Neuropsychological findings from older premutation carrier males and their noncarrier siblings from families with fragile X syndrome.

Objective: Carriers of the FMR1 premutation allele are at a significantly increased risk for a late-onset neurodegenerative disorder, fragile X-associated tremor/ataxia syndrome (FXTAS). The primary features of FXTAS are late-onset intention tremor and gait ataxia. Previous reports have shown global deficits in neuropsychological measures among males with FXTAS, particularly those related to executive functioning. The purpose of this study was to investigate the neuropsychological profile among older males with the premutation who are at risk for FXTAS. Method: Premutation carriers, 66 with motor symptoms and 23 without, and 18 noncarrier siblings were recruited from pedigrees diagnosed with fragile X syndrome, all over age 50. Subjects were examined with a neurological test battery to identify symptoms of FXTAS and a neuropsychological test battery to investigate cognitive and behavioral profiles. Linear regression and ANCOVA were used to determine the effect of the premutation on outcome measures adjusting for age and education. Results: We identified a significant decrease in scores of general intelligence and a marginally significant decrease in scores of logical memory among premutation carrier males with motor symptoms compared to the noncarrier male siblings. We did not identify deficits in executive functioning in our sample of premutation carrier males with motor symptoms. Conclusions: Similar to other reports, we found that the FMR1 premutation is associated with deficits in general intelligence and memory among older males with symptoms of FXTAS. However, our results differed in that we found no evidence of premutation-associated executive dysfunction. We provide possible explanations for this difference. (PsycINFO Database Record (c) 2011 APA, all rights reserved)     

Cognitive profile of fragile X premutation carriers with and without fragile X-associated tremor/ataxia syndrome.

Fragile X-associated tremor/ataxia syndrome (FXTAS) develops in a subset of fragile X premutation carriers and involves gait ataxia, action tremor, Parkinsonism, peripheral neuropathy, autonomic disorders, and cognitive impairment. The study was designed to define the nature of cognitive deficits affecting male premutation carriers with and without FXTAS. A sample of 109 men underwent motor, cognitive, genetic, and neurologic testing, as well as brain magnetic resonance imaging. Subjects were classified into 3 groups: (a) asymptomatic premutation carriers, (b) premutation carriers with FXTAS, and (c) normal controls. Men with FXTAS performed worse than controls on mental status, intelligence, executive cognitive functioning (ECF), working memory, remote recall of information, declarative learning and memory, information processing speed, and temporal sequencing, as well as 1 measure of visuospatial functioning. Language and verbal comprehension were spared. Asymptomatic carriers performed worse than controls on ECF and declarative learning and memory. This comprehensive examination of cognitive impairment in male premutation carriers suggests that FXTAS involves substantial executive impairment and diffuse deficits in other cognitive functions. Longitudinal research currently underway will provide insight into the progression of the disorder. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Mouse model of fragile X syndrome: Behavioral and hormonal response to stressors.

Fragile X syndrome, a form of mental retardation caused by inadequate levels of fragile X mental retardation protein (FMRP), is characterized by extreme sensitivity to sensory stimuli and increased behavioral and hormonal reactivity to stressors. Fmr1 knockout mice lack FMRP and exhibit abnormal responses to auditory stimuli. This study sought to determine whether Fmr1 knockout mice on an F1 hybrid background are normal in their response to footshock. Knockout mice were also examined for signs of hyperexcitation across an extended trial range, and serum corticosterone levels were evaluated in response to various stressors. The ability to acquire conditioned taste aversion was also assessed. Knockout mice exhibited no impairment in associative aversive learning or memory, since they successfully expressed conditioned taste aversion. Footshock-sensitivity, freezing behavior, and corticosterone response to various stressors did not differ between knockout and wild-type mice. However, knockout mice exhibited significantly increased responses during the extended test. The knockout mice’s increased responsiveness to footshock in the extended test may be an indication of increased vulnerability to stress or enhanced emotional reactivity. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Attentional dysfunction, impulsivity, and resistance to change in a mouse model of fragile X syndrome.

