Changes in Gait, Cognition May Be Early Signs of Idiopathic Parkinson’s, Research Suggests

gait and Parkinson's

Changes in gait and cognition precede a diagnosis of idiopathic (without known cause) Parkinson’s disease, and may occur earlier than typical non-motor symptoms, a study has found.

The study, “Prediagnostic markers of idiopathic Parkinson’s disease: Gait, visuospatial ability and executive function,” was published in Gait & Posture.

Motor symptoms in idiopathic Parkinson’s disease (IPD) are identified relatively late in the disease course, reducing the odds of neuroprotective benefit from available treatment options. Identifying individuals during the prodromal (early) period that precedes motor symptoms could be of great use for clinical studies seeking new therapies to prevent or delay disease progression.

A team of French researchers sought to determine the existence of any subtle gait disorders or other signs that precede the diagnosis of IPD, based on data from a long-standing study of human aging across the adult lifespan: the Baltimore Longitudinal Study of Aging (BLSA).

Conducted by the National Institute on Aging (NIA) Intramural Research Program, the BLSA continuously enrolls healthy volunteers age 20 and older who are followed throughout their life independently of the development of age-related diseases.

Ten pre-diagnosed IPD patients (eight men and two women) and 30 healthy control subjects were chosen for this study.

Subjects were assessed for the disease approximately 2.6 years before diagnosis. Clinical examination included gait speed, spatio-temporal gait parameters, balance, upper-limb motor skills, neuropsychological profile, and non-motor symptoms.

In comparison to the control group, IPD patients had shorter step length and reduced gait speed in a usual gait speed testing condition. Despite also having shorter step length when testing maximum gait speed, no differences between the IPD and control samples were found in walking speed.

Moreover, patients had worse mental rotation ability (the ability to rotate mental representations of two-dimensional and three-dimensional objects, which is related to the brain’s capacity for visual representation), and impaired ability to name different examples that could be inserted into a category (for instance, naming all types of flowers one can think of in one minute).

Compared to control subjects, IPD patients had no changes in upper-limb motor function, no depression, no sleep disturbances, no urinary symptoms, and no orthostatic hypotension (when blood pressure suddenly drops when standing up quickly).

Researchers concluded that the observed “changes might serve as markers to improve the early detection of IPD patients, who could then benefit from pharmacological neuroprotection trials and/or prevention trials of lifestyle-related interventions in order to delay, or even prevent, clinical manifestations.”

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Simple Breath Test May Aid in Early Diagnosis of Parkinson’s, Study Reports

breath test

A new device that uses just a breath sample might, in the future, help diagnose early-stage Parkinson’s patients or identify those who may be at risk, according to researchers.  

The innovative technology, developed by researchers at the Israel Institute of Technology, was able to detect alterations in the breath of newly diagnosed Parkinson’s patients, even before they begin medication.

Although the device and collection method still needs to be perfected to reach the sensitivity of other diagnostic approaches such as brain ultrasound scans, researchers believe the tool shows promise.

Findings were reported in the study, “Sensor Array for Detection of Early Stage Parkinson’s Disease before Medication, published in the journal ACS Chemical Neuroscience.

The team had already tested its device in the past, and were able to detect differences in the exhaled breath of people already being treated for Parkinson’s disease and healthy controls.

Now they wanted to see if the device could detect differences in the breath of patients with early-stage Parkinson’s who were not yet on any medications.

The device consists of an array of 40 cross-reactive sensors based on gold nanoparticles or single-walled carbon nanotubes, attached to different chemical ligands. Each of these ligands can bind certain airy or volatile molecules in the breath that change the electrical signals of the sensor.

They tested the device on 29 patients who had recently been diagnosed with idiopathic Parkinson’s disease — with no known cause — and were not yet on medication, and 19 healthy individuals of similar ages, used as controls.

The device’s performance was also compared with other currently used diagnosed tests, namely brain ultrasonography and smell detection.

The sensor was able to distinguish Parkinson’s patients from controls with a sensitivity of 79%, a specificity of 84%, and accuracy of 81%, better than smell detection tests, which have 62% sensitivity, 89% specificity and 73% accuracy, and almost as good as brain ultrasound scans, at 93% sensitivity, 90% specificity, and 92% accuracy.

“[O]ur studies provide additional confirmation of the ability of our sensors array to detect altered breath VOC [volatile organic compounds] composition characteristic of PD [Parkinson’s disease],” the researchers wrote.

Early diagnosis of Parkinson’s can help patients begin neuroprotective therapies sooner, before extensive loss of dopamine-producing nerve cells — those affected in Parkinson’s disease — has occurred in the brain. However, to date, diagnosis is still subject to considerable errors.

