TRACK-FA study IDs possible MRI biomarkers of disease progression
Researchers uncover differences in brain, spinal cord on imaging scans
Using MRI scans, a team of researchers identified several differences in the brain and spinal cord of people with Friedreich’s ataxia (FA) versus those without the rare genetic condition, which have the potential to serve as biomarkers of disease progression in clinical trials.
The findings come from TRACK-FA (NCT04349514), a large, international natural history study that’s monitoring long-term neuroimaging changes among people with and without FA.
“By assessing participants across ages and disease stages, including young children, we conclude that [MRI] scans of brain and spinal cord can detect significant abnormalities even in the earliest disease stages,” the researchers wrote. “Ultimately, based on this work, … TRACK-FA will contribute to the identification of the most sensitive neuroimaging biomarkers of progression.”
These MRI biomarkers potentially will help assess progression “according to age and disease stage,” the researchers added.
The study, “Neuroimaging Biomarkers for Friedreich Ataxia: A Cross-Sectional Analysis of the TRACK-FA Study,” was published in the journal Annals of Neurology.
Current clinical scales lack sensitivity for detecting changes
An inherited disease, FA is caused by mutations in the FXN gene that lead to the progressive degeneration of nerves in the spinal cord and brain that are involved in sensory perception and motor control.
Its hallmark neurological symptom is ataxia, or a loss of muscle control that leads to poor coordination and clumsy movements, which occurs alongside a range of other possible symptoms.
While FA clinical trials often rely on clinical scales to monitor disease progression, these measures are limited in their sensitivity for detecting subtle changes. As such, they may not be as useful in certain groups of patients, such as those who are very young patients and who are still developing, according to the researchers.
New neuroimaging biomarkers could help to overcome these limitations by revealing degeneration and structural changes in the brain and spinal cord, the team noted. Still, there’s a need for large-scale natural history studies to hone in on and validate the most useful biomarkers. That’s the goal of TRACK-FA.
The long-term study involves people with FA, ages 5 and older, whose symptoms started at age 25 or younger, and who have been living with the disease for no more than 25 years. Also included was a control group of people without FA.
All participants are being evaluated at three time points: the study’s start, or baseline, and after one and two years. This comprises neuroimaging via MRI scans and other age-appropriate clinical and laboratory assessments.
In this study, scientists assessed data from certain TRACK-FA participants — 169 people with FA and 95 individuals in the control group — at the baseline visit. Most participants with FA had mild or moderate disability, and still had the ability to walk.
MRI biomarkers show changes even in younger children
A total of 17 different imaging parameters were examined across the spinal cord and brain regions affected in FA. Among them were features related to size, structure, and biochemical markers of neurodegeneration in tissue.
The results showed that most of the evaluated parameters significantly differed between the FA and control groups.
For example, people with FA were found to have a smaller spinal cord area, and to have a lower volume of the dentate nucleus and super cerebellar peduncles (SCP) in the brain. In general, the greatest differences were observed in adults, and the smallest differences in younger children, ages 5-10.
Certain differences, such as ones in the SCPs and spinal cord, started emerging in childhood and dramatically increased with age, the researchers noted. While children in the control group showed normal development of these tissues, children with FA did not.
“This pattern suggests a failure to achieve full maturation … particularly of the spinal cord, followed by neurodegeneration, which aligns with previous … findings,” the researchers wrote.
For other brain biomarkers, including ones related to the cerebellum and cerebrum, differences between FA and controls only became evident in adulthood. These findings were consistent with previous observations that these structures tend to degenerate only in more advanced disease stages, according to the scientists.
Our results offer significant implications for identifying sensitive biomarkers of disease progression in Friedreich ataxia. … This will lay the critical groundwork required for advancing these biomarkers into future clinical trials.
Importantly, per the researchers, many of the imaging parameters also showed significant correlations with standard clinical scales of disease severity among those with FA, especially in older participants.
FA-causing mutations are characterized by an excessively repeated trio of DNA building blocks called a GAA repeat expansion. Generally, a greater number of repeats is linked to more severe disease. The results showed that certain imaging features also correlated with GAA repeat size or disease duration in adults with FA, but not younger children.
“Our results offer significant implications for identifying sensitive biomarkers of disease progression in Friedreich ataxia,” the researchers wrote, noting that analyses of findings from follow-up visits in TRACK-FA will offer more insights into how these biomarkers are changing over time at various ages and disease stages.
Longitudinal follow-up is planned for the one- and two-year marks, the team noted.
“This will lay the critical groundwork required for advancing these biomarkers into future clinical trials,” the researchers concluded.
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