Transient brain structure changes after high phenylalanine exposure in adults with phenylketonuria.

Phenylketonuria is a rare metabolic disease resulting from a deficiency of the enzyme phenylalanine hydroxylase. Recent cross-sectional evidence suggests that early-treated adults with phenylketonuria exhibit alterations in cortical grey matter compared to healthy peers. However, the effects of high phenylalanine exposure on brain structure in adulthood need to be further elucidated. In this double-blind, randomised, placebo-controlled crossover trial, we investigated the impact of a four-week high phenylalanine exposure on the brain structure and its relationship to cognitive performance and metabolic parameters in early-treated adults with phenylketonuria. Twenty-eight adult patients with early-treated classical phenylketonuria (19-48 years) underwent magnetic resonance imaging before and after the four-week phenylalanine and placebo interventions (four timepoints). Structural T1-weighted images were preprocessed and evaluated using DL+DiReCT, a deep-learning-based tool for brain morphometric analysis. Cortical thickness, white matter volume, and ventricular volume were compared between the phenylalanine and placebo periods. Brain phenylalanine levels were measured using 1H spectroscopy. Blood levels of phenylalanine, tyrosine, and tryptophan were assessed at each of the four timepoints, along with performance in executive functions and attention. Blood phenylalanine levels were significantly higher after the phenylalanine period (1441µmol/L) than after the placebo period (873µmol/L, P<0.001). Morphometric analyses revealed a statistically significant decrease in cortical thickness in 17 out of 60 brain regions after the phenylalanine period compared to placebo. The largest decreases were observed in the right pars orbitalis (point estimate=-0.095mm, P<0.001) and the left lingual gyrus (point estimate=-0.070mm, P<0.001). Bilateral white matter and ventricular volumes were significantly increased after the phenylalanine period. However, the structural alterations in the Phe-placebo group returned to baseline measures following the washout and placebo period. Additionally, elevated blood and brain phenylalanine levels were related to increased bilateral white matter volume (rs=0.43 to 0.51, P≤0.036) and decreased cortical thickness (rs=-0.62 to -0.39, not surviving FDR correction) after the phenylalanine and placebo periods. Moreover, decreased cortical thickness was correlated with worse cognitive performance after both periods (rs=-0.54 to -0.40, not surviving FDR correction). These findings provide evidence that a four-week high phenylalanine exposure in adults with phenylketonuria results in transient reductions of the cortical grey matter and increases in white matter volume. Further research is needed to determine the potential long-term impact of high phenylalanine levels on brain structure and function in adults with phenylketonuria.

Cortical thickness and its relationship to cognitive performance and metabolic control in adults with phenylketonuria.

Despite good control of phenylalanine (Phe) levels during childhood and adolescence, adults with phenylketonuria (PKU) often show abnormalities in the white matter of the brain, which have been associated with poorer cognitive performance. However, whether such a relationship exists with cortical gray matter is still unknown. Therefore, we investigated cortical thickness and surface area in adults with early-treated PKU and their relationship to cognitive functions and metabolic control. We included 30 adult patients with early-treated and metabolically well-controlled PKU (median age: 35.5 years) and 54 healthy controls (median age: 29.3 years). Surface-based morphometry was derived from T1-weighted magnetic resonance images using FreeSurfer, and general intelligence, executive functions, and attention were assessed. Concurrent plasma Phe, tyrosine, and tryptophan levels were measured in patients. In addition, Phe levels were collected retrospectively to calculate the index of dietary control. Patients showed a thinner cortex than controls in regions of the bilateral temporal, parietal, and occipital lobes (effect size r = -0.34 to -0.42, p < 0.05). No group differences in surface area were found. In patients, accuracy in the working memory task was positively correlated with thickness in the left insula (r = 0.45, p = 0.013), left fusiform gyrus (r = 0.39, p = 0.032), and right superior temporal gyrus (r = 0.41, p = 0.024), but did not survive false discovery rate correction. Neither concurrent nor historical metabolic parameters were related to cortical thickness. Taken together, adults with PKU showed widespread reductions in cortical thickness despite good metabolic control in childhood and adolescence. However, alterations in cortical thickness were unrelated to metabolic parameters and cognitive performance.

