Charles D. Chen

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.

Email | CV | Google Scholar | LinkedIn

Education and training

HAI 2025

San Juan, Puerto Rico | January 16, 2025

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

Poster | Slide

AAIC 2024

Philadelphia, Pennsylvania | July 28, 2024

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

AANP 2024

Olympic Valley, California | June 7, 2024

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

Slides

AD/PD 2024

Lisbon, Portugal | March 9, 2024

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

PET/MR in ADRD T32 Fellowship

Boston, Massachusetts | August 1, 2023

"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

Graduate research

St. Louis, Missouri | 2018-2023

In graduate school, 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. I also joined the Dominantly Inherited Alzheimer Network (DIAN) to study autosomal dominant Alzheimer disease. Together, these efforts resulted in several studies comparing antemortem PET imaging with postmortem neuropathology in autosomal dominant versus sporadic Alzheimer disease. In particular, I helped show that antemortem tau PET reflects total tau burden in Alzheimer disease, composed predominantly of neurofibrillary tangle and neuropil thread pathology, instead of neurofibrillary tangle pathology alone, which has been the more commonly held opinion.

Additionally, I showed that antemortem amyloid-β PET predominantly reflects diffuse plaques in autosomal dominant Alzheimer disease, but a mixture of diffuse and cored/compact plaques in sporadic Alzheimer disease. This finding, along with the observation that amyloid-β pathology in autosomal dominant Alzheimer disease affects the cerebellum and brainstem - two important reference regions in amyloid-β PET - more aggresively than in sporadic Alzheimer disease, helped emphasize that autosomal dominant Alzheimer disease has many differences from sporadic Alzheimer disease, and the methods and assumptions used when studying the latter may not always be reasonable when studying the former.

I also led and was an active collaborator in several projects designed to determine the reliability of novel imaging and fluid-based biomarkers in diagnosing Alzheimer disease and monitoring the treatment effects of anti-amyloid-β therapies. Regarding diagnosis, I investigated the reliability of using a newly FDA-approved tau PET radioligand to detect the presence of tau pathology in the brain and found that the manufacturer's guidelines for the visual interpretation of these PET images did not explicitly cover cases such as hemorrhagic infacts and meningiomas, both of which can imitate the appearance of tau pathology. Regarding treatment monitoring, I found that while it is technically possible to monitor amyloid-β removal even with two different amyloid-β PET radioligands by using established harmonization techniques, using different radioligands may increase type I error in a way that cannot be addressed by current harmonization techniques.

Chen et al. 2023

Journal of Alzheimer's Disease | May 16, 2023

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

Paper

Poletsky Award

St. Louis, Missouri | April 11, 2023

"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 Defense

St. Louis, Missouri | April 10, 2023

Dissertation
To ascertain scientific reliability in PET imaging for Alzheimer disease

Dissertation

Chen et al. 2023

European Journal of Nuclear Medicine and Molecular Imaging | April 5, 2023

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

RSNA 2021

Chicago, Illinois | November 29, 2021

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

Slides

Chen et al. 2021

Acta Neuropathologica | July 28, 2021

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

Paper

Knight ADRC T32 Fellowship

St. Louis, Missouri | June 1, 2021

"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

Chen et al. 2020

Annals of Clinical and Translational Neurology | November 5, 2020

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

Paper

AAIC 2020

Virtual | July 28, 2020

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

Slides

HAI 2020

Miami, Florida | January 16, 2020

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

Poster

Zhang et al. 2018

Current Biology | December 20, 2018

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

Paper

Cottaar et al. 2018

Neuroimage | August 1, 2018

Research article
A gyral coordinate system predictive of fibre orientations

Paper

NSF Graduate Research Fellowship Program

St. Louis, Missouri | April 3, 2018

"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

Post-baccalaurate research

St. Louis, Missouri | 2015-2018

In college I wanted to study brain function, but never got the chance. After college I found an opportunity to work with Dr. Ilya Monosov to study brain function in the context of learning risks and rewards in an uncertain environment. I thought that studying how biological neurons encoded risks and rewards could inform how to design artificial neural networks for reinforcement learning. At the time, there was a breakthrough in using neural networks to learn how to play Atari games without human supervision by using "only the pixels and the game score as inputs". However, when watching videos of how the neural network learned to play, I noticed it failed to score any points on the game "Montezuma's Revenge" and thus failed to learn anything at all. I thought that one way to remedy this was to add a "reward" signal for exploring the game environment instead of relying only on the final game score as the sole reward.

With this in mind, I ran experiments to measure a monkey's neuronal activity while it watched visual cues that were associated with different probabilities of future rewards. I ended up characterizing two relevant neuronal signals: one was associated with anticipating an uncertain reward (pre-reward ramping) and the other was associated with receiving a low-probability reward (post-reward spiking). These findings suggest that ramping and spiking can be signals that encode levels of uncertainty, which expands on previous work that focused on neuronal ramping and spiking strictly in the context of more deterministic tasks.

AAIC 2018

Chicago, Illinois | July 23, 2018

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

Poster

Ledbetter et al. 2016

Journal of Neuroscience | July 27, 2016

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

Paper

Undergraduate research

St. Louis, Missouri | 2011-2015

In college I joined the Van Essen Lab, and worked with Drs. David Van Essen, Matt Glasser, and Krikor Dikranian 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 the brain tissue, a microscope, 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 everything using Adobe Illustrator, which also gave a quantitative measure of axonal 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.

FMRIB Visiting Scholar

Oxford, UK | September 8, 2015

Senior Honors Thesis

St. Louis, Missouri | April 17, 2015

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

Thesis

Van Essen et al. 2014

Diffusion MRI: From Quantitative Measurement to In vivo Neuroanatomy | November 4, 2013

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

Book chapter

HHMI Summer Undergraduate Research Fellowship

St. Louis, Missouri | April 5, 2013

"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

ISMRM 2013

Salt Lake City, Utah | April 26, 2013

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

Abstract

National Merit Scholarship

Kansas City, Missouri | May 4, 2011

"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."

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