Sex differences in cognitive processing in children treated with CNS prophylaxis for acute lymphoblastic leukemia

Evaluated cognitive processing in 51 children (27 female, 24 male) who had been treated for acute lymphoblastic leukemia (ALL) with CNS prophylaxis (cranial radiation in combination with intrathecal chemotherapy) and were continuously disease-free for 5 to 12 years. The control group comprised 15 children treated for Wilm's tumor. Functions assessed included visuoperceptual skills, generation of organizational strategies, sensitivity to organizational structure, and attention. The ALL group showed performance deficits relative to the solid tumor controls in appreciating the organization inherent in complex visuospatial material and alertness, with females more severely affected than males. Sex differences favoring males on IQ and academic achievement were related to these cognitive processes.     

Processing speed, working memory, and IQ: a developmental model of cognitive deficits following cranial radiation therapy

IQ decrements following cranial radiation therapy (CRT) for acute lymphoblastic leukemia (ALL) are most apparent years after treatment. The authors examined a developmental model for delayed deficits by evaluating the relationship between processing speed, working memory, and IQ in long-term survivors of childhood ALL (n = 27) compared with demographically matched controls (n = 27). The ALL group treated with CRT showed deficits in IQ, working memory, and processing speed relative to controls. Differences in IQ between the CRT group and controls were mediated by differences in working memory. Processing speed did not fully account for the working memory deficit in the CRT group. Participants with ALL treated only with chemotherapy showed similar working memory and processing speed as matched controls. Data suggest that deficits in processing speed and working memory following CRT may underlie declines in IQ.     

Neuropsychological sequelae of central nervous system prophylaxis in survivors of childhood acute lymphoblastic leukemia

We assessed neuropsychologically 106 children with acute lymphoblastic leukemia (ALL) who had all received cranial irradiation for the prevention of central nervous system (CNS) leukemia 1-13 years previously. Children were assessed for adverse late effects of their therapy, using age-appropriate Wechsler measures of overall intellectual ability and supplementary tests. Forty-five siblings near in age to the patients were tested as controls. The patients who had had the most intensive central nervous system (CNS) prophylaxis were found to have a WISC-R Full Scale IQ 17 points lower than the sibling control group. Performance IQ was more affected than verbal IQ. The patients were more easily distracted and less able to concentrate. The severity of the aftereffects was related to younger age at the time of CNS prophylaxis and to a higher dose of cranial irradiation but not to time since CNS prophylaxis. CNS prophylaxis using a combination of cranial irradiation and intrathecal methotrexate has lowered the incidence of CNS relapse in childhood ALL but is associated with considerable long-term morbidity in survivors.     

Stability of computational deficits in math learning disability from second through fifth grades

This study utilized growth modeling to investigate the stability of two computational deficits that are strongly associated with math learning disability (MLD)-procedural deficits and fact fluency deficits. Math "deficit" was defined in two ways-having scores in the lower 10th percentile (MLD) and between the 11th and 25th percentiles (LA, low achieving). The longitudinal sample was composed of 214 children. Between the second and fifth grades, children who started at grade 2 with procedural deficits showed more rapid growth in procedural skills than typically achieving (TA) children. The procedural deficits group was able to narrow the initial gap in procedural skills and catch up with their normal peers. In contrast, children who started at grade 2 with fact fluency deficits showed the same growth in fact fluency skills as TA children. The fact fluency deficits group maintained their initial gap and was not able to catch up. This pattern of results held for both the MLD and LA criteria. Fact fluency deficits are more stable in the elementary years. Further results showed that fact fluency deficits may be associated with more pervasive and persistent cognitive deficits than procedural deficits. The fact fluency group showed persistent cognitive deficits in working memory, processing speed, and phonological processing, from grades 2-5. The group with procedural deficits at grade 2 showed persistent deficits in working memory and processing speed, but closed the gap in phonological skills. In addition, only the MLD procedural deficits group showed these cognitive deficits; the LA group was no different than the typical achievers. The present results support the hypothesis that fact fluency deficits and procedural deficits are dissociable and may represent distinct subgroups of MLD.     

Neuropsychological, neuroanatomical, and neurophysiological consequences of CNS chemotherapy for acute lymphoblastic leukemia.

