The impact of metabolic control and tetrahydrobiopterin treatment on health related quality of life of patients with early-treated phenylketonuria: A PKU-COBESO study.

The aim of this study was to examine Health-Related Quality of Life (HRQoL) of patients with Phenylketonuria (PKU) in three different age groups and to investigate the impact of metabolic control and tetrahydrobiopterin (BH4) treatment on HRQoL of these patients. Participants were 90 early-treated patients aged 7 to 40 years (M = 21.0, SD = 10.1) and 109 controls aged 7 to 40.8 years (M = 19.4, SD = 8.6). HRQoL was assessed with the (generic) TNO-AZL questionnaires. Overall, good HRQoL was reported for children below 12 years of age, although they were judged to be less autonomic than their healthy counterparts. Adolescents aged 12-15 years showed poorer HRQoL in the domain "cognitive functioning" compared to controls. For adults ≥16 years, poorer age-controlled HRQoL was found for the domains cognition, depressive moods, and anger, with a further trend for the domain "pain". With respect to metabolic control, only for adult PKU-patients robust associations were observed, indicating poorer functioning, most notably in the domains cognition, sleep, pain, sexuality and anger, with higher historical and concurrent Phe-levels. With respect to BH4-use, effects on HRQoL were again only observed for adult PKU-patients. After controlling for age and historical Phe-levels, small but significant differences in favor of adult BH4-users compared to non-users were observed for HRQoL-categories happiness, anger, and social functioning. Together, these results show that, particularly for adult PKU-patients, HRQoL-problems are evident and that many of these problems are related to (history of) metabolic control. Beneficial effects of BH4-use appear to be limited to those associated with relief from the practical burdens related to the strict dietary treatment regimen, i.e. general mood and sociability, whereas metabolic control is more strongly related to basic physical and cognitive functioning.

Late, but not early, arriving younger siblings foster firstborns' understanding of second-order false belief.

This study examined the influence of younger siblings on children's understanding of second-order false belief. In a representative community sample of firstborn children (N=229) with a mean age of 7years (SD=4.58), false belief was assessed during a home visit using an adaptation of a well-established second-order false belief narrative enacted with Playmobil figures. Children's responses were coded to establish performance on second-order false belief questions. When controlling for verbal IQ and age, the existence of a younger sibling predicted a twofold advantage in children's second-order false belief performance, yet this was the case only for firstborns who experienced the arrival of a sibling after their second birthday. These findings provide a foundation for future research on family influences on social cognition.

Long-Term Follow-Up of Cognition and Mental Health in Adult Phenylketonuria: A PKU-COBESO Study.

Cognitive and mental health problems in individuals with the inherited metabolic disorder phenylketonuria (PKU) have often been associated with metabolic control and its history. For the present study executive functioning (EF) was assessed in 21 PKU patients during childhood (T1, mean age 10.4 years, SD = 2.0) and again in adulthood (T2, mean age 25.8 years, SD = 2.3). At T2 additional assessments of EF in daily life and mental health were performed. Childhood (i.e. 0-12 years) blood phenylalanine was significantly related to cognitive flexibility, executive motor control, EF in daily life and mental health in adulthood (i.e. at T2). Patients with a greater increase in phenylalanine levels after the age of 12 performed more poorly on EF-tasks at T2. Group-based analyses showed that patients with phenylalanine <360 µmol/L in childhood and phenylalanine ≥360 µmol/L from age 13 onwards (n = 11) had better cognitive flexibility and executive motor control than those who had phenylalanine ≥360 µmol/L throughout life (n = 7), supporting the notion that phenylalanine should be below the recommended upper treatment target of 360 µmol/L during childhood for better outcome in adulthood. Despite some results indicating additional influence of phenylalanine levels between 13 and 17 years of age, evidence for a continued influence of phenylalanine levels after childhood on adult outcomes was largely lacking. This may be explained by the fact that the patients in the present study had relatively low phenylalanine levels during childhood (mean: 330 µmol/L, range: 219-581 µmol/L) and thereafter (mean Index of Dietary Control at T2: 464 µmol/L, range: 276-743 µmol/L), which may have buffered against transitory periods of poor metabolic control during adolescence and early adulthood.

