Brain pathway may track Huntington’s disease progression
Degeneration tied to worsening motor, cognitive symptoms
Neurodegeneration of the pathways that help relay information from the cerebellum — a brain area involved in motor and cognitive functions — is associated with worsening motor and cognitive symptoms in people with Huntington’s disease, a study reported.
Tracking changes in these pathways, or tracts, may help researchers follow Huntington’s progression, the authors said.
“The results provide insight into structural–functional relationships in HD [Huntington’s disease] and underscore the potential of predicting motor and cognitive functions in HD based on tract-specific MRI measurements,” they wrote.
The study, “Along-Tract Diffusion Alterations in the Dentato-Rubro-Thalamic Tract Correlate With Motor and Cognitive Decline in Huntington’s Disease,” was published in Human Brain Mapping.
Huntington’s is a genetic condition characterized by progressive damage and death of nerve cells, or neurons, ultimately resulting in motor, cognitive, and behavioral symptoms. As more neurons degenerate, these problems may worsen over time.
Analyzing the brain’s information highways
Previous research has suggested that Huntington’s-related neurodegeneration also affects the brain’s white matter, which contains the long, wire-like fibers that neurons use to connect with each other. White matter tracts are sometimes called information highways, because they contain nerve cell fibers relaying signals, or projecting, from one brain area to another.
However, little of this research has centered on pathways involving the cerebellum, a structure in the back of the brain that helps coordinate movement and balance, while influencing cognitive functions and emotional responses.
The dentate nucleus, an output center of the cerebellum, projects to the red nucleus, a part of the midbrain region involved in motor control that projects to the thalamus, a brain information relay center.
Other neurons then carry information from the thalamus to various parts of the cerebral cortex, the outer layer of the brain that plays a role in movement, higher cognitive functions, and processing sensory information.
“The dentato-rubro-thalamic tract (DRTT), the primary … pathway transmitting cerebellar output to the cerebral cortex via the red nucleus (RN) and thalamus, could be recognized as a significant pathway for integrating cerebellar influence on both motor and cognitive function,” the researchers wrote.
With this in mind, the team of researchers in the U.S. used diffusion tensor imaging (DTI), an MRI technique specialized for visualizing and characterizing white matter, to investigate the DRTT. “We hypothesized that HD patients would exhibit DRTT disruption,” they wrote.
Huntington’s patients show more DRTT damage
The researchers retrospectively analyzed 1,392 DTI scans from 451 people with Huntington’s-causing genetic mutations and 187 healthy controls. All had participated in one of three large observational studies. The Huntington’s group included people who had not yet experienced symptoms.
Using DTI data, the team calculated two primary metrics: fractional anisotropy (FA) and mean diffusivity (MD). FA measures the level of organization in tracts, with higher values indicating greater organization, while MD measures how water moves through the tracts, with higher scores often correlating to tissue damage.
As the researchers predicted, people with Huntington’s showed significantly more damage to the DRTT, as reflected by lower FA and higher MD, compared with healthy controls. This pattern also held for most DRTT segments in Huntington’s participants who weren’t yet showing symptoms.
Breaking the DRTT down by segment, the team saw particularly robust FA and MD differences in projections from the dentate nucleus to the red nucleus.
Over time, white matter integrity in the DRTT generally decreased in Huntington’s patients, reflected by a reduction in FA and an increase in MD, “reflecting the continuing degeneration of [white matter] microstructure,” the team wrote. The speed and magnitude of these changes differed across segments of the pathway.
“These findings suggest distinct mechanisms of [white matter] changes at different disease stages and across different pathways in HD progression,” the team wrote.
In several segments of the DRTT, greater white matter degeneration was significantly associated with more severe cognitive and motor symptoms.
Greater degeneration of earlier parts of the pathway, from the dentate nucleus to the red nucleus, was significantly linked to worse motor symptoms. Greater damage to the part of the pathway relaying signals from the thalamus to the cerebral cortex were significantly linked to worse motor and cognitive symptoms.
However, FA in the thalamus-to-cortex segment showed unusual patterns, being higher in Huntington’s participants than control participants. Lower FA, indicating more degeneration, was also linked to less severe motor symptoms. The team hypothesized that these unexpected findings could reflect brain mechanisms compensating for neurodegeneration.
These results complicate the overall finding that progressive DRTT white matter degeneration correlates with functional decline in Huntington’s. Differences in associations, degree of damage, and rate of change across tract segments suggest disease-related change isn’t uniform, potentially reflecting compensation and other processes.
Not all participants had follow-up data, which restricted the researchers’ analysis of white matter changes over time. They also included data from multiple sources, which can introduce variability in results.
“Future studies should consider incorporating a more comprehensive neurological assessment that includes measures more specific to cerebellar function,” the team wrote.
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