Jamie O. Edgin

The Neuropsychology of Down Syndrome: Evidence for Hippocampal Dysfunction

This study tested prefrontal and hippocampal functions in a sample of 28 school-aged (M = 14.7 years, SD = 2.7) individuals with Down syndrome (DS) compared with 28 (M = 4.9 years, SD = .75) typically developing children individually matched on mental age (MA). Both neuropsychological domains were tested with multiple behavioral measures. Benchmark measures of verbal and spatial function demonstrated that this DS sample was similar to others in the literature. The main finding was a significant Group x Domain interaction effect indicating differential hippocampal dysfunction in the group with DS. However, there was a moderate partial correlation (r = .54, controlling for chronological age) between hippocampal and prefrontal composite scores in the DS group, and both composites contributed unique variance to the prediction of MA and adaptive behavior in that group. In sum, these results indicate a particular weakness in hippocampal functions in DS in the context of overall cognitive dysfunction. It is interesting that these results are similar to what has been found in a mouse model of DS. Such a model will make it easier to understand the neurobiological mechanisms that lead to the development of hippocampal dysfunction in DS.

Executive functioning in preschool children born very preterm: Relationship with early white matter pathology

Despite evidence for executive dysfunction in school-aged preterm children, less is known about the early development of these difficulties or their underlying neuropathology. This study used prospective longitudinal data from a regional cohort of 88 very preterm and 98 full-term comparison children to examine the executive functioning (EF) of preschool children born very preterm. The relationship between the severity of neonatal cerebral white matter (WM) abnormalities on magnetic resonance imaging (MRI) at term equivalent and childrens EF at ages two and four years (corrected age) was examined. At age four, very preterm children with WM abnormalities performed less well than full-term children on the Detour Reaching Box, a measure of behavioral inhibition and cognitive flexibility, even after controlling for child IQ, SES, and medical background. Examination of patterns of EF performance between the ages of 2 and 4 years showed that the performance of all groups improved with age. However, very preterm children with mild and moderate-severe WM abnormalities were characterized by higher rates of consistent performance impairments. These findings support the presence of early and persistent executive difficulties in preschool children born very preterm, and highlight the importance of white matter pathology in the development of executive impairments.

Neuropsychological components of intellectual disability: the contributions of immediate, working, and associative memory

BACKGROUND Efficient memory functions are important to the development of cognitive and functional skills, allowing individuals to manipulate and store information. Theories of memory have suggested the presence of domain-specific (i.e. verbal and spatial) and general processing mechanisms across memory domains, including memory functions dependent on the prefrontal cortex (PFC) and the hippocampus. Comparison of individuals who have syndromes associated with striking contrasts in skills on verbal and spatial tasks [e.g. Down syndrome (DS) and Williams syndrome (WS)] allows us to test whether or not these dissociations may extend across cognitive domains, including PFC and hippocampal memory processes. METHODS The profile of memory function, including immediate memory (IM), working memory (WM) and associative memory (AM), was examined in a sample of adolescents and young adults with DS (n = 27) or WS (n = 28), from which closely CA- and IQ-matched samples of individuals with DS (n = 18) or WS (n = 18) were generated. Relations between memory functions and IQ and adaptive behaviour were also assessed in the larger sample. RESULTS Comparisons of the two matched groups indicated significant differences in verbal IM (DS < WS), spatial IM (DS > WS) and spatial and verbal AM (DS > WS), but no between-syndrome differences in WM. For individuals with DS, verbal IM was the most related to variation in IQ, and spatial AM related to adaptive behaviour. The pattern was clearly different for individuals with WS. Verbal and spatial AM were the most related to variation in IQ, and verbal WM related to adaptive behaviour. CONCLUSIONS These results suggest that individuals with these two syndromes have very different patterns of relative strengths and weaknesses on memory measures, which do not fully mirror verbal and spatial dissociations. Furthermore, different patterns of memory dysfunction relate to outcome in individuals with each syndrome.

Obstructive sleep apnea syndrome and cognition in Down syndrome

Good‐quality sleep is essential for normal learning and memory. Sleep fragmentation and disrupted sleep architecture are commonly observed throughout the lifespan of individuals with Down syndrome, a condition marked by cognitive deficits emerging within the first few months of life. While obstructive sleep apnea syndrome (OSAS) is known to contribute to the loss of sleep quality in Down syndrome, its relation to cognitive and behavioral impairment remains poorly understood.

Abnormal brain synchrony in Down Syndrome

Down Syndrome is the most common genetic cause for intellectual disability, yet the pathophysiology of cognitive impairment in Down Syndrome is unknown. We compared fMRI scans of 15 individuals with Down Syndrome to 14 typically developing control subjects while they viewed 50 min of cartoon video clips. There was widespread increased synchrony between brain regions, with only a small subset of strong, distant connections showing underconnectivity in Down Syndrome. Brain regions showing negative correlations were less anticorrelated and were among the most strongly affected connections in the brain. Increased correlation was observed between all of the distributed brain networks studied, with the strongest internetwork correlation in subjects with the lowest performance IQ. A functional parcellation of the brain showed simplified network structure in Down Syndrome organized by local connectivity. Despite increased interregional synchrony, intersubject correlation to the cartoon stimuli was lower in Down Syndrome, indicating that increased synchrony had a temporal pattern that was not in response to environmental stimuli, but idiosyncratic to each Down Syndrome subject. Short-range, increased synchrony was not observed in a comparison sample of 447 autism vs. 517 control subjects from the Autism Brain Imaging Exchange (ABIDE) collection of resting state fMRI data, and increased internetwork synchrony was only observed between the default mode and attentional networks in autism. These findings suggest immature development of connectivity in Down Syndrome with impaired ability to integrate information from distant brain regions into coherent distributed networks.

