Authors: Jessica Klusek, Jinkuk Hong, Audra Sterling, Elizabeth Berry-Kravis, and Marsha Mailick
The study team thanks the participants for their time and effort in participating in the study and Dr. Elizabeth Berry-Kravis and the Molecular Diagnostic Laboratory at Rush University for their assistance in molecular testing.
Doctoral student Walker McKinney, Dr. Matt Mosconi, and colleagues investigated how aging as a premutation carrier may affect sensorimotor (exactly as it sounds, both sensory and motor) brain systems. Premutation carriers of the FMR1 gene are at risk of developing Fragile X-associated tremor/ataxia syndrome (FXTAS), and although several studies have documented sensorimotor issues in aging premutation carriers before the onset of clinical symptoms of FXTAS, the brain processes associated with sensorimotor issues and their potential to serve as early indicators of FXTAS have not been determined.
This study included 16 FMR1 premutation carriers and 18 control participants. Participants’ brain activity was measured with functional magnetic resonance imaging (fMRI) while they performed a test of sensorimotor control. Participants were instructed to grip a handle that measured their force level while they received visual feedback about how hard they were pressing. Participants viewed a white force bar that moved upward with increased force and downward with decreased force and a red static target bar (A) that turned green to begin each trial. Participants were instructed to press (C) so that the white force bar stayed as steady as possible at the level of the green target bar (B). Participants completed this sensorimotor task while the fMRI machine recorded small changes in blood flow in the parts of the brain that were active during the task.
Sensorimotor test stimuli and custom fiber-optic transducer (C; Neuroimaging Solutions, Gainesville, FL). Participants pressed when the red bar (A) turned green (B) in order to move the white bar up to the target green bar. They were instructed to maintain their force level at the level of the green bar as steadily as possible.
Researchers found that the functional connectivity of the cerebellum (a brain area that controls movement accuracy and timing) and the extrastriate cortex (a brain area involved in processing visual information) is reduced in aging FMR1 premutation carriers. This suggests that communication between visual processing regions in the brain and the cerebellum, a brain region critical for monitoring and adjusting movements so that they are accurate, is disrupted during aging in FMR1 premutation carriers and may be an early indicator of FXTAS.
Why This Matters
Researchers have struggled to find biomarkers to indicate who might develop FXTAS and who is showing early signs of neurodegeneration before the emergence of clear clinical concerns. These findings meant that functional connectivity between the cerebellum and extrastriate cortex could serve as a biomarker for FXTAS. This potential biomarker could help researchers and clinicians better predict which premutation carriers may develop FXTAS before they experience the tell-tale symptoms (e.g., kinetic tremor, gait issues).
Researchers will need to follow these participants over time to see if these functional connectivity differences are in fact a biomarker or an early indicator for FXTAS. More research using sensorimotor tasks and connectivity measurements is needed to further understand this potential biomarker.
Funding: This work was supported by the Once Upon a Time Foundation and the National Institutes of Health (U54 HD090216).
more research results
This study is important for later-diagnosed individuals as it creates successful predictive models that can identify cases five years earlier than clinical diagnosis.
Data from 8 unique studies speaks to the necessity of early identification of FXS, which leads to earlier, effective medical and non-medical interventions.
Your summary of the results, including why it matters to you and next steps, from the Dr. Liz Berry-Kravis and Tetra Therapeutics BPN14770 trial results published in Nature Medicine. This was a randomized, double-blind, placebo-controlled, two-period crossover study.
Cortical Gyrification and Its Relationships With Molecular Measures and Cognition in Children With the FMR1 Premutation
Jun Yi Wang and the study team out of the UC Davis MIND Institute are interested in learning more about the premutation carrier condition in relations to brain development and its impact on cognition. These mental processes impact the higher-level functions of the brain including language, learning new things, and making decisions.
Telehealth-Enabled Behavioral Treatment for Problem Behaviors in Boys With Fragile X Syndrome: A Randomized Controlled Trial
Dr. Hall and his team at Stanford University are learning about potential behavioral treatments for problem behaviors. Previous research suggests that problem behaviors, like aggression, self-injury, and property destruction, may occur at higher rates in individuals with FXS.
A Genotype-Phenotype Study of High-Resolution FMR1 Nucleic Acid and Protein Analyses in Fragile X Patients with Neurobehavioral Assessments
We know that FMRP is expressed throughout our body, including our blood, tissues, and brain. Levels of FMRP in the blood of patients with FXS have been positively correlated with cognitive performance, specifically intelligence quotient and adaptive behavior.