Social-cognitive functioning and social skills in patients with early treated phenylketonuria: a PKU-COBESO study.

OBJECTIVE: Early treatment of phenylketonuria (ET-PKU) prevents mental retardation, but many patients still show cognitive and mood problems. In this study, it was investigated whether ET-PKU-patients have specific phenylalanine (Phe-)related problems with respect to social-cognitive functioning and social skills. METHODS: Ninety five PKU-patients (mean age 21.6 ± 10.2 years) and 95 healthy controls (mean age 19.6 ± 8.7 years) were compared on performance of computerized and paper-and-pencil tasks measuring social-cognitive abilities and on parent- and self-reported social skills, using multivariate analyses of variance, and controlling for general cognitive ability (IQ-estimate). Further comparisons were made between patients using tetrahydrobiopterin (BH4, N = 30) and patients not using BH4. Associations with Phe-levels on the day of testing, during childhood, during adolescence and throughout life were examined. RESULTS: PKU-patients showed poorer social-cognitive functioning and reportedly had poorer social skills than controls (regardless of general cognitive abilities). Quality of social-cognitive functioning was negatively related to recent Phe-levels and Phe-levels between 8 and 12 years for adolescents with PKU. Quality of social skills was negatively related to lifetime phenylalanine levels in adult patients, and specifically to Phe-levels between 0 and 7, and between 8 and 12 years. There were no differences with respect to social outcome measures between the BH4 and non-BH4 groups. CONCLUSION: PKU-patients have Phe-related difficulties with social-cognitive functioning and social skills. Problems seem to be more evident among adolescents and adults with PKU. High Phe-levels during childhood and early adolescence seem to be of greater influence than current and recent Phe-levels for these patients.

Parental Perceptions of Aggressive Behavior in Preschoolers: Inhibitory Control Moderates the Association With Negative Emotionality.

Inhibitory control (IC) and negative emotionality (NE) are both linked to aggressive behavior, but their interplay has not yet been clarified. This study examines different NE × IC interaction models in relation to aggressive behavior in 855 preschoolers (aged 2-5 years) using parental questionnaires. Hierarchical regression analyses revealed that NE and IC predict aggression both directly and interactively. The highest aggression levels were reported in children with high NE and low IC. Interestingly, the protective effect of IC for aggressive behavior increases with rising levels of NE. Analyses focusing on physical aggression revealed a significant NE × IC interaction in boys aged 4-5 years only. These findings shed new light on potential compensatory mechanisms for aggressive behavior in developing children.

Is BRIEF a useful instrument in day to day care of patients with phenylketonuria?

OBJECTIVES: Despite early and continuous treatment many patients with phenylketonuria (PKU) still experience neurocognitive problems. Most problems have been observed in the domain of executive functioning (EF). For regular monitoring of EF, the use of the Behavior Rating Inventory of Executive Function (BRIEF) has been proposed. The aim of this study was to investigate whether the BRIEF is indeed a useful screening instrument in monitoring of adults with PKU. STUDY DESIGN: Adult PKU patients (n = 55; mean age 28.3 ± 6.2 years) filled out the BRIEF-A (higher scores=poorer EF) and performed computerized tasks measuring executive functions (inhibition, cognitive flexibility, and working memory). The outcome of the BRIEF-A questionnaire was compared with the neurocognitive outcome as measured by three tasks from the Amsterdam Neuropsychological Tasks (ANT). RESULTS: Forty-two percent of the PKU patients scored in the borderline/clinical range of the BRIEF-A. Six of the 55 patients (11%) scored >1 SD above the normative mean, mostly on the Metacognition Index. With respect to ANT measurements, patients mainly showed deficits in inhibitory control (34-36%) and cognitive flexibility (31-40%) as compared to the general Dutch population. No significant correlations between the two methods were found, which was confirmed with the Bland-Altman approach where no agreement between the two methods was observed. Only with respect to inhibitory control, patients scored significantly worse on both BRIEF-A and ANT classifications. No other associations between classification according to the BRIEF-A and classifications according to the ANT tasks were found. CONCLUSIONS: Patients reporting EF problems in daily life are not necessarily those that present with core EF deficits. The results of this study suggest that regular self-administration of the BRIEF-A is not a sufficient way to monitor EF in adult PKU patients.

