Kim Cornish

Association of the dopamine transporter (DAT1) 10/10-repeat genotype with ADHD symptoms and response inhibition in a general population sample.

Association between attention-deficit hyperactivity disorder (ADHD) and the 10-repeat allele of the dopamine transporter gene (DAT1) has been reported in independent clinical samples using a categorical clinical definition of ADHD. The present study adopts a quantitative trait loci (QTL) approach to examine the association between DAT1 and a continuous measure of ADHD behaviours in a general-population sample, as well as to explore whether there is an independent association between DAT1 and performance on neuropsychological tests of attention, response inhibition, and working memory. From an epidemiological sample of 872 boys aged 6–11 years, we recruited 58 boys scoring above the 90th percentile for teacher reported ADHD symptoms (SWAN ADHD scale) and 68 boys scoring below 10th percentile for genotyping and neuropsychological testing. A significant association was found between the DAT1 homozygous 10/10-repeat genotype and high-scoring boys (χ2square=4.6, P<0.03; odds ratio=2.4, 95% CI 1.1–5.0). Using hierarchical linear regression, a significant independent association was found between the DAT1 10/10-repeat genotype and measures of selective attention and response inhibition after adjusting for age, IQ, and ADHD symptoms. There was no association between DAT1 and any component of working memory. Furthermore, performance on tasks of selective attention although associated with DAT1 was not associated with SWAN ADHD high scores after controlling for age and IQ. In contrast, impairment on tasks that tapped sustained attention and the central executive component of working memory were found in high-scoring boys after adjusting for age and IQ. The results suggest that DAT1 is a QTL for continuously distributed ADHD behaviours in the general population and the cognitive endophenotype of response inhibition.

A neuropsychological profile of attention deficits in young males with fragile X syndrome

Different processes of attention were examined in a group of 25 fragile X boys with FMR-1 full mutation and compared with three control groups: a learning disabled comparison group comprising 25 boys with Downs syndrome, matched to the fragile X boys on verbal mental age; and 50 mainstream school boys (controls) matched to the fragile X boys on verbal mental age. The controls were further divided into those matched on poor attention to the fragile X boys and a good attention group, as rated by the ACTeRS questionnaire. Four categories of attention tasks were employed: selective attention, divided attention, sustained attention and executive functioning. The main findings of the study indicate that fragile X boys display an attention deficit at higher levels of attention function/executive functioning and that this profile is different from the profile identified in Downs syndrome boys and more extreme than the profile identified in the poor attention control group. These findings are discussed in the context of functional neuroimaging and brain-behaviour correlates in fragile X syndrome.

TRACING SYNDROME-SPECIFIC TRAJECTORIES OF ATTENTION ACROSS THE LIFESPAN

This paper maintains that studies of atypical attention targeting one particular age group are unlikely to be informative of syndrome-specific deficits and their developmental changes. We propose a new approach to the study of attentional deficits in genetic disorders, arguing for tracing cross-syndrome developmental trajectories from infancy through childhood to adulthood. Few studies have incorporated a developmental approach to determine whether the pattern of deficits and proficiencies remains constant across developmental time. Fewer still have included a cross-syndrome perspective to address these issues. Focusing on the cognitive domain of attention and its component parts, and using a cross-syndrome developmental perspective, the present set of studies compared the trajectories of different aspects of attention in three developmental disorders: Fragile X syndrome (FXS), Down syndrome (DS) and Williams syndrome (WS). Hitherto, these syndromes have all been reported as displaying serious attentional deficits above those expected in the general population. We predicted that, when one considers in greater detail subcomponent processes of attention, then ostensibly common difficulties do not necessarily emerge from common developmental pathways. We addressed this question with two studies. The first focused on inhibitory control, orienting and selective attention in infants and toddlers, and the second concentrated on selective attention, sustained attention and inhibitory control in mid-late childhood. The current results and their integration with earlier findings in adults point both to commonalities and to important syndrome-specific differences in attentional component processes, questioning whether profiles remain constant across developmental time.

