Advancing Neuroimaging: Julie Price Talks with Henryk Barthel About Enhanced Understanding of the Brain and Neurodegeneration

Julie C. Price; Henryk Barthel

doi:10.2967/jnumed.124.267651

Julie C. Price, PhD

Henryk Barthel, MD, PhD, a professor in the Klinik und Poliklinik für Nuklearmedizin at the University of Leipzig (Germany), talked with Julie C. Price, PhD, a professor of radiology at the Harvard Medical School and director of PET Pharmacokinetic Modeling in the Athinoula A. Martinos Center for Biomedical Imaging at the Massachusetts General Hospital (MGH; Boston). She is also faculty codirector for research at the MGH Center for Diversity and Inclusion (CDI). She specializes in PET imaging methodology with a focus on kinetic modeling of ligand–protein binding interactions in studies of aging, neuropsychiatric disorders, and neurodegeneration.

Dr. Price received her PhD from Johns Hopkins University in the Radiation Health Sciences Program led by Henry N. Wagner, MD. She completed postdoctoral training in quantitative PET in the National Institutes of Health (NIH) PET/Nuclear Medicine Department. From 1994 to 2016, she was a faculty member in radiology at the University of Pittsburgh, where she led PET methodology and worked with the group that established amyloid PET using Pittsburgh Compound-B (PiB). At MGH, she continues multidisciplinary PET research, with a primary focus on methods to improve early detection and longitudinal assessments of tau protein deposition with Harvard Aging Brain Study colleagues. She is a fellow of the Society of Nuclear Medicine and Molecular Imaging and the American Institute for Medical and Biologic Engineering. She has served as chair of the NIH Clinical Neuroscience and Neurodegeneration Study section and on the advisory council to the director of the NIH Center for Scientific Review.

Dr. Barthel: Julie, thanks so much for this interview. From your CV I learned that in 2016 you moved to Boston to the Martinos Center. Can you elaborate on your role there?

Dr. Price: I lead a PET methodology and data analysis group and am a research principal investigator. We’re very collaborative and support various neuroimaging efforts. Much of my effort is also spent supporting research development for early-career researchers and helping to support the development of NIH-funded research applications in various areas, such as pain, addiction, and neurodegeneration, often involving PET/MR imaging. I’ve also helped to develop 2 NIH training grants at the Martinos Center. One is an AD-oriented T32 postdoctoral training program that aims to build a more diverse AD workforce across a range of clinical and technical research areas, in response to a targeted NIH funding announcement. Another NIH training grant with Bruce Fischl, PhD, is a summer internship program in neuroimaging that targets talented high school students from low income and ethnic or racial minority groups who are interested in STEM fields.

Dr. Barthel: Wonderful to hear that training is part of the focus of your Martinos activities. This is so important and much appreciated. What makes the Martinos Center such a special place to work?

Dr. Price: It’s special because of the good people, impressive imaging resources, rich history of innovative imaging developments and applications, and international diversity. The center has about 120 faculty, 100 fellows, 8 tomograph bays for human research (3-T, 7-T, PET/MR), and many other resources (e.g., small-bore MR and PET/MR, hyperpolarizer, and spectroscopy systems). People are encouraged to work independently but collaboratively. You can walk down the hallway and have interesting conversations with 2 or 3 people who might help to solve a problem or stimulate a new idea. The trainees and even research assistants or coordinators who come in for a couple of years before going to medical or graduate school are very interested in research. This makes it a dynamic environment for mentoring. I give a lot of credit to Bruce Rosen, MD, PhD, the director of the Martinos Center, who works with faculty to promote excellence and provide a supportive environment during challenging academic times. He is a great mentor and colleague.

Dr. Barthel: Harvard is also the home of the famous Harvard Aging Brain Study. In which way are you involved in this?

Dr. Price: Among other tasks, I am involved in the PET methodology and support decision making related to PET methodology. This is a remarkable study. The findings have contributed to the framework of understanding of early AD. From its beginning as a program project in 2010, it had a specific focus on older individuals who were not clinically impaired. This study has really helped set the stage for therapeutic trial enrollments, contributing to a better understanding of AD and in vivo mapping of neuropathology during this preclinical phase. This was done by imaging amyloid burden and, when tau PET tracers became available, tau burden. At that time, it also became possible to investigate the in vivo synergy between amyloid and tau during the disease course. It became evident that the time point when neuropathologic tau deposition kicks in is not clearly driven by a single level of amyloid load and that further understanding of this complex process might be crucial. Keith Johnson, MD, and Reisa Sperling, MD, are doing a great job as principal investigators leading this effort and stimulating new investigations, such as those studying resilience and resistance to AD pathology.

