August 10, 2023 | Researchers at the Swiss Federal Institute of Technology Lausanne (EPFL) have developed a novel biosensing tool combining multiple advanced technologies that shows promise in detecting misfolded proteins indicative of neurodegenerative diseases such as Parkinson’s and Alzheimer’s. It is hoped that the system will one day enable earlier disease detection as well as improve the evaluation of new drug treatments, according to Deepthy Kavungal, a Ph.D. student who works in both the Bionanophotonic Systems Laboratory of Professor Hatice Altug and the Laboratory of Molecular Neurobiology and Neuroproteomics of Professor Hilal Lashuel at EPFL.
The device is known as the ImmunoSEIRA (surface-enhanced infrared absorption spectroscopy) sensor and it employs nanotechnology and nanofabrication, optofluidics, an immunoassay, and neural network analysis, says Kavungal. Infrared spectroscopy is used to identify misfolded proteins based on how they respond to light, but the absorption signals are “very weak” and therefore unable to monitor tiny amounts of protein, she explains.
To overcome this limitation, the research team engineered gold nanorod arrays that were functionalized with antibodies for detecting oligomers and fibrils, known structural biomarkers of neurodegenerative disease. The sensor also incorporates microfluidic channels enabling measurement of the proteins in an aqueous environment and in body fluids like cerebrospinal fluid (CSF), Kavungal says.
But simply detecting oligomers and fibrils isn’t good enough, she continues. It is also important to quantify them when present together, which is not possible with existing assays. This is why the data collected by ImmunoSEIRA has been linked with an artificial neural network to enable this quantification which could calculate disease stages and progression, as covered in an article that published recently in Science Advances (DOI: 10.1126/sciadv.adg964).
The end goal of the multidisciplinary project, which started as a Ph.D. thesis, is a sensor for the clinical diagnosis of neurodegenerative disorders, disease monitoring, and evaluation of novel therapies—the holy grail of medical research on progressive neurological diseases. To that end, Kavungal and her colleagues plan to optimize the design so the device is sensitive enough for clinical application as a blood-based multiplex test that can simultaneously monitor multiple biomarker proteins associated with neurodegeneration from small sample volumes in complex biomatrices. At that point they would turn to wafer-scale nanofabrication of the sensor chips so that they could be produced at low cost.
Kavungal invites input from doctors and other technology developers, as well as patients, regarding the potential future value of ImmunoSEIRA and what they would want from the technology. “We are scientists and work for what the community needs,” she notes.
Prior studies have found that neurodegenerative disorders are characterized by misfolded proteins in the brain that are closely associated with the disease and its progression, says Kavungal. But whether those biomarker proteins are the cause or after-effects of disease remains unknown.
What has been established is that misfolded proteins can be present in body fluids, including CSF and blood and even in tears and saliva, and give an indication that a disease is developing, she says. Two of the newest drugs approved by the U.S. Food and Drug Administration for the treatment of Alzheimer’s disease target these misfolded proteins that make up amyloid plaques—one (aducanemab, Biogen) preferentially going after the fibril forms of the protein and the other (lecanemab, Eisai) the oligomer forms.
Identifying the structure as well as the abundance of misfolded proteins is important because the biomarkers of different neurodegenerative diseases have a lot of overlap, points out Kavungal. Misfolding of the alpha-synuclein protein is associated with Parkinson’s disease as well as other neurodegenerative diseases such as multiple system atrophy and dementia with Lewy bodies, whereas the protein tau is implicated in both Alzheimer’s and Parkinson’s.
It is hypothesized that heathy proteins misfold first into oligomers at early stages of neurodegenerative disorders and later convert into fibrils, so it could prove clinically important to know how much of each is present in defining a particular disease as well as for early detection, she adds. ImmunoSEIRA could be useful in clinical studies to detect these biomarkers and quantify their aggregation, and to help drug developers aim their drugs at the right structural abnormalities.
With forthcoming clinical studies, a key challenge will be obtaining the requisite number and diversity of patient samples, Kavungal says, although a small cohort study is likely to launch once the device is optimized. Another big hurdle will likely be convincing doctors to adopt a new and unfamiliar technology.