Parental report of sleep problems in Down syndrome

BACKGROUND Children with Down syndrome (DS) suffer from sleep problems, including sleep maintenance problems, as well as snoring, and other symptoms of disordered breathing. To examine sleep in DS, we gave parents a questionnaire assessing their childs sleep. MATERIALS AND METHODS The parents of 35 children with DS (mean age = 12.65 years, range = 7-18 years) completed the 33-item Childrens Sleep Habits Questionnaire. RESULTS Eighty-five per cent of our sample had sleep disturbance scores in the clinical range (mean = 48.63, SD = 7.15, range = 34-64). Our sample also had significantly elevated scores on the Bedtime Resistance, Sleep Anxiety, Night Wakings, Parasomnias, Sleep Disordered Breathing and Daytime Sleepiness subscales. CONCLUSIONS Children with DS are at risk for developing symptoms of sleep disordered breathing, and may have additional sleep problems that are unrelated to sleep disordered breathing.

The impact of sleep disruption on executive function in Down syndrome

The high prevalence of sleep disorders, particularly obstructive sleep apnea, is well established in children with Down syndrome. However, only a few studies have focused on older children and young adults in this population. Given the presence of sleep disorders and the early emergence of Alzheimers disease, more work is needed to examine the relationship between sleep and cognition in Down syndrome. Twenty-nine adolescents and young adults with Down syndrome participated in the present study. Parents reported on their sleep difficulties using a well-validated measure of sleep problems in intellectual disabilities. Based on theoretical models linking obstructive sleep apnea to prefrontal cortex dysfunction, we tested components of executive functions that have been shown to be impaired in previous studies of Down syndrome. First, results indicate that participants with Down syndrome with higher body mass index also had increased caregiver reports of sleep apnea symptoms. Individuals with high ratings of sleep disruption also showed greater difficulties with executive function. These results suggest that sleep disruption may place this set of functions at risk in young adults. Future work should examine if this risk may result in earlier onset of dementia or steeper decline with Alzheimers disease. Further, additional studies are needed to investigate the effect of exercise interventions and weight reduction on sleep disorders in this population.

Poor Sleep as a Precursor to Cognitive Decline in Down Syndrome : A Hypothesis

We propose that sleep disruption is a lever arm that influences how cognition emerges in development and then declines in response to Alzheimer disease in people with Down syndrome. Addressing sleep disruptions might be an overlooked way to improve cognitive outcomes in this population. This article is a contribution to a Special Issue on Down Syndrome curated by the editors of the Journal of Alzheimer’s Disease & Parkinsonism.

The extended trajectory of hippocampal development: Implications for early memory development and disorder.

Hippocampus has an extended developmental trajectory, with refinements occurring in the trisynaptic circuit until adolescence. While structural change should suggest a protracted course in behavior, some studies find evidence of precocious hippocampal development in the first postnatal year and continuity in memory processes beyond. However, a number of memory functions, including binding and relational inference, can be cortically supported. Evidence from the animal literature suggests that tasks often associated with hippocampus (visual paired comparison, binding of a visuomotor response) can be mediated by structures external to hippocampus. Thus, a complete examination of memory development will have to rule out cortex as a source of early memory competency. We propose that early memory must show properties associated with full function of the trisynaptic circuit to reflect “adult-like” memory function, mainly (1) rapid encoding of contextual details of overlapping patterns, and (2) retention of these details over sleep-dependent delays. A wealth of evidence suggests that these functions are not apparent until 18–24 months, with behavioral discontinuities reflecting shifts in the neural structures subserving memory beginning approximately at this point in development. We discuss the implications of these observations for theories of memory and for identifying and measuring memory function in populations with typical and atypical hippocampal function.

Human and mouse model cognitive phenotypes in Down syndrome: implications for assessment

The study of cognitive function in Down syndrome (DS) has advanced rapidly in the past decade. Mouse models have generated data regarding the neurological basis for the specific cognitive profile of DS (i.e., deficits in aspects of hippocampal, prefrontal, and cerebellar function) and have uncovered pharmacological treatments with the potential to affect this phenotype. Given this progress, the field is at a juncture in which we require assessments that may effectively translate the findings acquired in mouse models to humans with DS. In this chapter, we describe the cognitive profile of humans with DS and associated mouse models, discussing the ways in which we may merge these findings so as to more fully understand cognitive strengths and weaknesses in this population. New directions for approaches to cognitive assessment in mice and humans are discussed.