obtained using magnetic fields and powerful detectors that track water compositions in tissues. However, brain function depends vastly on molecular interactions within the brain that current MRI scans fail to detect.

“When we take a blood test, it shows us the exact number of white blood cells [key cells of the immune system] in our body and whether that number is higher than normal due to illness,” Shir Filo, a PhD student and the study’s first author, said in a press release.

“MRI scans provide images of the brain but don’t show changes in the composition of the human brain, changes that could potentially differentiate normal aging from the beginnings of Alzheimer’s or Parkinson’s,” Filo added.

Now, researchers found a way to “see” the brain composition at the molecular level. The technique, called quantitative MRI, is able to detect changes in the molecular composition of lipid (fat) molecules within the brain.

The research was led by Aviv Mezer and his team at the Hebrew University of Jerusalem (HUJI)’s Edmond and Lily Safra Center for Brain Sciences.

“Instead of images, our quantitative MRI model provides molecular information about the brain tissue we’re studying. This could allow doctors to compare brain scans taken over time from the same patient, and to differentiate between healthy and diseased brain tissue, without resorting to invasive or dangerous procedures, such as brain tissue biopsies,” Mezer said.

Researchers started by testing their new MRI technique in synthetic, or lab-made complex fat mixtures to validate whether the MRI scans were sensitive enough to detect changes at the molecular level.

The results revealed their technique was able to distinguish between different lipids with high sensitivity. Because the brain is rich in lipids — such as phosphatidylcholine, sphingomyelin or phosphatidylcholine-cholesterol — the team used a measurement called macromolecular tissue volume (MTV) that provides quantitative information about these molecules in a sample.

Quantitative MRI scans of human brains revealed that MTV measures changed depending on the brain region analyzed, demonstrating that this technique works like a detailed map of the living brain.

Importantly, using post-mortem (after death) brain samples, the team found that the variability of certain MTV parameters between human brain regions also correlated with specific gene-expression profiles. Gene expression is the process by which information in a gene is synthesized to create a working product, like a protein.

Next, the researchers investigated whether the molecular composition of the brain varied according to age, specifically young versus old. They scanned 23 young adults (mean age 27 years) and 18 older adults (mean age 67 years).

Researchers focused their analysis on the brain’s white and gray matter. White matter is made up of nerve cell projections, known as axons or fibers, that connect distinct parts of gray matter. The length and condition of the fibers influence the way the brain processes information. Gray matter includes neuronal cell bodies as well as synapses, or the junctions between nerve cells that allow them to communicate with each other.

The results showed not only evident changes in the brain’s size, but also tiny and region-specific molecular changes in various brain regions related to aging. Even in the absence of age-related reductions in brain size, molecular changes were detected using the new MRI technique.

Overall, this supports the potential of this new type of MRI method to better understand how our brains age.

“[W]hen we scanned young and old patients’ brains, we saw that different brain areas ages differently. For example, in some white-matter areas, there is a decrease in brain tissue volume, whereas in the gray-matter, tissue volume remains constant. However, we saw major changes in the molecular makeup of the gray matter in younger versus older subjects,” Mezer said.

Researchers hope that, in the future, they can apply this new MRI technique to provide an early diagnosis of diseases like Parkinson’s. That could allow access to treatment that may delay or even halt disease progression.

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MRI Technique Helps Distinguish Between Parkinson’s and Progressive Supranuclear Palsy, Study Reports

MRI technique

A specific magnetic resonance imaging (MRI) measure can accurately predict the development of eye movement abnormalities, helping to identify patients who develop progressive supranuclear palsy with parkinsonism (PSP-P) after an initial diagnosis of Parkinson’s, a study shows.

The study, “Refining initial diagnosis of Parkinson’s disease after follow‐up: A 4‐year prospective clinical and magnetic resonance imaging study,” appeared in the journal Movement Disorders.

A clinical diagnosis of Parkinson’s may be inaccurate in the early stages of the disease, when its characteristic motor symptoms are not fully manifested. PSP-P has a similar clinical presentation to idiopathic Parkinson’s (of unknown cause), including bradykinesia (slowness of movement), limb rigidity, and tremor, leading to difficulty in differentiating between the two.

