Q & A with Prof William Seeley: OHBM 2016 Keynote Speaker Series

BY NILS MUHLERT & JESSICA TURNER
Professor William Seeley is a neurologist and principal investigator at the Memory and Aging Centre in UC San Francisco. There, William (Bill) leads the selective vulnerability lab. His team combines neuroimaging with neuropathological experiments, to map the neural networks affected by disease and uncover the drivers of those network-level changes. Bill’s keynote speech focussed on ‘Network-based neurodegeneration’ – here we find out more about Bill’s background and the challenges of this converging macro- and micro-level approach.

OHBM - What is it that interests you about neuroimaging? 
William Seeley (WS) - Neuroimaging has the potential to address three key issues in neurodegeneration research. First, brain imaging can tell us when and where neurodegeneration begins in living patients. This critical information provides the “treasure maps” we can use to guide our search for the cellular-molecular mechanisms of disease within the right neuroanatomical context. Second, functional imaging can help us understand changes in network physiology underlying patient symptoms. Finally, the dawn of “connectomic” imaging has allowed us to test competing models of network-based disease progression.

OHBM - What difficulties have you faced balancing a research and clinical career? What benefits has it brought?
WS - My clinical life frames and motivates everything we do in research, and I continue to be impressed by how much clinical science can teach us about healthy brain organization. For me, the major challenges relate to time and not having enough of it to do everything I would like to do in my career. Overwhelmingly, though, my life as a clinician has added great meaning to my life as a researcher.

OHBM - What draws you to OHBM and how does it differ from other similar, large conferences?
WS - I’ve been coming to OHBM for about 10 years and I keep coming back because of the enthusiasm of the membership for this field. It feels like a cohesive group of people - they each bring a different perspective and a different set of tools. It’s also a good place to learn about those tools – the very front line of methodological advances is reported here first. That always makes it exciting.

OHBM – In your keynote talk you laid out a number of different variants of the dementias, then focused on frontotemporal dementia. The dementias vary based on both behavior and symptoms. Could networks and the connectivity between networks aid differential diagnoses? Do you envision scanning patients in order to distinguish between different types of dementias?
WS - Neuroimaging of brain structure and function can help us refine our assessment of a patient’s clinical syndrome. In my talk you heard me discuss syndromic diagnoses and pathological diagnoses as distinct and separate concepts. Structural and functional imaging can help with syndrome refinement, but when it comes to the underlying neuropathological cause of that syndrome, I think those strategies are going to fall just a bit short. Take the example of behavioural variant frontotemporal dementia (bvFTD), it has 15 different neuropathological causes – I doubt we could use neuroimaging alone to decide which of those 15 underlying histopathologies is the actual cause of a patient’s bvFTD. It’s more likely that we’ll need a molecular technique, whether that’s biomarker analysis from spinal fluid or molecular imaging using PET scanning, to decide which of those various underlying histopathologies is the cause. Alternatively we’ll use some kind of a merger, where the structural and functional imaging refines the syndrome to the point where the differential diagnosis gets shorter. Then we use molecular imaging to nail the final diagnosis.

OHBM - Some of your recent research centres on selective vulnerability. Can you tell us what this is, and why it might be relevant to many neurological conditions?
WS - All neurological diseases are selective in some way. In neurodegenerative disease, we can see that progression occurs in a selective manner that is governed by network connections. Where (in which cell type), how (in what manner), and most importantly why a disease begins where it does remains far more mysterious, but may be a key to developing early-stage treatment or prevention.

OHBM – What would it take to get to the point where we have screening for different vulnerabilities? Would that goal be a priority in the absence of effective neuroprotective recommendations – or are effective recommendations available?
WS – That’s already the reality in Alzheimer’s dementia. Alzheimer’s is a common disease. You can screen a healthy older population for amyloid-beta deposition using molecular imaging and then triage patients for experimental treatment trials based on that result. To imagine doing that for some of the less common dementias, such as frontotemporal dementia, is a little more daunting because of the lower population prevalence. FTD has a population prevalence of about 1 in 5000 in those aged over 45, so it would have to be either a very inexpensive test or a very powerful therapy to justify that kind of screening program.

OHBM – It’s been proposed that the salience network may switch activity between the default mode and the central executive networks – and impaired switching has been hypothesized to play a role in a number of psychiatric disorders. Do you see that playing a role in the frontotemporal dementias?
WS – I don’t think we really know the answer, as I don’t think there’s been a study yet that went straight after the switching concept. From a phenomenological standpoint the patients are pretty poor switchers. Sometimes they get stuck in ruts and perseverate on the same behavioral response over and over. Other times they fail to switch in other ways when switching would be helpful. Sometimes they switch too much, where they’re distractedly moving from task to task as opposed to finishing. I do think that behavioral switching is a deficit – whether that correlates with network switching is an open question and I think it’ll be an important one to address at some stage.

OHBM - What do you see as the next major goals of neuroimaging in dementia research?
​WS - Neuroimaging can play a critical role by providing short-term interval biomarkers of disease progress for use in early-stage drug development. To accomplish this goal may require that we develop better models to predict progression, and then use those models as a way of assessing whether a drug has had a meaningful impact.

OHBM: Thank you Prof Seeley!

Prof Seeley's keynote talk on 'Network-based neurodegeneration' will soon be available to view on the OHBM OnDemand portal. Keep checking for this and other great talks from OHBM 2016. 
Thanks to Sarabeth Fox for video recording.