Processing of facial and nonsocial information is differentially associated with severity of symptoms in patients with multiepisode schizophrenia.

Patients with schizophrenia show impairments in social cognitive abilities, such as recognizing facial emotions. However, the relation to symptoms remains unclear. The goal of this study was to explore whether facial emotion recognition and face identity recognition are associated with severity of symptoms and to which extent associations with symptoms differ for processing of social versus nonsocial information. Facial emotion recognition, face recognition, and abstract pattern recognition were evaluated in 98 patients with multiepisode schizophrenia. Severity of symptoms was measured using a five-factor model of the Positive and Negative Syndrome Scale. Results show that facial emotion recognition and, to a lesser extent, face recognition were predominantly associated with severity of disorganization symptoms. In contrast, recognition of nonsocial patterns was associated with negative symptoms, excitement, and emotional distress. Reaction time rather than accuracy of social cognition explained variance in symptomatology. These results lead to the conclusion that facial emotion processing in schizophrenia appears to be associated with severity of symptoms, especially disorganization.

Neurocognitive evidence for revision of treatment targets and guidelines for phenylketonuria.

OBJECTIVES: To compare the neurocognitive outcomes of patients with phenylketonuria (PKU) to determine whether decreasing phenylalanine (Phe) levels to <240 is preferable to the use of 360 µmol/L as an upper-target Phe level. An additional aim was to establish the influence of biochemical indices other than Phe on neurocognitive outcomes. STUDY DESIGN: Patients with PKU (n = 63; mean age 10.8 ± 2.3 years) and healthy controls (n = 73; mean age 10.9 ± 2.2 years) performed computerized tasks measuring neurocognitive functions (inhibitory control, cognitive flexibility, and motor control). Lifetime and concurrent blood Phe levels, Phe-to-tyrosine ratio (Phe:Tyr), and Phe variations were examined in relation to neurocognitive outcomes using nonparametric tests and regression analyses. RESULTS: Patients with PKU with Phe levels ≤240 µmol/L and healthy controls performed equally well. Patients with Phe levels between 240 and 360 µmol/L and ≥360 µmol/L performed more poorly than did controls across tasks. Patients with Phe levels ≤240 µmol/L performed significantly better than patients with levels between 240 and 360 µmol/L on tasks measuring inhibitory control and cognitive flexibility. Absolute Phe levels and Phe variation were the best predictors of motor control, whereas Phe:Tyr were the best predictors of inhibitory control. CONCLUSIONS: The results of this study suggest that upper Phe targets should be lowered to optimize neurocognitive outcomes. Moreover, Phe variation and Phe:Tyr appear to be of additional value in treatment monitoring.

Quality of life: a case-controlled long-term follow-up study, comparing young high-functioning adults with autism spectrum disorders with adults with other psychiatric disorders diagnosed in childhood.

BACKGROUND: Long term outcome in childhood autism spectrum disorders (ASD) was evaluated by studying quality of life (QoL) in young adulthood in comparison to the outcome of other child psychiatric disorders. METHODS: In this follow-up study, objective and subjective QoL of 169 high-functioning (IQ>70) adults with ASD (19 to 30 years) was contrasted with QoL data of age matched adults diagnosed with attention deficit/hyperactivity disorder (N=85), disruptive behaviour disorders (N=83), and affective disorders (N=85) during childhood. The mean follow-up period of the ASD patients was 13.9 years. Objective QoL included marital status, living arrangements, level of education, employment, and usage of mental health care. Subjective QoL included satisfaction concerning living arrangements, work or education, physical condition, partner relationship, social relationships, state of mind, and future perspective. RESULTS: QoL was more compromised in adults diagnosed with ASD in childhood than in adults with other psychiatric disorders in childhood. A relatively large proportion of the adults with ASD were single, few lived with a partner or a family and many of them were institutionalized. Adults with ASD had lower educational levels, relatively few had paid employment and many were social security recipients, as compared to the other psychiatric patients. In case the adults with ASD used medication, 47% used anti-psychotics. Regarding the subjective QoL, the adults with ASD were less satisfied about their work or education, partner relationship, and future perspective than the other groups. Even when highly educated adults with ASD were compared to highly educated adults diagnosed with other childhood disorders, the QoL appeared to be more disadvantageous in adults with ASD. CONCLUSION: Many studies have shown that QoL is threatened in psychiatric patients, but findings of this study indicate that young high-functioning adults diagnosed with ASD in childhood are at relatively high risk for poor QoL compared to other childhood psychiatric disorders.

