By Ilona Lipp
While there is nothing I would rather research than the brain, I dare say that brain imaging does not always feel like the most rewarding field of science to be in. A single study takes months - more often years - to plan and conduct, the methods can be very expensive and constantly under development, and the results, no matter how interesting, most often just seem like a tiny puzzle piece that (with a lot of luck) will have a (modest) impact in the (distant) future. Coming from this perspective, it was very refreshing for me to talk to somebody whose imaging research is as applied as it can possibly be: Gil Rabinovici. Gil is a professor in neurology, specialized in memory and aging. Using PET imaging with pathology-specific tracers, he does not only investigate mechanisms behind neurodegeneration, but also assesses the clinical applicability and utility of his imaging methods. He recently launched a study on amyloid-PET in more than 18000 people all across the US. Gil will be one of the keynote speakers in Rome and I had the pleasure to find out a bit about him and his research ahead of time.
Ilona Lipp (IL): Your research focuses on brain imaging in the context of neurodegeneration and dementia. What are these things called amyloids?
Gil Rabinovici (GR): Amyloids are biochemical structures, protein aggregates that form fibrillary beta-pleated sheets. While most protein aggregates associated with neurodegenerative diseases are amyloid fibrils, when people talk about amyloid they often refer to aggregates of the beta-amyloid polypeptide, first described as “miliary foci” by Alois Alzheimer in his seminal case report. In Alzheimer’s disease you have aggregated Tau protein in the neurofibrillary tangles and beta-amyloid in plaques. But amyloid is a very general term and there are various other kinds of amyloid that can cause diseases in the brain.
IL: How did imaging amyloids become one of your main research topics?
GR: I am a clinical neurologist and I realized early on that I am most interested in brain-behaviour relationships and in higher cognitive processes. So my research focuses on diseases that affect the core processes for us humans, such as memory. A problem with those diseases is that we often cannot offer a definite diagnosis. This is because for more than 100 years, diagnoses were purely based on symptoms. Brain tissue is not like other tissue where you could just do a biopsy for additional information. But the diagnosis that is given during somebody’s life only has 70% accuracy when compared to the diagnosis they would get based on their autopsy after death. This is a major barrier to developing effective treatments! And diagnoses are even less accurate early on in the disease stage where treatments often would be most beneficial.
I was a 3rd year resident when I read a paper about the first imaging agent for amyloid, a PET tracer named Pittsburgh Compound-B (PiB). This paper was the most exciting thing I had ever read because it had the potential to completely transform clinical practice. At that time, I was about to start a fellowship and I asked my mentor Bruce Miller whether we could also do something with that. A year later we started a collaboration with Bill Jagust, a PET expert at University of California Berkeley. We recruited patients in our memory clinic and referred them to Bill for scans, and that is really how my research career started.
IL: Since then, you have studied whether imaging data indeed helps to improve clinical diagnosis and prognosis. Are the results so far promising? Where are the methodological bottlenecks?
GR: My research follows two major themes. One is to use molecular imaging and combine it with structural and functional MRI to understand disease mechanisms by studying how disease processes evolve during life in a longitudinal fashion. This is now feasible with the advances in the imaging techniques, especially with PET, where it has been validated that we are really capturing the biology. The other theme is to think about how these advanced imaging techniques can be translated from the lab into the clinic, to improve the diagnosis and care of patients. The bottlenecks for my research are that the diseases that I study are slowly progressing. The earliest biological changes often happen 10 years or more before the first symptoms appear. To follow people from their earliest changes onwards requires very long, longitudinal studies, which are practically and logistically challenging. An even bigger bottleneck in terms of clinical applications at the moment is that our diagnostic abilities exceeds our treatment abilities. So how can we translate expensive scans into clinical practice when the diagnostic information they provide does not immediately lead to successful treatment?
IL: So what is the idea behind IDEAS then?
GR: Even though three amyloid PET markers have been approved by the FDA for clinical use, in the US, these scans are currently not covered by health insurance, and they cost several thousand dollars, so most patients would not be able to afford them privately. However, Medicare, the US health care for people over 65, does cover scans if they are part of research studies that test their clinical utility. IDEAS is a national strategy, funded by government, industry partners, and non-profit organizations. The aim is to assess two things: whether having PET scans can change short-term patient management and whether they improve patient outcomes. We are testing 18000 patients with cognitive impairment of unclear origin in the whole of the US across 600 sites and in 350 PET facilities. We have, so far, been able to demonstrate that having this additional diagnostic information does have a very high effect on short-term management. It did change management in over 60% of cases, this is twice as much as what we expected. And the effects are not necessarily in form of pharmaceutical treatment, but also just making small changes in the patients’ lives to avoid medical events that could be a result of their diagnosed condition.
IL: Having worked on such multi-center studies, how many knowledge gaps do you think can individual brain imaging labs still fill – or should we all be pushing towards multi-center and consortium data?
GR: I am not sure I recommend managing 600 sites, that was really an exercise in losing control (laughs). IDEAS is quite exceptional, but other multi-site studies do also have a role. Individual labs are still important, they play a role in pushing the methodology and innovating techniques. It can take years between the development of a new technique and its application. For example, it took years to get a structural imaging sequence ready that is suitable for multi-site studies. So individual labs push this innovation, multi-site studies just generate big data that can be used, for example, for machine learning to detect relationship and patterns that our brains would not be able to see. But I still think we can learn from small studies with clean data and specific hypotheses.
IL: And what direction is your own research going to take in the next few years?
GR: I would like to keep pushing the research on disease mechanism, also using more Tau-imaging with PET. I am also more and more interested in what we yet cannot see. While there has been a lot of progress, we still have a very limited set of tools to study brain aging and disease. I am hoping to develop new tracers that also allow imaging other proteins, neuroinflammation, synaptic density etc.
IL: Your research requires various areas of expertise: the imaging itself, the image processing side, the clinical side and then the statistical analysis. Can you tell us what your secret for successfully conducting inter-disciplinary research is?
GR: I have the great fortune of working with a wonderful team with complementary skills and great collaborators. To do clinical research, you really need multi-disciplinarity, it is a team science, both within and across centers. I also think that the idea that one modality is enough to study a disease lies in the past. We need all tools we can get to understand a disease on a more holistic level.
IL: If a junior scientist came up to you and asked: “Gil, one day I also want to be an OHBM keynote speaker, how do I do it?”, what advice would you give them?
GR: Find something you are passionate about and follow your heart. Science is a calling, not a 9 to 5 job, I mean, you can do it as a job, but you would not be successful or happy. Also, find something that is meaningful, for example, for me as a physician, doing research with very direct implications for my patients. Another piece of advice I would give is to say yes more often than to say no to new opportunities. It is important to focus, but equally important to expand your horizon. If you are too focused on a narrow topic, you may miss the opportunity to lead your research in a promising new direction. Also, choose great mentors. Great not as in famous people who won a lot of prizes, but people you can work with and who care for your development. I find that often the role of mentors is underestimated. I have been really lucky that way and could not have done it without having had such great mentors.
IL: Last but not least, can you give us a little teaser about your OHBM talk, without spoiling too much?
GR: I can say as much: it will be better than the last episode of Game of Thrones (laughs). I will give some background on Alzheimer’s disease, explain the biology, and describe how imaging techniques in longitudinal studies have changed our approach to understanding diagnosis, treatment and care.
IL: I am very much looking forward to this, thank you.
GR: See you in Rome!