Cognition, psychosocial functioning, and health-related quality of life among childhood cancer survivors.

Long-term sequelae of cancer and its treatment render childhood cancer (CC) survivors vulnerable to cognitive and behavioural difficulties and likely affect their quality of life (QoL). Our aim was to compare levels of cognition, psychosocial functioning, and health-related QoL of CC survivors to healthy controls and examine the associations between these three domains. Seventy-eight CC survivors (age range = 7-16 years, ≥ one year since cancer treatment) and 56 healthy controls were included. Cognition (i.e., fluid intelligence, executive functions, memory, processing speed, and selective attention), psychosocial functioning, and health-related QoL were assessed using standardized tests and questionnaires. The cognitive performance, parent-reported psychosocial behaviour, and health-related QoL of the CC survivors were within the normative range. However, working memory was significantly poorer in survivors than controls, and visuospatial working memory below the normative range was more commonly observed among survivors than among controls. Processing speed significantly predicted survivors' performance in executive functions. Among survivors, greater peer problems were significantly associated with poorer cognitive functions and health-related QoL. Despite the evidence for good intellectual functioning, which might point towards adequate reserves, in some survivors, domain-specific difficulties may emerge years after cancer relating to psychosocial development and QoL.

Effects of Correcting for Prematurity on Executive Function Scores of Children Born Very Preterm at School Age.

OBJECTIVE: To investigate whether correction for prematurity affects executive function scores in school-aged children born very preterm. STUDY DESIGN: Executive functions were assessed with standardized neuropsychological tests in 142 children born very preterm (born at ≤32 weeks of gestational age or with a birth weight of ≤1500 g) and 391 control children, aged 7-13 years. Four-month age bands were established from the data of control children. Differences between uncorrected and corrected scores were compared against zero difference and between very preterm children born before and after 28 weeks of gestation. Regression models were used to compare the uncorrected and corrected scores of children born very preterm with control children. RESULTS: For all executive functions, significant, larger-than-zero differences between uncorrected and corrected scores were apparent in children born very preterm. Mean differences ranged from 0.04 to 0.18 SDs. Weak evidence was found that the effect of age correction is more pronounced in very preterm children born before 28 weeks of gestation than in those born after 28 weeks. Differences in executive function scores between children born very preterm and control children were attenuated if scores were corrected for prematurity. CONCLUSIONS: Test scores based on corrected rather than uncorrected age may more accurately determine the developmental stage of very preterm children's executive functions at school age. Potential consequences for clinical and research practice need to be discussed in the future.

Functional topography of the thalamo-cortical system during development and its relation to cognition.

The thalamus has complex connections with the cortex and is involved in various cognitive processes. However, little is known about the age-related changes of thalamo-cortical connections and their relation to cognitive abilities. The present study analyzed resting-state functional connectivity between the thalamus and nine cortical functional networks (default mode network (DMN), posterior DMN, left/right executive, dorsal attention, salience, motor, visual and auditory network) in a healthy human sample (N = 95, aged 5-25 years). Cognitive abilities, including processing speed, selective attention, and cognitive flexibility were assessed using neuropsychological tests. All nine cortical resting-state networks showed functional connections to the thalamus at rest, with no effect for sex (p > 0.05). For the motor, visual, auditory, DMN, posterior DMN, salience and dorsal attention network, we found mainly bilateral thalamic projections in the mediodorsal nucleus, pulvinar and in nuclei of the lateral group. For the right and left lateralized executive network, corresponding lateralized thalamic projections were found. Thalamo-cortical connectivity strength showed significant age-related changes from distinct sub-nuclei of the thalamus to different cortical networks including the visual, DMN, salience and dorsal attention network. Further, connectivity strength of thalamo-cortical networks was associated with cognitive abilities, including processing speed, selective attention and cognitive flexibility. Better cognitive abilities were associated with increased thalamo-cortical connectivity in the pulvinar, mediodorsal nucleus, intralaminar nucleus, and nuclei from the lateral group. Alterations in the integrity of the thalamo-cortical system seem to be crucial for the development of cognitive abilities during brain maturation.

