Hypoxia and Inflammation in Children with Sickle Cell Disease: Implications for Hippocampal Functioning and Episodic Memory

Children with sickle cell disease (SCD) suffer from systemic processes (e.g., chronic anemia, recurrent hypoxic-ischemic events, chronic inflammation) that have been associated with neurocognitive impairment in a range of clinical populations, but which have been largely understudied in relation to specific domains of cognitive functioning in children with SCD. This review focuses on episodic memory, as the hippocampus may be especially vulnerable to the systemic processes associated with SCD. The first part of the paper outlines the pathophysiology of SCD and briefly reviews the extant literature on academic and cognitive functioning in children with SCD, emphasizing the dearth of research on episodic memory. Next, the complex systemic processes of hypoxia and inflammation associated with SCD are reviewed, along with research that has associated these processes with hippocampal damage and memory impairment. The paper concludes with suggestions for future research that are informed, in part, by the literature on developmental amnesia.     

Neurocognitive Complications of HIV Disease

Neurocognitive complications are the most common sequelae of HIV infection if the full spectrum of HIV disease—from initial seroconversion to death from advanced AIDS—is considered. Though resembling subcortical neurological disorders from a neuropsychological standpoint, the presentation is variable, and almost any pattern can be seen. Although neuropsychological impairment is often subtle, it can affect day-to-day life and is associated with earlier mortality. It is not clear if milder forms of neurocognitive disturbance necessarily presage advanced dementia, and current data suggest a two-factor model: a subacute relapsing-remitting condition that can occur at any stage of HIV disease and a progressive, more fulminant dementia. The pathological substrates of these conditions are not well characterized, although recent data support the notion that synaptodendritic damage underlies the neuropsychological impairment, and may precede the neuronal loss and other pathological features more characteristic of HIV encephalitis. Some reversibility of neurocognitive disturbance has been reported with zidovudine therapy, though the data are not consistent. New regimens involving protease inhibitors need to be evaluated in terms of benefit to the central nervous system because many drugs of this class do not penetrate the blood-brain barrier efficiently. Finally, studies utilizing experimental treatments that may affect the putative mechanisms of neural injury are in progress.     

Sickle cell disease as a neurodevelopmental disorder

Sickle cell disease (SCD) is a blood disorder; however, the central nervous system (CNS) is one of the organs frequently affected by the disease. Brain disease can begin early in life and often leads to neurocognitive dysfunction. Approximately one-fourth to one-third of children with SCD have some form of CNS effects from the disease, which typically manifest as deficits in specific cognitive domains and academic difficulties. We discuss SCD as a neurodevelopmental disorder by reviewing the mechanisms of neurological morbidity in SCD, the timing of these mechanisms, the types of cognitive and behavioral morbidity that is typical, and the interaction of social-environmental context with disease processes. The impact of the disease on families shares many features similar to other neurodevelopmental disorders; however, social-environmental factors related to low socioeconomic status, worry and concerns about social stigma, and recurrent, unpredictable medical complications can be sources of relatively higher stress in SCD. Greater public awareness of the neurocognitive effects of SCD and their impact on child outcomes is a critical step toward improved treatment, adaptation to illness, and quality of life.     

Executive functioning and health-related quality of life in pediatric sickle cell disease

Research consistently indicates that children with sickle cell disease (SCD) face multiple risk factors for neurocognitive impairment. Despite this, no empirical research to date has examined the impact of neurocognitive functioning on quality of life for this pediatric group. Thus, the current study aims to examine the relationship between executive functioning and quality of life in a sample of children with SCD and further explore psychosocial and family/caregiver resources as moderators of this relationship. A total of 45 children with SCD aged 8 to 16 years and their caregivers completed measures of quality of life, behavioral ratings of executive functioning, and psychosocial functioning. Hierarchical linear regression models were utilized to determine the impact of executive functioning on quality of life and further test the interaction effects of proposed moderating variables. Controlling for age, pain, and socioeconomic status (SES), executive functioning was found to significantly predict child- and parent-reported quality of life among youth with SCD. Psychosocial resources of the primary caregiver or family was not found to moderate the relationship between executive functioning and quality of life. These results provide the first empirical evidence that lower executive skills negatively predict quality of life for children with SCD, supporting clinical and research efforts which aim to establish efficacious interventions that target cognitive decrements within this pediatric population.     

