NEW YORK (360Dx) – Researchers at Technion Israel Institute of Technology have built a benchtop breath test that they are validating in preliminary studies in the hope that they will eventually be able to launch a commercial diagnostic test for the early detection of Parkinson's disease.
The system undergoing preliminary clinical evaluation is an advance on an earlier laboratory prototype that demonstrated a 79 percent level of sensitivity, but a commercial in vitro diagnostic test with high enough sensitivity that effectively detects early-stage Parkinson's could still be between 10 and 20 years away, John Finberg, a professor at Technion and one of the test developers, said in an interview.
Nonetheless, if a robust commercial test can be developed, it would be a big step forward for the detection and potential treatment of a neurological disorder whose diagnosis presents challenges to clinicians.
The main point of this study is that the technology detected early Parkinson's disease in preliminary studies with patients who hadn't taken medication for the condition, said Finberg, who was instrumental in the early clinical development of the Teva Pharmaceuticals anti-Parkinson drug Azilect (rasagiline). Importantly, the developers of the new nanoarray-based test also used "sophisticated computational techniques" to detect chemical modifications in the body that occur during Parkinson's disease, he said.
The Technion team reported the results of a study last month in Chemical Neuroscience, in which they ran a small clinical trial on the laboratory version of the benchtop test that they have developed. In the study using the laboratory version, the researchers tested the device on the exhaled breath of 29 newly diagnosed patients who had not yet begun taking medication. When they compared the sensor's results for these patients with results from control subjects of similar age, they found that the array detected early Parkinson's disease with 79 percent sensitivity, 84 percent specificity, and 81 percent accuracy.
"That's good, but of course not good enough for complete detection or to achieve an absolute diagnosis of the disease," Finberg said. As a result, the group has already designed and built a benchtop system that it believes will improve sensitivity.
A team led by Hossam Haik, one of Finberg's colleagues at Technion, is evaluating the benchtop test on a new group of patients. It's an improvement over the earlier prototype that requires storing and freezing of breath molecules prior to lab-based analysis, largely because its sensor array enables detection of chemical changes directly from breath, and its results can be electronically transferred directly to the laboratory for analysis, Finberg said.
The clinical challenge
Currently, diagnosing Parkinson's is as much art as science, relying on observations of symptoms, family history, and neurological exams. No objective test for the disease exists.
Meanwhile, the number of people diagnosed with the condition each year is growing. New data indicate the number of people living with Parkinson's will reach 1 million by 2020, double previous projections, the Parkinson's Foundation said on Tuesday. As a result, it is investing $6.2 million in its latest round of research funding.
"Right now, we do not understand what triggers Parkinson’s disease in the vast majority of cases, [and] solving that is really a key to our future success," James Beck, chief scientific officer of the Parkinson's Foundation, said in an interview. "Another key will be identifying people as early as possible in their disease — hopefully before symptoms appear. Success on those two fronts will then enable effective early treatments to be developed."
Diagnosing Parkinson's at an early stage during a routine doctor's visit, for example, could help these patients begin neuroprotective therapy sooner, the Technion researchers said.
Further, early detection and diagnosis of Parkinson’s disease and differentiation between idiopathic Parkinson’s disease and other Parkinsonian syndromes, such as essential tremor and multiple system atrophy, "are highly important, because they affect the choice of therapy," the researchers noted.
Parkinson's-associated motor disorders result from a deficiency in certain brain neurons that release the neurotransmitter dopamine. About half of these neurons have died by the time the first clinical symptoms of Parkinson's become apparent, Finberg said.
In the beginning, "the brain compensates in various ways, and motor activity appears normal," he noted. But later, "motor effects manifest in problems with gait, walking, spastic contractions of muscles in various parts of the body, and various other symptoms."
Even if more effective drugs were already available to treat Parkinson's disease, the condition is so tricky to diagnose early on that trained neurologists who are experts in motor disorders usually only detect the condition when it is too late for early intervention. "Interpretations tend to vary from clinician to clinician, and as a result of that there are a lot of errors in diagnosing Parkinson's disease in the early stages," Finberg said.