Is Asymmetry of the Pons Associated with Hand Function and Manual Ability after Arterial Ischemic Stroke in Children?

AIM: This study was designed to investigate how the asymmetry of the brain stem is related to hand function and manual ability after arterial ischemic stroke (AIS) diagnosed during childhood. METHOD: Patients diagnosed with AIS during childhood (> 5 years old, diagnosis > 2 years before recruitment) and typically developing peers were recruited by the Swiss Neuropediatric Stroke Registry. Brainstem cross-sectional areas of each side at the level of the pons were measured. Pinch and grip strength were measured with a dynamometer, quality of upper limb movement by the Melbourne Assessment 2 and manual ability by the ABILHAND-kids. An asymmetry index was calculated for all measures (except the ABILHAND-kids). Differences between groups and correlations were calculated using nonparametric statistics. RESULTS: Fourteen AIS survivors without hemiparesis, 10 AIS survivors with hemiparesis, and 47 typically developing peers were assessed. Patients with hemiparesis showed the highest brainstem asymmetry. There was a significant positive correlation between brainstem asymmetry, the asymmetry of strength and quality of upper limb movement, and a significant negative correlation between brainstem asymmetry and manual ability. INTERPRETATION: In pediatric AIS survivors, brainstem asymmetry can serve as an indirect measure of corticospinal tract integrity. It is significantly correlated with strength, quality of movement, and manual ability.

The Brainfit study: efficacy of cognitive training and exergaming in pediatric cancer survivors - a randomized controlled trial.

BACKGROUND: Cancer survival comes at a price: pediatric cancer survivors bear a high risk for a wide range of cognitive difficulties. Therefore, interventions targeting these difficulties are required. The aim of the present clinical trial is to extend empirical evidence about efficacy of cognitive and physical training in pediatric cancer survivors. It is hypothesized that early cognitive and physical interventions affect the remediation of pediatric cancer survivors in terms of improved executive functions (primary outcome). Additional positive effects of cognitive and physical intervention to other areas such as memory and attention are expected (secondary outcome). Changes in cognitive performance are expected to be associated with structural and functional changes in the brain. METHODS: Overall, 150 pediatric cancer survivors and 50 matched controls will be included in this trial. The cancer survivors will be randomly assigned to either a computerized cognitive training, a physical training (exergaming) or a waiting control group. They will be assessed with neuropsychological tests, tests of sport motor performance and physical fitness before and after 8 weeks of training and again at a 3-months follow-up. Moreover, neuroimaging will be performed at each of the three time points to investigate the training impact on brain structure and function. DISCUSSION: With increasing cancer survival rates, evidence-based interventions are of particular importance. New insights into training-related plasticity in the developing brain will further help to develop tailored rehabilitation programs for pediatric cancer survivors. TRIAL REGISTRATION: KEK BE 196/15; KEK ZH 2015-0397; ICTRP NCT02749877 ; date of registration: 30.11.2016; date of first participant enrolment: .18.01.2017.

Cortical reorganisation of cerebral networks after childhood stroke: impact on outcome.

BACKGROUND: Recovery after arterial ischaemic stroke is known to largely depend on the plastic properties of the brain. The present study examines changes in the network topography of the developing brain after stroke. Effects of brain damage are best assessed by examining entire networks rather than single sites of structural lesions. Relating these changes to post-stroke neuropsychological variables and motor abilities will improve understanding of functional plasticity after stroke. Inclusion of healthy controls will provide additional insight into children's normal brain development. Resting state functional magnetic resonance imaging is a valid approach to topographically investigate the reorganisation of functional networks after a brain lesion. Transcranial magnetic stimulation provides complementary output information. This study will investigate functional reorganisation after paediatric arterial ischaemic stroke by means of resting state functional magnetic resonance imaging and transcranial magnetic stimulation in a cross-sectional plus longitudinal study design. The general aim of this study is to better understand neuroplasticity of the developing brain after stroke in order to develop more efficacious therapy and to improve the post-stroke functional outcome. METHODS: The cross-sectional part of the study will investigate the functional cerebral networks of 35 children with chronic arterial ischaemic stroke (time of the lesion >2 years). In the longitudinal part, 15 children with acute arterial ischaemic stroke (shortly after the acute phase of the stroke) will be included and investigations will be performed 3 times within the subsequent 9 months. We will also recruit 50 healthy controls, matched for age and sex. The neuroimaging and neurophysiological data will be correlated with neuropsychological and neurological variables. DISCUSSION: This study is the first to combine resting state functional magnetic resonance imaging and transcranial magnetic stimulation in a paediatric population diagnosed with arterial ischaemic stroke. Thus, this study has the potential to uniquely contribute to the understanding of neuronal plasticity in the brains of healthy children and those with acute or chronic brain injury. It is expected that the results will lead to the development of optimal interventions after arterial ischaemic stroke.

