Altered Brain Connectivity in Kids at Risk for Huntington's

Megan Brooks

October 23, 2015

CHICAGO — Children at genetic risk for Huntington's disease (HD) have weak connections between the striatum and frontal lobe, areas known to be affected by HD, new research indicates.

"The results suggest that decades before the onset of HD, having the genetic mutation for HD actually affects brain development, causing changes in the strength of brain connections," said lead author Jessica Lee, PhD, from the Department of Psychiatry, University of Iowa, Iowa City.

Further study "could help determine the most effective timing and target area in the brain to intervene before irreversible structural degeneration," she added.

Dr Lee presented her research at a media briefing October 18 at the Society for Neuroscience (SfN) 2015 Annual Meeting.

Mutant Protein Affects Brain Development

HD is an inherited neurodegenerative disorder that typically begins around age 40 years and is caused by a mutation in the gene encoding for the huntingtin (HTT) protein. The normal HTT gene is important for normal brain development, and this gene is activated throughout the entire lifespan. Mutated HTT is also present in the brain across the lifespan and appears to affect brain development before symptoms appear, Dr Lee explained.

The research team used resting-state functional MRI (fMRI) to compare the brains of 26 children with mutant HTT with the brains of 36 healthy children.

"Using fMRI, we can measure how effectively brain areas within a circuit work together. By comparing the strength of the striatal circuitry in the children at risk for HD compared to healthy controls, we can evaluate how mutant HTT can affect brain networks during development," Dr Lee explained.

Compared with their healthy peers, the children with mutant HTT had significantly weaker correlational strength between the putamen and the motor cortex, as well as the ventral striatum and the anterior cingulate cortex, "brain regions that work together to control motor function and emotions," Dr Lee noted.

"Interestingly," however, the children with mutant HTT also showed significantly stronger functional coupling between other areas of the brain that work together to control cognition, which may reflect a potential compensatory mechanism, she said.

"Brain development is not just about growing the brain. Because the brain works by communicating in circuits, it's really important to form the right connections during development," Dr Lee commented. This study offers new insights into how the HD-affected brain works long before symptoms arise, she said.

"We are entering an exciting area of gene therapy, and we do hope that our findings could help serve as a guide for treatment target areas and help determine the best timeline to deliver any kind of disease-modifying treatments," Dr Lee noted.

This study illustrates "how alterations to brain circuitry can set the scene for future neurologic impairment long before it arises," Jay Giedd, MD, University of California, San Diego, who moderated the briefing, said in a news release. "These new discoveries could one day help lessen the burden of early-life neurologic abnormalities."

This and other research presented at the conference really "highlight how important the idea of connecting is, connecting within the brain and across time. How the brain is connected amongst itself is really what separates old from young, male from female, and healthy from ill," Dr Giedd told reporters.

The study was supported by the National Institute of Neurological Disorders and Stroke and the CHDI Foundation, a nonprofit biomedical research organization focused on HD research.

Society for Neuroscience (SfN) 2015 Annual Meeting. Abstract 42.03. Presented October 18, 2015.

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