Age-related functional brain changes in FMR1 premutation carriers

Abstract

The FMR1 premutation confers a 40–60% risk for males of developing a neurodegenerative disease called the Fragile X-associated Tremor Ataxia Syndrome (FXTAS). FXTAS is a late-onset disease that primarily involves progressive symptoms of tremor and ataxia, as well as cognitive decline that can develop into dementia in some patients. At present, it is not clear whether changes to brain function are detectable in motor regions prior to the onset of frank symptomatology. The present study therefore aimed to utilize an fMRI motor task for the first time in an asymptomatic premutation population.Premutation carriers without a diagnosis of FXTAS (n = 17) and a group of healthy male controls (n = 17), with an age range of 24–68 years old, were recruited for this cross-sectional study. This study utilized neuroimaging, molecular and clinical measurements, employing an fMRI finger-tapping task with a block design consisting of sequential finger-tapping, random finger-tapping and rest conditions. The imaging analysis contrasted the sequential and random conditions to investigate activation changes in response to a change in task demand. Additionally, measurements were obtained of participant tremor, co-ordination and balance using the CATSYS-2000 system and measures of FMR1 mRNA were quantified from peripheral blood samples using quantitative real-time PCR methodology.Premutation carriers demonstrated significantly less cerebellar activation than controls during sequential versus random finger tapping (FWEcorr < 0.001). In addition, there was a significant age by group interaction in the hippocampus, inferior parietal cortex and temporal cortex originating from a more negative relationship between brain activation and age in the carrier group compared to the controls (FWEcorr < 0.001).Here, we present for the first time functional imaging-based evidence for early movement-related neurodegeneration in Fragile X premutation carriers. These changes pre-exist the diagnosis of FXTAS and are greatest in older carriers suggesting that they may be indicative of FXTAS vulnerability.

Cerebellar-cortical function and connectivity during sensorimotor behavior in aging FMR1 gene premutation carriers

“…Reduced activation of extrastriate cortex in premutation carriers may reflect difficulties attending to and processing basic visual input during rapid motor action. These findings extend the one known prior fMRI study of motor behavior in premutation carriers to indicate that decreased modulation of precision motor behavior in premutation carriers is associated with reduced processing of sensory feedback information ( Brown et al, 2018 ). We also found that extrastriate functional differences in premutation carriers were age-dependent; increased age was associated with increased extrastriate activation in premutation carriers, but reduced extrastriate activation in controls.…”

“…Although sensorimotor deficits are frequently observed in premutation carriers with and without FXTAS, only one known task-based functional MRI study has investigated sensorimotor control in aging premutation carriers. Brown and colleagues reported reduced activation in cerebellar lobules V-VI in asymptomatic premutation carriers during visually-guided sequential finger tapping ( Brown et al, 2018 ). These findings suggest cerebellar dysfunction during manual motor behavior may represent a quantifiable trait dimension associated with atypical aging in premutation carriers and putative FXTAS risk.…”

Neuroimaging Insight Into Fragile X-Associated Neuropsychiatric Disorders: Literature Review

“…Indeed, brain function is also affected by FMR1 premutation status in relatively young premutation carriers without FXTAS who demonstrate no overt neurological symptoms (5,6,9,11). Contrary to movementrelated neurodegeneration, which increases over time, emotional symptoms seem to be consistent over the lifespan in FMR1 premutation carriers; suggesting a neurodevelopmental origin, different from the neurodegeneration seen in FXTAS (7,11,19).…”

FMR1 Carriers Report Executive Function Changes Prior to Fragile X‐Associated Tremor/Ataxia Syndrome: A Longitudinal Study

“…A growing body of research suggests that deterioration of frontal-cerebellar circuits is especially sensitive to the FMR1 premutation and appear to impact both control of movement (ataxia and tremor) and executive control of cognition (eg, working memory) in PC. 9,19,[33][34][35] For example, we previously showed that compared with HC, PC with and without FXTAS performing a verbal working memory EF task showed reduced activation in the right ventral inferior frontal cortex and left premotor/dorsal inferior frontal cortex. 9 In a cross-sectional structural brain imaging study of 322 males from age 8 to 81, we discovered that compared to age-matched HC, PC without FXTAS showed significantly accelerated age-related volume decreases in the cerebellum and brainstem and increased ventricular volume.…”