Research reportDelineation of the working memory profile in female FMR1 premutation carriers: The effect of cognitive load on ocular motor responses
Introduction
The CGG trinucleotide expansions of the fragile X mental retardation gene (FMR1) are associated with a wide spectrum of early and late onset conditions. The full mutation (>200 CGG repeats) causes silencing of the FMR1 gene and loss of the FMR1 protein (FMRP), which is essential for normal neurodevelopment [1], [2], resulting in the neurodevelopmental disorder known as fragile X syndrome (FXS). In contrast, the medium sized premutation expansions (PM: 55–200 CGGs), found in approximately 1 in 430 males and 1 in 209 females within the general population [3], causes over-expression of the FMR1 gene. This over-expression results in mRNA “gain-of-function” toxicity accompanied by ubiquitin-positive intracellular inclusion bodies and reduced cell viability in neuronal cells [4], [5]. These molecular changes are the postulated cause of a late onset neurodegenerative disorder known as fragile X-associated tremor/ataxia syndrome (FXTAS). FXTAS affects approximately 45% of male and 8–17% of female PM-carriers over the age of 50 [6]. Besides the characteristic intention tremor, ataxia, and dementia, FXTAS also results in a range of molecular and structural abnormalities throughout the central nervous system, as well as executive functioning deficits [7], [8], [9], [10], [11], [12], [13], [14], [15].
There is strong evidence for the existence of a dysexecutive profile in asymptomatic PM-carriers (those without FXTAS) [16], [17], [18], [19]. The male asymptomatic PM-carrier phenotype is currently characterised by impairments in executive processing, with specific deficits in tasks reliant upon working memory, inhibitory processing, visuospatial processing and attentional control [20], [21], [22], [23], [24], [25], [26]. Significantly, higher CGG repeat levels (>100) have been associated with impaired working memory and response inhibition performance in male PM-carriers [21], [22], [23], [24].
There is also evidence suggests that there is at-least a sub-group of female PM-carriers demonstrating weakness in executive functioning (i.e. attentional and inhibitory control), processing speed, and visuospatial processing [27], [28], [29], [30], [31], [32], [33], [34], [35], [36], [37]. The extent to which working memory is affected in female PM-carriers is not well understood. Research indicates that the female PM-carrier phenotype may be less easily resolved and milder in nature than males, a consequence of the protective effects attributed to the presence of a normal allele (CGG <45 repeats) on the second X chromosome [38]. Hence a sensitive cognitive measure is required to ascertain whether or not female PM-carriers exhibit impaired working memory functionality, and if this is related to genetic or molecular markers.
Working memory is a limited-capacity system which enables the temporary storage, manipulation, and retrieval of information for use in complex cognitive tasks [39]. It is a process which relies upon widespread cortical and subcortical involvement [40], [41], [42], [43], [44], with the precise network activated dependent on the type of information involved [45]. Specifically, when visuospatial working memory circuitry is overwhelmed (or near capacity due to increases in cognitive load), neural activation is found to be highest in the frontal eye fields and along the intraparietal sulcus (IPS) [46]. Both of these are key ocular motor regions, and central to the support of visual attention [47], [48].
Ocular motor (saccadic) paradigms have been used extensively to assess cognitive (dys)function in a range of disorders; for example multiple sclerosis [49], Parkinson's [50], and Huntington's [51]. Indeed, we have previously utilised ocular motor paradigms, demonstrating reduced capacity to inhibit reflexive eye movements (inhibitory errors) in asymptomatic female PM-carriers, compared to healthy controls [33]. Not only did these female PM-carriers perform more inhibitory errors, they also showed greater difficulty responding to and learning motor/hand sequences compared to controls.
The extensive and well defined ocular motor network encompasses cortical (i.e. parietal and prefrontal regions), subcortical and cerebellar structures [52]. Further, the frontal-parietal connections required for cognitively driven saccades are also key networks required for visuospatial working memory tasks [53]. A range of saccadic paradigms have been developed to investigate working memory. An elegant example of one is the task devised by Jeter [54], which is based on the classic n-back task. The task involves the presentation of a continuous sequence of visual stimuli, and requires participants to identify the location of the stimulus presented ‘n’ locations—back in the sequence. The greater the ‘n’ value, the higher the cognitive load. Jeter, Patel and Sereno [54] have used their ocular motor n-back task to characterise developmental changes in working memory ability, as well as the effects of increasing cognitive load, in neurologically healthy individuals.
