Elsevier

Neurobiology of Aging

Volume 36, Issue 3, March 2015, Pages 1400-1408
Neurobiology of Aging

Regular article
Evidence linking FMR1 mRNA and attentional demands of stepping and postural control in women with the premutation

https://doi.org/10.1016/j.neurobiolaging.2014.11.012Get rights and content

Abstract

Recent studies in young adult females with the fragile X mental retardation 1 (FMR1) gene premutation (PM) have shown subtle but significant impairments in executive control and postural stability. Less is known about the influence of age and FMR1 gene expression on executive control and postural stability in females with the PM. Here, we examined the attentional demands of reactive stepping using a well-validated measure of choice stepping reaction time under dual-task interference. We explored the interrelationships between step initiation times during a concurrent verbal fluency task and specific impairments in executive control previously reported in females with the PM. Our results showed increased dual-task interference on step initiation times and variability in female PM compared with control subjects. In addition, we observed greater choice stepping reaction time dual-task costs above the breakpoint of 81 CGG repeats relative to below this CGG range. Dual-task interference on both reaction time and movement time were significantly predicted by low working memory capacity in female PM carriers. Importantly, we revealed that FMR1 messenger RNA level is the most significant predictor accounting for dual-task stepping variability in both reaction time and movement time in PM females. These findings for the first time provide evidence linking elevated FMR1 messenger RNA levels that have been previously associated with FMR1 RNA toxicity and deficits in cerebellar motor and cognitive networks in a subgroup of at-risk PM women.

Introduction

Fragile X syndrome is the most common single gene cause of inherited intellectual disability and autism with estimated frequency in the general population of 1 in 4000 males and 1 in 8000 females (Hagerman et al., 2009). The condition is usually caused by a large trinucleotide expansion of >200 CGG repeats in the 5′ untranslated region of the fragile X mental retardation 1 (FMR1) gene, termed full mutation. Typically, this leads to epigenetic silencing of FMR1 transcription and low or absent production of the fragile X mental retardation protein (FMRP) (Verkerk et al., 1991). More recently, attention has focused on a smaller class of expansions between 55 and 199 CGG repeats known as the premutation (PM). It is estimated that 1 in 151 females and 1 in 468 males carry the PM alleles (Seltzer et al., 2012b) and between 8%–16% of females and 45% of males over the age of 50 years who carry the PM develop executive dysfunction, dementia, tremor, and ataxia associated with fragile X-associated tremor and/or ataxia syndrome (FXTAS). Furthermore, approximately 20% of PM females will develop premature menopause associated with fragile X-associated primary ovarian insufficiency (Sullivan et al., 2011). Although the protective effects of the second X chromosome result in lower penetrance of FXTAS and a milder clinical presentation in women, recent studies indicate that young adult PM females show a subtle cognitive and motor phenotype that might portend later onset of more severe dementia and neurodegenerative decline (for a review see, Kraan et al., 2013a).

Although previous studies have not always consistently found a cognitive neuropsychological phenotype in the PM (Hunter et al., 2008b, Hunter et al., 2009), more recent studies in young adult PM females have provided evidence for subtle impairments in executive functioning (Kraan et al., 2014b, Sterling et al., 2013), visuospatial processing (Goodrich-Hunsaker et al., 2011a, Goodrich-Hunsaker et al., 2011b), mathematical reasoning (Lachiewicz et al., 2006, Semenza et al., 2012), and frontally mediated tasks of processing speed and working memory (Yang et al., 2013). Alongside these neurocognitive impairments in PM females, there is evidence to support the presence of subtle motor abnormalities in relation to poor balance (Chonchaiya et al., 2010, Narcisa et al., 2011) and enhanced psychomotor speed, perhaps suggestive of poor control, in older females with the PM (Goodrich-Hunsaker et al., 2011c, Steyaert et al., 1994). Studies that have utilized the coordination tremor balance test system (CATSYS), a quantitative measure of tremor and ataxia, have shown that subtle difficulties in postural sway can be detected in older PM females compared with control subjects, albeit the postural differences did not obtain corrected levels of significance (Narcisa et al., 2011). However, the CATSYS is limited by the measurement of only postural sway during quiet stance rather than postural changes during voluntary step initiation. The ability to rapidly initiate and complete a voluntary step in response to environmental stimuli is a vital human sensorimotor function. Thus, measures of postural control during step initiation may provide earlier and perhaps more sensitive indicators of motor system dysfunction for tracking disease onset and progression in women with the PM.