Cognitive deficits related to major organ failure: The potential role of neuropsychological testing

Until recently, little attention has been paid to the possibility of cognitive deficits in patients with disease or failure of major organs such as the liver, kidney, or heart. However, there is a growing awareness that major organ failure often has neuropsychological sequelae. These sequelae may at times be quite subtle and not detectable under gross. examination. Nevertheless, even subtle deficits may have a major impact on adherence to medical regimens, psychosocial adjustment, and quality of life of patients. Neuropsychological assessment has a potentially valuable role to play both in research and in clinical work. It can be useful in adding to our knowledge of the cognitive effects of various types, severity and duration of major organ disease, as well as sequelae associated with treatment. It also is a potentially valuable clinical tool for identifying cognitive deficits that will affect the quality of life and probability of survival for organ failure patients.     

Health-Related Quality of Life and Adaptive Behaviors of Adolescents with Sickle Cell Disease: Stress Processing Moderators

The objective of this study was to examine resilience among adolescents with sickle cell disease (SCD), focusing on the interaction of health-related quality of life with stress processing to explain adaptive behavior. Forty-four adolescents with SCD completed paper-and-pencil measures of health-related quality of life, appraisals (hope), pain coping strategies (e.g. adherence), and adaptive behavior. Self-reported health-related quality of life was significantly associated with adaptive behavior, as was adherence. Findings for moderation were mixed. Pain coping strategies moderated the association of health-related quality of life with adaptive behavior such that at lower levels of Coping Strategies Questionnaire (CSQ) Adherence, better quality of life was associated with higher adaptive behavior. Similarly, at higher levels of hope, better quality of life was associated with higher adaptive behavior, and poorer quality of life was associated with lower adaptive behavior. Adolescents with SCD showed resilience, particularly in terms of personal adjustment, that may be explained by their appraisals and stress processing strategies. Interventions to support an optimistic or hopeful outlook and improve adherence to recommendations for medical management of sickle cell pain may result in improved resilience/adaptive behavior.     

Physiological correlates of intellectual function in children with sickle cell disease: hypoxaemia, hyperaemia and brain infarction

Lowered intelligence relative to controls is evident by mid-childhood in children with sickle cell disease. There is consensus that brain infarct contributes to this deficit, but the subtle lowering of IQ in children with normal MRI scans might be accounted for by chronic systemic complications leading to insufficient oxygen delivery to the brain. We investigated the relationship between daytime oxyhaemoglobin saturation (SpO2), cerebral blood flow velocity (CBFV) and intellectual function (IQ) using path-analysis in 30 adolescents with sickle cell disease (mean age 17.4 years, SD 4.2). Initial analyses revealed that the association between SpO2 and Full Scale IQ (FSIQ) was fully mediated by increased CBFV, whereby SpO2 was negatively correlated with CBFV and CBFV was negatively correlated with FSIQ, i.e. decreases in oxygen saturation are associated with increases in velocity, and increased velocity is associated with lowered IQ scores. The mediated relationship suggests that lowered IQ may be a function of abnormal oxygen delivery to the brain. Further analyses showed that the association between CBFV and IQ was significant for verbal but not for performance IQ. The pathophysiology characteristic of SCD can interfere with brain function and constrain intellectual development, even in the absence of an infarct. This supports the hypothesis that lowered intellectual function is partly explained by chronic hypoxia, and has wider implications for our understanding of SCD pathophysiology.     

Young adult female fragile X premutation carriers show age- and genetically-modulated cognitive impairments

The high frequency of the fragile X premutation in the general population and its emerging neurocognitive implications highlight the need to investigate the effects of the premutation on lifespan cognitive development. Until recently, cognitive function in fragile X premutation carriers (fXPCs) was presumed to be unaffected by the mutation. Here we show that young adult female fXPCs show subtle, yet significant, age- and FMR1 gene mutation-modulated cognitive impairments as tested by a quantitative magnitude comparison task. Our results begin to define the neurocognitive endophenotype associated with the premutation in adults, who are at risk for developing a neurodegenerative disorder associated with the fragile X premutation. Results from the present study may potentially be applied toward the design of early interventions wherein we might be able to target premutation carriers most at risk for degeneration for preventive treatment.     

