Longitudinal Changes in Intellectual Development in Children with Fragile X Syndrome

Structural equation modeling (SEM) was used to examine the development of intellectual functioning in 145 school-age pairs of siblings. Each pair included one child with Fragile X syndrome (FXS) and one unaffected sibling. All pairs of children were evaluated on the Wechsler Intelligence Scale for Children-Third Edition (WISC-III) at time 1 and 80 pairs of children received a second evaluation at time 2 approximately 4 years later. Compared to their unaffected siblings, children with FXS obtained significantly lower percentage correct scores on all subtests of the WISC at both time points. During the time between the first and second assessments, the annual rate of intellectual development was approximately 2.2 times faster in the unaffected children compared to the children with FXS. Levels of the fragile X mental retardation protein (FMRP) were highly associated with intellectual ability scores of the children with FXS at both time points (r=0.55 and 0.64 respectively). However, when gender, age, and the time between assessments were included as covariates in the structural equation model, FMRP accounted for only 5% of the variance in intellectual ability scores at time 1 and 13% of the variance at time 2. The results of this study suggest that slower learning contributes to the low and declining standardized IQ scores observed in children with FXS.     

Supplementary WMS-III tables for determining primary subtest strengths and weaknesses

It is common practice to evaluate the age-adjusted subtest scores from the Wechsler intelligence scales to determine strengths and weaknesses within a profile. The Wechsler Memory Scale-III (WMS-III; D. Wechsler, 1997a) represents a significant improvement over its predecessors and, for the first time, provides age-adjusted subtest scores for interpretation, just as the Wechsler intelligence scales have done for 60 years. It is reasonable to assume that examiners will evaluate the WMS-III subtest profiles for strengths and weaknesses. However, the WMS-III Administration and Scoring Manual and the WAIS-III-WMS-III Technical Manual (The Psychological Corporation, 1997) provide no assistance for accomplishing this goal. Data from the WMS-III standardization sample, as described in the WAIS-III-WMS-III Technical Manual, were used to develop tables for determining both confidence levels and infrequency of differences between individual subtest scores and the means of 5 subtest combinations that may be clinically relevant for individual cases.     

Ego development and intelligence in a psychiatric population: Wechsler subtest scores

The relationship between Loevinger's measure of ego development and the Wechsler Intelligence Scales subtest scores was investigated in 91 adolescent and young adult psychiatric inpatients. Correlations with Verbal IQ and verbal subtests in general were positive and significant. The correlation with the Comprehension subtest was the highest and remained significant when Full Scale IQ was partialled. Post-conformists obtained the highest mean scores on Picture Arrangement; however, there was no difference among the lower stages on this subtest. The results lend support to a social reasoning component of ego development.     

The fragile X syndrome: from molecular genetics to neurobiology

Since the identification of the FMR1 gene basic research has been focused on the molecular characterization of the FMR1 gene product, the fragile X mental retardation protein (FMRP). Recent developments in fragile X research have provided new insights and knowledge about the physiological function of FMRP in the cell and the nerve cell in particular. Currently, compelling evidence suggests a role for FMRP in the transport/translation of dendritically localized mRNAs. In addition, the identification of some of the target mRNAs of FMRP have led to an increased interest in the neurobiology of the syndrome. This review highlights the role of FMRP in dendritic mRNA transport/translation in relation to synaptic plasticity, a molecular mechanism implicated in learning and memory.     

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.     

Fragile X mental retardation protein levels increase following complex environment exposure in rat brain regions undergoing active synaptogenesis

Fragile X mental retardation protein (FMRP), which is absent in fragile X syndrome, is synthesized in vitro in response to neurotransmitter activation. Humans and mice lacking FMRP exhibit abnormal dendritic spine development, suggesting that this protein plays an important role in synaptic plasticity. Previously, our laboratory demonstrated increased FMRP immunoreactivity in visual cortex of rats exposed to complex environments (EC) and in motor cortex of rats trained on motor-skill tasks compared with animals reared individually in standard laboratory housing (IC). Here, we use immunohistochemistry to extend those findings by investigating FMRP levels in visual cortex and hippocampal dentate gyrus of animals exposed to EC or IC. Rats exposed to EC for 20 days exhibited increased FMRP immunoreactivity in visual cortex compared with animals housed in standard laboratory caging. In the dentate gyrus, animals exposed to EC for 20 days had higher FMRP levels than animals exposed to EC for 5 or 10 days. In light of possible antibody crossreactivity with closely related proteins FXR1P and FXR2P, FMRP immunoreactivity in the posterior-dorsal one-third of cerebral cortex was also examined by Western blotting following 20 days of EC exposure. FMRP levels were greater in EC animals, whereas levels of FXR1P and FXR2P were unaffected by experience. These results provide further evidence for behaviorally induced alteration of FMRP expression in contrast to its homologues, extend previous findings suggesting regulation of its expression by synaptic activity, and support the theories associating FMRP expression with alteration of synaptic structure both in development and later in the life-cycle.     