So far, studies on early Parkinson’s diagnosis using volatile biomarkers have only been done in patients who are already being treated and medicated. “There is a great need to evaluate untreated patients for establishing a real world screening and diagnostic technology,” the authors said.

Further improvements, as well as more testing in patients, are still necessary for the device to reach the sensitivity of other diagnostic methods like brain ultrasound scans.

“Future development of the sensors array technique has the potential to produce a small, portable system with the advantage of unbiased determination which could be used in initial screening of at-risk subjects without the need for experienced clinical personnel,” the researchers concluded.

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New Brain PET Scanner Shows Promise for Earlier and Less Expensive Diagnosis of Parkinson’s

PET scanner

A new brain scanner, which is 10 times less expensive and much smaller than current models, has the potential to significantly improve the diagnosis of dementia linked to neurodegenerative diseases, such as Parkinson’s disease, Alzheimer’s, and amyotrophic lateral sclerosis (ALS).

The scanner, which uses Positron Emission Tomography (PET) imaging, is being developed by two particle physicists, Jannis Fischer and Max Ahnen, PhDs, at ETH Zurich in Switzerland. Their work was recently recognized by Forbes magazinewhich included the duo in its “30 Under 30 Europe” list for 2018, in the category of Science and Healthcare.

PET scanning is an imaging technique commonly used to diagnose cancer, but it recently has also been used for neurological and cardiovascular diseases.

After a patient is injected intravenously with a tracing substance — called radioisotopes — the PET tracer travels through the blood vessels allowing clinicians to see its distribution over time to determine the health status of the brain.

While PET scanners can help diagnose certain neurological diseases 10 to 20 years before the development of the first symptoms, its practical use is limited because of the scanners’ high cost and large size — a conventional scanner requires 15 square meters of floor space and costs between US$1.5 and $5.5 million.

Ahnen and Fischer’s work, being conducted at ETH Zurich’s Institute for Particle Physics and Astrophysics, follows seminal work by researchers and doctors at the University of Zurich and the University Hospital of Zurich.

The new brain scanner, called Brain PET, will be a fraction of the cost of conventional scanners now found in hospitals and will take up less than 2 square meters.

“It looks a bit like a hair salon chair with an integrated hairdryer hood,” Ahnen said in a university news release. Its  compact size makes it much more mobile and useful for smaller clinical facilities.

Brain PET is also much cheaper to use. PET scanners now are at the top of hospital expenses, and many facilities are unable to afford them. The affordability of the new scanner will make it available for a broader range of patients.

“We will be able to reach much wider sections of the population than in the past,” Fischer said.

A prototype of Brain PET is expected to be completed by September 2018, after the project won ETH’s Pioneer Fellowship, a grant fostering the development of highly innovative products for the benefit of society.

The two physicists are setting up their new company, Positrigo, and hope Brain PET will be on the market in 2021, a goal both “optimistic, but also realistic,” they said.

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New PET Tracer with Potential to Diagnose Parkinson’s to Be Tested in First-in-Human Study

PET tracer

An innovative Positron Emission Tomography (PET) tracer that has the potential to diagnose Parkinson’s disease will soon be tested in humans for the first time.

Led by Switzerland-based AC Immune, which developed the technology, the study is expected to begin in the second half of 2018. The company recently presented the data on its new product at the AAT-AD/PDTM Focus Meeting 2018 in Turin, Italy.

“We are excited about this significant step in our development of potentially the first ever PET tracer for earlier and more accurate diagnosis of Parkinson’s,” Andrea Pfeifer, CEO of AC Immune, said in a press release. “This important milestone underlines our vision to become a global leader in precision medicine of neurodegenerative diseases, leveraging our proprietary technology platform.”

The company used its Morphomer platform, designed to interact with misfolded and aggregated proteins, to develop the PET tracer, which is highly selective for alpha-synuclein, enabling an earlier and more accurate Parkinson’s diagnosis.

AC Immune’s technology is aimed at not only detecting alpha-synuclein in patients, but also monitoring the effects of treatments targeting protein clumps. The research program has been spotting small molecules selective for alpha-synuclein and suitable for development as PET tracers.

Upon entering the brain, the new imaging agent, called a PET tracer, binds to abnormal or misfolded alpha-synuclein. Its radioactive label enables the imaging device to detect bound alpha-synuclein, informing clinicians on the amount and distribution of pathological brain alpha-synuclein.

