Scientists link shrinkage of key brain pathway to FA motor symptoms
Discoveries on MRI scans could lead to new targeted treatments
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In adults with Friedreich’s ataxia (FA), a brain communication pathway connecting the cerebellum to the motor cortex, which coordinates and controls movement, showed signs of tissue shrinkage, disrupted brain signaling, and reduced energy production on MRI scans.
According to the imaging study, FA-related changes across the so-called dentato-thalamo-cortical (DTC) pathway were linked to coordination problems and impaired daily functioning, providing a more detailed explanation of how FA affects movement.
“This study provides multimodal imaging evidence for comprehensive alterations along the DTC pathway in [FA], including first insights into energy metabolism and effective connectivity,” the scientists wrote. The team added that “a better … understanding of early metabolic and dynamic pathway disruptions might inform potential … interventions targeting this pathway.
The study, “Multimodal Imaging Investigation of the Dentato-Thalamo-Cortical Pathway in Friedreich’s Ataxia,” was published in the journal Movement Disorders.
Muscle weakness in FA is often caused by damage to the spinal cord and the cerebellum, a structure at the back of the brain that controls balance and coordination.
So-called DTC pathway is major brain communication route
The DTC pathway is a major brain communication route that carries signals from the dentate nucleus, a region deep within the cerebellum, to the motor cortex, the brain structure responsible for planning, controlling, and executing voluntary movements.
A recent imaging study found damage in the DTC pathway in FA patients, mostly within the cerebellum, with less damage as it approached the motor cortex.
To learn more, scientists in Germany now conducted a detailed MRI study to measure changes in regions along the DTC pathways in adults with FA. The team looked at volume, function, connectivity, and energy metabolism.
MRI scans were acquired for 22 adults with FA, split equally by sex. The patients had a mean age of 36, with an average age at FA onset of about 16. The mean FA duration was nearly 20 years.
The team also acquired imaging scans for the same number of healthy individuals, matched to patients for age, sex, and handedness.
On the images, the scientists detected significant tissue shrinkage in certain brain areas in FA patients relative to the controls. This was seen in regions such as the dentate nucleus and the motor cortex.
A more detailed analysis found additional microstructural abnormalities along segments within the DTC pathway. Pronounced damage was revealed along segments that connected the dentate nucleus to a nerve fiber tract called the superior cerebellar peduncle (SCP). Additionally, damage was noted in the section between the SCP and the thalamus, which serves as the primary relay for transmitting motor signals to the motor cortex.
Lower energy production found in key brain areas
The researchers then compared MRI findings with clinical data. This showed damage across most segments of the DTC pathway, significantly correlated with disease severity, as assessed by the Scale for the Assessment and Rating of Ataxia (SARA). Damage in the segment that connected the SCP to the thalamus also correlated with difficulties in daily functioning, as indicated by scores on the Activities of Daily Living assessment.
When the researchers studied how different parts of the DTC pathway communicate, two FA-related changes stood out: stronger-than-normal signaling from the right thalamus to the left dentate nucleus and weaker internal regulation within the left thalamus.
And, these changes were linked with disease severity via the SARA assessment, showing a curved (“U-shaped”) relationship, indicating a complex course of motor functional changes within the DTC pathway in FA, the team noted.
Our work provides new insights into developing and evaluating [FA] treatment strategies.
Energy production in the DTC pathway was also explored, given that FA affects the function of mitochondria, which effectively serve as a cell’s power plant.
These results showed that FA patients had lower energy production in key brain areas, particularly in the dentate nucleus and the right motor cortex, compared with matched controls. FA patients also had higher levels of glycerophosphoethanolamine (GPE), a breakdown product of fat-like molecules, in both thalamic regions and the left motor cortex, suggesting alterations in brain cell metabolism.
Here, lower energy production in the left dentate region was associated with more severe disease. Conversely, higher GPE levels in the left motor cortex correlated with an older age of FA onset.
“This study provides multimodal imaging evidence for regional and connectivity changes along the DTC pathway in [FA] patients, especially from the dentate nuclei to the thalami,” the researchers wrote. “Our work provides new insights into developing and evaluating [FA] treatment strategies targeting the DTC pathway.”
