Fellowship provides immersion in HD research

Friday, December 13, 2013

 

By Jolene Luther
Huntington's Disease Society of America Donald A. King Summer Research Fellow

University of Iowa senior and Spanish and pre-medicine major Jolene Luther was chosen as one of two nationwide recipients of the Huntington's Disease Society of America Donald A. King Summer Research Fellowship. The Belgium, Wis., native conducted Huntington disease research for 12 weeks this summer at the UI HDSA Center of Excellence, where she continues to work during the fall semester. Click here to learn more about her motivation for wanting to do Huntington disease research.

After years of seeking ways to get more involved in the Huntington disease (HD) community, I was given the incredible opportunity to immerse myself in the world of HD research. With the support of Drs. Jane Paulsen and Hans Johnson, I spent 12 weeks gaining vast insight into research and all the work that goes into it.

Jolene on Keyboard

My research project focused on the role iron plays in the progression of Huntington disease. There is increasing evidence that iron has a key role in neurodegenerative diseases like Alzheimer and Parkinson diseases, and increased iron levels have been detected in Huntington disease brain tissue analysis after death. However, there has been very little research done to see if increased iron levels in the brain occur during prodromal (prediagnosed) Huntington disease and how exactly iron accumulation affects people who have tested positive for the HD gene.

Since we can't examine the brain tissue of living people, magnetic resonance imaging (MRI) can be used to study iron accumulation in the prodromal HD stage. Much like the popular photo application Instagram allows you to apply different filters to your photos, MRI scans allow you to see the brain with different contrasts. Areas of the brain with more iron accumulation than normal will show up as dark areas and can be identified by the trained eye of a professional and are classified as "hypointense."

In one study, "MRI T2 Hypointensities in basal ganglia of premanifest Huntington's disease," Caroline Jurgens and coauthors found these hypointense areas in study participants with prodromal HD, suggesting there is already more iron accumulation in the brain than normal in those with Huntington disease before they reach a clinical motor diagnosis of HD. They also showed that an increased amount of hypointensities (more iron accumulation) was associated with a higher probability of reaching a motor diagnosis within five years. Using this study as a base, I came up with a proposal to replicate and extend the Jurgens study using the large PREDICT-HD database. A multi-site observational study of prodromal Huntington disease, PREDICT-HD has collected thousands of MRI scans, allowing for study of a large sample of prodromal HD participants.

Before I started working on the project, the PREDICT-HD MRI scans had already been processed by a computer program that labeled certain areas of the brain to make a "map" of the basal ganglia. The basal ganglia is an important area of the brain that plays a role in controlling cognition (thinking ability) as well as movement coordination. My work began by figuring out how I could use those label maps and some basic computer programming skills to find the hypointense areas within the basal ganglia region. To do this, I spent weeks learning how to use the computer programming language Python. By writing code in Python, I could create a very basic program that would use the mapped MRI scans to find the hypointense areas in the basal ganglia.

First, I looked at many MRI scans and determined the threshold for which iron accumulation can be considered normal. In other words, just how dark, or hypointense, can this area of the brain be before it is considered abnormal and possibly attributed to Huntington disease? This allowed for the program to produce a new image that would only show the area of the basal ganglia that was hypointense.

Brain Label Map

I then used a statistics program to calculate the percentage of the basal ganglia that was hypointense for each scan to see if the basal ganglia of prodromal Huntington disease scans had larger percentages of hypointense area compared to scans of gene-negative control participants. I also used statistical tests to see if there was a relationship between the percentages of hypointense area and things like the motor (movement) assessment score given to the participant, their probability of experiencing Huntington disease onset within five years, and their CAG repeat length (which is generally associated with when HD symptoms begin and how rapidly they progress).

My very basic statistical analysis showed a small correlation between the percentage of hypointensities and some clinical characteristics like motor score, which suggests that having more hypointense areas in the basal ganglia negatively affects Huntington disease functioning. However, there are many more statistical tests to run and adjustments that need to be made before a more definitive conclusion can be reached. The work that I completed this summer could be used as a foundation for the PREDICT-HD research team in the future as they continue to explore biomarkers for HD.

Being mentored by an incredible researcher like Dr. Johnson was both demanding and exceptionally rewarding. I had to push myself harder every day to continue to learn and open my mind to face new and unexpected challenges.

I owe a warm thank you to all those who contributed to providing me this outstanding experience, including all the participants who have given their time and effort to be part of the PREDICT-HD study. Your contributions allowed for this fellowship that has solidified my aspiration of working to better the lives of those affected by Huntington disease.