Cognition after a 4-week high phenylalanine intake in adults with phenylketonuria - a randomized controlled trial.

BACKGROUND: Phenylketonuria (PKU) is an autosomal recessive metabolic disorder characterized by increased phenylalanine (Phe) concentrations in the blood and brain. Despite wide agreement on treatment during childhood, recommendations for adults are still controversial. OBJECTIVE: To assess the impact of a 4-week increase in Phe intake (simulating normal dietary Phe consumption) on cognition, mood, and depression in early-treated adults with PKU in a double-blind, randomized controlled trial (RCT). METHODS: In a single-site crossover trial, 30 adult patients with classical PKU diagnosed at birth were recruited. All patients underwent a 4-week period of oral Phe administration (1500-3000 mg Phe/d) and a 4-week placebo period in a randomly assigned order with age, sex, and place of usual medical care as stratification factors. Analyses were based on the intention-to-treat (ITT) and per protocol (PP) approach to claim noninferiority (noninferiority margin -4%), with working memory accuracy as the primary endpoint and additional cognitive domains, mood, and depression as secondary endpoints. RESULTS: For the primary endpoint, a 4-week increase of Phe intake was noninferior to placebo with respect to working memory accuracy in both the ITT [point estimate 0.49; lower limit 95% confidence interval (CI): -1.99] and the PP analysis (point estimate -1.22; lower limit 95% CI: -2.60). Secondary outcomes (working memory reaction time, manual dexterity, mood, and depression) did not significantly differ between the Phe and placebo period, except for sustained attention (point estimate 31.0; lower limit 95% CI: 9.0). Adverse events were more frequent during the Phe than during the placebo period (95% CI: 1.03, 2.28, P = 0.037). CONCLUSIONS: In early-treated adult patients with PKU, a 4-week high Phe intake was noninferior to continuing Phe restriction regarding working memory accuracy, and secondary outcomes did not differ except for sustained attention. Longer-term RCTs are required to determine whether low Phe levels need to be maintained throughout different periods of adulthood. This trial was registered at the clinicaltrials.gov as NCT03788343.

Cerebral blood flow and white matter alterations in adults with phenylketonuria.

BACKGROUND: Phenylketonuria (PKU) represents a congenital metabolic defect that disrupts the process of converting phenylalanine (Phe) into tyrosine. Earlier investigations have revealed diminished cognitive performance and changes in brain structure and function (including the presence of white matter lesions) among individuals affected by PKU. However, there exists limited understanding regarding cerebral blood flow (CBF) and its potential associations with cognition, white matter lesions, and metabolic parameters in patients with PKU, which we therefore aimed to investigate in this study. METHOD: Arterial spin labeling perfusion MRI was performed to measure CBF in 30 adults with early-treated classical PKU (median age 35.5 years) and 59 healthy controls (median age 30.0 years). For all participants, brain Phe levels were measured with 1H spectroscopy, and white matter lesions were rated by two neuroradiologists on T2 weighted images. White matter integrity was examined with diffusion tensor imaging (DTI). For patients only, concurrent plasma Phe levels were assessed after an overnight fasting period. Furthermore, past Phe levels were collected to estimate historical metabolic control. On the day of the MRI, each participant underwent a cognitive assessment measuring IQ and performance in executive functions, attention, and processing speed. RESULTS: No significant group difference was observed in global CBF between patients and controls (F (1, 87) = 3.81, p = 0.054). Investigating CBF on the level of cerebral arterial territories, reduced CBF was observed in the left middle and posterior cerebral artery (MCA and PCA), with the most prominent reduction of CBF in the anterior subdivision of the MCA (F (1, 87) = 6.15, p = 0.015, surviving FDR correction). White matter lesions in patients were associated with cerebral blood flow reduction in the affected structure. Particularly, patients with lesions in the occipital lobe showed significant CBF reductions in the left PCA (U = 352, p = 0.013, surviving FDR correction). Additionally, axial diffusivity measured with DTI was positively associated with CBF in the ACA and PCA (surviving FDR correction). Cerebral blood flow did not correlate with cognitive performance or metabolic parameters. CONCLUSION: The relationship between cerebral blood flow and white matter indicates a complex interplay between vascular health and white matter alterations in patients with PKU. It highlights the importance of considering a multifactorial model when investigating the impact of PKU on the brain.