Medical treatment for acute lymphoblastic leukemia (ALL) has improved survival rates to 70% for children currently diagnosed with this disease. Intrathecal (IT) chemotherapy replaced CNS radiation therapy (CRT) for those with a favorable diagnosis as research revealed cognitive deficits associated with CRT. The literature pertaining to the potential adverse intellectual and neurophysiological consequences of IT chemotherapy is reviewed. It is concluded that IT chemotherapy may not be a benign form of treatment, although its effects may be more subtle than those produced by CRT. Future studies implementing more comprehensive test batteries are needed to illuminate these deficits so that remediation may be possible for ALL survivors.     

Working Memory in Children With Neurocognitive Effects From Sickle Cell Disease: Contributions of the Central Executive and Processing Speed

Children with sickle cell disease (SCD) are at risk for working memory deficits due to multiple disease processes. We assessed working memory abilities and related functions in 32 school-age children with SCD and 85 matched comparison children using Baddeley’s working memory model as a framework. Children with SCD performed worse than controls for working memory, central executive function, and processing/rehearsal speed. Central executive function was found to mediate the relationship between SCD status and working memory, but processing speed did not. Cognitive remediation strategies that focus on central executive processes may be important for remediating working memory deficits in SCD.     

Cognitive status of children treated with central nervous system prophylactic chemotherapy for acute lymphocytic leukemia.

Treatment-related cognitive impairments have been reported for survivors of childhood leukemia following prophylactic central nervous system (CNS) treatment with craniospinal radiation. We examined the neurocognitive status of 46 children with acute lymphocytic leukemia (ALL) to assess the impact of a regimen consisting of systemic chemotherapy and prophylactic CNS chemotherapy. By comparing three groups of ALL children (i.e., patients whose diagnosis was recent, patients 1 year postdiagnosis currently receiving CNS prophylactic chemotherapy, and off-therapy patients who had been treated with chemotherapy for 3 years) and their healthy siblings on measures of sequential and simultaneous processing, we were able to examine the effects of CNS prophylactic and systemic chemotherapy at various points during treatment. Results indicate that the children who had received a 3-year course of chemotherapy (off-therapy patients) were more impaired on tasks involving right-hemisphere simultaneous processing than were sibling controls or ALL children whose diagnosis was recent and whose treatment had just begun. Age at diagnosis did not interact with the effects of chemotherapy. These findings support the need for continued evaluation of cognitive functioning in ALL, children receiving CNS prophylactic chemotherapy to identify potential harmful neurocognitive sequelae of treatment.     

Cognitive Development in School-Age Children With Vertically Transmitted HIV Infection

We examined a broad range of neuropsychological functioning in school-age children with vertically transmitted HIV infection and a control group made up of siblings of children with HIV infection. Fourteen children with HIV (2 asymptomatic, 8 mildly symptomatic, and 4 with AIDS) and 11 control children were administered a battery of neuropsychological tests assessing intelligence, receptive language, expressive language, visual and verbal memory, visual-motor speed and coordination, visual-motor and visual-spatial processing, fine motor skill, and academic achievement. Results revealed that school-age children with vertically transmitted HIV infection show many areas of cognitive function within the normal range. Despite normal cognitive development, subtle motor impairments were documented in children with vertically transmitted HIV infection. Our results are the first report of fine motor and motor strength deficits in school-age children with vertically transmitted HIV. Lastly, computed tomography (CT) results suggest that children with HIV who have documented structural anomalies in the brain may be at risk for deficits in visual-motor and visual-spatial processing. This finding should be explored with larger samples and other measures to determine its generalizability.     

Cognitive development in school-age children with vertically transmitted HIV infection

We examined a broad range of neuropsychological functioning in school-age children with vertically transmitted HIV infection and a control group made up of siblings of children with HIV infection. Fourteen children with HIV (2 asymptomatic, 8 mildly symptomatic, and 4 with AIDS) and 11 control children were administered a battery of neuropsychological tests assessing intelligence, receptive language, expressive language, visual and verbal memory, visual-motor speed and coordination, visual-motor and visual-spatial processing, fine motor skill, and academic achievement. Results revealed that school-age children with vertically transmitted HIV infection show many areas of cognitive function within the normal range. Despite normal cognitive development, subtle motor impairments were documented in children with vertically transmitted HIV infection. Our results are the first report of fine motor and motor strength deficits in school-age children with vertically transmitted HIV. Lastly, computed tomography (CT) results suggest that children with HIV who have documented structural anomalies in the brain may be at risk for deficits in visual-motor and visual-spatial processing. This finding should be explored with larger samples and other measures to determine its generalizability.     