Factor analysis of the Wechsler adult intelligence scale-revised (WAIS-R): An examination of the standardization sample

Orthogonal and oblique factor analyses were performed using the Wechsler Adult Intelligence Scale-Revised (WAIS-R) standardization sample (Wechsler, 1981). Using objective criteria, it was decided to retain two factors. Evidence for a strong general intelligence (g) factor was found from both the orthogonal and oblique rotations. Whereas the verbal IQ provided an acceptable estimate of the Verbal Comprehension factor, a purer measure was found in the form of a Verbal Comprehension Deviation Quotient containing only the Information, Vocabulary, Comprehension, and Similarities subtests. The performance IQ was found to be an inadequate measure of the Perceptual Organization factor. A Perceptual Organization Deviation Quotient, containing only the Block Design and Object Assembly subtests, was recommended as an effective alternative. Analysis of the variance components for each subtest at every age level revealed that a substantial proportion of subtests at a wide range of age levels evidence either high or intermediate levels of specific variance. These results are discussed in terms of interpreting individual subtest scores and patterns. Each of the study's major findings are compared with prior work done with the Wechsler Adult Intelligence Scale (WAIS) (Wechsler, 1955).     

Parallel-form reliability of the Wechsler Memory Scale in a geriatric population with suspected dementia

The present study examined parallel-form reliability of the Wechsler Memory Scale (WMS) in a population where such forms are particularly useful, that is, among patients who are suspected of having some type of dementing illness. Comparative analyses were made for total raw scores. Memory Quotient (MQ) scores, and individual subtest scores. Thirty geriatric patients originally referred for neuropsychological testing because of suspected dementia were given both Forms 1 and 2 of the WMS. The results yielded high overall reliability coefficients for MQ and total raw scores. Individual subtest scores also yielded rather high coefficients, and only one subtest (Associate Learning) had a significant mean difference. Apparently, the two forms have sufficient parallel-form reliability to be considered clinically interchangeable. Thus, the WMS may be a useful tool for repeat evaluations of memory functioning in a demented population.     

Evaluation of the validity of the Wechsler Intelligence Scale for Children--Third Edition comprehension and picture arrangement subtests as measures of social intelligence

Clinical lore suggests that the Wechsler Intelligence Scale for Children--Third Edition (D. M. Wechsler, 1991) Comprehension and Picture Arrangement scores may be used as indices of social intelligence. This study evaluated this supposition by comparing these subtest scores with mother- and teacher-reported social functioning in 142 children with ADHD and 30 control children. After general intelligence was partialled out, the Comprehension subtest related to some aspects of social functioning, but the clinical significance of this was limited. The Picture Arrangement subtest was unrelated to social functioning, once general intelligence was controlled. These findings were consistent across study groups.     

Fragile X mental retardation protein regulates heterosynaptic plasticity in the hippocampus

Silencing of a single gene, FMR1, is linked to a highly prevalent form of mental retardation, characterized by social and cognitive impairments, known as fragile X syndrome (FXS). The FMR1 gene encodes fragile X mental retardation protein (FMRP), which negatively regulates translation. Knockout of Fmr1 in mice results in enhanced long-term depression (LTD) induced by metabotropic glutamate receptor (mGluR) activation. Despite the evidence implicating FMRP in LTD, the role of FMRP in long-term potentiation (LTP) is less clear. Synaptic strength can be augmented heterosynaptically through the generation and sequestration of plasticity-related proteins, in a cell-wide manner. If heterosynaptic plasticity is altered in Fmr1 knockout (KO) mice, this may explain the cognitive deficits associated with FXS. We induced homosynaptic plasticity using the β-adrenergic receptor (β-AR) agonist, isoproterenol (ISO), which facilitated heterosynaptic LTP that was enhanced in Fmr1 KO mice relative to wild-type (WT) controls. To determine if enhanced heterosynaptic LTP in Fmr1 KO mouse hippocampus requires protein synthesis, we applied a translation inhibitor, emetine (EME). EME blocked homo- and heterosynaptic LTP in both genotypes. We also probed the roles of mTOR and ERK in boosting heterosynaptic LTP in Fmr1 KO mice. Although heterosynaptic LTP was blocked in both WT and KOs by inhibitors of mTOR and ERK, homosynaptic LTP was still enhanced following mTOR inhibition in slices from Fmr1 KO mice. Because mTOR will normally stimulate translation initiation, our results suggest that β-AR stimulation paired with derepression of translation results in enhanced heterosynaptic plasticity.     