If successful, the new PET tracer would be the first alpha-synuclein tracer to receive regulatory approval for commercial distribution. Its specificity would be important not only for Parkinson’s patients, but also for other disorders characterized by aggregated alpha-synuclein, collectively called synucleinopathies.

AC Immune has been collaborating with Biogen on this program since April 2016. The companies will proceed with the development and seek clinical validation for the use of the PET tracer as an imaging biomarker for Parkinson’s.

The Michael J. Fox Foundation for Parkinson’s Research (MJFF) is supporting this project. “We are very pleased about this next important step in the development of an alpha-synuclein imaging agent,” Jamie Eberling, PhD, director of research programs at MJFF, said.

“Having a PET tracer to detect and track Parkinson’s disease would be transformative for Parkinson’s research and patient care,” she said.

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Motion-Capture 3D Technology May Help Design Effective Therapies for Parkinson’s

motion-capture 3D

University of Pennsylvania researchers used a new technology that mimics the way animated movies capture a person’s movement to show the different shapes of alpha-synuclein protein, which, when badly arranged, become toxic to neurons and trigger Parkinson’s disease.

The results advance researchers’ knowledge of the mechanisms leading to Parkinson’s, and may lead to the development of new, more efficient therapies.

The study, “Using a FRET Library with Multiple Probe Pairs To Drive Monte Carlo Simulations of α-Synuclein,” was published in the Biophysical Journal.

To function properly, proteins need to be arranged, or folded, in certain 3D structures, which vary according to what they need to do inside our bodies.

This spatial arrangement is so vital that when the process goes wrong by proteins folding into strange 3D structures, they can aggregate into toxic clumps leading, in the case of neurons, to the death of cells – the underlying cause of neurodegenerative diseases like Parkinson’s or Alzheimer’s.

Tracking how proteins fold and change shape would be highly advantageous to understand the basic processes underlying these diseases.

“One of the big fundamental questions in biochemistry is how proteins fold into a certain shape, and this is dictated by the sequence of amino acids in the protein. The information in all of the interactions of the amino acid side chains somehow leads to it folding into a proper shape,” E. James Petersson, associate professor of chemistry at Penn’s School of Arts and Sciences, said in a press release.

Researchers at Penn, along with colleagues at international research institutions, used a method similar to that used in animated movies, the motion-capture technology, where a person uses a tracking suit covered with small colored balls. A camera is connected to each ball, capturing each position the person makes and recording its movement.

To do the same for proteins, Penn’s researchers labeled the protein with fluorescent probes (like the small colored balls) to different positions of the protein.

They then tracked the fluorescence data, using a technique called fluorescence resonance energy transfer, in each position to reconstitute the protein structure in detail. In the end they were able to obtain atomic-resolution “movies” of the protein’s structure.

“There are a number of different techniques that can be used to do this, but we like fluorescence because you can acquire fluorescence data fast enough that you can actually watch proteins fold in real-time. Ultimately we’d like to try to watch proteins folding in cells,” Petersson said.

This fluorescence-tracking technology was used to study the alpha-synuclein protein, which misfolds and forms toxic clumps in Parkinson’s disease.

A total of 30 measurements of the alpha-synuclein protein were made under different conditions that cause the protein to change its shape. The data were later analyzed using one of the most advanced programs for modeling proteins, called Rosetta. The program was developed in the David Baker’s laboratory at the University of Washington.

“Rosetta is designed to model stable well-folded proteins,” Petersson said, “not disordered proteins that can change shape, so Jack had to do a lot of rewriting of the code himself to be able to model these unruly proteins.”

This study is the stepping stone for future work where researchers hope to use their new technique to model alpha-synuclein aggregates that cause neuronal death and assess how therapies may stop

the proteins’ folding to prevent this aggregation.

“We’re working on being able to generate model structures that actually show what is the effect of these drugs,” Petersson said. “We take the protein with the fluorescent labels, add the drug, allow the protein to change shape, make fluorescence measurements and then take those back to the computational modeling so we can actually see the structural effect of these drugs. Hopefully this will lead to more of a rational understanding so that better second and third generation drugs can be made.”

This method may lead to new imaging techniques that could be used for early detection of protein clumps.

“There are some promising drugs for treating neurodegenerative diseases such as Alzheimer’s and Parkinson’s, that could block this formation of aggregates, but the problem is that, by the time people show cognitive or motor-tremor symptoms, it’s too late to use these drugs because there’s already too much neurodegeneration,” Petersson explained.

“If you’re getting aggregates in your brain, even if you’re not showing any behavioral changes or learning deficits, these probes could noninvasively image the aggregates. By achieving a rational understanding of what the protein structure is, we hope we can help with that work moving forward,” he added.

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