Next steps
For the first time in diagnostics research, Finberg said, the Technion researchers have described a clinical trial to identify de novo Parkinson's disease patients — people who have not yet had Parkinson's drugs.
In earlier versions of their test, Finberg and his colleagues developed an array of 40 sensors based on gold nanoparticles or single-walled carbon nanotubes. Each sensor has a different chemical attached that binds to volatile molecules in the breath, which in turn alter the electrical resistance of the sensor. The device detects differences in the exhaled breath of healthy controls and people already being treated for Parkinson's disease.
In the recently published study, they analyzed the ability of the device to detect differences in the breath of patients with early-stage Parkinson's disease that had not yet been treated. In practice, a patient's breath, blown into a bag, passes over an absorbent column of material that stores the molecules. The column is frozen and later taken to a lab where the molecules are released and analyzed by the sensor-based instrument.
Recognizing that the process would be too cumbersome for practical use, the researchers used the existing technology to develop the benchtop system, which reduced the larger laboratory system by incorporating a microchip array. Rather than storing, freezing, and releasing the molecule, the system's sensor array is in immediate contact with the patient's breath.
"This is why we think that [the benchtop system] will substantially improve the results and the sensitivity of the process," Finberg said. "The new system is online, so its results can immediately be transferred to a laboratory for sophisticated computer modeling and analysis, and it obviates the necessity for storage and absorbing the molecule on a chemical matrix." Although the device needs to be improved and validated by larger studies, the researchers said that it has potential as a small, portable system to screen at-risk individuals without the need for highly trained specialists.
The Parkinson's Foundation's Beck noted that "most putative tests, while showing statistical relevance, really remain unable to differentiate" individuals from populations of individuals.
"Even if that can be ably satisfied, reproducibility in a large population — not just a small study cohort — has yet to be achieved," he said. "Diagnosis at the earliest stages of disease are tough clinically and remain unreachable by potential testing."
Beck said that the Technion study represents "an interesting and potentially useful screening tool," but better confirmation through longitudinal follow-up are clearly necessary. "Moreover, additional work will be needed in larger groups and in different centers to demonstrate whether this test is robust enough to handle different atmospheric environments," Beck said.
Ali Torkamani, director of the genomics and genome informatics at the Scripps Research Translation Institute, said in an interview that the Technion researchers' approach "looks quite interesting, but the small sample size and lack of independent sample validation make the potential of this test very difficult to evaluate.
"They will definitely need to do more clinical studies before a conclusion can be made," said Torkamani, who is not involved in the test's development, but is separately doing diagnostics research to improve screening accuracy of Parkinson's disease.
His group at the Scripps Translational Science Institute is collaborating with the Michael J. Fox Foundation and Intel in a clinical study to improve screening accuracy.
Meanwhile, several other efforts are being directed at developing diagnostic tools for Parkinson's. Scientists at Hebrew University of Jerusalem, for example, are developing a lipid-based ELISA that captures and quantifies the alpha-synuclein protein biomarker in blood to provide an earlier diagnosis for Parkinson's disease than is currently possible.
In February, US researchers published the results of a study in the open access journal Acta Neuropathologica Communications that incorporated an α-synuclein real time quaking-induced conversion (αSyn RT-QuIC) test to detect and differentiate Parkinson's and dementia with Lewy bodies from other neurodegenerative diseases.
In separate studies, Claudio Soto, a professor of neurology at the University of Texas Houston Medical School, and Alison Green, a researcher at the University of Edinburgh, said that the same technology could be used in the early detection of Parkinson's. Amprion, a company that Soto cofounded, expects to launch a test service within a year that uses an α-synuclein assay for detection of Parkinson's. The firm plans to launch the service from a CLIA-certified/CAP-accredited clinical laboratory that it has built in San Diego.