Dual-task paradigms, which examine performance on a primary cognitive or motor task while concurrently performing a secondary task, can provide a sensitive approach to examine the attentional demands on postural control. The need to prioritize our attention when engaging in concurrent motor and cognitive activities is ubiquitous in everyday life. The attentional cost associated with postural dual-tasks has been attributed to capacity interference when two tasks exceed the capability of limited attentional resources (Sheridan et al., 2003, Yogev-Seligmann et al., 2008). The attentional demands on postural control may depend on the attentional load of the cognitive or motor task and individual differences in executive control (Montero-Odasso et al., 2012). Executive control is a broad term encompassing an extensive set of higher order operations that organize and regulate goal-directed behavior. This can be further fractionated into 3 interdependent component processes—that is, mental set-shifting, updating of representations in working memory, and inhibition of prepotent responses (Miyake and Friedman, 2012, Miyake et al., 2000). We have recently demonstrated that PM females show greater postural displacement when performing a concurrent excluded-letter-verbal-fluency task under reduced proprioceptive input (Kraan et al., 2013b). The age-dependent dual-task effects on postural sway were significantly moderated by CGG-repeat size in PM females. This was suggestive of increased susceptibility of cerebellar networks to the neurotoxic effects of the expansion, although associations with FMR1 messenger RNA (mRNA) levels were not reported. In addition, we have shown interactive influences between low working memory capacity and dual-task costs for gait domains of pace and variability in the same cohort of females with the PM (Kraan et al., 2014a). However, it remains unclear which specific aspects of executive control show important influences on both reactive stepping and balance stability, which will be important for evaluation of future interventions for PM females.

In the present study, we investigated the effects of cognitive dual-tasks on choice reaction time step initiation in PM females. Step initiation is a functional task that has been shown to involve executive control in healthy older adults (Cohen et al., 2011, Sparto et al., 2013). The choice stepping reaction time (CSRT) paradigm is a well-validated measure of dual-task effects on stepping performance and falls risk in older adults (St George et al., 2007, Sturnieks et al., 2008) and is sensitive to stepping risk factors associated with falls in people with multiple sclerosis (Hoang et al., 2014). We used the CSRT paradigm as it is particularly applicable to anticipatory postural adjustments that occur through slow or inappropriate stepping responses to late visual detection of hazards or unanticipated changes in the gait path (St George et al., 2007, Sturnieks et al., 2008). The differential effects of a secondary verbal fluency task on CSRT were explored to determine the effect on reaction times and initial motor program errors. We explored the association between dual-task stepping responses and specific impairments in executive control (response inhibition, working memory) and attention deficit hyperactivity disorder (ADHD) symptoms that have been previously reported in females with the PM (Hunter et al., 2010, Hunter et al., 2012, Kraan et al., 2014b). In this study, we compared dual-task interference on choice reaction time step initiation between PM females and matched controls with normal alleles (CGG<45). On the basis of our previous study showing associations between low working memory capacity and dual-task gait interference in female PM carriers (Kraan et al., 2014a), we hypothesized that dual-task interference during stepping would be associated with specific impairments in working memory in PM females. Furthermore, we examined the relationships between dual-task stepping interference, age, and molecular parameters (CGG repeat length, FMR1 mRNA levels, and FMR1 activation ratio) in females with the PM.

Section snippets

Study participants

We recruited a total of 35 PM females ranging in age from 22 to 55 years through fragile X syndrome support groups and a population-based fragile X carrier screening study (Martyn et al., 2013, Metcalfe et al., 2008). The comparison group comprised 34 age-matched nonaffected adult females with normal FMR1 alleles who were recruited through the fragile X carrier screening study, local networks, and via online advertisements. The PM carriers and controls were the same cohort that formed part of a

Sample characteristics and molecular relationships

The PM and control groups did not show significant differences in mean age (t = −0.027, p = 0.979), IQ (FSIQ: t = −0.822, p = 0.414; VIQ: t = −0.618, p = 0.538; PIQ: t = −1.23, p = 0.224), height (t = −0.965, p = 0.338), or weight (t = −0.315, p = 0.754) (Table 1). Intergroup comparisons for the molecular measures showed that FMR1 mRNA levels were significantly increased in the PM group compared with control subjects, whereas AR was significantly different above the breakpoint of 102 CGG

Discussion

This study examined the interaction between executive control and voluntary step initiation during dual-task performance in PM females. The attentional demands of a step response were explored in the context of dual-task stepping costs and their relationship with FMR1 genetic factors. First, PM females showed proportionally greater attentional costs associated with stepping response times and variability during concurrent performance of a verbal fluency task relative to control subjects.

Disclosure statement

David E. Godler is an inventor on patents related to the technology targeting epigenetic modifications of the FMR1 gene. The authors report no other disclosures or conflicts of interest.

Acknowledgements

This work was supported by an Australian Research Council Discovery grant (DP110103346) to Kim Cornish, Nellie Georgiou-Karistianis, Sylvia A. Metcalfe, Julian Trollor, Joanne Fielding and John L. Bradshaw, and a Monash University Research Fellowship to Darren R. Hocking. David E. Godler and Xin Li were supported by NHMRC project grant (No 104299 to David E. Godler), the Victorian Government's Operational Infrastructure Support Program and in part by Murdoch Childrens Research Institute,

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