The emerging fragile X premutation phenotype: evidence from the domain of social cognition.

Fragile X syndrome is a neurodevelopmental disorder that is caused by large methylated expansions of a CGG repeat (>200) region upstream of the FMR1 gene that results in the lack of expression of the fragile X mental retardation protein (FMRP). Affected individuals display a neurobehavioral phenotype that includes a significant impairment in social cognition alongside deficits in attentional control, inhibition and working memory. In contrast, relatively little is known about the trajectory and specificity of any cognitive impairment associated with the fragile X premutation (carrier-status) (approximately 55-200 repeats). Here, we focus on one aspect of cognition that has been well documented in the fragile X full mutation, namely social cognition. The results suggest that premutation males display a pattern of deficit similar in profile, albeit milder in presentation, to that of the full mutation. However, little evidence emerged for a correlation between CGG repeat length and severity of phenotypic outcomes. The findings are discussed in the context of functional neuroimaging and brain-behaviour-molecular correlates. We speculate that the deficiencies in social cognition are attributable to impairment of neural pathways modulated by the cerebellum.

The fragile X continuum: new advances and perspectives

Fragile X syndrome is the worlds most common hereditary cause of intellectual disability in men and to a lesser extent in women. The disorder is caused by the silencing of a single gene on the X chromosome, the Fragile X Mental Retardation Gene-1. A substantial body of research across the disciplines of molecular genetics, child psychiatry and developmental neuroscience bears testament to a decade of exciting and innovative science that has advanced our knowledge about the fragile X signature or influence across cognitive and social development. The core aims of this review are to first discuss fragile X syndrome and premutation involvement in the context of current advances that demonstrate the dynamic nature of the genotype on phenotypic outcomes. Second, to discuss the implications of these recent advances for the development of clinical and educational interventions and resource tools that target specific phenotypic signatures within the fragile X continuum.

Differential Impact of the FMR-1 Full Mutation on Memory and Attention Functioning: A Neuropsychological Perspective

Memory and attention processing were examined in a group of 15 adult Fragile-X syndrome (FXS) males with Fragile-X mental retardation 1 (FMR-1) full mutation and compared to two control groups: a learning disabled (LD) control and a normal functioning control. Performance was assessed across a wide range of tasks including working memory, recognition memory, selective attention, sustained attention, and attentional switching. All three groups performed at a comparable level on recognition memory tasks, and the Fragile-X males and LD control group performed worse than the control group on tasks of working memory and sustained attention. On a task of executive function, the Fragile-X males demonstrated a significant deficit in comparison to the LD control group and the normal control group, but performed better than the LD control group and at a comparable level to the control group on tasks of selective attention. Molecular analyses of the lymphocyte DNA provided little evidence for a correlation between expansion size and performance on tasks of memory and attention. The findings from the present study are discussed in the context of functional neuroimaging and brain-behavior-molecular correlates.

Age-dependent cognitive changes in carriers of the fragile X syndrome

Fragile X syndrome is a neurodevelopmental disorder that is caused by the silencing of a single gene on the X chromosome, the fragile X mental retardation 1 (FMR1) gene. Affected individuals display a unique neurocognitive phenotype that includes significant impairment in inhibitory control, selective attention, working memory, and visual-spatial cognition. In contrast, little is known about the trajectory and specificity of any cognitive impairment associated with the fragile X premutation (i.e., carrier status) or its relationship with the recently identified neurodegenerative disorder, fragile X-associated tremor/ataxia syndrome (FXTAS). In the present study, we evaluated a broad sample of 40 premutation males (PM) aged 18-69 years matched on age and IQ to 67 unaffected comparison males (NC). Performance was compared across a range of cognitive domains known to be impaired in fragile X syndrome (i.e., full mutation). Tremor was also assessed using a self-report neurological questionnaire. PM displayed statistically significant deficits in their ability to inhibit prepotent responses, differentiating them from NC from age 30 onwards. With increasing age, the two groups follow different trajectories, with PM developing progressively more severe problems in inhibitory control. This deficit also has a strong co-occurrence in males displaying FXTAS-related symptomatology (p<.001). Selective attention was also impaired in PM but did not show any disproportionate aging effect. No other cognitive deficits were observed. We conclude that an inhibitory deficit and its impact across the lifespan are specifically associated with the fragile X premutation status, and may be a precursor for development of a more severe form of cognitive impairment or dementia, which has been reported in patients with the diagnosis of FXTAS.

