MRI Study Finds Elevated Sodium in FA Brains Before Structural Changes
Increased sodium levels were found in regions of the brain commonly affected by Friedreich ataxia (FA) — the cerebellum and brainstem — before structural changes, an MRI imaging study has demonstrated for the first time.
The findings showed that increased sodium in these regions was related to an earlier age on disease onset and longer disease duration, supporting the role of sodium MRI as an indicator of FA progression, the scientists said.
However, measuring changes in sodium over time will help determine whether sodium MRI is a reliable and sensitive method to detect early metabolic impairment and monitor disease progression, they noted.
The study, “Increased brain tissue sodium concentration in Friedreich ataxia: a multimodal MR Imaging study,” was published in NeuroImage: Clinical.
People with FA commonly have atrophy (shrinkage) in the nervous system, with certain structures appearing to be smaller than in otherwise healthy individuals, including the brainstem, spinal cord, and cerebellum — a part of the brain important for coordinating voluntary movement.
MRI scans can detect these structural abnormalities, whereas changes in other regions of the brain are less pronounced in FA. As such, more sensitive image markers are needed to track disease progression and measure outcomes in clinical trials.
Sodium plays an essential role in many cellular functions, such as balancing metabolic processes and electrical signaling pathways. In healthy tissue, sodium levels are higher outside the cell than inside, but sodium levels inside the cell increase when cells are impaired. Imbalances in sodium levels may indicate cellular impairment before tissue atrophy.
Therefore, MRI specifically detecting sodium can be used to examine metabolic changes that may precede structural changes in FA by measuring the total tissue sodium concentration (TSC).
For the first time, researchers based at the RWTH Aachen University, Germany led a study using MRI to measure sodium in the brains of 24 adults with a genetically-confirmed FA diagnosis, but without any other neurological impairment.
The mean age of participants was 35 years, with a mean disease duration of 19 years. Thirteen women (54%) and 11 men (46%) took part in the study. Most (88%) had typical disease onset, which occurred around puberty, while three had a later-onset, at 25 years of age and older. A group of 23 age- and sex-matched healthy controls were analyzed as a comparison.
The team first compared whole-brain volumes and confirmed that, compared to controls, FA patients had a significant reduction in the volume exclusively in the cerebellum and brainstem. Subregion analysis found atrophy in the right cerebellum lobes and cerebellar white matter and regions of the brainstem, including the medulla, midbrain, and pons. White matter is composed of nerve fibers.
Similar results were seen after excluding the three late-onset patients, except for volume changes in the right cerebellar lobes.
Consistent with structural MRI findings, the analysis did not find differences in sodium concentration across the whole brain, but specifically in the brainstem and anterior cerebellum, the portion of it responsible for mediating the sense of self-movement and body position.
Subregion analysis found significant increases in tissue sodium concentration in the whole cerebellum, its left and right lobes, as well as the vermis, the area that separates the cerebellum into two hemispheres. Significant sodium level differences were not seen in the cerebellar white matter, except when the late-onset patients were excluded.
Likewise, increased sodium concentrations were observed in the total brainstem, with the highest differences in the midbrain, followed by pons, then the medulla.
In the control group, older age was significantly correlated to small brain volume across different areas of the brain. Higher sodium concentrations were also related to age in several regions, including the cerebellum.
In those with FA, older age was also related to lower volumes across different brain areas as well as higher sodium in one region called the right parietal lobe.
After controlling for age, lower volumes in the cerebellar white matter correlated with higher disability stages and worse disease severity as assessed by the Scale for the Assessment and Rating of Ataxia (SARA) and the Activity of Daily Living scale (ADL).
Lower brain volume in the left cerebellum lobes also correlated with more GAA repeats in the FXN gene — the genetic defect that causes FA. More GAA repeats correspond to a younger age at onset, with more severe and rapidly progressing disease.
Increased sodium concentrations in the right cerebellum lobes were significantly correlated with younger age at onset and longer disease duration, supporting the role of “sodium MRI as an indicator of disease progression,” the research team wrote.
“Our findings suggest the potential of in vivo [in living tissue] sodium MRI to detect quantitative metabolic changes of total tissue sodium concentration in the key regions in Friedreich ataxia, the cerebellum and brainstem,” the authors concluded. Increases in several regions of the cerebellum without atrophy indicated that “sodium MRI as a new bioscale may shed additional insights into metabolic pathophysiological [disease] mechanisms of Friedreich ataxia.”
The researchers said longitudinal studies are needed to “assess TSC changes over time and to further elucidate the reliability and sensitivity of sodium MRI to detect early metabolic changes and monitor disease progression in Friedreich ataxia.”
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