This study aimed to further delineate the female PM-carrier cognitive profile by characterising working memory performance under differing and increasing cognitive loads. Given the emerging similarities between the male and female PM-carrier cognitive phenotypes, we anticipated impaired working memory performance in female PM-carriers, with working memory performance being inversely correlated with increases in FMR1 mRNA levels and CGG expansions. This would provide the first evidence for a role of RNA toxicity as a predictor of impaired working memory performance in female PM-carriers.
Section snippets
Participants
All participants were aged between 18 and 55 years of age at the time of recruitment, were English speaking, had no history of serious head injury, had normal or corrected vision, and had around average IQ (as assessed using the Wechsler Abbreviated Scale of Intelligence). The cohort included 14 female PM-carriers (61–102 CGG repeats; mean = 79.36 repeats, standard deviation (SD) = 11.705) who had previously participated in our earlier studies [29], [30], [33], [37], [55] and a comparison group of
Results
The two groups were well matched for age (control: mean = 41.2, SD = 12.6, range 33.00; PM-carrier: mean = 41.9, SD = 7.26, range = 27.00; p = 0.859). There was no significant difference in full scale IQ scores for these two groups (control: mean = 115.4, SD = 12.9, range = 44.00; PM-carrier: mean = 112.9, SD = 9.23, range = 27.00; p = 0.671), with all participants demonstrating IQ's within the normal/average population range.
Discussion
FMR1 CGG expansions are associated with subtle to severe cognitive dysfunction. This study revealed female PM-carriers to have attenuated working memory processes, characterised by prolonged RT and significantly, little effect of increasing cognitive load on error rate. Furthermore, FMR1 mRNA levels in PM-carrier females were significantly correlated with differences in RT as a function of cognitive load for correctly executed responses, suggesting a molecular basis for these alterations. These
Competing interests
The authors report no competing interests.
Funding
Supported by an Australian Research Council (ARC) Discovery grant (DP110103346) to KC and JF. Further, D.E.G. was supported by NHMRC project grant [No. 104299 to D.E.G.], the Victorian Government's Operational Infrastructure Support Program and in part by Murdoch Childrens Research Institute Genetics Theme funding.
Acknowledgments
We express our thanks to the Fragile X Association of Australia and Fragile X Alliance for their support in recruitment. We also thank Jonathan Whitty from Healthscope Pathology and Erin Turbitt from the Murdoch Childrens Research Institute for their assistance on the molecular procedures. Finally, we are indebted to all the families who participated in this research.
References (75)
- et al.
Prepulse inhibition in patients with fragile X-associated tremor ataxia syndrome
Neurobiol Aging
(2012) - et al.
The emerging fragile X premutation phenotypes: evidence from the domain of social cognition
Brain Cogn
(2005) - et al.
Lifespan changes in working memory in fragile X premutation males
Brain Cogn
(2009) - et al.
Age-dependent cognitive changes in carriers of the fragile X syndrome
Cortex
(2008) - et al.
Selective spatial processing deficits in an at-risk subgroup of the fragile X premutation
Brain Cogn
(2012) - et al.
Mapping self-reports of working memory deficits to executive dysfunction in fragile X mental retardation 1 (FMR1) gene premutation carriers asymptomatic for FXTAS
Brain Cogn
(2010) - et al.
A neuropsychological investigation of male premutation carriers of fragile X syndrome
Neuropsychologia
(2004) - et al.
Young adult female fragile X premutation carriers show age- and genetically-modulated cognitive impairments
Brain Cogn
(2011) - et al.
Cognitive-motor interference during postural control indicates at-risk cerebellar profiles in females with the FMR1 premutation
Behav Brain Res
(2013) - et al.
Language dysfluencies in females with the FMR1 premutation
Brain Cogn
(2013)