Selective Vulnerability of the Locus Coeruleus in Tau versus TDP Proteinopathies

Selective Vulnerability of the Locus Coeruleus in Tau versus TDP Proteinopathies



Assistant Professor of Neurology

Project Summary


This summer I had the honor of working in Dr. Irwin’s Digital Neuropathology Lab. Our lab integrates immunohistochemical techniques with quantitative digital analysis tools to examine post-mortem tissue and improve the diagnosis of neurodegenerative diseases and clinical disorders.

My current project involves studying the pathological differences of two main types of frontotemporal lobar degeneration (FTLD): FTLD-Tau and FTLD-TDP, in a region of the brain called the locus coeruleus (LC). Finding an accurate way to differentiate these neuropathologies in living patients is necessary for clinical trials that plan to target these abnormal protein buildups. The purpose of this research is to determine if the LC is more vulnerable in FTLD-tau compared to FTLD-TDP. We measured TDP and tau inclusion burden as well as the extent of neurodegeneration of the LC, including degree of cellular loss, vacuolation, depigmentation, and extracellular pigmentation. Melanin pigments are markers of a healthy LC. Therefore, digital imaging software tools were used to quantify levels of pigmentation in LC neurons of subsample of a FTLD-tau and FTLD-TDP patients, resulting in measures of percent area occupied of healthy melanin within LC neurons in addition to  the number of LC  neurons with melanin. Our findings suggest that the LC is more vulnerable to abnormal tau inclusions compared to TDP inclusions, and that the greater burden of tau is associated with more neurodegeneration of the LC in FTLD-tau compared to FTLD-TDP.

This experience has allowed me to learn a variety of techniques ranging from “dry-lab” analyses of digital images,  basic coding and statistics to “wet-lab” immunostaining in addition to strengthening my understanding of the field of neuropathology. In this lab I have found a very collaborative and supportive environment that I know will help me grow and develop the skills I need to become a better researcher. As a young scientist, I truly appreciate having an environment where I can be myself and ask for help whenever I don’t understand something. In this lab, everyone is always patient and helpful.

I am currently a pre-med student majoring in biochemistry. My career goal is to become a neurologist, but I also want to explore the field of medical research- particularly the diagnosis of neurodegenerative diseases. Having the privilege of working in Dr. Irwin’s lab was an invaluable opportunity to be involved with my career interests and directly interact with renowned experts in the field of neuropathology who have inspired me to continue studying this field.  Additionally, I learned a variety of techniques by contributing to the development of the image analysis methods and learning about the preparation of tissue for histopathology  from prosection of  gross brains as well as paraffin embedded sections and performing immunohistochemical staining. From clinical shadowing Dr. Irwin to observing brain autopsies and examining proteinopathies under the microscope, I have gained a better understanding of the neuropathological biomarkers of frontotemporal disorders. I will continue working on the LC project throughout the school year and perhaps pursue a more independent project in the future.