Brief report: Neurocognitive functioning in adolescents following childhood maltreatment and evidence for underlying planning & organizational deficits

Children and adolescents with a history of childhood maltreatment are at risk for a host of psychiatric conditions, although the underlying neurocognitive functioning of these individuals remains largely understudied. This study examined the neurocognitive functioning of childhood maltreatment victims in an adolescent psychiatric inpatient setting. The sample consisted of adolescent inpatients (ages 13–19) that completed intellectual testing as part of a neuropsychological/psychological assessment during hospitalization (n = 39). The sample was grouped based on childhood maltreatment history with one group categorized by maltreatment history (n = 15) and the other group characterized by no maltreatment history (n = 24). Analyses revealed statistically significant differences (p < .01) between maltreatment groups on the majority of assessed domains. When controlling for intelligence, only performance differences on the RCFT remained. RCFT differences remained after controlling for the influence of visual-motor and visual-perceptual/visual-spatial functioning, highlighting the influence of organizational and planning difficulties in those individuals with maltreatment history. Group differences in the frequency of impaired performance for neuropsychological tasks were largest (p < .001) for FSIQ and RCFT. Compromised neurocognitive functioning may negatively contribute to the clinical presentation of this population, highlighting the importance of the child neuropsychologist in the effective treatment of children and adolescents with a history of childhood maltreatment.     

The impact of lesion laterality on neuropsychological change following posterior pallidotomy: a review of current findings

This paper reviews seven studies evaluating the impact of lesion laterality on the neuropsychological sequelae of posterior pallidotomy for treatment of Parkinson's disease. Left lesions of the internal globus pallidus (GPi) were associated with subtle deficits on measures sensitive to frontal lobe function. The findings of a randomized clinical trial including a patient control group indicated that many of these deficits were transient, resolving by 6 months following surgery. Right GPi lesions were not consistently associated with neuropsychological deficit, except in one study that included a significant proportion of demented patients. It is hypothesized that when neuropsychological decline is present following surgery, this reflects impingement of posterior GPi lesions into proximal regions such as anterior GPi or the external pallidum that participate in cognitive basal ganglia-thalamocortical circuits. The findings from neuroimaging will be important for elucidating the relationship between lesion locus and neuropsychological sequelae.     

Hypoxic adaptation during development: relation to pattern of neurological presentation and cognitive disability

Children with acute hypoxic-ischaemic events (e.g. stroke) and chronic neurological conditions associated with hypoxia frequently present to paediatric neurologists. Failure to adapt to hypoxia may be a common pathophysiological pathway linking a number of other conditions of childhood with cognitive deficit. There is evidence that congenital cardiac disease, asthma and sleep disordered breathing, for example, are associated with cognitive deficit, but little is known about the mechanism and whether there is any structural change. This review describes what is known about how the brain reacts and adapts to hypoxia, focusing on epilepsy and sickle cell disease (SCD). We prospectively recorded overnight oxyhaemoglobin saturation (SpO2) in 18 children with intractable epilepsy, six of whom were currently or recently in minor status (MS). Children with MS were more likely to have an abnormal sleep study defined as either mean baseline SpO2 <94% or >4 dips of >4% in SpO2/hour (p = .04). In our series of prospectively followed patients with SCD who subsequently developed acute neurological symptoms and signs, mean overnight SpO2 was lower in those with cerebrovascular disease on magnetic resonance angiography (Mann-Whitney, p = .01). Acute, intermittent and chronic hypoxia may have detrimental effects on the brain, the clinical manifestations perhaps depending on rapidity of presentation and prior exposure.     

The functional equivalence of mental images and errors of movement.

