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Highly Sensitive, Multiplexed Alzheimer's Biosensor Takes Aim at Early Detection


NEW YORK – Researchers at the Korea Advanced Institute of Science and Technology have developed a diagnostic test for Alzheimer's disease using a multiplexed electrical biosensor that they said demonstrated significantly improved sensitivity using low-cost fabrication.

The KAIST researchers recently published the results of a study of their technology in Nature Communications, describing the development of an ultrasensitive sensor array that uses densely aligned single-walled carbon nanotube thin films to detect concentrations of beta-amyloid42, beta-amyloid40, total tau protein, and phosphorylated tau protein — markers that are correlated with the pathology of Alzheimer's disease.

"To detect Alzheimer's disease in human plasma, biomarkers need to be measured at very low concentrations — in the range of femtomolars to picomolars," said Steve Park, a study author and professor in the Department of Materials Science and Engineering at KAIST. The challenge, he added, has been that "making sensors with such sensitivity and accuracy has been difficult."

To overcome that, the KAIST team began with a basic consideration — how their platform would be manufactured. In their devices, antibodies anchored on the surface of carbon nanotubes bind specifically to targeted biomarkers, Park said, adding, "When the biomarkers bind onto their corresponding antibodies, the electrical resistance of the carbon nanotubes changes." As a result, the platform detects changes in electrical resistance that increase with greater biomarker concentrations.

The investigators tested clinical blood plasma samples from 20 Alzheimer's patients and 20 healthy people obtained from the Biobank of Chungbuk and Chungnam National University Hospital, members of the Korea Biobank Network.

In sample testing, the closely packed and unidirectionally aligned carbon nanotube sensor array exhibited a femtomolar-level limit of detection in measuring levels of t-tau/Aβ42, p-tau181/Aβ42, and Aβ42/Aβ40 in clinical blood samples. The sensor array distinguished clinically diagnosed Alzheimer's disease patients from healthy controls with an average sensitivity of 90 percent, a selectivity of 90 percent, and an average accuracy of 88.6 percent.

Park and his colleagues fabricated the biosensor using a low-cost fabrication technique and boosted its sensitivity by making aligned high-density carbon nanotubes that minimized nanotube-to-nanotube resistance compared with randomly distributed carbon nanotubes.

The highly dense and unidirectionally aligned carbon-nanotube sensor array can reliably detect target analytes down to femtomolar concentrations because of its low density of tube-to-tube junctions and uniform number of nanotubes per device.

In the study, the resistive sensor exhibited a sensitivity more than one hundredfold higher than conventional carbon nanotube-based biosensors.

Using a fabrication technique known as Langmuir Blodgett, carbon nanotubes were densely aligned on a substrate, and different types of antibodies in the sensor were bound to specific biomarkers to enable multiplex sensing. By simultaneously measuring the concentrations of four Alzheimer's disease biomarkers in patients confirmed with Alzheimer's disease, the group distinguished patients with disease from healthy patients at levels of detection that demonstrate clinical significance, according to Park.

The precise diagnosis of Alzheimer's is complicated and mainly performed by cerebrospinal fluid analysis or neuroimaging techniques such as positron emission tomography and magnetic resonance imaging, all of which have drawbacks. For example, cerebrospinal fluid sampling via lumbar puncture is a highly invasive procedure that is difficult to implement in clinical practice, and imaging techniques are expensive and not accessible to many parts of the population.

In the pursuit of blood-based alternatives, some researchers believe that biosensors could become promising alternatives, enabling simple, rapid, and low-cost diagnosis.

Researchers are exploring a variety of methods to improve Alzheimer's disease detection, and some are suggesting that the most scientifically productive way forward for research and treatment would be to adopt a biological definition of Alzheimer's disease.

At Washington University School of Medicine in St. Louis, a research group is exploring use of mass spectrometry as part of a study to obtain accurate measurements of amyloid beta, a protein biomarker for Alzheimer's, to predict whether the protein has accumulated in the brain. Meanwhile, researchers at the University of Central Lancashire, in Preston, UK, have reported highly accurate results using infrared spectroscopy to identify Alzheimer's disease and other forms of dementia in patients' blood.

A multigene test under development at the University of California, San Francisco, and the University of California, San Diego, combines the effects of more than 31 genetic variants as part of a polygenic risk score for preclinical Alzheimer's dementia.

"At the end of the day, we want what is best for the world and for those suffering from these neurological diseases," said Quanterix CEO Kevin Hrusovsky. "The question that drives us forward is what if we could identify Alzheimer’s at stage zero and direct treatments to potentially prevent the disease completely? The answer is in biomarkers. By measuring concentrations of biomarkers, most recently, with less-invasive blood tests, we can better understand how diseases like Alzheimer’s manifest, progress, and respond to medications."

The biomarkers detected in the study by the KAIST researchers are important for Alzheimer's disease detection, "but we would also add Nf-L to this list," Hrusovsky said.

Quanterix's single-molecule enzyme-linked immunosorbent assay (Simoa) technology detects serum proteins at subfemtomolar concentrations. However, the platform comes with size, expense, and suitability for use in laboratories.

For their part, Park and his colleagues are doing research and development into ultrasensitive protein biomarker tools that could one day compete with platforms like Simoa on price and accessibility. Further development work is needed to move the KAIST test toward commercialization. The Korean researchers are working to improve the sensor's performance and lower the cost of manufacturing, Park said. He declined to discuss the group's plans for commercialization — whether it would form a start-up company or look to collaborate with a diagnostic company, for example — but he said the researchers are planning to undertake additional clinical trials to advance the platform's development.

Though the Langmuir Blodgett fabrication technique that the group is using can enable low-cost manufacturing, further development is needed to implement it, Park said, adding that large-area fabrication "of densely aligned carbon nanotubes with uniform density for high sensitivity and device-to-device uniformity is required to drive the cost down."

Hrusovsky noted that for Alzheimer's disease diagnosis, commercial biomarker technologies are relatively new. "While a significant amount of work has been done, there is much more to do," he said.