I am a research fellow at the Martinos Center, and I am supported by a T32 fellowship to work on the neuropathologic validation of novel biomarkers and antibodies for the diagnosis and treatment of Alzheimer disease. I did my PhD in Imaging Science at Washington University in St. Louis, where I was supported by the NSF GRFP and the Knight ADRC T32 Program.

Email | CV | Google Scholar | LinkedIn

Post-doctoral research | Doctoral research | Post-baccalaurate research | Undergraduate research

After graduate school, I continued to study the brain's molecular changes during Alzheimer disease. I developed a PET-to-histology approach to evaluate anti-amyloid-β therapies in the first clinical trial in dominantly inherited AD (DIAN-TU-001). To quantify the level of amyloid-β deposition, tauopathy, microgliosis, and astrocytosis from hundreds of brain tissue sections, I developed a method that first used a deep-learning based method originally designed to detect cell nuclei, to derive an initial guess of where the amyloid-β and tau deposits or microglia or astrocyte cell bodies were, then derived a threshold that would separate these stained features from the background, which yielded an estimate of the stained area fraction (the amount of area these features occupied compared to the brain region overall). Using this approach, I found that while anti-amyloid-β therapies remove amyloid-β deposits, they didn't seem to alter the levels of tauopathy, microgliosis, and astrocytosis.

I also developed a method to segment the meninges from MR images. The meninges are a thin layer of tissue that wrap around the brain, which make them difficult to segment as their own structure (often they are lumped together with brain parenchyma or CSF and sometimes even skull bone). I developed a method that first used a whole-head segmentation tool as a starting point, which contains the meninges within its CSF label, then used a ratio of T1-weighted to T2-weighed MRI contrast to separate the meninges from CSF (meninges are bright on T1-weighted images and dark on T2-weighted images, while CSF is dark on T1-weighted images and bright on T2-weighted images). Segmenting the meninges is important for studying the characteristics of off-target signals of the ¹⁸F-MK-6240 tau PET radioligand, which typically localize to the meninges, but these signals can spill into the cerebral and cerebellar cortices and interfere with the quantification of tau burden.

Poster presentation
Preliminary autopsy findings from the Harvard Aging Brain Study

Poster

Research article
Regional effects of gantenerumab on neuroimaging biomarkers in the DIAN-TU-001 trial

Paper

Research article
Immunohistochemical evaluation of a trial of gantenerumab or solanezumab in dominantly inherited Alzheimer disease

Paper

Poster presentation | Blitz talk
Two distinct sources of ¹⁸F-MK-6240 off-target signal identified by individualized head modeling and PET kinetics

Poster | Slide

Poster presentation
Anti-Aβ treatment effects on dominantly inherited AD: comparing neuropathology findings with biomarker outcomes from the DIAN-TU-001 trial of gantenerumab or solanezumab

Poster

Oral presentation (AANP Travel Award)
Autopsy findings versus biomarker outcomes in a clinical trial of anti-Aβ therapies in dominantly inherited Alzheimer disease

Slides

Oral presentation
Anti-amyloid-beta treatment effects on dominantly inherited Alzheimer disease neuropathology: Preliminary autopsy findings from the DIAN-TU-001 trial of gantenerumab or solanezumab

Slides

"The main goal of this T32 program is to provide a 2-year postdoctoral training experience, rich in multimodal neuroimaging, that focuses on three key research areas in Alzheimer’s disease and AD-related dementias (AD/ADRD): [1] the biology of aging and neurodegeneration; [2] data sciences, computational biology, statistics, mathematics, engineering, biophysics; and [3] drug discovery and drug development disciplines."

Website

In graduate school, I studied the brain's molecular changes during Alzheimer disease (AD). I co-founded the Pathology And Imaging Neuroinflammation and Tau (PAINT) committee to coordinate imaging-pathology studies between the Imaging and Neuropathology Cores of the Knight ADRC, and joined the Dominantly Inherited Alzheimer Network (DIAN) to study autosomal dominant AD. Together, these efforts resulted in several studies comparing antemortem PET imaging with postmortem neuropathology in autosomal dominant and sporadic AD. In particular, I derived an estimate of the typical amount of amyloid-β plaques that accumulate in the brain during AD, which is now being used to investigate whether removing amyloid-β plaques during anti-amyloid-β treatment could be leading to brain shrinkage.

