HD Insights™

H D I N S I G H T S HD INSIGHTS: Can you tell us about the Institute for Neurodegenerative Disorders? (IND) MAREK: The IND is a research institute with about 80 staff in New Haven, Connecticut. Our focus for the last 12 years has been on evaluating neurodegenerative disorders such as HD, Parkinson disease and Alzheimer disease. In particular, we are developing imaging biomarkers to understand, diagnose, and monitor the progression of these diseases. HD INSIGHTS: Why don't we have such markers for HD? MAREK: In a way, HD is ideal, because we have a genetic marker that tells us who will develop the disease. Until recently, however, opportunities for identifying a specific PET ligand were limited. One thing that has changed over the past five to ten years is that we now have a number of PET tracers that target different neurochemicals in the striatum, an important site of the pathology of HD. PET tracers are radioactively labeled compounds which are injected into the bloodstream and bind to a target brain chemical. We can then assess the activity of the target enzyme in different brain regions using a PET camera and a computer analysis. There are a number of potential targets that might help us to identify the neurodegenerative process in individuals with HD at the time of their diagnosis or even earlier, and to track that neurodegenerative process over time. HD INSIGHTS: Which of these targets are most common? MAREK: One of the most promising is adenosine 2A, because the adenosine receptor resides on the medium spiny neurons in the striatum, and we know those neurons degenerate in HD. Similarly, the metabotropic glutamate receptor, the mGluR5 receptor, has been another important target. Most recently we have looked at another target, the phosphodiesterase 10A (PDE10A) receptor. It's possible to effectively target these phosphodiesterases using PET tracers. There is data to suggest this, too, may be a marker that changes very early in the course of HD. HD INSIGHTS: At the most recent CHDI meeting, you presented results from your PDE10A imaging. Can you tell us a little bit about what you did and what you found? MAREK: Our group has developed a PDE10A PET tracer, labeled with fluorine-18, that targets PDE10A with high specificity and high affinity. In human studies with our PDE10A tracer we see that there is a very specific and very robust signal in the striatal region. This localization of PDE10A in the brain is consistent with animal studies. In these studies, we began by validating the radio tracer by testing it in healthy subjects to ensure that the activity we detect in the brain does in fact reflect PDE10A activity. We also assessed safety, because there is a radiation load with a PET tracer. We wanted to make sure that we can inject this safely and repeatedly, because we would like to use this tracer to monitor changes over time. We then compared the activity that we detected in the striatum in healthy subjects to individuals with HD, and there was a striking reduction in the HD individuals. In individuals with relatively mild HD symptoms, there was a 60 to 70 percent reduction in their PDE10A activity compared to healthy subjects, consistent with the mouse model of HD. We also tested pre-symptomatic HD gene – positive individuals, and we could detect smaller but clear changes in PDE10A activity. The PDE10A PET imaging that we've done so far shows a very strong correlation between the relative loss of PDE10A and clinical measures of HD, including the UHDRS and the burden of pathology score that has been developed for monitoring HD. HD INSIGHTS: So the next step is to see how PDE10A levels respond to a PDE10A inhibitor? MAREK: Right. It would be interesting to evaluate whether PDE10A inhibition might modify the reductions we see in these subjects. HD INSIGHTS: What are your other hopes for HD imaging? MAREK: We hope to initiate a study soon, in which we evaluate PDE10A and additional targets in the same subject: in particular, the cannabinoid-1 receptor and the adenosine 2A receptor. We will try to track a number of measures of HD, to get a sense of the temporal pattern of how this type of pathology occurs. HD INSIGHTS: The use of PET ligands in PET imaging is a relatively new field that you've helped pioneer. How did you first become interested in this area of research? MAREK: PET imaging is an amazing opportunity to combine my interest in neurology with my interest in brain chemistry. It's also been fascinating to explore, in real diseases and in real people, how the chemistry of the brain works. This interest was sparked by my interaction with Paul Hofer, who was a nuclear medicine physician at Yale University. He had Parkinson disease himself, and he was instrumental in pointing out the research possibilities of PET imaging. On a personal level, it was very gratifying to work on a project that was so relevant to somebody who was also a mentor. HD Insights, Vol. 5 Copyright © Huntington Study Group 2013. All rights reserved. 3

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