A lab-on-a-chip device for measuring multiple biochemical and biophysical biomarkers of Alzheimer’s disease - PROJECT SUMMARY Alzheimer’s disease (AD) is the most common form of dementia, causing 50–75% of all dementia cases, and currently affecting approximately 50 million people worldwide. A major problem in AD research is that we still do not have accepted measures of biomarkers that are useful in clinical trials for AD, which makes it difficult to enroll the most relevant cohorts and test the mechanism of action of drug candidates. This is compounded by the fact that current biomarker testing is dominated by cerebrospinal fluid (CSF) analysis and positron emission tomography (PET) scans. CSF testing is invasive, while PET scans are expensive and not easily accessible. Research on alternative drug targets for AD has recently started to grow, and as a result, there is a strong need for new biomarker targets and new modalities to measure these biomarkers. These modalities would be ideally low-cost, non-invasive, and easily scalable. Raman spectroscopy has shown good promise in distinguishing early-stage AD from cognitively healthy controls, while mass spectrometry has shown good potential in distinguishing certain neurological disorders from cognitively healthy controls using the novel concept of conformational biomarkers. Different from classical concentration-based disease biomarkers, conformational biomarkers reflect the changes in structure. However, conventional Raman spectroscopy systems are not scalable, and mass spectrometry is both expensive and time consuming. An emerging concept is waveguide enhanced Raman spectroscopy (WERS). Along with providing increased light efficiencies, it can also make use of current CMOS fabrication techniques, allowing nanophotonic chips to be mass produced. In terms of conformational sensing, light scattering spectroscopy has been demonstrated as a reliable technique for sensing nanoscale changes in conformational properties. Given these findings, we hypothesize that a scalable photonics-based lab-on-a-chip device can be used for the simultaneous investigation of multiple novel biochemical and biophysical AD biomarkers. These hypotheses will be addressed in the experiments of the following Specific Aims: (1) Develop a low-cost, scalable, and label- free testing platform based on waveguide enhanced Raman spectroscopy to detect existing and novel biomarkers in blood plasma; and (2) Develop a prototype label-free testing platform based on light scattering spectroscopy for characterizing misfolded proteins in CSF samples. Should these aims be successful, it opens the possibility of developing a scalable lab-on-a-chip device for straightforward screening of AD patients and monitoring of disease progression, both of which are critical requirements for future AD therapeutic development. The results would also have broad implications for other neurological disorders.
