Penn Medicine researchers will leverage an $18 million grant from the National Institutes of Health/National Institutes of Health to understand the underlying causes of cognitive decline in patients with Lewy body diseases such as Parkinson’s disease. We plan to identify biomarkers that predict which individuals are likely to develop dementia. Aging Research Institute. The goal of this extensive program is to understand the factors that determine who develops dementia and to what extent, in order to develop treatments that may slow the progression of the disease.
Currently, nearly 1 million Americans have Parkinson’s disease (PD), and an estimated 1.4 million have PD or Lewy body dementia. Both are caused by the accumulation of an abnormal protein in the brain called alpha-synuclein (αSyn). Accumulation of αSyn forms clumps called Lewy bodies, which cause motor and cognitive problems. These diseases share a common underlying cause, but the symptoms vary from person to person. Some people experience cognitive decline, such as poor memory and judgment, at the beginning of diagnosis, others develop symptoms several years later, and others never develop symptoms. Similarly, some people may have early struggles with motor functions such as walking or swallowing, while others may develop these symptoms years after diagnosis. Currently, there are no FDA-approved treatments that slow the progression of these diseases.
“Regardless of their timing, these symptoms appear to share some underlying processes. We hope that individual disease differences may help uncover the root causes of neurodegeneration and influence the onset of cognitive decline. We hope that this will help us develop treatments that can slow this down,” said Alice Chen-Plotkin. M.D., Ph.D., is the Parker Family Professor of Neurology, director of the Molecular Integration in Neurological Diagnosis (MIND) Initiative, and general director of this newly funded program. “Ideally, Parkinson’s disease could be significantly slowed down and be only a minor inconvenience, rather than a disease that could eventually interfere with every aspect of a person’s life. .”
Looking at Lewy body disease through four different lenses
This grant supports four different projects across the Perelman School of Medicine and focuses on interdisciplinary collaboration. Edward Lee, MD, co-director of the University of Pennsylvania Institute on Aging and leader of the Penn Medicine Brain Bank, and Sharon centrally managed and shared with all collaborators.
David Irwin, MD, associate professor of neurology, explains how αSyn accumulation interacts with β-amyloid plaques (amyloid) and tau neurofibrillary tangles (tau), which cause other neurodegenerative diseases, particularly Alzheimer’s disease. He plans to lead a project to investigate whether it works. His goal is to understand how the interactions between these factors affect cognitive loss.
Virginia M.-Y. Lee, Ph.D., MBA, John H. Ware Third Endowed Professor of Alzheimer’s Disease Research in the Department of Pathology and Laboratory Medicine, said misfolding and aggregation of αSyn may lead to its spread throughout the brain. We plan to study how it affects She hypothesizes that how αSyn folds and aggregates may influence the rate at which αSyn spreads within an individual’s brain.
Lee, along with her late partner John Q. Troyanowski, Professor of Geriatrics and Gerontology in Pathology and Laboratory Medicine, first discovered the role of αSyn, as well as amyloid and tau, in neurodegenerative diseases.
Chen Plotkin will oversee one of two projects investigating how different genetic factors in individuals influence the prevalence of αSyn. Chen-Plotkin’s project draws on previous research that identified genetic markers for PD. Using brain bank tissue collected from thousands of individuals with neurodegenerative diseases, she searches for additional genetic markers that correlate with the development of various Lewy body diseases, and studies these genetic markers in neurons. We plan to model change.
In the second project, Kelvin C. Luke, Ph.D., associate professor of pathology and laboratory medicine, will model these genetic variations in mice and determine whether gene editing techniques can control the spread of αSyn and slow its progression. We plan to determine whether it can be delayed. Neurodegenerative diseases.
The team plans to validate their findings by identifying patients with specific biomarkers in the clinic and then follow patients over time in a clinical cohort led by Daniel Weintraub, MD, professor of psychiatry. That is, if researchers believe that a genetic marker is associated with early motor loss and late cognitive decline, genetic testing can identify patients with that marker and determine whether this is actually the case. The disease will likely be tracked over a long period of time to confirm. They experience the symptoms they hypothesized.
Although these projects have a specific focus, the multi-project nature of the program allows us to jointly learn how these different systems work together to drive individual disease manifestations. We hope that constant feedback from our collaborators will accelerate our research and help translate our discoveries into real-world treatments that improve the lives of individuals and their families. ”
Alice Chen Plotkin, MD, Parker Family Professor of Neurology and Director of the Molecular Integration in Neurological Diagnosis (MIND) Initiative
This project was supported by a grant (P01 AG084497) from the NIH/NIA.
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