I also led or collaborated in projects evaluating the reliability of a newly FDA-approved tau PET radioligand (¹⁸F-flortaucipir) and novel fluid-based biomarkers (MTBR-tau243 and %p-tau217) in diagnosing AD. One project I led investigating ¹⁸F-flortaucipir found that the manufacturer's guidelines for the visual interpretation of these images did not cover cases such as hemorrhagic infacts and meningiomas, which can imitate the appearance of tau pathology. I was also part of the first clinical trial in dominantly inherited AD (DIAN-TU-001), which investigated the effects of anti-amyloid-β therapies in autosomal dominant AD. One project I led found that while it is technically possible to monitor amyloid-β removal with two different amyloid-β PET radioligands by using an established harmonization technique, doing so will increase type I error.

Research article
Comparing tau PET visual interpretation with tau PET quantification, CSF biomarkers, and longitudinal clinical assessment

Paper

"The Richard and Mildred Poletsky Education Fund was initiated in 1995 by the family of Mr. Richard Poletsky, a native of St. Louis and alumnus of Washington University. Beginning in 1996, Mrs. Poletsky presented the award annually in memory of her husband until her death in 2016. Rhonda & David Banford continue to support the Poletsky Award in honor of Rhonda’s parents and almost always attend the recognition ceremony. The award is intended to enhance the career development of a promising student or fellow working towards a research, clinical and/or other service career focusing on aging and dementia."

News

Dissertation
To ascertain scientific reliability in PET imaging for Alzheimer disease

Dissertation

Research article
Longitudinal head-to-head comparison of ¹¹C-PiB and ¹⁸F-florbetapir PET in a Phase 2/3 clinical trial of anti-amyloid-β monoclonal antibodies in dominantly inherited Alzheimer's disease

Paper

Oral presentation
Concordance of PET tau visual reads with PET tau quantification and CSF pTau

Slides

Research article
Comparing amyloid-β plaque burden with antemortem PiB PET in autosomal dominant and late-onset Alzheimer disease

Paper

"The Washington University T32 training grant 'Multidisciplinary Training in Alzheimer and Related Dementias' is designed to prepare the next generation of researchers in Alzheimer disease and related dementias. The program emphasizes the collaborative, multi- disciplinary research that will be needed to find treatments for Alzheimer disease and other dementias."

Application | Website

Research article
Ante- and postmortem tau in autosomal dominant and late-onset Alzheimer’s disease

Paper

Oral presentation
Tauopathy in autosomal dominant and late-onset Alzheimer disease

Slides

Poster presentation (Young Investigator Award Finalist)
Quantifying tau PET imaging reliably in the presence of off-target binding

Poster

Research article
Novelty, Salience, and Surprise Timing Are Signaled by Neurons in the Basal Forebrain

Paper

Research article
A gyral coordinate system predictive of fibre orientations

Paper

"The purpose of the NSF Graduate Research Fellowship Program (GRFP) is to help ensure the quality, vitality, and diversity of the scientific and engineering workforce of the United States. A goal of the program is to broaden participation of the full spectrum of diverse talents in STEM. The five-year fellowship provides three years of financial support inclusive of an annual stipend of $37,000."

Application | Website

After college I had the opportunity to work with Dr. Ilya Monosov to study brain function when learning risks and rewards in an uncertain environment. My thought was that studying how biological neurons encoded risks and rewards could inform the design of artificial neural networks. At the time, there was a breakthrough in using neural networks to learn how to play video games without human supervision by using "only the pixels and the game score as inputs". However, when watching videos of the neural network's performance, I noticed it failed to learn how to play a game where the game score only increased after successfully navigating a complex environment. I thought one way to remedy this was to design a cost function that could "motivate" the network to explore the game environment even in the absence of explicit reward (in this case, the game score).