Dr. Barthel: These results are now moving into the clinical arena as drugs are developed that can potentially be applied at exactly the time point when the tau kicks in. It’s fantastic to see how research translates into clinical use.

Before you moved to Boston, you worked at the University of Pittsburgh, famous as the place where amyloid imaging was invented. The first human amyloid PET data were published by the Pitt group together with the Uppsala (Sweden) group in 2004. These are exciting times for amyloid imaging because now, nearly 20 years later, we have a chance to see amyloid imaging truly entering the clinical arena and making a difference to our patients. How were you involved in the development and testing of PiB, the first successful amyloid tracer?

Dr. Price: I was more involved with PiB in an operational and validation sense, particularly when they were moving to human imaging. I was less involved in the preclinical studies that Chester A. Mathis, PhD, William E. Klunk, MD, PhD, and others were performing. When they started to translate research into humans, then I became very involved. I remember when Chet and Bill asked me to go to Uppsala with them to review the initial human data; we were really excited. It was a great opportunity for me. The proof-of-concept human imaging study performed in Uppsala provided critical evidence that cortical PiB SUV measures were about 2-fold greater in AD patients than in control subjects. The next step was to apply for NIH funding, which provided the opportunity to perform a quantitative in vivo evaluation and analysis of human PiB PET data, including subjects with mild cognitive impairment, incorporating structural MRI data and full kinetic modeling. We also compared PiB retention against ¹⁸F-FDG metabolism and ¹⁵O-water blood flow measures. We also performed PiB PET test/retest studies.

“…it would be beneficial to have a new generation of brain PET scanners that are both improved and more affordable. This would allow greater public access to advanced brain imaging technology across various settings. Both expense and expertise are required to achieve this—that’s why it is so important to mentor new generations of dedicated scientists who can improve technology translation.”

Dr. Barthel: This was groundbreaking work. It quickly became apparent that kinetic modeling can be done in amyloid imaging quite easily without arterial sampling. This brings me to another topic. I would also like to talk a bit about the AD Neuroimaging Initiative (ADNI). For our readers, the ADNI provides a very large database of imaging and nonimaging data in subjects at different AD stages and in controls, which can be used for various research purposes. How important do you consider the ADNI for our research?

Dr. Price: The ADNI is immensely important to our research field. It began in 2004, and its data have been used to generate thousands of publications, about 1,400 just from 2021 and 2022. The ADNI has had a significant impact. It was one of the largest NIH public–private partnership studies in our field. It changed the landscape for those in the United States who were focused on federal funding for AD research. This framework has been extended internationally. It helped to standardize methods for AD biomarkers testing by standardizing protocols. Altogether, the great success of this data-sharing project stimulated other public–private partnerships. It has had a profound additional effect on the field by laying the groundwork for therapeutic trial considerations.

Dr. Barthel: I agree. ADNI is a role model of a data-sharing platform that can serve as a paradigm for other imaging fields. Another question: I have observed over the years that for many brain PET tracers, static imaging is chosen over dynamic imaging, mainly to save time. By doing so, we lose the capability for absolute quantification. This is true even for the use of brain PET to test drug effects over time. Why do you think that we are struggling to use dynamic imaging and kinetic modeling more often?

Dr. Price: There is a conception (in some cases correct) that dynamic imaging is too expensive, too labor-intensive, and associated with significant patient burden. However, dynamic imaging can be uniquely beneficial. Kinetic modeling of dynamic scan data acquired over a 60-min period or even a split acquisition of early- and late-postinjection imaging (such as the Amsterdam coffee-break approach) is feasible and can provide more quantitative outcome measures. As we move earlier and earlier in the disease process, which is likely in some future drug testing trials, as dynamic imaging is more and more feasible in terms of participant burden. But what is really important is the notion of the tissue uptake ratio. In the case of amyloid PET imaging, for example, the amount of amyloid load can affect the degree to which the tissue ratio is biased and the appropriate time interval for making the assessment. Dynamic studies are needed to carefully map these issues and to understand what is lost or gained by late scan ratio simplification, because bias will arise in ratio uptake measures (relative to quantitative measures) as a result of radioligand clearance effects (lack of equilibrium). Our field often accepts this bias, because the late scan uptake ratio measure is feasible. The ratio is also generally less biased when working in that preclinical space with lower amyloid or tau load when trying to detect earlier stages of deposition within the brain. With some of these amyloid or tau tracers we can assess more than just the pathology load from a dynamic study, such as surrogate measures of relative blood flow from the early postinjection PET data that are reflective of radioligand delivery from the vasculature into the brain. This is exciting and potentially relevant for studies of vascular factors that might cause someone to be more vulnerable to the deleterious effects of therapies—in addition to providing more in vivo information on patient status. So, certainly for the Harvard Aging Brain Study, amyloid PET information is still collected dynamically over 60 min, and I think this has been a positive approach.

