They have chosen a crystal ball peak into a dismal future: Each carries a gene that will trigger the uncontrolled dance-like movements and psychiatric symptoms of Huntington’s disease. Now, scientists at The Feinstein Institute for Medical Research in Manhasset, NY, have identified a damaged brain network that kicks in well before the symptoms do, offering a chance that future medications may be able to stave off this disease process and push back – and even prevent -- the onset of symptoms.

“This is the first time that we can actually see the evolving brain abnormalities before people experience symptoms,” said Andrew Feigin, MD, lead author of the study that is published in the journal Brain. “We can observe the brain compensating for the damaged circuits and then watch as the system fails and they begin to show signs of disease.”

Despite decades of work unraveling the puzzle of Huntington’s disease, there are no federally approved drugs to stop the progressive and disabling degenerative process. There are 30,000 to 40,000 people in the United States living with the devastating symptoms of Huntington’s and another 150,000 who are at-risk for carrying the mutated form of the gene. Besides the uncontrollable chorea movements, patients can experience a range of psychiatric problems, including psychosis, depression, obsessive thoughts and dementia.

Dr. Feigin and his colleagues at The Feinstein Institute have used positron emission tomography (PET) scans in people with a family history of the disease who chose to have the genetic test that will show their fate. A dozen people from the US and Canada signed on for a study that would help scientists identify the brain structures involved in the disease process and track these circuits over time. They had brain scans conducted three times during the four year study. At the end of that time, four of the 12 patients had already experienced their first symptoms. They were, on average, about 48 years old.

And the changes in the brain patterns were sharp enough for doctors to pick out these patients – just by looking at the changes in the network from one scan to the next. “People who develop symptoms have a change in the network we identified,” explained David Eidelberg, MD, head of The Feinstein’s Center for Neurosciences and co-author of the new study.

Cells damaged in the disease process are located primarily in the striatum, but the PET scans also revealed decreased activity in cingulate cortex and increased activity in thalamus; this network was defined by The Feinstein scientists as the Huntington Disease-Related Pattern. On the first baseline scan, people who went on to develop symptoms up to four years down the road expressed this neural network more than the others. A year and a half later, the second scan showed a hyperactive metabolism of the network’s thalamus. By the third and last scan, this hypermetabolic response was decreasing. The eight subjects who did not develop symptoms retained the same thalamic activity throughout the study.

“A key node in the network is down in these patients,” said Dr. Eidelberg. “If we could figure out how to maintain this thalamic control, we may be able to prevent symptoms.” Ultimately, the tracking of changes in the network over time will also help in the search for treatments that work to protect this network.

“It’s a fascinating study,” said Nancy Wexler, PhD, the Higgens professor of neuropsychology at Columbia University Medical School and president of the Hereditary Disease Foundation. “The scans taken over time reveal a dynamic process. You see the brain trying to cope with the disease. Maybe there are ways to enhance these coping mechanisms.”

The first clinical description of the disease was made by a 22-year-old doctor in 1872. Dr. George Huntington was a third-generation physician who had spent his early years in East Hampton, Long Island, watching his father and grandfather tend to families replete with people with “grotesque” abnormal movements. Never affiliated with an academic hospital, Dr. Huntington found himself talking to a group of doctors in a town near Pomeroy, Ohio, where he practiced family medicine. He told his colleagues about these Long Island patients, the hereditary nature of their movements and “its manifestation as a grave disease in adult life.” Dr. Wexler’s sister, Alice Wexler, PhD, is about to publish a book on Dr. Huntington and his talk, which made it into the Medical and Surgical Reporter of Philadelphia a few months later and would set the stage for the science of the condition.

More than 110 years after Dr. Huntington’s talk about the Long Island families, Dr. Wexler collaborated with Harvard Medical School’s James Gusella, Michael Conneally and others to identify a marker on the chromosome 4. A decade later, the hunt ended when the gene that confers Huntington’s disease was identified and cloned. According to Dr. Wexler, the number of repeats in the genetic code determines whether someone will develop the disease. People with up to 34 repeats do not have Huntington’s. Patients can have anywhere between 40 and 130 repeats, copying the same string of letters that provide the recipe to make glutamine. Excessive glutamine can make proteins misfold and accumulate in the cell.

Dr. Wexler has a personal reason for her scientific pursuit. “The brain is hard to fix,” said Dr. Wexler, noting that things are “just as bad for patients today as they were when my mother was diagnosed with Huntington’s in 1968.” She said that scientists are working hard to develop treatments to alter this genetic process. “These scans can be used to track the process and deliver treatments,” she said. “It’s easier to prevent damage than to reverse it.”

About The Feinstein Headquartered in Manhasset, NY, The Feinstein Institute for Medical Research is home to international scientific leaders in Parkinson's disease, Alzheimer’s disease, psychiatric disorders, rheumatoid arthritis, lupus, sepsis, inflammatory bowel disease, diabetes, human genetics, leukemia, lymphoma, neuroimmunology, and medicinal chemistry. The Feinstein Institute, part of the North Shore-LIJ Health System, ranks in the top 6th percentile of all National Institutes of Health grants awarded to research centers. Feinstein researchers are developing new drugs and drug targets, and producing results where science meets the patient. For more information, please visit www.FeinsteinInstitute.org or http://feinsteininstitute.typepad.com/feinsteinweblog

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