Comparative relationships of the Wechsler Adult Intelligence Scale—Revised (WAIS-R) and the Wechsler Adult Intelligence Scale (WAIS) to the Wechsler Memory Scale (WMS)

This study investigated whether the Wechsler Adult Intelligence Scale — Revised (WAIS-R) and Wechsler Adult Intelligence Scale (WAIS) demonstrate similar patterns of relationship with the Wechsler Memory Scale (WMS). Sixty VA patients were administered the WAIS-R and WMS and 60 completed the WAIS and WMS. The groups were comparable in terms of demographic variables. Pearson correlations were computed between the subtest and IQ scores from the intelligence scales and the scores from the WMS for each group. Comparison of the resulting correlations for the WAIS-R group with those of the WAIS subjects demonstrated only four significant differences, indicating that the WAIS-R and WAIS variables covary in a similar manner with the WMS scores. Following factor analysis of the test data for both groups, coefficients of congruence indicated a high degree of similarity between the two factor solutions. Essentially the same relationships emerged between intelligence variables and the WMS regardless of which scale was administered.     

Diagnosing written language disabilities using the Woodcock-Johnson Tests of Educational Achievement-Revised and the Wechsler Individual Achievement Test

The writing portions of the Woodcock-Johnson Tests of Educational Achievement-Revised and the Wechsler Individual Achievement Test are often administered when establishing eligibility for special education services due to learning disabilities. The scores on these measures are typically regarded as equivalent although little is known about how scores on the two measures differ for the same students. Differences of only a few points, however, may affect eligibility for special education services. These tests were administered to 25 sixth grade students previously diagnosed with learning disabilities in written expression only. Students' Wechsler scores were consistently higher on the overall writing composite, while there was no difference in the mean scores on the language mechanics subtests. The WIAT Written Expression subtest mean, however, was significantly higher than the Woodcock-Johnson Writing Samples subtest mean. Use of the Wechsler test would be less likely to identify children for special education services in written expression when point discrepancy criteria are utilized for eligibility. Clinicians should be cognizant of the effect of the specific test chosen on eligibility outcome.     

Subregion-specific dendritic spine abnormalities in the hippocampus of Fmr1 KO mice

Fragile X syndrome (FXS) is the most common inherited form of mental retardation and is caused by the lack of fragile X mental retardation protein (FMRP). In the brain, spine abnormalities have been reported in both patients with FXS and Fmr1 knockout mice. This altered spine morphology has been linked to disturbed synaptic transmission related to altered signaling in the excitatory metabotropic glutamate receptor 5 (mGluR5) pathway. We investigated hippocampal protrusion morphology in adult Fmr1 knockout mice. Our results show a hippocampal CA1-specific altered protrusion phenotype, which was absent in the CA3 region of the hippocampus. This suggests a subregion-specific function of FMRP in synaptic plasticity in the brain.     

Change and stability in adult intellectual functioning assessed by Wechsler item responses

Change in adult intellectual performance was assessed with longitudinal data from the Intergenerational Studies at the Institute of Human Development. Wechsler Intelligence data from two age cohorts spanning ages 18 to 61 were analyzed at the subtest and item level. Hotelling T2 analyses on sets of equivalent items from Wechsler subtests were studied to determine if change in response occurred between pairwise combinations of occasions of test administrations. We used Bowker's test to analyze data at the item level to determine the direction of change in performance. Consistent improvement in performance occurred between the ages of 18-40 and 18-54. Between the ages of 40 and 61, results showed mostly improved performance on the Information, Comprehension, and Vocabulary subtests, mixed change on the Picture Completion subtest, and decline on the Digit Symbol and Block Design subtests. The pattern of mixed change on the Picture Completion subtest indicated improvement on the easy items and decline on the difficult items. Decline in performance on the Block Design test occurred only for the most difficult items.     

WISC-R subtest but no overall VIQ-PIQ difference in Dutch children with PDD-NOS

VIQ-PIQ differences have been studied in children with autism and Asperger syndrome but have not been studied in a separate group of children with PDD-NO, although, PDD-NOS has a much higher prevalence rate than autism and deficits in communication and social interaction are severe. The Wechsler Intelligence Scale for Children-Revised (WISC-R) was administered to 100 children, aged 6-12 years, with PDD-NOS (n = 76), autism (n = 13), and Asperger syndrome (n = 11). PDD-NOS was diagnosed using explicit research criteria. No overall differences between VIQ and PIQ were found in PDD-NOS and autism. Peaks in the subtest scores on Information, Similarities, Picture Arrangement, and Mazes, and troughs in the subtest scores on Comprehension, Digit Span, and Coding were demonstrated in children with PDD-NOS. Their score on the Freedom from Distractibility factor was lower than the scores on the Verbal Comprehension factor and the Perceptual Organization factor. Children with PDD-NOS seemed to have a similar VIQ-PIQ profile as children with autism, and on the subtest level children with PDD-NOS showed some similarities to children with Asperger syndrome or autism. It was not possible to distinguish PDD-NOS from autism or Asperger syndrome by using IQ scores.     