Executive functions of children born very preterm--deficit or delay?

UNLABELLED: This cross-sectional study examined the performance of children born very preterm and/or at very low birth weight (VPT/VLBW) and same-aged term-born controls in three core executive functions: inhibition, working memory, and shifting. Children were divided into two age groups according to the median (young, 8.00-9.86 years; old, 9.87-12.99 years). The aims of the study were to investigate whether (a) VPT/VLBW children of both age groups performed poorer than controls (deficit hypothesis) or caught up with increasing age (delay hypothesis) and (b) whether VPT/VLBW children displayed a similar pattern of performance increase in executive functions with advancing age compared with the controls. Fifty-six VPT/VLBW children born in the cohort of 1998-2003 and 41 healthy-term-born controls were recruited. All children completed tests of inhibition (Color-Word Interference Task, Delis-Kaplan Executive Function System (D-KEFS)), working memory (Digit Span Backwards, HAWIK-IV), and shifting (Trail Making Test, Number-Letter Sequencing, D-KEFS). Results revealed that young VPT/VLBW children performed significantly poorer than the young controls in inhibition, working memory, and shifting, whereas old VPT/VLBW children performed similar to the old controls across all three executive functions. Furthermore, the frequencies of impairment in inhibition, working memory and shifting were higher in the young VPT/VLBW group compared with the young control group, whereas frequencies of impairment were equal in the old groups. In both VPT/VLBW children and controls, the highest increase in executive performance across the ages of 8 to 12 years was observed in shifting, followed by working memory, and inhibition. CONCLUSIONS: This study provides evidence that (a) poor performance in inhibition, working memory, and shifting of young VPT/VLBW children might reflect a delay rather than a deficit and (b) that VPT/VLBW children are likely to display a similar pattern of performance increase in these three executive functions compared with that of controls.

Lesion size and long-term cognitive outcome after pediatric stroke: A comparison between two techniques to assess lesion size.

BACKGROUND: There is little consensus on how lesion size impacts long-term cognitive outcome after pediatric arterial ischemic stroke (AIS). This study, therefore, compared two techniques to assessed lesion size in the chronic phase after AIS and determined their measurement agreement in relation to cognitive functions in patients after pediatric stroke. METHODS: Twenty-five patients after pediatric AIS were examined in the chronic phase (>2 years after stroke) in respect to intelligence, memory, executive functions, visuo-motor functions, motor abilities, and disease-specific outcome. Lesion size was measured using the ABC/2 formula and segmentation technique (3D Slicer). Correlation analysis determined the association between volumetry techniques and outcome measures in respect to long-term cognitive outcome. RESULTS: The measurements from the ABC/2 and segmentation technique were strongly correlated (r = 0.878, p < .001) and displayed agreement in particular for small lesions. Lesion size from both techniques was significantly correlated with disease-specific outcome (p < .001) and processing speed (p < .005) after controlling for age at stroke and multiple comparison. CONCLUSION: The two techniques showed convergent validity and were both significantly correlated with long-term outcome after pediatric AIS. Compared to the time-consuming segmentation technique, ABC/2 facilitates clinical and research work as it requires relatively little time and is easy to apply.