Recognition of facial emotion and affective prosody in children with ASD (+ADHD) and their unaffected siblings.

Autism is a highly heritable and clinically heterogeneous neuropsychiatric disorder that frequently co-occurs with other psychopathologies, such as attention-deficit/hyperactivity disorder (ADHD). An approach to parse heterogeneity is by forming more homogeneous subgroups of autism spectrum disorder (ASD) patients based on their underlying, heritable cognitive vulnerabilities (endophenotypes). Emotion recognition is a likely endophenotypic candidate for ASD and possibly for ADHD. Therefore, this study aimed to examine whether emotion recognition is a viable endophenotypic candidate for ASD and to assess the impact of comorbid ADHD in this context. A total of 90 children with ASD (43 with and 47 without ADHD), 79 ASD unaffected siblings, and 139 controls aged 6-13 years, were included to test recognition of facial emotion and affective prosody. Our results revealed that the recognition of both facial emotion and affective prosody was impaired in children with ASD and aggravated by the presence of ADHD. The latter could only be partly explained by typical ADHD cognitive deficits, such as inhibitory and attentional problems. The performance of unaffected siblings could overall be considered at an intermediate level, performing somewhat worse than the controls and better than the ASD probands. Our findings suggest that emotion recognition might be a viable endophenotype in ASD and a fruitful target in future family studies of the genetic contribution to ASD and comorbid ADHD. Furthermore, our results suggest that children with comorbid ASD and ADHD are at highest risk for emotion recognition problems.

Neuropsychological task outcomes among survivors of childhood acute lymphoblastic leukemia in Malaysia.

This study intended to explore the neuropsychological ramifications in childhood acute lymphoblastic leukemia (ALL) survivors in Malaysia and to examine treatment-related sequelae. A case-control study was conducted over a 2-year period. Seventy-one survivors of childhood ALL who had completed treatment for a minimum of 1 year and were in remission, and 71 healthy volunteers were enlisted. To assess alertness (processing speed) and essential executive functioning skills such as working memory capacity, inhibition, cognitive flexibility, and sustained attention, seven measures from the Amsterdam Neuropsychological Tasks (ANT) program were chosen. Main outcome measures were speed, stability and accuracy of responses. Mean age at diagnosis was 4.50 years (SD ± 2.40) while mean age at study entry was 12.18 years (SD ± 3.14). Survivors of childhood ALL underperformed on 6 out of 7 ANT tasks, indicating poorer sustained attention, working memory capacity, executive visuomotor control, and cognitive flexibility. Duration of treatment, age at diagnosis, gender, and cumulative doses of chemotherapy were not found to correlate with any of the neuropsychological outcome measures. Childhood ALL survivors in our center demonstrated significantly poorer neuropsychological status compared to healthy controls.

Mental health and social functioning in early treated Phenylketonuria: the PKU-COBESO study.