Electrophysiological Signs of Neurocognitive Deficits in Long-Term Leukemia Survivors

The long-term effects of disease and treatment on electrophysiologicalmeasures of neurocognitive function were studied in childrenwho had survived acute lymphoblastic leukemia (ALL) for at least4 years and were currently in remission. We report here changesin cognitive processing time as shown by the latency of theP3 wave of the auditory event-related EEG potential (ERP). P3latency was significantly prolonged in long-term ALL surivors,as well as in patients successfully trreated for solid tumors(ST)outside the CNS who received similar chemotherapy but did notreceive prophylactic treatment to the CNS. P3 latencies werestrongly correlated with measures of school performance andIQ in these individuals. The similarity in P3 latency betweenthe ALL and ST groups suggests that the treatments used on thesepateints produce changes in electrophysiological responses thatare associated with mild, but significant, cognitive deficits.     

Cognitive functioning in young and middle-aged unmedicated out-patients with major depression: testing the effort and cognitive speed hypotheses

BACKGROUND: Cognitive deficits are common in major depressive disorder, but their nature is unclear. The effort hypothesis states that performance on effortful tasks is disproportionately impaired compared with the performance on automatic tasks. The cognitive speed hypothesis states that depression is characterized by cognitive slowness, which is a source of cognitive dysfunctioning. The present study investigated both theories in unmedicated adult depressive patients. It was also investigated whether the cognitive deficits can be attributed to more general physical illness-related factors or specifically to depressive disorder. METHOD: Thirty non-psychotic depressive out-patients were compared with 38 healthy control subjects and 25 patients with severe allergic rhinitis. The effects of group on more automatic and more effortful aspects of cognitive tasks measuring cognitive speed (Concept Shifting Task, Stroop Colour Word Test, Memory Scanning Test) and memory retrieval (Visual Verbal Learning Task, Verbal Fluency Test) were evaluated by MANCOVA. Age, sex, education and pre-morbid intelligence were treated as covariates. RESULTS: The depressive group had cognitive deficits in the automatic processing subtask of the Stroop, memory scanning and memory span. Performance on more effortful tasks was not impaired. CONCLUSIONS: Our results are more consistent with the cognitive speed hypothesis. Cognitive functioning in depressive disorder seems to be characterized by a reduced speed of information processing in automatic subtasks.     

Short-term memory in children with sickle cell disease: Executive versus modality-specific processing deficits

Prior research has identified a number of areas of cognitive deficit among children with sickle cell disease (SCD), including decrements in memory span and working memory. The present study examined short-term memory span and working memory performance among children with SCD (n = 25) and demographically matched comparison children (n = 25) using digit span, spatial span, and the self-ordered pointing test. Children with SCD showed difficulties only for digit span-backward. Additional cognitive ability measures administered indicated auditory processing was an area of deficit related to digit span-backward performance. The study suggests that modality specific deficits are one factor in short-term memory span for children with SCD. The cause of this deficit is unclear, but may involve both central and peripheral components of auditory processing.     

Visual and Verbal Short-Term Memory Deficits in Childhood Leukemia Survivors After Intrathecal Chemotheraphy

Assessed survivors of childhood lymphoblastic leukemia (ALL)treated with intrathecal chemotherapy, using the Wide RangeAssessment of Memory and Learning (WRAML), compared to controlswithout cancer, matched as closely as possible-in age, SES,and gender. Mild, but consistent, deficits were found in bothvisual-spatial and verbal single-trial memory tasks. In multitriallearning, only visual-spatial tasks resulted in deficient scores,while verbal learning was within the normal range. IQ resultsindicated scores 10–20 points lower in the ALL group.Memory results are related to deficits in strategic planningand attentional distractiveness. The WRAML may be a useful clinicaltool to evaluate differential memory deficits in children withALL.     

Executive Function and Theory of Mind in 2 Year Olds: A Family Affair?