Aging and vocabulary scores: a meta-analysis

Vocabulary scores were examined in a total of 210 articles, containing 324 independent pairings of younger and older adults, from the 1986-2001 issues of Psychology and Aging. The average effect size, favoring the old, was 0.80 SD. Production tests yielded smaller effects (0.68 SD) than multiple-choice tests (0.93 SD). Both age and education were found to be partially independent determinants of performance in production tests; age effects disappeared in multiple-choice tests as soon as education was taken into account. In addition, the Wechsler Adult Intelligence Scale--Revised Vocabulary subtest (D. Wechsler, 1981) was also found to be sensitive to the Flynn effect (J. R. Flynn, 1987; i.e., increasing test scores with advancing birth year). The results question the approach of using age-group equality in vocabulary scores as a check on sample equivalence.     

Social perception and WAIS-IV Performance in adolescents and adults diagnosed with Asperger's Syndrome and Autism

Previous research using the Wechsler scales has identified areas of cognitive weaknesses in children, adolescents, and adults diagnosed with Autism or Asperger's syndrome. The current study evaluates cognitive functioning in adolescents and adults diagnosed with Autism or Asperger's syndrome using the Wechsler Adult Intelligence Scale-Fourth Edition (WAIS-IV) and the Social Perception subtest from the Advanced Clinical Solutions. Deficits in social perception, verbal comprehension, and processing speed were found in the Autism sample. Additionally, they exhibited inconsistent performance on auditory working memory and perceptual reasoning tasks. The Asperger's syndrome group had better overall cognitive skills than the Autism group, but compared with controls, they had weaknesses in processing speed, social perception, and components of auditory working memory. Both groups had relatively low scores on the WAIS-IV Comprehension subtest compared with the other verbal comprehension subtests. Clinical application and utility of the WAIS-IV and Social Perception in Autism Spectrum Disorders are discussed.     

Factor structure and sex differences on the Wechsler Preschool and Primary Scale of Intelligence in China, Japan and United States

This study presents data on the factor structure of the Wechsler Preschool and Primary Scale of Intelligence (WPPSI) and sex and cultural differences in WPPSI test scores among 5- and 6-year-olds from China, Japan, and the United States. Results show the presence of a verbal and nonverbal factor structure across all three countries. Sex differences on the 10 subtests were generally consistent, with a male advantage on a subtest of spatial abilities (Mazes). Males in the Chinese sample obtained significantly higher Full Scale IQ scores than females and had lower variability in their test scores. These observations were not present in the Japan and United States samples. Mean Full Scale IQ score in the Chinese sample was 104.1, representing a 4-point increase from 1988 to 2004.     

WISC-R Subtest But No Overall VIQ–PIQ Difference in Dutch Children with PDD-NOS

VIQ–PIQ differences have been studied in children with autism and Asperger syndrome but have not been studied in a separate group of children with PDD-NO, although, PDD-NOS has a much higher prevalence rate than autism and deficits in communication and social interaction are severe. The Wechsler Intelligence Scale for Children-Revised (WISC-R) was administered to 100 children, aged 6–12 years, with PDD-NOS (n = 76), autism (n = 13), and Asperger syndrome (n = 11). PDD-NOS was diagnosed using explicit research criteria. No overall differences between VIQ and PIQ were found in PDD-NOS and autism. Peaks in the subtest scores on Information, Similarities, Picture Arrangement, and Mazes, and troughs in the subtest scores on Comprehension, Digit Span, and Coding were demonstrated in children with PDD-NOS. Their score on the Freedom from Distractibility factor was lower than the scores on the Verbal Comprehension factor and the Perceptual Organization factor. Children with PDD-NOS seemed to have a similar VIQ–PIQ profile as children with autism, and on the subtest level children with PDD-NOS showed some similarities to children with Asperger syndrome or autism. It was not possible to distinguish PDD-NOS from autism or Asperger syndrome by using IQ scores.     

Abbreviated form of the Wechsler Memory Scale-III Faces subtest

A major criticism of the Wechsler Memory Scale-III Faces subtest is the number of items, which can be daunting and time-consuming for an impaired client or boring for a normal client. An analysis of several versions, with data from a sample of 50 clinical referrals, revealed that a 32-item subtest was best overall. Using this version, 100% (Faces I) and 94% (Faces II) of the predicted raw scores were less than 4 points away from the actual raw scores, whereas 66% (Faces I) and 70% (Faces II) were less than 2 points away. Limitations of this procedure are discussed.