Four experiments are reported demonstrating that mental images are functionally equivalent to physical errors of movement in producing changes in visual-motor coordination, at both central and peripheral levels of the visual-motor system. In the first experiment, subjects in one condition pointed at a target seen through laterally displacing prisms and were instructed to imagine pointing errors identical to those recorded previously for subjects in a separate condition who actually observed their pointing errors. Changes in pointing accuracy during adaptation procedures and visual-motor aftereffects following these procedures for subjects who imagined their errors were proportional to visual-motor shifts and aftereffects for subjects who observed their errors. In the second experiment, these same imagery instructions resulted in identical pointing shifts and aftereffects even in the case where prisms did not displace the target. The third experiment showed that when subjects believe that their mental images of pointing errors do not correspond to their actual pointing errors, pointing aftereffects result that are characteristic of the processing of error information at peripheral, but not central, levels of the visual motor system. The final experiment showed that when subjects do believe that their images of pointing errors correspond to actual pointing errors, but imagine the pointing movement itself in addition to their errors, pointing aftereffects result that are characteristic of the processing of error information at central, but not peripheral, levels of the visual-motor system. Contributions to visual-motor aftereffects from these two levels appear to be additive. Another significant result was that, in the imagery feedback conditions of each experiment, subjects who gave high ratings of vividness to their mental imagery showed the greatest magnitude of pointing aftereffects. These findings establish that mental images for errors of movement can produce stable visual-motor changes that cannot be accounted for simply by subjects' expectations regarding the actual consequences of their actions.     

Neurocognitive and functional outcomes in persons recovering from West Nile virus illness

Long‐term neurocognitive and functional impairments following West Nile virus (WNV) disease are poorly understood. We assessed quality‐of‐life indices and neurocognitive performance in a cohort of 54 persons recovering from one of three WNV disease syndromes (fever [WNF], meningitis [WNM], or encephalitis [WNE]) approximately 1.5 years following acute illness. We compared findings between the three syndromic groups; the study cohort and a demographically similar group of 55 controls from a study of chronic fatigue syndrome (CFS); and the study cohort and a ‘normative’ control population based on cognitive test data. Persistent symptoms, diminished quality of life, and functional impairment were reported by 50% of WNF patients, and 75% each of WNM and WNE patients. Overall, objective neurocognitive performance did not differ significantly between the three syndromic groups, or between the study cohort and the CFS controls or the normative controls. In some neurocognitive subtests, the study cohort scored below the 15th percentile when compared with normative control data. Most persons who returned to independent living following hospitalization for WNV illness had persistent subjective complaints, but had normal cognitive function. However, a minority displayed subtle neurocognitive deficits more than 18 months following acute disease.     

Neurocognitive Manifestations of Human Immunodeficiency Virus

Is human immunodeficiency virus still a terminal condition? Recent advances in treatment have significantly reduced both mortality and morbidity associated with HIV, but these treatments have not been successful in eradicating the virus itself. As such, HIV has evolved into a chronic condition that is complicated by neurocognitive factors. Cognitive difficulties associated with HIV are characterized by a subcortical pattern with primary deficits in information processing speed and psychomotor speed. These deficits interfere with the ability of patients to complete important instrumental activities of daily living even in the absence of dementia. Treatment of HIV improves neurocognitive functioning, but the regimens are complex and patient adherence is critical. Cognitive factors can negatively impact treatment adherence, which in turn results in poorer immunological, cognitive, and psychiatric outcome. This cycle emphasizes the important interrelationships between symptom expression and treatment outcome in patients with HIV. The nature of these relationships will change with further developments in treatment regimens such as once-daily dosing. Less complex treatment approaches should improve health outcome as well as provide additional opportunities to further understand the impact of HIV on brain function.     

What Does Diffusion Tensor Imaging Reveal About the Brain and Cognition in Fetal Alcohol Spectrum Disorders?

Over the past 5 years, Diffusion Tensor Imaging (DTI) has begun to provide new evidence about the effects of prenatal alcohol exposure on white matter development. DTI, which examines microstructural tissue integrity, is sensitive to more subtle white matter abnormalities than traditional volumetric MRI methods. Thus far, the available DTI data suggest that white matter microstructural abnormalities fall on a continuum of severity in Fetal Alcohol Spectrum Disorder (FASD). Abnormalities are prominent in the corpus callosum, but also evident in major anterior-posterior fiber bundles, corticospinal tracts, and cerebellum. These subtle abnormalities are correlated with neurocognitive deficits, especially in processing speed, non-verbal ability, and executive functioning. Future studies using larger samples, increasingly sophisticated DTI methods, and additional functional MRI connectivity measures will better characterize the full range of abnormalities in FASD. Ultimately, these measures may serve as indices of change in future longitudinal studies and in studies of interventions for FASD.     