This study aimed to enhance our understanding of neuropsychological functioning in children with early-treated phenylketonuria (PKU) and assess the relative impact of white matter abnormalities (WMA) and neurotransmitter deficiencies on cognitive functions in this population. The study consisted of 33 children with early-treated PKU and 34 healthy control children aged between 7 to 18 years. All children had a neuropsychological evaluation that included measures of general intelligence, attention, processing speed, memory and learning, executive function, and academic achievement. Children in the PKU group also had a magnetic resonance (MR) brain scan. When compared with the control group, the PKU group exhibited global cognitive impairment including lower IQ, attention problems, slow information processing, reduced learning capacity, mild executive impairments, and educational difficulties. Children in the PKU group with extensive WMA (n = 14) displayed significant impairments across all cognitive domains. Metabolic control correlated weakly to moderately with attention, executive, and memory/learning factors. Within the PKU group, regressions revealed that executive function and attention factors were independently related to severity of WM pathology and age, while the memory and learning factor was independently related to metabolic control and age. It is concluded that children with early-treated PKU exhibit a global pattern of impairment, with a particular deficit in processing speed. WM pathology extending into frontal and subcortical regions correlates with the greatest deficits and a profile of impairment consistent with diffuse WM damage. Our findings also offer some support for dopamine depletion in the prefrontal cortex, however adverse consequences as a result of norepinephrine and serotonin deficiencies should not be discounted.     

Are neuropsychological impairments in children with early-treated phenylketonuria (PKU) related to white matter abnormalities or elevated phenylalanine levels?

This study aimed to enhance our understanding of neuropsychological functioning in children with early-treated phenylketonuria (PKU) and assess the relative impact of white matter abnormalities (WMA) and neurotransmitter deficiencies on cognitive functions in this population. The study consisted of 33 children with early-treated PKU and 34 healthy control children aged between 7 to 18 years. All children had a neuropsychological evaluation that included measures of general intelligence, attention, processing speed, memory and learning, executive function, and academic achievement. Children in the PKU group also had a magnetic resonance (MR) brain scan. When compared with the control group, the PKU group exhibited global cognitive impairment including lower IQ, attention problems, slow information processing, reduced learning capacity, mild executive impairments, and educational difficulties. Children in the PKU group with extensive WMA (n = 14) displayed significant impairments across all cognitive domains. Metabolic control correlated weakly to moderately with attention, executive, and memory/learning factors. Within the PKU group, regressions revealed that executive function and attention factors were independently related to severity of WM pathology and age, while the memory and learning factor was independently related to metabolic control and age. It is concluded that children with early-treated PKU exhibit a global pattern of impairment, with a particular deficit in processing speed. WM pathology extending into frontal and subcortical regions correlates with the greatest deficits and a profile of impairment consistent with diffuse WM damage. Our findings also offer some support for dopamine depletion in the prefrontal cortex, however adverse consequences as a result of norepinephrine and serotonin deficiencies should not be discounted.     

Beyond executive function: Non-executive cognitive abilities in individuals with PKU

Individuals with early-treated phenylketonuria (ETPKU) most often present with impairment in executive function (EF) and average intelligence compared to the general population. The topic of this review, which is less often discussed, is non-EF impairments that may be associated with ETPKU. Studies that have included assessment of non-EF cognitive functions such as information processing speed, fine motor skills, and perception and visual–spatial abilities suggest that individuals with ETPKU are compromised in these areas. Those assessing non-EF cognitive functions of language skills, long-term memory, and learning skills have yielded mixed results, with some suggesting impairment and others suggesting intact abilities. Although more studies are required, research to date suggests that mechanisms for non-EF deficits may include prefrontal cortex dopamine deficiency and/or white matter abnormalities related to elevated blood phenylalanine levels. For individuals with ETPKU to reach their full potential in life, it is vital to address the challenges associated with EF and non-EF deficits by identifying impairments and appropriate treatment strategies.     

