People who have a so-called "pre-mutation" in FRM1, the gene linked to Fragile X syndrome, have an increased risk of a related neurodegenerative disorder called fragile X-associated tremor/ataxia syndrome (FXTAS). FXTAS, often called a "Parkinson's-like" disorder because its symptoms include tremors, balance problems, and cognitive impairments, does not manifest until they are in their 50s or 60s. Now, researchers at the University of California at Davis (UC Davis) MIND Institute have found distinct connective differences in the brain between those with the pre-mutation and controls using a new neuroimaging technique.
Grandfathered in by a genetic repeat
Fragile X syndrome is a genetic neurodevelopmental disorder that often results in intellectual disabilities, including trouble with attention, communication, and social interaction. It occurs in approximately 1 in 4,000 males and 1 in 8,000 females, and its symptoms have quite a bit of overlap with those seen on the autism spectrum. The gene behind fragile X is FMR1, which makes a protein that guides the development of synapses.
"The FMR1 gene can experience a mutation where a series of CGG base pairs repeat. Most folks have somewhere around 40 to 45 of those repeats. But in some families you see a mutation, and that repeat sequence gets expanded in the offspring of those with the mutation," says Tony Simon, a developmental cognitive neuroscientist at UC Davis. "When you have 200 or more repeats, then the FMR1 gene is silent. It isn't making any of its protein. And that leads to the very significant neurodevelopmental disorder called Fragile X."
Over the past few decades, fragile X has received a lot of attention from clinicians and neuroscientists alike. Those who studied the disorder knew that the parents and grandparents of children with the disorder often had expanded CGG repeats sequences-but they did not realize that the expansion was linked to its own set of neurodegenerative consequences.
"Researchers working on fragile X, particularly the Hagerman team at UC Davis, soon realized that a lot of the grandfathers of the fragile X kids they were seeing were also having problems," says Simon. "They were very highly functional adults but then suddenly started having significant Parkinson's like symptoms including brain degenerations in their late 50s or early 60s. Once this became formally studied, it turned out that a full degenerative syndrome could be defined, which was called fragile X-associated tremor ataxia syndrome, or FXTAS."
Historically, FXTAS, like many neurodegenerative disorders, could only be diagnosed after the tell-tale movement symptoms presented themselves in later life. But since fragile X itself is a neurodevelopmental disorder, Simon and colleagues wondered if they might be able to see hints of the disease in the brain before symptoms developed.
Detection through connections
To test the idea, Simon and colleagues recruited 88 men and women ages 18 to 44, 46 of whom had the FMR1 pre-mutation, to have their brain scanned using diffusion tensor imaging (DTI) and whole brain tractography, which shows the connections in the brain. The group found that males with the pre-mutation had smaller brain stems, in terms of volume, than controls. They also found that those same males had less efficient networking across the brain-and the longer their genetic CCG repeat expansion the less-efficient the networking was. Both of these differences could be observed decades before symptoms would typically present themselves. The results were published in Human Brain Mapping in April.
Alex Leow, who helped develop the DTI methods used in the study, says that research into other disorders, including Alzheimer's disease, have also yielded early biomarkers of interest. Those biomarkers may not only provide an opportunity for doctors to one day identify which people with a particular genetic make-up may develop a disorder but also provide a substantial time window where they might intervene to try to delay or prevent symptoms.
"There are some really exciting opportunities coming out of the bench research," she says. "And if we can see some of these changes as early as 20 or 30 years earlier in a particular patient population, we may have the ability to treat them when they are young, with some kind of cognitive exercise or perhaps some kind of drug. The hope being that we could prevent them from developing these terrible symptoms decades later."
Simon is quick to caution that his study cannot yet predict which people with the FMR1 pre-mutation will ultimately develop FXTAS. But with more longitudinal studies, he says, it is likely that they may one day be able to.
The hope of early intervention
Joseph Masdeu, director of the Nantz National Alzheimer Center and Neuroimaging at Houston Methodist Hospital, says that more and more, researchers are trying to go back in time when it comes to neurodegenerative disease and identify biomarkers in the pre-symptomatic stages of these disorders. (See, A Window Into Alzheimer's).
"Think about cardiovascular disease. We give people statins to reduce cholesterol in the plasma, preventing arterosclerosis, heart attack, and stroke," he says. "But you can't give that statin to someone who already has had a bunch of strokes. It's too late. The disease is there. It's the same with neurodegenerative disorders. We have to go back and try to stop the problem before it becomes a problem. So in Alzheimer's we have a similar situation, where we have to reduce amyloid-beta plaques years before symptoms happen."
His own research using a combination of ApoE genotyping, a gene linked to Alzheimer's disease, and positron emission tomography (PET) scanning, found that amyloid beta, the sticky plaque found in excess amounts in the brains of people with Alzheimer's, starts to build up 15-20 years before symptoms show. That work has gone on to clinical trial, where patients are being given different pharmacological compounds to try to remove the amyloid from the brain before it does its damage. Masdeu thinks we will see similar approaches with other neurodegenerative disorders in the future.
"We now have ways to look at axonal integrity, at brain metabolism, and at connections. So if there are changes happening in the brain before the person gets a disease, we have more opportunities to intervene," he says. "Neuroimaging techniques are evolving into a very powerful set of tools for clinicians. And when they are used accurately and thoughtfully, we can, with luck, find better ways of treating so many of these disorders and helping people before they ever get sick."