An analysis of neurological soft signs in children with learning problems

Eighty children with learning problems were systematically evaluated for neurological soft signs, general intelligence, scholastic achievement, hyperactivity, and neurocognitive dysfunction. A factor analysis yielded six factors, and a higher order, general ability factor was derived from an orthogonal rotation. Neurocognitive functions appeared in three factors suggesting “types” of dysfunctions. The higher order general ability factor represents a broad range of skills. The two other factors with neurocognitive loads suggest a distinction between verbal-motor integration and visual-motor integration. Age, sex, and hyperactivity formed the remaining clusters.     

不同编码对听写困难儿童字形记忆的促进效应

听写困难是一种发生率较高的儿童学习障碍现象。实验考察笔画语音编码和动作编码对听写困难儿童字形记忆水平的影响。结果发现, 笔画语音编码对听写困难儿童的字形记忆成绩没有明显影响, 但却明显促进了正常儿童的字形记忆成绩; 与之相对, 动作编码对正常儿童的字形记忆成绩没有明显影响, 但却明显促进了听写困难儿童的字形记忆成绩。上述现象, 既可能源于编码加工阶段, 也可能源于字形表征的提取阶段。     

Timed performance weaknesses on computerized tasks in pediatric brain tumor survivors: A comparison with sibling controls

With more children surviving a brain tumor, insight into the late effects of the disease and treatment is of high importance. This study focused on profiling the neurocognitive functions that might be affected after treatment for a pediatric brain tumor, using a broad battery of computerized tests. Predictors that may influence neurocognitive functioning were also investigated. A total of 82 pediatric brain tumor survivors (PBTSs) aged 8–18 years (M = 13.85, SD = 3.15, 49% males) with parent-reported neurocognitive complaints were compared to a control group of 43 siblings (age M = 14.27, SD = 2.44, 40% males) using linear mixed models. Neurocognitive performance was assessed using measures of attention, processing speed, memory, executive functioning, visuomotor integration (VMI), and intelligence. Tumor type, treatment, tumor location, hydrocephalus, gender, age at diagnosis, and time since diagnosis were entered into regression analyzes as predictors for neurocognitive functioning. The PBTSs showed slower processing speeds and lower intelligence (range effect sizes .71–.82, p < .001), as well as deficits in executive attention, short-term memory, executive functioning, and VMI (range effect sizes .40–.57, p < .05). Older age at assessment was associated with better neurocognitive functioning (B = .450, p < .001) and younger age at diagnosis was associated with lower intelligence (B = .328, p < .05). Medical risk factors, e.g., hydrocephalus, did not show an association with neurocognitive functioning. Late effects in PBTSs include a broad range of neurocognitive deficits. The results suggest that even PBTSs that were traditionally viewed as low risk for neurocognitive problems (e.g., surgery only, no hydrocephalus) may suffer from decreased neurocognitive functioning.     

Cognitive discernible factors between schizophrenia and schizoaffective disorder

BACKGROUND: Schizophrenia (SZ) and schizoaffective disorders (SA) are associated with cognitive deficits. Generally, a schizoaffective diagnosis is associated with better prognosis on the level of social integration. It is also well established that cognition is an important factor for good social outcome in schizophrenia. We hypothesized that, although patients suffering from SA share symptoms with SZ, they can be differentiated on the basis of neurocognitive function and that SA perform better in several domains. METHOD: Performances of two groups SA (N = 13) and SZ (N = 44) were compared on several visual-motor tasks using CANTAB [Motor Screening (MOT), Reaction Time (RTI), Paired Associates Learning Task (PAL), and Stockings of Cambridge items (SOC)]. The two groups were matched for symptom severity. ANOVA with repeated measures was employed to determine whether any difference in cognitive scores during a 2-year period was significantly related to the diagnostic status. RESULTS: A significant and durable difference was observed between SZ and SA on motor screening and explicit memory tests where SA performed better. CONCLUSION: Neurocognitive tests may be relevant for distinguishing schizoaffective from schizophrenia, chiefly via tests tapping into visuo-spatial and visuo-motor coordination abilities (e.g., paired associated learning and motor screening).