This article presents a new Dutch multicenter study ("PKU-COBESO") into cognitive and behavioral sequelae of early and continuously treated Phenylketonuria (PKU) patients. Part of the study sample will consist of young adult PKU patients who have participated in a large neuropsychological study approximately 10 years ago, when they were 7-to-15-year-olds (Huijbregts et al., 2002 [1]). Their neurocognitive development will be mapped in association with their earlier and continued metabolic history, taking into account possible changes in, for instance, medication. A second part of the sample will consist of PKU patients between the ages of 7 and approximately 40 years (i.e., born in or after 1974, when neonatal screening was introduced in The Netherlands), who have not participated in the earlier neuropsychological study. Again, their cognitive functioning will be related to their metabolic history. With respect to aspects of cognition, there will be an emphasis on executive functioning. The concept of executive functioning will however be extended with further emphasis on the impact of cognitive deficits on the daily lives of PKU patients, aspects of social cognition, social functioning, and behavior/mental health (i.e., COgnition, BEhavior, SOcial functioning: COBESO). In addition to a description of the PKU-COBESO study, some preliminary results with respect to mental health and social functioning will be presented in this article. Thirty adult PKU patients (mean age 27.8, SD 6.4) and 23 PKU patients under the age of 18 years (mean age 11.0, SD 3.3) were compared to 14 (mean age 26.9 years, SD 5.9) and 7 matched controls (mean age 10.5, SD 2.6) respectively, with respect to their scores on the Adult Self-Report or Child Behavior Checklist (measuring mental health problems) and the Social Skills Checklist or Social Skills Rating System (measuring social skills). Whereas there were very few significant group differences (except for mental health problems in the internalizing spectrum for adult PKU patients), possibly due to the small control groups, several significant associations between mental health problems and Phe levels were observed for the PKU patients. Childhood Phe levels and internalizing problems for adult PKU patients were related; concurrent Phe was associated with both internalizing and externalizing behavioral problems for those under the age of 18. These preliminary results underline the importance of early dietary adherence.

Cognitive control of feature bindings: evidence from children with autistic spectrum disorder.

Understanding how the brain integrates features from different domains that are processed in distinct cortical regions calls for the examination of integration processes. Recent studies of feature-repetition effects demonstrated interactions across perceptual features and action-related features: repeating only some features of the perception-action episode hinders performance. These partial-repetition costs point to the existence of temporary memory traces (event files). However, the principles and the constraints that govern the management of such traces are still unclear. Here, we investigated whether children with autistic spectrum disorder (ASD) differ from typically developing children in managing episodic memory traces. The results show that both groups integrate stimulus features along with action features, but children with ASD exhibit larger partial-repetition costs, suggesting lesser control and flexibility in updating episodic memory traces. The findings are discussed in the light of evidence for a central role of the dopaminergic system in cognitive integration, ASD, and cognitive control.

Development of schizotypal symptoms following psychiatric disorders in childhood or adolescence.

It was examined how juvenile psychiatric disorders and adult schizotypal symptoms are associated. 731 patients of the Department of Child and Adolescent Psychiatry of the University Medical Centre Utrecht, the Netherlands, with mean age of 12.1 years (SD = 4.0) were reassessed at the mean age of 27.9 years (SD = 5.7) for adult schizotypal symptoms using the Schizotypal Personality Questionnaire-Revised (Vollema, Schizophr Bull 26(3):565-575, 2000). Differences between 13 juvenile DSM categories and normal controls (n = 80) on adult schizotypal total and factor scores were analyzed, using (M)ANCOVA. Pervasive developmental disorders (PDD), attention deficit hyperactivity disorders (ADHD), deferred diagnosis, sexual and gender identity disorders and depressive disorders had higher SPQ total scores when compared to normal controls (p < 0.001). Higher levels of disorganized schizotypal symptoms were found for PDD, ADHD, and deferred diagnosis (p < 0.001). The same diagnostic groups showed higher level of negative schizotypal symptoms, which was likewise true for sexual and gender identity disorders, depressive disorders, disruptive disorders, and the category of 'Other conditions that may be a focus of clinical attention' (p < 0.001). No differences with normal controls were found for adult positive schizotypal symptoms (p < 0.110). The current findings are suggestive of the idea that psychiatric disorders in childhood or adolescence are a more general expression of a liability to schizophrenia spectrum pathology in future life. In addition, specific patterns of adult schizotypal symptomatology are associated with different types of juvenile psychiatric disorder.