How is Cerebral Perfusion Associated with Functional Outcome in Pediatric Cancer Survivors?

Pediatric cancer survivors (PCS) experience functional difficulties and brain alterations. However, little is known about cerebral perfusion and its relationship to functional outcome (cognitive and motor performance) in PCS. We examined cerebral blood flow (CBF) in non-brain tumor PCS and the associations between CBF and age, as well as functional outcome. Forty PCS and 40 age-comparable controls were included. CBF did not differ between PCS and controls. CBF decreased with age only in controls. In PCS, CBF was associated with functional outcome. Our data indicate an altered relationship between age and CBF in survivors, with stronger brain-behavior mechanisms after cancer.

Compromised white matter is related to lower cognitive performance in adults with phenylketonuria.

Despite increasing knowledge about the effects of phenylketonuria on brain structure and function, it is uncertain whether white matter microstructure is affected and if it is linked to patients' metabolic control or cognitive performance. Thus, we quantitatively assessed white matter characteristics in adults with phenylketonuria and assessed their relationship to concurrent brain and blood phenylalanine levels, historical metabolic control and cognitive performance. Diffusion tensor imaging and 1H spectroscopy were performed in 30 adults with early-treated classical phenylketonuria (median age 35.5 years) and 54 healthy controls (median age 29.3 years). Fractional anisotropy and mean, axial and radial diffusivity were investigated using tract-based spatial statistics, and white matter lesion load was evaluated. Brain phenylalanine levels were measured with 1H spectroscopy whereas concurrent plasma phenylalanine levels were assessed after an overnight fast. Retrospective phenylalanine levels were collected to estimate historical metabolic control, and a neuropsychological evaluation assessed the performance in executive functions, attention and processing speed. Widespread reductions in mean diffusivity, axial diffusivity and fractional anisotropy occurred in patients compared to controls. Mean diffusivity and axial diffusivity were decreased in several white matter tracts and were most restricted in the optic radiation (effect size rrb = 0.66 to 0.78, P < 0.001) and posterior corona radiata (rrb = 0.83 to 0.90, P < 0.001). Lower fractional anisotropy was found in the optic radiation and posterior corona radiata (rrb = 0.43 to 0.49, P < 0.001). White matter microstructure in patients was significantly associated with cognition. Specifically, inhibition was related to axial diffusivity in the external capsule (rs = -0.69, P < 0.001) and the superior (rs = -0.58, P < 0.001) and inferior longitudinal fasciculi (rs = -0.60, P < 0.001). Cognitive flexibility was associated with mean diffusivity of the posterior limb of the internal capsule (rs = -0.62, P < 0.001), and divided attention correlated with fractional anisotropy of the external capsule (rs = -0.61, P < 0.001). Neither concurrent nor historical metabolic control was significantly associated with white matter microstructure. White matter lesions were present in 29 out of 30 patients (96.7%), most often in the parietal and occipital lobes. However, total white matter lesion load scores were unrelated to patients' cognitive performance and metabolic control. In conclusion, our findings demonstrate that white matter alterations in early-treated phenylketonuria persist into adulthood, are most prominent in the posterior white matter and are likely to be driven by axonal damage. Furthermore, diffusion tensor imaging metrics in adults with phenylketonuria were related to performance in attention and executive functions.

Health-related quality of life in a european sample of adults with early-treated classical PKU.