Recent diagnostic criteria defined probable PSP-P as vertical gaze abnormalities (VGA) — difficulty in moving the eyes up and/or down — associated with levodopa‐resistant parkinsonism, a term for neurological disorders that cause movement problems similar to those of Parkinson’s. However, patients with PSP-P may never develop VGA, meaning the prevalence of this disorder could be underestimated.

MRI has been a helpful tool to diagnose PSP and to predict the appearance of gaze abnormalities in people with PSP-P. A new version of the Magnetic Resonance Parkinsonism Index (MRPI), named MRPI 2.0, has shown high accuracy in distinguishing cases of Parkinson’s from those of PSP-P. The MRPI can be used in MRI studies to predict the presence of PSP in patients with clinically unclassifiable parkinsonism.

However, studies on the clinical features of PSP-P in patients initially diagnosed with Parkinson’s are still lacking.

To address this, researchers in Italy followed a group of 110 individuals — 73 of whom were men, with a mean age at examination of 62.9 years, and a mean disease duration of 4.4 years — with probable or possible Parkinson’s and 74 healthy individuals used as controls over four years.

The investigators conducted annual clinical evaluations to assess the appearance of VGA without early postural instability, which strongly suggests PSP‐P. MRI scans were performed at the beginning of the study and at the end of the follow-up period.

They also evaluated whether MRPI 2.0 helped predict the development of PSP-P in patients initially diagnosed with Parkinson’s.

At the start, 21 of 40 individuals with possible Parkinson’s and all 70 individuals with probable Parkinson’s were responsive to levodopa. Of all the patients, 100 retained their initial diagnosis, and 10 (9.1%) developed VGA and had their diagnosis changed to PSP-P, nine of whom only showed a moderate response to levodopa.

Specifically, all 10 patients whose diagnosis changed showed slowness of vertical saccades during follow-up, which refers to quick, simultaneous movements of both eyes that abruptly change the point of fixation. Vertical supranuclear gaze palsy (resulting from a cerebral impairment) in five patients was associated with higher imaging biomarkers values than slowness in vertical saccades. All 10 patients had at least three years of parkinsonism without postural instability.

All MRI measures — including MRPI and MRPI 2.0 — were significantly different between patients with Parkinson’s and those at PSP-P both at the start of the study and at the end of follow-up. At the beginning, MRPI 2.0 was the most accurate (100%) biomarker in predicting the appearance of VGA, “enabling [PSP-P] patients to be identified at the earliest stage of the disease,” according to the researchers.

Although the number of patients whose diagnosis was changed is small, the researchers said that their findings “demonstrate the usefulness of these new imaging biomarkers, and specifically of the MRPI 2.0, in predicting the development of VGA and the clinical evolution towards PSP phenotypes in patients with the initial diagnosis of [Parkinson’s].”

Most clinical variables — including motor function, assessed with the Unified Parkinson’s Disease Rating Scale–Motor Examination (UPDRS‐ME), and cognitive function, measured with the Mini-Mental State Exam — also showed a marked difference between the two groups at follow-up. However, clinical variables were less accurate than imaging biomarkers in predicting VGA.

Data further showed that disease progression was more signficant in patients with PSP‐P, as assessed with MRI and UPDRS‐ME.

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Benefits of Exercise for Parkinson’s Patients Linked to Increased Dopamine Release, Study Suggests

exercise and Parkinson's

Engaging in regular exercise can help preserve the motor and non-motor function of Parkinson’s disease patients, most likely as a result of an increased release of dopamine in the brain, a small study suggests.

The study, “Habitual Exercisers Versus Sedentary Subjects With Parkinson’s Disease: Multimodal PET and fMRI Study,” was published in the journal Movement Disorders.

Exercise has been shown to ease both motor and non-motor symptoms of Parkinson’s disease, including bradykinesia (slowness of movement) and balance, as well as cognition and mood.

While the mechanisms underlying these benefits are largely unknown, researchers hypothesize that exercise may enhance dopamine release. The progressive degeneration and death of nerve cells in the brain that produce dopamine, called dopaminergic neurons, is one of the underlying causes of Parkinson’s disease.

In this study, researchers investigated how dopamine release and other clinical features of Parkinson’s disease differ between patients who exercise and those who remain sedentary.

A total of 17 patients with mild to moderate Parkinson’s disease were recruited, eight of whom engaged in regular exercise at least three times a week for more than three hours total, while nine were sedentary.

