Executive functions among youth with Down Syndrome and co-existing neurobehavioural disorders.

BACKGROUND: Executive function (EF) deficits are a recognised component of the cognitive phenotype of youth with Down Syndrome (DS). Recent research in this area emphasises the use of behaviour ratings, such as the Behavior Rating Inventory of Executive Functions-Preschool Version (BRIEF-P), to capture the real-world applications of executive functions. To account for the intellectual functioning of youth with DS, this measure is used out of age range; however, its psychometric properties when used in this fashion are unknown. The goals of this study are to evaluate psychometric characteristics of the BRIEF-P among youth with DS and to examine the pattern of EF strengths/weaknesses in children with DS and co-occurring psychiatric conditions. METHOD: A total of 188 clinically referred youth with DS, ages 3-13 were rated by their caregivers using the BRIEF-P. These youth were evaluated by a clinician with expertise in DS and were characterised as having no co-occurring behavioural disorder (Typical DS group), co-occurring Autism Spectrum Disorder (DS + ASD) or co-occurring Disruptive Behaviour Disorder (DS + DBD). RESULTS: An exploratory factor analysis of item-level BRIEF-P data from clinically referred youth with DS supported the theoretically derived three-factor structure originally proposed for the BRIEF-P (Emergent Metacognition, Flexibility and Inhibitory Self-Control); however, the item composition of each factor varied somewhat in comparison to the original structure of the measure. Group comparisons indicate that, while youth with typical DS evidence fewer executive function difficulties across all domains, youth with DS + ASD show the greatest weaknesses in Emergent Metacognition, and youth with DS + DBD show significant difficulties in both Emergent Metacognition and Inhibition. CONCLUSIONS: These findings offer preliminary support for use of the BRIEF-P with clinically referred youth with Down Syndrome. Some scoring modifications may be necessary if the theoretically derived index scores are to be used with this population. BRIEF-P scores may offer an empirical basis for differentiating DS youth with varying behavioural profiles.

Autism spectrum disorder in Down syndrome: cluster analysis of Aberrant Behaviour Checklist data supports diagnosis.

BACKGROUND: The diagnostic validity of autism spectrum disorder (ASD) based on Diagnostic and Statistical Manual of Mental Disorders (DSM) has been challenged in Down syndrome (DS), because of the high prevalence of cognitive impairments in this population. Therefore, we attempted to validate DSM-based diagnoses via an unbiased categorisation of participants with a DSM-independent behavioural instrument. METHODS: Based on scores on the Aberrant Behaviour Checklist - Community, we performed sequential factor (four DS-relevant factors: Autism-Like Behaviour, Disruptive Behaviour, Hyperactivity, Self-Injury) and cluster analyses on a 293-participant paediatric DS clinic cohort. The four resulting clusters were compared with DSM-delineated groups: DS + ASD, DS + None (no DSM diagnosis), DS + DBD (disruptive behaviour disorder) and DS + SMD (stereotypic movement disorder), the latter two as comparison groups. RESULTS: Two clusters were identified with DS + ASD: Cluster 1 (35.1%) with higher disruptive behaviour and Cluster 4 (48.2%) with more severe autistic behaviour and higher percentage of late onset ASD. The majority of participants in DS + None (71.9%) and DS + DBD (87.5%) were classified into Cluster 2 and 3, respectively, while participants in DS + SMD were relatively evenly distributed throughout the four clusters. CONCLUSIONS: Our unbiased, DSM-independent analyses, using a rating scale specifically designed for individuals with severe intellectual disability, demonstrated that DSM-based criteria of ASD are applicable to DS individuals despite their cognitive impairments. Two DS + ASD clusters were identified and supported the existence of at least two subtypes of ASD in DS, which deserve further characterisation. Despite the prominence of stereotypic behaviour in DS, the SMD diagnosis was not identified by cluster analysis, suggesting that high-level stereotypy is distributed throughout DS. Further supporting DSM diagnoses, typically behaving DS participants were easily distinguished as a group from those with maladaptive behaviours.

Neuroanatomy of Down's syndrome: a high-resolution MRI study.

OBJECTIVE: Down's syndrome, the most common genetic cause of mental retardation, results in characteristic physical and neuropsychological findings, including mental retardation and deficits in language and memory. This study was undertaken to confirm previously reported abnormalities of regional brain volumes in Down's syndrome by using high-resolution magnetic resonance imaging (MRI), determine whether these volumetric abnormalities are present from childhood, and consider the relationship between neuroanatomic abnormalities and the cognitive profile of Down's syndrome. METHOD: Sixteen children and young adults with Down's syndrome (age range=5-23 years) were matched for age and gender with 15 normal comparison subjects. High-resolution MRI scans were quantitatively analyzed for measures of overall and regional brain volumes and by tissue composition. RESULTS: Consistent with prior imaging studies, subjects with Down's syndrome had smaller overall brain volumes, with disproportionately smaller cerebellar volumes and relatively larger subcortical gray matter volumes. Also noted was relative preservation of parietal lobe gray and temporal lobe white matter in subjects with Down's syndrome versus comparison subjects. No abnormalities in pattern of brain asymmetry were noted in Down's syndrome subjects. CONCLUSIONS: The results largely confirm findings of previous studies with respect to overall patterns of brain volumes in Down's syndrome and also provide new evidence for abnormal volumes of specific regional tissue components. The presence of these abnormalities from an early age suggests that fetal or early postnatal developmental differences may underlie the observed pattern of neuroanatomic abnormalities and contribute to the specific cognitive and developmental deficits seen in individuals with Down's syndrome.

