There is a simple genetic test that will tell you if you are a carrier of the genetic mutation that causes Huntington's Disease (HD). There is a 50 percent chance that a child will have the gene if one of the parents has HD - and if you have the mutation, there is a virtually 100 percent chance you will develop the disease.
This neurodegenerative disease leads to psychomotor symptoms once disease progression begins around middle age. The disease is inevitably fatal within a few years.
However, several scientists, including Jason Brandt at the School of Medicine, are investigating whether there are preclinical symptoms that can be used to diagnose when an HD carrrier is close to the onset of the disease, in hopes of eventually being able to intervene before the onset of symptoms.
Brandt has been following HD patients as well as carriers of the disease in a longitudinal study that began in 1987. Because he observes the symptoms of a patient over an extended period of time, his research contains data of people before as well as after the disease onset.
With extensive neuropsychological testing of patients, Brandt and colleages were able to publish in a recent Journal of Neuropsychiatry article that there might be slight cognitive deficits as carriers approach the age of onset of the disease.
HD is usually defined in terms of its motor deficits; however, a patient's cognitive and emotional capabilites are also affected. While it is easy to determine if one is a carrier and will have HD through a genetic test, it is more difficult to determine when that person might exhibit symptoms of HD.
In previous studies, Brandt used an estimated age of onset, a relatively accurate measure that is based on length of the nucleotide repeat in the gene as well as the parent's age of onset, to predict how far patients were from showing symptoms.
However, the advantage of a longitudinal study, with over 200 participants, is that the actual age of disease onset can be recorded as patients are followed over time. "It provides an incredible opportunity to study the evolution of the disease in a person," Brandt said. "You can look at the unfolding of a dementia syndrome, which you can't do in a lot of other conditions."
Within previous studies, Brandt and colleagues have not been able to find any cognitive differences between people known to have the HD mutation and a control group without the mutation.
"People have shown in our own center that there are changes on MRI brain scans in the basal ganglia that precede the disease onset by a certain amount of time. So we can see changes on the scans, the question is if can we see the changes in the people and if there are any early indicators," Brandt said.
In carriers of the Huntington's mutation, the MRI scans reveal a reduction in size before clinical symptoms appear, in the putamen and caudate, which are two regions of the basal ganglia. While the putamen is mostly involved with motor control, the caudate has several connections to cognitive processing areas.
In this recent study, Brandt showed that a cohort of early converters, or people who exhibited HD symptoms a short time after their baseline measurements were taken, differed on the Wisconsin Card Sorting Test from the late converters, or people farther from age of onset.
The Wisconsin Card Sorting Test is a measure of cognitive functioning that is sensitive to the functioning of the basal ganglia and prefrontal cortex. The test can pick up subtle differences in the functioning of these brain regions.
"When we take people who have the mutation and who are estimated to be close to onset of the disease, we begin to see some deficits in cognitive functioning and especially in psychomotor skills," Brandt said.
It is not clear why this particular test shows a difference in cognitive functioning whereas other neuropsychological tests did not show any differences between the early and late groups. Brandt is working on more sensitive techniques to show early indicators of cognitive or motor deficits.
Brandt recognizes that evidence of early deficits in the disease carrier might have clinical implications as well. "I think it is widely believed that interventions will work better in early stages of the disease rather than later stages, and preferably presymptomatically."
"If you have someone who is showing mild cognitive or motor changes, who is not yet diagnosable to the casual observer, then this might be the place to intervene," Brandt said.
Presymptomatic deficits could allow therapeutic drug treatments to be used before the actual disease onset. By the time the major symptoms of Huntington's appear, many cells are already dead. Many experts believe the key to treatment is to do it early.
This longitudinal study of HD patients is just one of the projects on which Brandt is working. His larger research goals are to study early indicators of neurodegenerative diseases. In diseases such as Alzheimer's, it is more difficult to identify at-risk patients.
Huntington's Disease is unique because all carriers can be identified by a genetic test and their preclinical symptoms can be measured. This creates a possibility of therapeutic drug intervention if specific deficits are observed in the years prior to onset.