Further delineation of the executive deficit in males with fragile-X syndrome.

This paper presents a detailed analysis of one aspect of performance by young males with fragile-X syndrome (FMR-1 full mutation) who were assessed on a computerised visual search task as part of a larger study examining aspects of attention [Neuropsychologia 38 (2000) 1261]. They were matched on chronological and mental age to 25 boys with Downs syndrome (trisomy 21) and on mental age to 50 mainstream school boys (controls). The controls were further divided into those matched on poor attention to the fragile-X boys and a good attention group, as rated by the comprehensive teacher rating scale (ACTeRS) questionnaire. Both fragile-X and Downs syndrome boys made significantly more repeated responses on targets (but a lower proportion of errors based on confusion of shape) than the two control groups and these differences were stronger in the fragile-X group. In the single target condition, search was for a single type of target throughout. In the dual target condition, participants were required to alternate between two different targets. Fragile-X boys showed significantly greater inability than Downs syndrome and normal boys to switch attention between targets and both learning-disabled groups were inferior to the control groups. Thus, both learning-disabled groups displayed a weakness in inhibiting repetition and in switching attention from one type of target to another and the impairments were more acute in fragile-X boys. The results provide further support for an attention deficit in this population at higher levels of attention control/executive functioning that involve switching visual attention and inhibiting repetitious behaviour.

Spatial cognition in males with Fragile-X syndrome: evidence for a neuropsychological phenotype.

Spatial performance in a group of young Fragile-X syndrome males with FMR-1 full mutation was compared to a learning disabled control group comprising young Downs syndrome males and two control groups of mainstream schoolchildren. Performance was assessed across a wide range of spatial tasks including visuo-construction, visuo-spatial memory, visuo-motor, and visuo-perception. The findings indicate a task-specific rather than global deficit in spatial performance in Fragile-X males with visuo-constructive and visuo-motor skills most vulnerable. Molecular analysis of the lymphocyte DNA found minimal evidence for a correlation between CGG expansion size and spatial performance, although tasks with a visuo-perceptual component correlated negatively with expansion size indicating that the further away the number of repeats are from the 200 threshold the poorer the performance.

Lifespan changes in working memory in fragile X premutation males

Fragile X syndrome is the worlds most common hereditary cause of developmental delay in males and is now well characterized at the biological, brain and cognitive levels. The disorder is caused by the silencing of a single gene on the X chromosome, the FMR1 gene. The premutation (carrier) status, however, is less well documented but has an emerging literature that highlights a more subtle profile of executive cognitive deficiencies that mirror those reported in fully affected males. Rarely, however, has the issue of age-related declines in cognitive performance in premutation males been addressed. In the present study, we focus specifically on the cognitive domain of working memory and its subcomponents (verbal, spatial and central executive memory) and explore performance across a broad sample of premutation males aged 18-69 years matched on age and IQ to unaffected comparison males. We further tease apart the premutation status into those males with symptoms of the newly identified neurodegenerative disorder, the fragile X-associated tremor/ataxia syndrome (FXTAS) and those males currently symptom-free. Our findings indicate a specific vulnerability in premutation males on tasks that require simultaneous manipulation and storage of new information, so-called executive control of memory. Furthermore, this vulnerability appears to exist regardless of the presence of FXTAS symptoms. Males with FXTAS symptoms demonstrated a more general impairment encompassing phonological working memory in addition to central executive working memory. Among asymptomatic premutation males, we observed the novel finding of a relationship between increased CGG repeat size and impairment to central executive working memory.