Amygdala and hippocampal volumes in children with Down syndrome: a high-resolution MRI study.

The objective of this study was to use high-resolution MRI techniques to determine whether children with Down syndrome exhibit decreases in hippocampal and amygdala volumes similar to those demonstrated in recent studies of adults with this condition. When corrected for overall brain volumes, amygdala volumes did not differ between groups but hippocampal volumes were significantly smaller in the Down syndrome group. These findings suggest that the hippocampal volume reduction seen in adults with Down syndrome may be primarily due to early developmental differences rather than neurodegenerative changes.

Down syndrome: advances in molecular biology and the neurosciences.

The entire DNA sequence for human chromosome 21 is now complete, and it is predicted to contain only about 225 genes, which is approximately three-fold fewer than the number initially predicted just 10 years ago. Despite this remarkable achievement, very little is known about the mechanism(s) whereby increased gene copy number (gene dosage) results in the characteristic phenotype of Down syndrome. Although many of the phenotypic traits show large individual variation, neuromotor dysfunction and cognitive and language impairment are observed in virtually all individuals. Currently, there are no efficacious biomedical treatments for these central nervous system-associated impairments. To develop novel therapeutic strategies, the effects of gene dosage imbalance need to be understood within the framework of those critical biological events that regulate brain organization and function.

Behavior problems of children with Down syndrome and life events.

Behavior problems of 44 children with Down syndrome between the ages of 6 and 15 and 44 controls without mental retardation matched for age, sex, and socioeconomic status were compared on the basis of mother and teacher ratings. Ratings from both sources indicated that children with Down syndrome had more behavior problems, in particular attention deficit, noncompliance, thought disorder, and social withdrawal. Life events from the past year were significantly associated with mother but not teacher ratings of Down syndrome behavior problems.

Familial tandem duplication of bands q31.1 to q32.3 on chromosome 4 with mild phenotypic effect.

We describe a family carrying a direct duplication of an interstitial segment of the distal long arm of chromosome 4(q31.1q32.3) with a mild clinical phenotype. Affected family members include a 27-year-old woman and 2 of her 4 children, 1 of whom also has Klinefelter syndrome. Although 8 cases of simple duplications or insertions of 4q material have been described, only 3 include bands q31-q32, and these involve additional adjacent material. Affected members of the pedigree reported here have some of the manifestations of previously described cases of duplication 4q, but are less severely affected, suggesting that the genetic material in this region is well tolerated as a partial trisomy.

Developmental expression of the gene encoding growth-associated protein 43 (Gap43) in the brains of normal and aneuploid mice.

The gene encoding growth-associated protein 43 (Gap43), a neuronal phosphoprotein associated with axonal outgrowth and synaptic plasticity, is located on mouse chromosome 16 (MMU16). We examined the developmental expression of Gap43 in normal, trisomy 16 (Ts16), and trisomy 19 (Ts19) mouse brain using northern blot analysis and in situ hybridization as a first step toward understanding the neurobiologic consequences of increased gene dosage on brain development. Gap43 expression was detected by in situ hybridization throughout the mesencephalon, rhombencephalon, spinal cord, and first branchial arch in whole embryos as early as day 10 of gestation (E10). By E15, Gap43 expression was localized to cells in the retina, the olfactory bulbs, and anterior olfactory structures, the cortical plate, the basal telencephalon, diencephalon, midbrain, hindbrain, and spinal cord. Northern blot analysis detected a three-fold increase in Gap43 mRNA levels in the brains of normal mice between E12-E18. At E15, Gap43 mRNA levels were increased 35-40% in Ts16 mouse brain and decreased 10% in Ts19 mouse brain, relative to euploid littermate controls. Using in situ hybridization we found that overexpression of Gap43 occurred in the diencephalon, medial and lateral basal telencephalon, and cortical plate region in Ts16 mice relative to littermate controls. Thus, the degree of overexpression of Gap43 mRNA in Ts16 mice is consistent with that expected from gene dosage effects.

Dual control of cell growth by somatomedins and platelet-derived growth factor.

Quiescent BALB/c 3T3 cells exposed briefly to a platelet-derived growth factor (PDGF) become "competent" to replicate their DNA but do not "progress" into S phase unless incubated with growth factors contained in platelet-poor plasma. Plasma from hypophysectomized rats is deficient in progression activity; it does not stimulate PDGF-treated competent cells to synthesize DNA, demonstrating that somatomedin C is required for progression. Various growth factors were tested for progression activity and competence activity by using BALB/c 3T3 tissue culture assays. Multiplication stimulating activity and other members of the somatomedin family of growth factors are (like somatomedin C) potent mediators of progression. Other mitogenic agents, such as fibroblast growth factor, are (like PDGF) potent inducers of competence. Growth factors with potent progression activity have little or no competence activity and vice versa. In contrast, simian virus 40 provides both competence and progression activity. Coordinate control of BALB/c 3T3 cell growth in vitro by competence factors and somatomedins may be a specific example of a common pattern of growth regulation in animal tissues.