Early Career Breakthroughs: Insights from the Derek Denny-Brown 2018 Awardees

The Derek Denny-Brown Young Neurological Scholar Award is the ANA’s most prestigious award. It recognizes early- to mid-career neurologists and neuroscientists who have made outstanding basic and clinical scientific advances toward the prevention, diagnosis, treatment, and cure of neurological diseases. Award winners present their work at the Derek Denny-Brown Young Neurological Scholar Symposium at the ANA Annual Meeting. Below, two of the 2018 winners fill us in on the newest directions in their research and how this opportunity has helped them.

Advancing dementia prediction and treatment through biomarkers
Alice Chen-Plotkin, MD: 2018 Winner, Derek Denny-Brown Young Neurological Scholar Award (Clinical)


Q: What was your experience like presenting your work at the 2018 ANA Annual Meeting?

I enjoyed it so much. It's rare that one gets the chance to present a body of work — rather than a specific result — to an audience of people with the academic neurology background that ANA members have. I've always weighted my attention by the likelihood that a given line of research might translate into real change for patients. An audience of academic neurologists intuitively understands this type of weighting.

Q: How has your research into neurodegenerative disease progressed since the 2018 ANA Annual Meeting?

At the meeting, I presented two lines of work: one focused on our investigations of the frontotemporal dementia (FTD) risk gene TMEM106B and one focused on our efforts to develop Parkinson's Disease (PD) biomarkers.

TMEM106B: My group recently published (in Annals of Neurology!) our analysis demonstrating that genetic variants in TMEM106B may not only affect risk for developing FTD, but also influence the rate of cognitive reliance in both FTD and PD. This result — found in 870 longitudinally-followed subjects and led by Tom Tropea — was surprising to us, as PD does not generally have a lot of TDP-43 neuropathology, and most prior work suggests that TMEM106B may influence levels of TDP-43 pathology. It is personally gratifying to me, of course, that two things I have worked on — TMEM106B and PD — are coming together unexpectedly. We are also putting together a manuscript now that is focused on the cell biology of TMEM106B — we think we have identified the protein partner that mediates an effect of increased TMEM106B expression on cells.

PD biomarkers: We have a manuscript in review describing our efforts to screen 1000+ proteins from the blood plasma of ~500 subjects across multiple cohorts (one based at Penn, the NIH Parkinson's Disease Biomarker Program cohort, and the Michael J. Fox Foundation BioFIND cohort). We find four new proteins that differentiate PD vs. control subjects at Penn and replicate in the national PDBP cohort. Moreover, these proteins don't change based on whether the patient is ON vs. OFF levodopa (this is what we used the BioFIND cohort to prove), and some of them predict the trajectory of cognitive decline over time. These are entirely novel blood-based biomarkers, found by unbiased large-scale screening, which survive cross-cohort replication. I think this kind of discovery-replication design is so important for biomarker work. Genetics/genomics adopted this many years ago to avoid getting a lot of false positives, and I'd like to see it adopted universally in the biomarker field as well. 

Q: What else are you currently working on?

One thing that is a real labor of love for me right now is an effort to turn our Parkinson’s Disease clinic at Penn into a truly translational clinic. I think we need to do this, because for PD (and, really, all the neurodegenerative diseases), we don’t have any FDA-approved disease-modifying therapy yet. So many patients really want to know what clinical trials aimed at disease modification might be a good idea for them. 

What I wanted was a way to molecularly characterize all of our patients, so that we could rationally decide, for the current trials as well as future trials, which specific patients might profile as more suitable for various experimental treatments. Fortunately for me, Penn wanted to invest in this idea, too, so we launched the Molecular Integration in Neurological Diagnosis (MIND) Initiative in September 2018. Over a 2-year period, we’re hoping to enroll basically everyone in our clinic for genetic characterization. We’re also offering to disclose back, on the clinical side, any mutations we find that would make specific patients eligible for currently enrolling trials. 