Dr. Barthel: This might be even more relevant for the tau tracers.

Dr. Price: This is true. For at least some of these tracers, static tissue uptake ratios do not reach a plateau during the late-scan PET acquisition interval, particularly for high binders, making the imaging outcome susceptible to variations in the scan start time (i.e., higher uptake ratio values when postinjection imaging start times are delayed).

Dr. Barthel: This brings me to the exciting ongoing development of new-generation tau tracers. One tau tracer, flortaucipir, is already approved by the U.S. Food and Drug Administration. What is your impression of these emerging new-generation tracers? Do we need better tau tracers?

Dr. Price: It’s important to reduce off-target signal in tau PET and to use a radiotracer with the best signal-to-noise and dynamic range. I haven’t worked with all of the tau radiotracers, but those that allow robust assessment of uptake in brain areas where neuropathologic protein deposition occurs early in AD, such as the mesial temporal areas, would be good tracers of choice.

Apart from amyloid and tau tracers and in terms of emerging new-generation radiotracers, it would be of great significance to have new radioligands that enable robust imaging of α-synuclein and TAR DNA-binding protein 43 neuropathology. These capabilities would expand our primary pathology imaging approach to Parkinson disease, frontotemporal dementia, and other disorders.

Dr. Barthel: Let’s talk about an interesting technology development we are currently seeing. Different groups worldwide are working on dedicated brain PET scanners. What is your opinion? Does this make sense to you?

Dr. Price: In my opinion, technological advances for dedicated brain scanners are important in terms of targeting very early disease. Just within the AD realm, it would be important for us to accurately image emergent tau pathology in the small locus coeruleus to further our in vivo understanding of the aging process and AD. But these imaging systems can be quite expensive and require top-level expertise. So, in addition, it would be beneficial to have a new generation of brain PET scanners that are both improved and more affordable. This would allow greater public access to advanced brain imaging technology across various settings. Both expense and expertise are required to achieve this—that’s why it is so important to mentor new generations of dedicated scientists who can improve technology translation.

Dr. Barthel: This aim of broadening access to imaging technology brings me to my last point: diversity. Diversity is increasingly considered to be important in science, as well as in everyday life. You are working at the CDI at MGH. Can you tell us a bit more about your efforts in this regard?

Dr. Price: The MGH CDI has been clinically focused since it began almost 30 years ago. The goals included working to improve recruitment and retention of diverse individuals who are underrepresented in medicine (UiM) and to increase opportunities for these individuals to advance to senior positions in academic medicine at MGH. In October 2021, an initiative was launched to further expand CDI efforts into the research realm. Cesar Castro, MD, and I were chosen to be faculty codirectors for research at that center. There we have a strong focus on supporting individuals and networking. My efforts focus more on PhD researchers within the medical school environment. We try to understand an individual’s aspirations and resources and provide support through one-on-one meetings on funding opportunities, the processes of grant development and review, CVs, and career development opportunities. Sometimes more difficult issues are addressed, such as challenges with mentors. On a more general level, we also support larger initiatives within MGH research training programs, ranging from undergraduates, medical students, graduate students, and postdocs to residents and early career faculty, for whom internal career development awards are available. My efforts involve a range of research initiatives targeting UiM recruitment and retention and building a diverse research community.

Dr. Barthel: This sounds like very important work. Diversity is becoming a huge topic in clinical trials, with the Imaging Dementia—Evidence for Amyloid Scanning (IDEAS) study representing just 1 example in our field. We are living in a diverse world, and clinical studies need to reflect the diversity in the population.

Dr. Price: We know that for some of the AD therapeutics currently being tested, differences in efficacy could depend on side effects, comorbidities, and genetic factors. Also, the impact of a diagnosis or of a positive amyloid scan may lead in specific cases to consideration of therapeutic options requiring frequent treatment visits. An individual’s ability to take part might depend on access to a nearby health center that can provide the treatment.

Dr. Barthel: Thanks so much, Julie, for these great insights and for your time.