$18M grant investigates Cognitive decline in Lewy body diseases

PHILADELPHIA—Penn Medicine researchers will advance their understanding of the underlying causes of cognitive decline in individuals with Lewy body diseases, like Parkinson’s, and identify biomarkers that predict which individuals are more likely to develop dementia with a $18 million grant from the National Institutes of Health/National Institute on Aging. The goal of this wide-ranging program is to understand the factors that govern who develops dementia, and how quickly, in order to develop therapies that might slow the progression of disease.
Nearly one million Americans currently live with Parkinson’s disease (PD), and an estimated 1.4 million have PD or dementia with Lewy bodies. Both are caused by the buildup of an abnormal protein in the brain, called α-synuclein (αSyn). The buildup of αSyn forms clumps called Lewy bodies, leading to issues with movement and cognition. While these diseases share a common underlying cause, individuals express symptoms differently. Some people experience cognitive decline, like impaired memory and judgement, at the outset of their diagnosis, other develop it a few years after, and some never do. Likewise, some individuals struggle with motor functions early, like walking or swallowing, while others develop these symptoms years after diagnosis. There are currently no FDA-approved treatments available that slow the progression of these diseases.
“Regardless of timing, these symptoms appear to share some underlying processes. We hope that the differences in individuals’ diseases can illuminate the root cause of  neurodegeneration and help us develop therapies that delay the onset of cognitive decline,” said Alice Chen-Plotkin, MD, the Parker Family professor of Neurology, director of the Molecular Integration in Neurological Diagnosis (MIND) Initiative, and overall director of this newly funded program. “Ideally, instead of Parkinson’s being a disease that eventually may disrupt all aspects of an individual’s life, we could slow its progression so much that it would just be a minor inconvenience.”
The grant supports four different projects across the Perelman School of Medicine, and emphasizes collaboration across disciplines. Edward Lee, MD, PhD, co-director of Penn’s Institute on Aging and leader of the Penn Medicine Brain Bank, and Sharon X. Xie, PhD, a professor of Biostatistics, will ensure that tissue, DNA samples, and data are centralized and shared with all collaborators.
David Irwin, MD, an associate professor of Neurology, will lead one project investigating how αSyn buildup interacts with b-amyloid plaques (amyloid) and tau neurofibrillary tangles (tau), which drive other neurodegenerative diseases, most notably Alzheimer’s. His goal is to understand how the interplay between these elements impact loss of cognition.
Virginia M.-Y. Lee, PhD, MBA, John H. Ware 3rd Endowed Professor in Alzheimer’s Research in the department of Pathology and Laboratory Medicine, will research how the mis-folding and clumping of αSyn affects how it spreads throughout the brain. She hypothesizes that how the αSyn folds and clumps impacts the rate at which it spreads in an individual’s brain. 
Lee first discovered the role of αSyn, as well as amyloid and tau in neurodegenerative diseases, alongside her late partner, John Q. Trojanowski, a professor of Geriatric Medicine and Gerontology in Pathology and Laboratory Medicine.
Chen-Plotkin will oversee one of two projects examining how different genetic factors in individuals impact the spread of αSyn. Chen-Plotkin’s project draws upon previous research that identified a genetic marker for PD. She will use tissue from the Brain Bank collected from thousands of individuals with neurodegenerative diseases to search for additional genetic markers that correlate with the development of different Lewy body diseases and then model these genetic changes in neurons.
For the second project, Kelvin C. Luk, PhD, an associate professor of Pathology and Laboratory Medicine, will model these genetic variations in mice, and determine if gene-editing techniques can regulate the spread of αSyn, and potentially slow the progression of these neurodegenerative diseases.
The team will validate their findings by identifying patients within the clinic who have a specific biomarker and track their progress over time in a clinical cohort led by Daniel Weintraub, MD, Professor of Psychiatry. That is, if the researchers believe a genetic marker is tied to early loss of motor function, but late onset cognitive decline, they would identify patients with that marker through genetic testing, and follow their disease over time to see if it they do in fact experience the symptoms they hypothesized. 
“While these projects have specific focuses, the multi-project nature of the program allows us to collaborate to learn how these different systems work together to cause individual expressions of disease,” said Chen-Plotkin. “We hope that the constant feedback from the collaborators will accelerate our research and help us translate our findings into real therapies that improve the lives of individuals and their families.”
This project is supported by a grant from the NIH/NIA (P01 AG084497).
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