Biomarkers in brain derived exosomes

Diagnosing neurodegenerative diseases, monitoring their progression, and evaluating the efficacy of treatments for these diseases is notoriously difficult. In most cases, the diagnosis, evaluation of disease progression and assessment of treatment effectiveness rely on clinical evaluation, which is error-prone because patient-to-patient variability is high and because the symptoms of many diseases overlap, especially at early stages. To improve the diagnostic accuracy, many labs search and develop biomarkers. However, obtaining reliable biomarkers is difficult due to the inaccessibility of the brain. Two approaches have been used traditionally - brain imaging and analysis of cerebrospinal fluid (CSF). However, both approaches suffer from important drawbacks. Brain imaging in many cases is not accurate and the associated costs are high. The more informative imaging techniques for soft tissues, such as MRI or PET scans, are done typically in large medical centers and therefore are less accessible in rural communities or small towns. CSF analysis requires a lumbar puncture, which is relatively invasive and refused by many patients, particularly when multiple tests are needed over time for monitoring disease progression or treatment effect.

To address these issues, multiple groups have been testing ways to measure biomarkers in more accessible body fluids, such as blood, urine, saliva, or organs, such as the skin or the eye. In many cases, substantial differences in levels of particular biomarkers have been observed on average between patients and healthy controls or among patients with closely related diseases. However, even when on average the groups differ significantly, there can be considerable overlap among them, resulting in low sensitivity and specificity of the test.

A promising approach is to analyze biomarkers in brain-derived exosomes from the plasma or serum. This approach provides a window into changes in the biochemistry of the brain using a simple blood test. The methodology involves first isolation of all the exosomes from the plasma/serum by chemical precipitation, followed by immunoprecipitation using antibodies against specific brain markers, such as the neuronal cell-adhesion molecule, which are present on the surface of exosomes coming from central nervous system neurons.

We have been using this approach for distinguishing among parkinsonian disorders, which display a large symptom overlap in early stages. In particular, we found that by measuring α-synuclein concentration levels in brain-derived exosomes, we could distinguish between Parkinson's disease and multiple system atrophy with high sensitivity and specificity. We reported these findings at the 143rd Annual Meeting of the American Neurological Association, Atlanta, October 2018 and the Annual Meeting of the Society for Neuroscience, San Diego, November 2018 and the research was featured on MedScape and MedPage.