On a series of attention tasks, male mice with a mutation targeted to the fragile X mental retardation 1 (Fmrl) gene (Fmrl knockout [KO] mice) committed a higher rate of premature responses than wild-type littermates, with the largest differences seen when task contingencies changed. This finding indicates impaired inhibitory control, particularly during times of stress or arousal. The KO mice also committed a higher rate of inaccurate responses than controls, particularly during the final third of each daily test session, indicating impaired sustained attention. In the selective attention task, the unpredictable presentation of potent olfactory distractors produced a generalized disruption in the performance of the KO mice, whereas for controls, the disruption produced by the distractors was temporally limited. Finally, the attentional disruption seen following an error was more pronounced for the KO mice than for controls, further implicating impaired regulation of arousal and/or negative affect. The present study provides the first evidence that the Fmrl KO mouse is impaired in inhibitory control, attention, and arousal regulation, hallmark areas of dysfunction in fragile X syndrome. The resistance to change also seen in these mice provides a behavioral index for studying the autistic features of this disorder. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Evidence for social anxiety and impaired social cognition in a mouse model of fragile X syndrome.

This study assessed social behavior in a mouse model of Fragile X syndrome (FXS), the Fmr1 tm1Cgr or Fmr1 knockout (KO) mouse. Both the KO and wild-type (WT) mice preferred to be near a novel conspecific than to be alone. However, during the initial interaction with a novel conspecific, (1) a greater proportion of the KO mice exhibited high levels of grooming; and (2) the average duration of nose contact with the stimulus mouse was significantly shorter for the KO mice, both indicative of increased arousal and/or anxiety. Both groups exhibited a robust novelty preference when the novel animal was a preferred mouse. However, when the novel mouse was a nonpreferred animal, both groups showed a diminished novelty preference but this effect was more pronounced for the WT mice. This blunted negative reaction of the KO mice to a nonpreferred animal may indicate that they were less proficient than controls in distinguishing between positive and negative social interactions. These findings provide support for the use of this animal model to study the autistic features of FXS and autism spectrum disorders. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Links between theory of mind and executive function in young children with autism: Clues to developmental primacy.

There has been much theoretical discussion of a functional link between theory of mind (ToM) and executive function (EF) in autism. This study sought to establish the relationship between ToM and EF in young children with autism (M = 5 years, 6 months) and to examine issues of developmental primacy. Thirty children with autism and 40 typically developing children, matched on age and ability, were assessed on a battery of tasks measuring ToM (1st- and 2nd-order false belief) and components of EF (planning, set shifting, inhibition). A significant correlation emerged between ToM and EF variables in the autism group, independent of age and ability, while ToM and higher order planning ability remained significantly related in the comparison group. Examination of the pattern of ToM-EF impairments in the autism group revealed dissociations in 1 direction only: impaired ToM with intact EF. These findings support the view that EF may be 1 important factor in the advancement of ToM understanding in autism. The theoretical implications of these findings are discussed. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Skill development in different components of arithmetic and basic cognitive functions: Findings from a 3-year longitudinal study of children with different types of learning difficulties.

Arithmetic and cognitive skills of children with mathematical difficulties (MD-only), with comorbid reading difficulties (MD-RD), with reading difficulties (RD-only), and normally achieving children were examined at 3 points from Grades 3–4 to Grades 5–6 (age range, 9–13 years). Both MD groups displayed severe weaknesses in 4 domain-specific arithmetic components (factual, conceptual, procedural, and problem-solving skills) during all 3 measure points. Telling time and approximate arithmetic were also problematic for children with MD. Both MD groups displayed a small weakness related to visual–spatial working memory, and the MD-RD group also displayed small weaknesses related to verbal short-term memory, processing speed, and executive functions. The 4 groups developed at similar rates within all domain-specific components as well as basic cognitive functions. These findings demonstrate that children identified as having MD when they are 9 years old do not catch up with their normally achieving peers in later school grades, when they are 13 years old. They also continue to lag behind their peers with respect to the domain-general cognitive system. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Development of depression from preadolescence to young adulthood: Emerging gender differences in a 10-year longitudinal study.

