In fall 2013, a French neurologist who identified the gene responsible for a rare small vessel disease in the brain, CADASIL, approached University of Vermont researcher Mark Nelson, Ph.D., after a workshop honoring the 20th anniversary of her discovery. She expressed her frustration that as a neurologist, she had nothing new to offer her patients about the mechanisms and progression of CADASIL – Cerebral Autosomal Dominant Arteriopathy with Subcortical Infarcts and Leukoencephalopathy – after two decades.
In the 18 months since Nelson had that discussion with Marie-Germaine Bousser, M.D., renowned neurology chief at Hospital Lariboisière in Paris, he and an international research team studying CADASIL and other small artery disease are uncovering what occurs in the brains of people born with the genetic mutation of a protein known as Notch3.
“It’s a cascade of things that happen afterward,” says Nelson, University Distinguished Professor and chair of pharmacology at the UVM College of Medicine.
CADASIL is rare, affecting about 1 in 50,000 people. But the researchers’ insights inform the study of stroke and dementia.
The 10-person team’s research is supported by a Transatlantic Networks of Excellence grant worth about $6 million from Fondation Leducq, an organization based in Paris that supports efforts to combat cardiovascular and neurovascular disease. Nelson oversees the work in North America, and his longtime collaborator at the University of Paris, Anne Joutel, M.D., Ph.D., directs their activities in France and Germany.
Joutel and colleagues developed a new mouse model with the human mutation for CADASIL, which exhibits the pre-clinical CADASIL pathology. Since they received the five-year Leducq grant in October 2012, the team of investigators has focused on the disease progression starting early in life, and thereby has gained crucial information about its effects on blood flow and role in brain function.
The researchers found that they can restore some normal blood flow within the tiniest arteries within the brain by correcting the early deficits caused by CADASIL. And if they can control function, Nelson says, that suggests the possibility of controlling and diminishing the consequences of the disease at an early stage and throughout a patient’s life. Their findings are published in the February 17, 2015 PNAS.
That’s “the holy grail of this area,” Nelson says. “It puts us in the position of now having targets for intervention.”
One function they managed to restore is functional hyperemia, the process by which the brain knows to rapidly and precisely supply extra blood to regions needed for motor control and cognition, such as the ability of the brain to recognize someone’s face.
“The parts of the brain that are working need blood immediately,” Nelson says.
Nelson and his colleagues are now writing an application for a Horizon 2020 grant from the European Union, which provides funding to translate research and innovation from the lab to the marketplace and – in this case – to patients.
“This is a window into the more common, sporadic small vessel disease that affects millions of people,” Nelson says. “We’re now making very significant inroads.”
Learn more about UVM’s work on the Leducq grant here.