BACKGROUND: Phenylketonuria (PKU) is a rare inborn error of metabolism affecting the catabolism of phenylalanine (Phe). To date, findings regarding health-related quality of life (HRQoL) in adults with early-treated classical PKU are discrepant. Moreover, little is known about metabolic, demographic, and cognitive factors associated with HRQoL. Hence, we aimed to investigate HRQoL and its association with demographic, metabolic, and cognitive characteristics in a large European sample of adults with early-treated classical PKU. RESULTS: This cross-sectional study included 124 adults with early-treated classical PKU from Hungary, Italy, Spain, Switzerland, and Turkey. All participants prospectively completed the PKU quality of life questionnaire (PKU-QoL), a questionnaire specifically designed to evaluate the impact of PKU and its treatment on HRQoL in individuals with PKU. In addition, information about Phe levels (concurrent and past year), demographic (age and sex), and cognitive variables (intelligence quotient, IQ) were collected. Most domains revealed little or no impact of PKU on HRQoL and more than three-quarters of the patients rated their health status as good, very good, or excellent. Nevertheless, some areas of concern for patients were identified. Patients were worried about the guilt that they experience if they do not adhere to the dietary protein restriction and they were most concerned about high Phe levels during pregnancy. Further, tiredness was the most affected symptom, and the supplements' taste was considered a main issue for individuals with PKU. The overall impact of PKU on HRQoL was higher in women (U = 1315.5, p = .012) and in adults with a lower IQ (rs = - 0.448, p = .005). The overall impact of dietary protein restriction was higher in adults with higher concurrent Phe levels (rs = 0.272, p = .007) and higher Phe levels during the past year (rs = 0.280, p = .009). CONCLUSION: The impact of PKU on most domains assessed in the PKU-QoL was considered to be low. These results likely reflect the successful implementation of the newborn screening resulting in the prevention of severe adverse long-term outcomes. However, a particular clinical focus should be given to patients with lower IQ, higher Phe levels, and women, as these variables were associated with a lower HRQoL.

Personal and Social Resources Are Linked to Cognition and Health-Related Quality of Life in Childhood Cancer Survivors.

Personal and social resources may buffer the adverse effects of childhood cancer and its impact on cognition and quality of life. While childhood cancer survivors show domain-specific cognitive difficulties, little is known about their personal and social resources. We therefore investigated personal and social resources and their association with cognitive and quality-of-life outcomes in childhood cancer survivors. Seventy-eight survivors of childhood cancer of different etiologies (aged 7−16 years; ≥one year since treatment) and fifty-six healthy controls were included. Cognitive outcome was assessed by neuropsychological tests; personal and social resources, as well as health-related quality of life, were assessed by standardized questionnaires. In the social resource domain, peer integration was worse in survivors than in controls (puncorr < 0.04, d = 0.33). Personal resources and all other subscales of social resources did not significantly differ between survivors and controls. In survivors, the global resource score was significantly correlated with processing speed (r = 0.39, pcorr < 0.001) and quality of life (parent: r = 0.44; self-report: r = 0.46; pscorr < 0.001). In controls, no association occurred between resources and cognitive outcome, and the correlation between the global resource score and quality of life did not withstand correction for multiple comparison (parent: r = 0.28; self-report: r = 0.40, psuncorr < 0.001). After an adverse event such as childhood cancer, resources might play a particularly buffering role on cognitive performance and quality of life (when compared to the everyday life of healthy controls). This highlights the importance of interventions that strengthen the resources of children and their families, even years after cancer. Such resource-focused intervention could help to counteract long-term sequelae in cognitive outcomes and health-related quality of life.

Cognitive outcome is related to functional thalamo-cortical connectivity after paediatric stroke.

The thalamus has complex connections with the cortex and is involved in various cognitive processes. Despite increasing interest in the thalamus and the underlying thalamo-cortical interaction, little is known about thalamo-cortical connections after paediatric arterial ischaemic stroke. Therefore, the aim of this study was to investigate thalamo-cortical connections and their association with cognitive performance after arterial ischaemic stroke. Twenty patients in the chronic phase after paediatric arterial ischaemic stroke (≥2 years after diagnosis, diagnosed <16 years; aged 5-23 years, mean: 15.1 years) and 20 healthy controls matched for age and sex were examined in a cross-sectional study design. Cognitive performance (selective attention, inhibition, working memory, and cognitive flexibility) was evaluated using standardized neuropsychological tests. Resting-state functional magnetic resonance imaging was used to examine functional thalamo-cortical connectivity. Lesion masks were integrated in the preprocessing pipeline to ensure that structurally damaged voxels did not influence functional connectivity analyses. Cognitive performance (selective attention, inhibition, and working memory) was significantly reduced in patients compared to controls. Network analyses revealed significantly lower thalamo-cortical connectivity for the motor, auditory, visual, default mode network, salience, left/right executive, and dorsal attention network in patients compared with controls. Interestingly, analyses additionally revealed higher thalamo-cortical connectivity in some subdivisions of the thalamus for the default mode network (medial nuclei), motor (lateral nuclei), dorsal attention (anterior nuclei), and the left executive network (posterior nuclei) in patients compared with controls. Increased and decreased thalamo-cortical connectivity strength within the same networks was, however, found in different thalamic subdivisions. Thus, alterations in thalamo-cortical connectivity strength after paediatric stroke seem to point in both directions, with stronger as well as weaker thalamo-cortical connectivity in patients compared with controls. Multivariate linear regression, with lesion size and age as covariates, revealed significant correlations between cognitive performance (selective attention, inhibition, and working memory) and the strength of thalamo-cortical connectivity in the motor, auditory, visual, default mode network, posterior default mode network, salience, left/right executive, and dorsal attention network after childhood stroke. Our data suggest that the interaction between different sub-nuclei of the thalamus and several cortical networks relates to post-stroke cognition. The variability in cognitive outcomes after paediatric stroke might partly be explained by functional thalamo-cortical connectivity strength.