Does cognitive impairment explain behavioral and social problems of children with neurofibromatosis type 1?

Thirty NF1-patients (mean age 11.7 years, SD = 3.3) and 30 healthy controls (mean age 12.5 years, SD = 3.1) were assessed on social skills, autistic traits, hyperactivity-inattention, emotional problems, conduct problems, and peer problems. Cognitive control, information processing speed, and social information processing were measured using 5 computer tasks. GLM analyses of variance showed significant group differences, to the disadvantage of NF1-patients, on all measures of behavior, social functioning and cognition. General cognitive ability (a composite score of processing speed, social information processing, and cognitive control) accounted for group differences in emotional problems, whereas social information processing accounted for group differences in conduct problems. Although reductions were observed for group differences in other aspects of behavior and social functioning after control for (specific) cognitive abilities, group differences remained evident. Training of cognitive abilities may help reducing certain social and behavioral problems of children with NF1, but further refinement regarding associations between specific aspects of cognition and specific social and behavioral outcomes is required.

Pre-attentive processing in children with early and continuously-treated PKU. Effects of concurrent Phe level and lifetime dietary control.

Sixty-four children, aged 7 to 14 years, with early-treated PKU, were compared with control children on visual evoked potential (VEP) amplitudes and latencies and auditory mismatch negativity (MMN) amplitudes. It was further investigated whether indices of dietary control would be associated with these evoked potentials parameters. There were no significant differences between controls and children with PKU in VEP- and MMN-indices. However, higher lifetime Phe levels were, in varying degree and stronger than concurrent Phe level, related to increased N75 amplitudes, suggesting abnormalities in attention, and longer P110 latencies, indicating a reduction in speed of neural processing, possibly due to deficits in myelination or reduced dopamine levels in brain and retina. Similarly, higher lifetime Phe levels and Index of Dietary Control (IDC) were associated with decreased MMN amplitudes, suggesting a reduced ability to respond to stimulus change and poorer triggering of the frontally mediated attention switch. In summary, the present study in children with PKU investigated bottom-up information processing, i.e., triggered by external events, a fundamental prerequisite for the individual's responsiveness to the outside world. Results provide evidence that quality of dietary control may affect the optimal development of these pre-attentive processes, and suggest the existence of windows of vulnerability to Phe exposure.

High phenylalanine levels directly affect mood and sustained attention in adults with phenylketonuria: a randomised, double-blind, placebo-controlled, crossover trial.

The main debate in the treatment of Phenylketonuria (PKU) is whether adult patients need the strict phenylalanine (Phe)-restricted diet. Physicians and patients lack evidence-based guidelines to help them make well-informed choices. We have carried out the first randomised double-blind placebo-controlled trial into the effects of short-term elevation of Phe levels on neuropsychological functions and mood of adults with PKU. Nine continuously treated adults with PKU underwent two 4-week supplementation periods: one with Phe, mimicking normal dietary intake, and one with placebo in randomly allocated order via a randomisation coding list in a double-blind cross-over design. A set of neuropsychological tests (Amsterdam Neuropsychological Tasks) was administered at the end of each study period. In addition, patients and for each patient a friend or relative, completed weekly Profile of Mood States (POMS) questionnaires, evaluating the patients' mood. Phe levels were measured twice weekly. Mean plasma Phe levels were significantly higher during Phe supplementation compared with placebo (p = 0.008). Neuropsychological tests demonstrated an impairment in sustained attention during Phe supplementation (p = 0.029). Both patients and their friend or relative reported lower scores on the POMS questionnaires during Phe supplementation (p = 0.017 and p = 0.040, respectively). High plasma Phe levels have a direct negative effect on both sustained attention and on mood in adult patients with PKU. A Phe-restricted "diet for life" might be an advisable option for many.

Executive function in early-treated phenylketonuria: profile and underlying mechanisms.