All patients underwent two positron emission tomography (PET) scans, one before and one after exercising on a stationary cycle, to determine whether exercise affects the release of natural dopamine in the dorsal striatum — a region of the brain involved in the control of movement. PET scans were performed after overnight withdrawal from dopaminergic medication.

Additionally, participants underwent functional magnetic resonance imaging (MRI) of the brain during a monetary reward task that required randomly selecting one of four cards.

“Subjects were explicitly informed about the probability of obtaining a monetary reward ($0.50) for selecting a winning card during each block. Subjects were also instructed that the task was purely chance (analogous to a slot machine), and there was no pattern to learn that could improve odds,” the researchers wrote.

However, for each selected card, subjects were provided visual (happy or sad face) and auditory (cheers or sighs) feedback, which could alter the card selection process, even though the success of each trial was by chance.

This test allowed researchers to evaluate possible behavioral differences in card selection between groups. Specifically, researchers measured the response of the brain’s ventral striatum, a region involved in the evaluation of rewards.

Participants also completed other tests to evaluate motor and non-motor function, including the Beck Depression Inventory to assess depression and the Starkstein Apathy Scale to measure apathy.

Results showed that habitual exercisers had an increased release of dopamine compared with sedentary patients. They also had greater activation of ventral striatum during the MRI reward task. Their apathy and bradykinesia scores were also lower than sedentary patients.

These results suggest that exercise is associated with improved motor and non-motor functions in Parkinson’s patients, which is likely linked to exercise-enhanced dopamine release.

“Although it appears that exercise plays a role in the clinical outcome of subjects with PD, future randomized control trials are needed to determine the cause-effect relationship between exercise and enhanced DA [dopamine] release, response to anticipation of reward, and clinical outcomes,” the researchers wrote.

“Future studies should also investigate other potential mechanisms of benefit from exercise,” they added.

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First Parkinson’s Patient Treated with Insightec’s Incisionless Brain Therapy

Insightec

Insightec has treated the first patient in a pivotal study of its non-invasive ultrasound therapy, ExAblate Neuro, for patients with advanced Parkinson’s who have not responded to medication.

The device uses focused ultrasound and magnetic resonance imaging (MRI) to destroy a target deep in the brain — the Vim nucleus of the thalamus — through an intact skull. This area has been identified as responsible for causing Parkinson’s tremors. The MRI technology enables physicians to guide treatment planning and deliver thermal feedback in real-time monitoring.

The therapy aims to improve motor function and treat the characteristic involuntary movements of arms and legs, which may occur as a side effect of medication, and impair patients’ quality of life and ability to perform daily activities.

In July 2016, Insightec’s therapy become the first focused ultrasound device approved by the U.S. Food and Drug Administration (FDA) for the treatment of medication-resistant essential tremors with non-invasive thalamus destruction. In October 2017 the FDA granted approval to initiate the trial for these patients.

The trial (NCT03454425) evaluates the safety and effectiveness of the ExAblate System for the treatment of Parkinson’s motor features. It is currently enrolling patients who are 30 or older and have predominant motor disability from one side of the body. Insightec plans to recruit a total of 40 participants and expects to complete the research by December 2020.

“Building on the success of the incisionless focused ultrasound treatment for essential tremor, we are excited to extend its application to the debilitating effects of Parkinson’s,” Howard Eisenberg, MD, the study’s principal investigator and a neurosurgery professor at the University of Maryland School of Medicine, said in a press release.

Eisenberg is recognized as one of the nation’s top neurosurgeons and an expert on traumatic brain injury and the blood brain barrier.

“INSIGHTEC is committed to supporting focused ultrasound research, which is much less invasive than conventional surgery, and has the potential of improving the lives of people living with Parkinson’s,” said  Maurice R. Ferré, MD, CEO at Inisightec.

The company recently began a parallel Phase 3 trial (NCT03319485) of its MRI-guided focused ultrasound system for treating motor symptoms in Parkinson’s. It plans to recruit more than 100 patients with advanced idiopathic Parkinson’s not responding to available therapies. Patient enrollment is ongoing at sites in Maryland, New York, Ohio, Pennsylvania, and Virginia. More information is available here.

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Source: Parkinson's News Today