A team of researchers—including Yale School of Medicine’s Thomas Biederer, PhD, associate professor of neurology, who is the coordinating lead investigator; Elena Gracheva, PhD, associate professor of cellular and molecular physiology and of neuroscience; and Michael Higley, MD, PhD, associate professor of neuroscience—has been awarded funding through the Aligning Science Across Parkinson’s (ASAP) initiative. The $9 million grant will support work to understand cognitive impairments in Parkinson’s disease. The team also includes Danielle Bassett, PhD, professor of bioengineering at the University of Pennsylvania, and Michael Henderson, PhD, assistant professor of neurodegenerative science at the Van Andel Research Institute.
ASAP is dedicated to advancing research studies and treatments of Parkinson’s. Its mission is to accelerate discovery through supporting highly collaborative teams and providing resources for the field including data sharing. The Michael J. Fox Foundation for Parkinson’s Research is working with ASAP as its implementation partner and issues grants through its Collaborative Research Network.
“Each team selected for the Collaborative Research Network brings unique expertise and perspective to ASAP’s mission of tackling key knowledge gaps in disease understanding through open science. We are proud to partner with Yale School of Medicine on this innovative and impactful project that will position the field closer to new treatments for the millions living with and at risk of Parkinson’s disease,” says Ekemini Riley, PhD, ASAP’s managing director.
Motor dysfunction often leads to a diagnosis of Parkinson’s disease, but around 80% of patients also develop debilitating cognitive impairments that profoundly impact them and their families. With the support of the ASAP grant, the researchers hope to better understand brain connectivity changes that underlie these cognitive impairments. “ASAP provides unique and exciting opportunities to advance Parkinson’s disease research,” says Biederer. “It takes a broad approach to moving the field forward through focusing on intense collaboration, open data sharing, and bringing in investigators who may not have traditionally worked in the Parkinson’s disease space.”
Specifically, the team will study how pathology progression impacts the cortex, which is where all critical cognitive functions occur. “We want to understand how cortical connectivity becomes impaired as Parkinson’s progresses. Based on this knowledge, we will manipulate vulnerable network points to restore circuit functions underlying cognitive processing,” says Biederer.
The team, he continues, has three goals. First, it aims to measure cellular and circuit vulnerabilities in the cortex in an animal model of Parkinson’s disease through imaging of neural activity patterns and synaptic connections. Second, the team plans to map gene expression patterns that mark vulnerable and protected cell types. Finally, the researchers will use advanced mathematical modeling to integrate their data sets, identify potential network points vulnerable to disease progression, and go directly into the brain to manipulate those cell types and see where they can restore circuit functions.
“We have very little understanding of the cognitive dysfunctions that occur in patients with Parkinson’s disease,” says Biederer. “These processes develop slowly, and the earlier we can intervene, the better chance we have of restoring function.” One of the strengths of his team, he says, is that it is highly multidisciplinary—allowing the scientists to bring together their expertise in network physiology, synaptic integrity, quantitative pathology, and computational modeling of complex systems.
Biederer was recruited to Yale from Tufts University right before the start of the pandemic. He was drawn to the School of Medicine, he says, because of the opportunity to work with other Yale researchers in the neuroscience and neurology fields. Even when COVID-19 shut down the campus, his team persevered in putting together a successful proposal. “Neuroscience at Yale is driven by curiosity, the willingness to engage, and a big picture view across our all too specialized fields, which enabled me to explore exciting new ideas with my colleagues and develop this innovative project together,” he says.