In Vivo Stable Isotope Labeling and Quantitative Mass Spectrometry Imaging of Aβ Plaque Deposition in Human Alzheimer’s
Alzheimer’s disease (AD) is a devastating neurological disease for which there currently are no effective therapeutics. Critical to the development of therapeutics that may treat and even cure AD is an understanding of the dynamics (the change over time) of certain amyloid-beta (Aβ) proteins that are a likely cause of AD in the human brain. We are using the most advanced imaging technology to answer these questions in patients in order to accelerate drug development and improve patient outcomes.
Our goal is to measure, for the first time in human Alzheimer’s disease (AD) brain, the rate of plaque pathology using the most advanced imaging technology. We have developed an advanced imaging protocol called SILK-SIMS, which enables us to image and measure plaque growth at the nanometer level; which this allows us to see structures much smaller than cells and measure the growth during life. Plaque growth is measured with a label given to patients (like a dye which tags newly made plaque), which we then image with SILK-SIMS, noting both the location and amount of the new growth of the plaque. We aim to measure plaque growth, using SILK-SIMS imaging, in the brain of people with mild to severe cases of AD and compare these measurements to those taken from patients without dementia. These findings will enable us to model how fast AD pathology occurs in the living human brain.
This research is unique in that we will be providing the first direct measures of plaque growth rates in the human AD brain by utilizing cutting-edge methodologies never before leveraged in the AD field. The outcomes of this study will provide new insights in order to better understand AD amyloid pathology, which can accelerate drug development and inform clinical trials. In addition, we will have established a blueprint for the investigation of other devastating neurodegenerative diseases, such as Parkinson’s disease, frontal-temporal dementia, and amyotrophic lateral sclerosis (ALS; also known as Lou Gehrig's disease).
About the Researcher
Dr. Bateman received B.S. degrees in electrical engineering and biology from Washington University and his medical degree from Case Western Reserve University School of Medicine. He completed a neurology residency at Barnes Jewish Hospital and did post-doctoral research at Washington University School of Medicine, where he is the Charles F. and Joanne Knight Distinguished Professor of Neurology, director of the Dominantly Inherited Alzheimer Network (DIAN), and director of the DIAN Trials Unit (DIAN-TU). Dr. Bateman’s research focuses on the pathophysiology and development of improved diagnostics and treatments of Alzheimer’s disease (AD). The accomplishments of his lab include pioneering the central nervous system Stable Isotope Labeling Kinetics (SILK) measurements in humans, furthering insights of human circadian patterns of amyloid-beta (Aβ) and soluble amyloid precursor protein (APP), and human in vivo control of the alpha-secretase, beta-secretase, and gamma-secretase processing of Aβ. His lab has developed methods to quantify the pharmacodynamic action of drugs targeting Aβ, APP, and apolipoprotein E. Dr. Bateman’s research in DIAN has provided evidence for a cascade of events beginning decades before symptom onset that leads to AD dementia. He has received a number of awards including the Beeson Award for Aging Research, Alzheimer’s Association (Zenith Award), Scientific American, Chancellor’s Award for Innovation and Entrepreneurship (Washington University), the Glenn Award for Aging Research, and the MetLife Foundation Award for Medical Research. Dr. Bateman has been the primary mentor for junior faculty, clinical fellows, post-doctoral researchers, and graduate and medical students, who have been successful in their desired scientific careers.
My love of science and interest in aging and how the mind works led me to research one of the greatest challenges of our time--Alzheimer’s disease. Alzheimer’s not only disables and ultimately takes the life of a person; it robs so much of a person’s identity, such as memory and thinking. This is poignantly clear in taking care of hundreds of patients with the disease. But it wasn’t until my own grandfather developed Alzheimer’s that I experienced the disease in my own family. He was a brilliant and determined man who had an unassailable optimism and confidence in every day until Alzheimer’s took these away from him. He continued the fight against Alzheimer’s by working and exercising as long as he could, and also by taking an interest in my research. Despite his dislike of being near medical centers, my granddad frequently volunteered in Alzheimer’s research, including our work on understanding how the brain makes and clears proteins that are thought to cause Alzheimer’s.
He died unexpectedly from sudden heart failure and donated his brain to Alzheimer’s research. Amazingly, the studies he did in life labeled or painted the Alzheimer’s proteins in his brain, thus leaving a unique map that enabled a whole new technology to be developed. This new approach, now allows us to see the actual microscopic growth of the plaques and tangles that cause Alzheimer’s in a living person. This has opened a whole new area of research, which will provide new understandings of Alzheimer’s and suggest better ways to detect and treat the disease.
I know my granddad would be proud to have been the pioneering first patient that contributed to these breakthrough studies, and I am proud of him for his contributions, even after he is gone. Although he is no longer with us, we will continue the fight against Alzheimer’s and will beat this disease someday soon.
Paterson RW, Gabelle A, Lucey BP, Barthélemy NR, Leckey CA, Hirtz C, Lehmann S, Sato C, Patterson BW, West T, Yarasheski K, Rohrer JD, Wildburger NC, Schott JM, Karch CM, Wray S, Miller TM, Elbert DL, Zetterberg H, Fox NC, Bateman RJ. SILK studies - capturing the turnover of proteins linked to neurodegenerative diseases. Nat Rev Neurol. 2019 Jun 20. doi: 10.1038/s41582-019-0222-0. [Epub ahead of print] Review. PubMed PMID: 31222062.
Bateman, R. J., Mawuenyega, K. G., & Wildburger, N. C. (2019). The structure of amyloid-β dimers in Alzheimer’s disease brain: a step forward for oligomers. Brain, 142(5), 1168-1169. PMID: 31032843 DOI: 10.1093/brain/awz082
State of the Art Imaging Technique to Study Alzheimer's Plaque and Tangle Formation
Video credit: Norelle C. Wildburger, PhD, Washington University School of Medicine
First published on: June 22, 2017
Last modified on: August 10, 2020