With this in mind, I ran experiments to measure a monkey's neuronal activity while it watched visual cues that revealed the probability that it would receive a fruit juice reward in the next few seconds. I ended up characterizing two neuronal signals: one was a pre-reward ramping signal that was associated with anticipating a probablistic reward in the future, and the other was a post-reward spiking signal that was associated with receiving a reward with a low probability of occuring. These findings - along with the observation that monkeys started licking in anticipation of receiving a reward - suggest that ramping and spiking can be signals that encode the possibility of future rewards, which could participate in circuits motivating behavior even in the absence of reward or when receiving a reward is not guaranteed.

Poster presentation
Evaluating neuroinflammation imaging as a biomarker of tissue cellularity in the post-mortem human brain

Poster

Research article
Multiple Mechanisms for Processing Reward Uncertainty in the Primate Basal Forebrain

Paper

In college I joined the Van Essen Lab, and worked with Drs. David Van Essen, Matt Glasser, and Krikor Dikranian to study brain structure, specifically on a problem they called the "gyral bias". Drs. Van Essen and Glasser were using diffusion MRI to visualize the axonal fibers that connect different parts of the brain together. Diffusion MRI suggested that axonal fibers tend to terminate in gyral crowns, as opposed to sulcal banks or fundi. However, using brain tissue stained to visualize axonal fibers, Dr. Dikranian observed that axonal fibers seemed to terminate evenly along the cortical surface, with no preference toward gyral crowns. The problem was how to compare diffusion MRI and brain tissue in a quantitative way.

I worked on how to quantify axonal fiber directions with respect to the cortical surfaces from Dr. Dikranian's brain tissue sections. In the beginning, I was given brain tissue, a microscope, a pencil, and a stack of paper, and was asked to draw what I saw. This took a lot of time, and I felt that even if I drew the axonal fibers perfectly, they would still not be quantitative. I decided to digitize the tissue sections. Then I manually annotated the axonal fibers using Adobe Illustrator, which gave a quantitative measure of fiber directions. This still took a lot of time, though, so I taught myself how to code in MATLAB, and wrote a script that estimated axonal fiber directions using structure tensors and delineated the cortical surface using B-splines.

When comparing these digital microscopy estimates with diffusion MRI estimates of axonal fiber directions, I found that digital microscopy and diffusion MRI showed similar axonal fiber directions along gyral crowns, but different fiber directions along the sulcal banks and fundi. These findings received pushback from other investigators who believed there was no gyral bias, and that the fiber directions estimated by diffusion MRI reflected the true fiber architecture of the brain. But by promoting the idea that there was a gyral bias in diffusion MRI tractography, these findings motivated the development of new tractography algorithms that more closely reflected what I quantified from brain tissue sections.

"The FMRIB Building and FMRIB Annexe are on the John Radcliffe Hospital Site in Headington, Oxford. As well as hosting around 100 researchers, the FMRIB Building is the location of one of our 3 Tesla MRI scanners and our 7 Tesla Human MRI. The FMRIB Annexe, just across the car park from the FMRIB building, hosts another 60 researchers and most of our meeting rooms."

Website

Thesis
Comparison of Diffusion MRI with Axonal Trajectories Near Cortex to Estimate Folding-Related Biases of Tractography-based Connectivity in the Macaque Brain

Thesis

Book chapter
Mapping Connections in Humans and Non-Human Primates: Aspirations and Challenges for Diffusion Imaging

Book chapter

"The Summer Undergraduate Research Fellows (SURF), funded by the Howard Hughes Medical Institute and various other agencies, is an opportunity for freshmen, sophomores and juniors to apply for a 10 week research project with faculty mentors, earning a summer stipend."

Slides | Poster

Oral presentation (ISMRM Merit Award summa cum laude)
Comparison of Diffusion MRI Predictions and Histology in the Macaque Brain

Abstract

"The National Merit Scholarship Program is an annual academic competition among high school students for recognition and college scholarships that began in 1955. The program is conducted by National Merit Scholarship Corporation (NMSC®), a not-for-profit organization that operates without government assistance. United States high school students enter the National Merit Scholarship Program by taking the Preliminary SAT/National Merit Scholarship Qualifying Test (PSAT/NMSQT®), which serves as an initial screen of over 1.3 million entrants each year, and by meeting published program entry and participation requirements."

Website