It’s such a simple and intuitive concept to do this, but in reality almost all clinics (including ours before we launched MIND) study only about 10% of their patients on the research side and don’t disclose research results back to patients. So, to take this to the whole clinic (of ~2200 patients!), it was a matter of figuring out how to scale, how to make methods/results valid enough for clinical disclosure, and how to do this in an ethical way that would benefit and not harm patients. 

I couldn’t do this by myself, of course, so it’s also been a great chance to learn how to work with partners who are more clinical in their research than me (in particular Tom Tropea, who is also an academic neurologist), partners who are lab medicine specialists (in particular Vivianna Van Deerlin, who is a translational molecular pathologist), partners who are patients, partners from the Penn Center for Precision Medicine, foundation partners such as the Parkinson’s Foundation, etc.

Q: How did receiving the Derek Denny-Brown Award affect your work or career?

It’s such an honor. To be a physician-scientist means having to deal with disappointments on a regular basis — projects, papers, grants that didn’t work out — and having to juggle different duties all the time. I really enjoy this job, which is why I do it, but it’s still also great to have something celebratory to balance out the challenges.

Q: Why are opportunities like the Derek Denny-Brown Award important for early- and mid-career academic neurologists?

In many other walks of life, being 40 is being middle-aged, and one is not in early career but rather well-established. It is crazy that we’ve become so developmentally delayed as a profession that half of your life might be over, and your career might just be starting! So I love the fact that the Derek Denny Brown Award is both recognized as the highest award that the ANA gives AND recognizes people in their 40s.

Q: How has the ANA been useful to you as an early- to mid-career academic neurologist?

The world of academic neurologists is small, although that is hard to recognize this fact as a starting investigator. The ANA brings together that community and fosters relationships that may be the basis for really great collaborations down the road.

Understanding the "repeatome" and neurological disease

Peter K. Todd, MD, PhD: 2018 Winner, Derek Denny-Brown Young Neurological Scholar Award (Basic Science)


Q: What was your experience like presenting your work at the 2018 ANA Annual Meeting?

I had a very positive experience presenting at the ANA. Giving a talk in a plenary session to the leaders of academic neurology was an honor and I received valuable feedback on our work from multiple sources. 

Q: How has your research into neurodegenerative disease progressed since the 2018 ANA Annual Meeting?

We have continued to make significant progress on the mechanisms by which repeat expansions cause human disease. In the past 8 months we have identified new modifiers of repeat associated translation at repeats associated with ALS and with FXTAS and demonstrated that modulating these pathways can correct disease relevant phenotypes in multiple model systems. We have also made advances in understanding how cellular stress pathways interface with repeat biology in ways that I think are informative to the larger field of neurodegeneration.

Q: What else are you currently working on?

We have become quite interested in exploring both the native functions of nucleotide repeats in the genome and in identifying new repeat expansions associated with human disease. We still know so little about the broader “repeatome” and I feel as though this area of neurobiology will provide new insights into both neuronal function and neurological disease.

Q: Are you attending the 2019 Annual Meeting? If so, what are you looking forward to most?

Receiving the award and attending the ANA meeting let me know that the work we are doing on a set of relatively rare neurological disorders is of interest to the broader neurological community.

Q: Why are opportunities like the Derek Denny-Brown Award important for early- and mid-career academic neurologists?

Receiving this award allowed me to meet many leaders in the field and to have them know what I work on. These networking connections have a lot of value, I think, in the relatively small world of academic neurology.

Q: How has the ANA been useful to you as an early- to mid-career academic neurologist?

The meeting offers an up-to-date take on cutting-edge activities in clinical, translational, and basic neurology research. I have also made new collaborations at the ANA in the past and have strengthened existing collaborations through interactions at the meeting which should aid our work going forward.

Thank you again to the ANA for the award in 2018 and I look forward to attending the meeting this coming year and being a member and regular attendee for years to come.