Neural correlates of working memory and its association with metabolic parameters in early-treated adults with phenylketonuria.

BACKGROUND: Phenylketonuria (PKU) is an inborn error of metabolism affecting the conversion of phenylalanine (Phe) into tyrosine. Previous research has found cognitive and functional brain alterations in individuals with PKU even if treated early. However, little is known about working memory processing and its association with task performance and metabolic parameters. The aim of the present study was to examine neural correlates of working memory and its association with metabolic parameters in early-treated adults with PKU. METHODS: This cross-sectional study included 20 early-treated adults with PKU (mean age: 31.4 years ± 9.0) and 40 healthy controls with comparable age, sex, and education (mean age: 29.8 years ± 8.2). All participants underwent functional magnetic resonance imaging (fMRI) of working memory to evaluate the fronto-parietal working memory network. Fasting blood samples were collected from the individuals with PKU to acquire a concurrent plasma amino acid profile, and retrospective Phe concentrations were obtained to estimate an index of dietary control. RESULTS: On a cognitive level, early-treated adults with PKU displayed significantly lower accuracy but comparable reaction time in the working memory task compared to the control group. Whole-brain analyses did not reveal differences in working memory-related neural activation between the groups. Exploratory region-of-interest (ROI) analyses indicated reduced neural activation in the left and right middle frontal gyri and the right superior frontal gyrus in the PKU group compared to the control group. However, none of the ROI analyses survived correction for multiple comparisons. Neural activation was related to concurrent Phe, tyrosine, and tryptophan concentrations but not to retrospective Phe concentrations. CONCLUSION: In early-treated adults with PKU, cognitive performance and neural activation are slightly altered, a result that is partly related to metabolic parameters. This study offers a rare insight into the complex interplay between metabolic parameters, neural activation, and cognitive performance in a sample of individuals with PKU.

Relationship between motor abilities and executive functions in patients after pediatric stroke.

Patients after pediatric stroke typically experience varying extent of motor and cognitive impairments. During rehabilitation, these impairments are often treated as separate entities. While there is a notion claiming that motor and cognitive functions are interrelated to some degree in healthy children, a minimal amount of evidence exists regarding this issue in patients after pediatric stroke. The purpose of this study was to investigate the association between motor abilities and executive functions in patients after pediatric arterial ischemic stroke. Twenty-seven patients (6 - 23 years) diagnosed with pediatric arterial ischemic stroke in the chronic phase (≥ 2 years after diagnosis, diagnosed < 16 years) and 49 healthy controls (6 - 26 years) were included in this study. Participants completed six tasks from standardized neuropsychological tests assessing the dimensions of executive functions, namely working memory, inhibition, and shifting. Additionally, we assessed hand strength and upper limb performance with two tasks each. In the patient group, the association between upper limb performance and executive functions was stronger than between hand strength and executive functions. Our results point toward the idea of a close interrelation between upper limb performance and executive functions. Training more complex and cognitively engaging motor abilities involving upper limb performance rather than basic motor abilities such as hand strength during a rehabilitation program may have the power to foster executive function development and vice versa in patients after stroke.