Neuropsychological analyses of comorbidity between reading disability and attention deficit hyperactivity disorder: in search of the common deficit

Measures of component reading and language skills, executive functions, and processing speed were administered to groups of children with attention deficit hyperactivity disorder (ADHD; n = 113), reading disability (RD; n = 109), both RD and ADHD (n = 64), and neither RD nor ADHD (n = 151). Groups with RD exhibited pronounced deficits on all measures of component reading and language skills, as well as significant weaknesses on measures of verbal working memory, processing speed, and response inhibition. Groups with ADHD exhibited weaknesses on all response-inhibition and processing speed tasks and were impaired on some measures of component reading skills and verbal working memory. The group with comorbid RD and ADHD exhibited the combination of the deficits in the RD-only and ADHD-only groups, providing evidence against the phenocopy and cognitive subtype hypotheses as explanations for the co-occurrence of RD and ADHD. Slow and variable processing speed was characteristic of all 3 clinical groups, suggesting that measures of this domain may be useful for future studies that search for the common genes that increase susceptibility to RD and ADHD.     

Effects of seasonal allergic rhinitis on selected cognitive abilities.

BACKGROUND: Many allergy patients complain of slowed thinking, memory problems, and difficulty sustaining attention during their allergy seasons. OBJECTIVE: This study evaluated the effect of symptomatic allergic rhinitis on speed of cognitive processing, ability to divide and sustain attention, working memory, and recent verbal memory. METHODS: Symptomatic ragweed-allergic rhinitis patients and nonatopic control subjects did cognitive testing in, out of, and in ragweed seasons. RESULTS: Test results indicate that, during ragweed seasons, allergic patients experience subtle slowed speed of cognitive processing but not deficits in attention and recent memory. Some patients also have difficulties in working memory. CONCLUSIONS: These findings suggest that having allergic reactions to ragweed pollen causes significant cognitive difficulties in a subgroup of patients.     

Early detection of isolated memory deficits in the elderly: the need for more sensitive neuropsychological tests

BACKGROUND: Early detection of cognitive decline in the elderly is important because this may precede progression to Alzheimer's disease. The aim of this study was to see whether sensitive neuropsychological tests could identify pre-clinical cognitive deficits and to characterize the cognitive profile of a subgroup with poor memory. METHODS: A neuropsychological test battery was administered to a community-dwelling sample of 155 elderly volunteers who were screened with CAMCOG at enrolment (mean age 74.7 years). The battery included tests of episodic memory. semantic and working memory, language and processing speed. RESULTS: Episodic memory test z scores below 1 S.D. from the cohort mean identified 25 subjects with non-robust' memory performance. This group was compared to the remaining 'robust memory' group with a General Linear Model controlling for age, IQ, education and gender. Test performance was significantly different in all tests for episodic and semantic memory, but not in tests for working memory, processing speed and language. CANTAB paired associates learning and spatial recognition tests identified the highest percentages of those in the 'non-robust memory group. Processing speed partialled out the age effect on memory performance for the whole cohort, but the 'non-robust memory' group's performance was not associated with age or processing speed. CONCLUSIONS: Sensitive neuropsychological tests can detect performance below the norm in elderly people whose performance on MMSE and CAMCOG tests is well within the normal range. Age-related decline in memory performance in a cohort of the elderly may be largely due to inclusion within the cohort of individuals with undetected pre-clinical Alzheimer's disease or isolated memory impairment.     

Dyslexia in 47,XXXY boys identified at birth

The 47, XXY karyotype has been associated with diminished language skills in the presence of average intelligence, but specific deficits in cognitive abilities have not been clearly and consistently established. The present study examined cognitive skills in 14 unselected 47,XXY boys (ages 8 to 18 years) and 14 euploid control boys matched for age and socioeconomic status. No significant differences were found on measures of intelligence, perception, and language, although mean score trends suggested mildly diminished skills in these areas. The 47,XXY group demonstrated significantly poorer auditory short-term memory and reading skills. One-half of the propositi exhibited a common constellation of deficits suggesting that their karyotype may represent a risk factor for a language-based dyslexia with primary features including deficits in memory and speed of processing. Small sample size necessitates caution in making generalizations which await verification from other studies of unselected 47,XXY boys. Possible biological mechanisms responsible for neurocognitive variations in children with sex chromosome anomalies have been hypothesized, but evidence for their existence remains elusive.This work was supported by U.S. Public Health Services Grant 5R01-HD10032; by Grant RR-69 from the General Clinical Research Centers Program of the Division of Research Resources, National Institutes of Health; and by The Genetic Foundation.