The authors investigated the emergence of gender differences in clinical depression and the overall development of depression from preadolescence to young adulthood among members of a complete birth cohort using a prospective longitudinal approach with structured diagnostic interviews administered 5 times over the course of 10 years. Small gender differences in depression (females greater than males) first began to emerge between the ages of 13 and 15. However, the greatest increase in this gender difference occurred between ages 15 and 18. Depression rates and accompanying gender differences for a university student subsample were no different than for a nonuniversity subsample. There was no gender difference for depression recurrence or for depression symptom severity. The peak increase in both overall rates of depression and new cases of depression occurred between the ages of 15 and 18. Results suggest that middle-to-late adolescence (ages 15–18) may be a critical time for studying vulnerability to depression because of the higher depression rates and the greater risk for depression onset and dramatic increase in gender differences in depression during this period. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Social behavior phenotypes in fragile X syndrome, autism, and the Fmr1 knockout mouse: Theoretical comment on McNaughton et al. (2008).

Comments on the article by C. H. McNaughton et al. ((see record 2008-03769-005). Individuals with fragile X syndrome (FXS) show varying degrees of social behavior disturbances, from social anxiety to autism. This variability of social behavior phenotypes in FXS is likely to be due to interactions of Fmr1 with other gene variants and environmental factors during brain development, although very little is known about the specific genetic and neural mechanisms involved. The Fmr1 knockout mouse is an important experimental resource for elucidating the neural mechanisms of social anxiety, social reward, and social cognition. However, studies of social behavior phenotypes in the Fmr1 knockout mouse are still in early stages. McNaughton et al provide important new information on these phenotypes in the Fmr1 knockout mouse through their use of novel, detailed behavioral analysis to identify signs of increased social anxiety and social cognition deficits. Their significant refinements in measurement of social behavior phenotypes will help to advance future efforts to elucidate the genetic and neural mechanisms underlying social behavior disturbances in FXS and autism. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Gender differences and developmental change in externalizing disorders from late adolescence to early adulthood: A longitudinal twin study.

Using data from over 1,000 male and female twins participating in the Minnesota Twin Family Study, the authors examined developmental change, gender differences, and genetic and environmental contributions to the symptom levels of four externalizing disorders (adult antisocial behavior, alcohol dependence, nicotine dependence, and drug dependence) from ages 17 to 24. Both men and women increased in symptoms for each externalizing disorder, with men increasing at a greater rate than women, such that a modest gender gap at age 17 widened to a large one at age 24. Additionally, a mean-level gender difference on a latent Externalizing factor could account for the mean-level gender differences for the individual disorders. Biometric analyses revealed increasing genetic variation and heritability for men but a trend toward decreasing genetic variation and increasing environmental effects for women. Results illustrate the importance of gender and developmental context for symptom expression and the utility of structural models to integrate general trends and disorder-specific characteristics. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Relations of positive and negative affectivity to anxiety and depression in children: Evidence from a latent variable longitudinal study.

The tripartite model of anxiety and depression has been studied with adults; however, support is still emerging with children concerning measurement and relations between positive (PA) and negative (NA) affect and psychopathology. In this longitudinal study of 270 4th- to 11th-grade children (mean age=12.9 years, SD=2.23), confirmatory factor analysis supported a 2-factor orthogonal model of children's self-reported affect and revealed that the concurrent relations of NA and PA to anxiety and depression symptoms were consistent with the tripartite model. Structural equation modeling demonstrated moderate cross-time stability of trait PA and NA, consistent with a temperament view of these factors, as well as partial support for the role of NA and PA in the development of anxiety and depression symptoms in children. (PsycINFO Database Record (c) 2010 APA, all rights reserved)