HTT Mutations Seen to Cause Extensive Brain Remodeling, Affecting Motor and Cognitive Skills

Alice Melão avatar

by Alice Melão |

Share this article:

Share article via email

Mutations linked to Huntington’s disease cause more extensive remodeling of functional connectivity in various regions of the brain than previously thought, affecting patients’ motor and cognitive skills, research looking at whole brain connectivity in disease carriers reports.

These findings — in “Whole-Brain Connectivity in a Large Study of Huntington’s Disease Gene Mutation Carriers and Healthy Controls“— offer new insights into the impact of Huntington’s genetic abnormalities and the disease’s complexity. The study was published in the journal Brain Connectivity.

Expansion of CAG repeats in the huntingtin (HTT) gene is the genetic cause underlying Huntington’s disease. The length of CAG repeats is known to be associated with disease onset and motor symptom progression. Cognitive decline, psychiatric symptoms, and brain abnormalities can be detected at early disease stages.

To better understand the link between CAG repeats and brain alterations, researchers performed whole-brain functional analysis in 183 carriers of mutated HTT (mHTT) and 78 healthy volunteers, using resting-state functional magnetic resonance imaging (fMRI) data. fMRI  detects neuronal signals that translate to spontaneous connectivity across the brain, providing a profile of its functional networks.

Data for participants were collected from the PREDICT-HD trial (NCT00051324), an observational study that enrolled 1,500 people with the Huntington’s gene expansion but no disease symptoms to identify early brain and behavioral changes.

Researchers found that mHTT carriers had poorer connectivity in the putamen — a brain region that controls movement and is highly affected in Huntington’s patients — when compared to healthy controls.

Interestingly, the number of CAG repeats increased the functional wiring between 11 resting-state network pairs — anatomically separated, but functionally connected regions in the brain — which comprise the brain’s visual, subcortical, and salience domains. But poorer functional wiring was seen in two networks linking the visual and cognitive control domains as CAG repeats increased.

These findings show that the brain activity of mHTT carriers is significantly impaired compared to healthy controls and is dependent on the length of CAG repeats. In addition to brain areas already known to be related to Huntington’s, such as the subcortical region, strong alterations affecting the visual regions were found.

“These results provide a step forward in understanding connectivity alterations in Huntington’s disease gene carriers,” Bharat Biswal, the journal’s co-editor-in-chief and chair of biomedical engineering at  New Jersey Institute of Technology, said in a press release.

Further analysis of a subgroup of patients with more than 40 CAG repeats found changes in a total of 17 resting state network pairs compared to controls. This suggests that “weakened connectivity is more pronounced in individuals in the full penetrance range” of Huntington’s, the researchers stated.

These altered wirings were linked to brain areas that control cognitive and motor function. In particular, an impaired network that connects the putamen — a round structure located at the base of the forebrain — with the insular cortex region — situated deep within the folds of the brain’s outer layer — was found to be associated with both brain functions.

Researchers believe this and similar studies are essential to better understanding the brain’s “anatomical and functional” profile in the earliest stages of Huntington’s disease.