Despite early and continuous dietary intervention, individuals with early-treated phenylketonuria (PKU) experience significant neurocognitive sequelae. An area of cognitive ability that is believed to be particularly affected is executive function (EF). This paper provides a critical review of the evidence for EF impairment in early-treated PKU within the context of recent advances in neuropsychological theory and research. The most consistent findings of PKU-related EF impairment were in executive working memory and prepotent response inhibition. Surprisingly, findings on shifting ability and other more complex aspects of EF were largely equivocal. Cohort (e.g., age, phenylalanine (Phe) levels) and task (e.g., standard clinical versus experimental tasks) related differences likely contributed to the variability in findings reported by these studies. Day-to-day EF also appears to be impaired although the precise pattern of impairment remains unclear, as does the relationship between laboratory measures of EF and questionnaires assessing day-to-day EF. Similarly, whereas several studies have found a relationship between Phe levels and EF, the best predictor variable (e.g., concurrent Phe level, lifetime Phe level, Phe level variability) of current EF performance varied from study to study. Neurologic compromise related to dopamine deficiency, white matter abnormalities, and disruptions in functional connectivity likely underlies the EF impairments described in this review. In closing, this review identifies remaining unanswered questions and future avenues for research.

Event-related potential correlates of selective processing in early- and continuously-treated children with phenylketonuria: effects of concurrent phenylalanine level and dietary control.

This study focused on important characteristics of attentional (selective) processing in children with early-treated phenylketonuria (PKU). Seven to 14-year-old children with PKU were allocated to high phenylalanine (Phe) and low Phe groups and compared with control children on amplitudes and latencies of early and late event-related potential (ERP) components elicited during a selective processing task. These components are thought to measure early sensory processes (stimulus encoding/perception) and later selection processes (target detection). The effects of concurrent Phe level and dietary control on brain activity and behavioural performance were studied. Results showed that children with PKU with high Phe levels were less accurate and made more false alarms than controls and children with PKU with low Phe levels. Both children with PKU and controls displayed the expected early fronto-central selection negativity and a late positive peak over posterior sites associated with sensory aspects of the selective attention task. However, in contrast with controls, children with PKU showed an absence of condition differences for selection positivity over anterior sites associated with target detection. Negative and positive selection potentials over fronto-central sites were dependent on concurrent and historical Phe levels, whereas sensory potentials depended more strongly on historical Phe levels. It is concluded that both sensory and selection aspects of attention are affected by Phe levels. The relative predictive strength of historical Phe levels suggests that high Phe levels during sensitive periods for brain maturation may have long-lasting influences on selective attention.

Cognitive Improvement After Kidney Transplantation Is Associated With Structural and Functional Changes on MRI.

BACKGROUND: Several studies have reported improved cognitive outcomes after kidney transplantation, but most studies either did not include controls or lacked extensive neuroimaging. In addition, there is uncertainty whether kidney donation is a safe procedure in terms of cognitive outcomes. METHODS: We prospectively studied neurocognitive function in kidney transplant recipients. The primary outcome was change in neurocognitive function after 1 year compared with baseline, which was evaluated using the Amsterdam Neuropsychological Task battery and verbal fluency tests. Secondary outcomes included changes in depression and anxiety (measured by the Hospital Anxiety and Depression scale) and changes in fatigue (measured by the Checklist for Individual Strength). We included kidney donors to control for learning effects, socioeconomic status, and surgery. In addition, kidney transplant recipients were evaluated with MRI scans at baseline and at year 1. The MRI protocol included conventional MRI, automated volumetric measurement, diffusion tensor imaging, magnetic resonance spectroscopy, arterial spin labeling, and a resting state functional MRI. RESULTS: Twenty-seven recipients and 24 donors were included. For both recipients and donors, neuropsychologic testing scores improved 1 year after transplantation (donation). Recipient improvement significantly exceeded donor improvement on tasks measuring attention and working memory. These improvements were associated with increases in white matter volume and N-acetylaspartate/creatine (a marker for neuronal integrity). CONCLUSIONS: Attention and working memory improve significantly 1 year after kidney transplantation. Learning effects do not account for these improvements because recipient improvement in these areas exceeds donor improvement and correlates with an improvement in white matter integrity after transplantation. Kidney donation appears to be a safe procedure in terms of cognitive outcomes.