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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

Effect of Age at Pediatric Stroke on Long-term Cognitive Outcome.

BACKGROUND AND OBJECTIVES: To investigate the effect of age at pediatric arterial ischemic stroke on long-term cognitive outcome in order to identify patients particularly at risk for the development of long-term cognitive sequelae. METHODS: This cross-sectional study included patients in the chronic phase of stroke (>2 years after stroke) previously diagnosed with neonatal or childhood arterial ischemic stroke and a control group. Participants with active epilepsy, severe learning difficulties, or behavioral problems hindering the cognitive assessment were excluded. Several cognitive domains, including intelligence, executive functions (working memory, inhibition, and cognitive flexibility), processing speed, memory, letter fluency, and visual-motor skills were assessed with neuropsychological tests. Cognitive long-term outcome was compared across patients after neonatal stroke (stroke between 0 and 28 days of life), early childhood stroke (stroke between 29 days and <6 years), and late childhood stroke (stroke between ≥6 and <16 years). RESULTS: Fifty-two patients after neonatal or childhood arterial ischemic stroke (median age 15.3 years, interquartile range [IQR] 10.6-18.7) and 49 healthy controls (median age 13.6 years, IQR 9.8-17.2) met the inclusion criteria. Cognitive outcome was significantly worse in the pediatric stroke group compared to the control group. A nonlinear effect of age at stroke (irrespective of lesion size and lesion location) was found for cognitive flexibility, processing speed, and verbal learning with early childhood stroke (29 days to <6 years), showing significantly worse cognitive outcome compared to neonatal or late childhood stroke (p < 0.05, false discovery rate-corrected). DISCUSSION: Age at stroke is an important factor for poststroke recovery and modulates long-term cognitive outcome irrespective of lesion size and lesion location. Children after early childhood stroke are at particular risk for long-term alterations in cognitive functions.

Cerebral blood flow and cognitive outcome after pediatric stroke in the middle cerebral artery.

Adaptive recovery of cerebral perfusion after pediatric arterial ischemic stroke (AIS) is sought to be crucial for sustainable rehabilitation of cognitive functions. We therefore examined cerebral blood flow (CBF) in the chronic stage after stroke and its association with cognitive outcome in patients after pediatric AIS. This cross-sectional study investigated CBF and cognitive functions in 14 patients (age 13.5 ± 4.4 years) after pediatric AIS in the middle cerebral artery (time since AIS was at least 2 years prior to assessment) when compared with 36 healthy controls (aged 13.8 ± 4.3 years). Cognitive functions were assessed with neuropsychological tests, CBF was measured with arterial spin labeled imaging in the anterior, middle, and posterior cerebral artery (ACA, MCA, PCA). Patients had significantly lower IQ scores and poorer cognitive functions compared to healthy controls (p < 0.026) but mean performance was within the normal range in all cognitive domains. Arterial spin labeled imaging revealed significantly lower CBF in the ipsilesional MCA and PCA in patients compared to healthy controls. Further, we found significantly higher interhemispheric perfusion imbalance in the MCA in patients compared to controls. Higher interhemispheric perfusion imbalance in the MCA was significantly associated with lower working memory performance. Our findings revealed that even years after a pediatric stroke in the MCA, reduced ipsilesional cerebral blood flow occurs in the MCA and PCA and that interhemispheric imbalance is associated with cognitive performance. Thus, our data suggest that cerebral hypoperfusion might underlie some of the variability observed in long-term outcome after pediatric stroke.

Participation after childhood stroke: Is there a relationship with lesion size, motor function and manual ability?

BACKGROUND: Childhood arterial ischemic stroke (AIS) is associated with significant morbidity with up to 50% of affected children developing hemiparesis. Hemiparesis is assumed to influence participation within the peer group, but it is unclear to what extent its severity affects participation in different areas of social life. METHODS: Thirteen children (mean age 9y6m) with AIS (6 without hemiparesis, 7 with hemiparesis) and 21 controls (mean age 9y8m) participated. We scored hemiparesis severity with hand strength asymmetry (pinch and grip strength), measured with a dynamometer. We assessed manual ability (ABILHAND-Kids), socioeconomic status (Family Affluence Scale) and participation (Participation and Environment Measure - Children and Youth). From structural MRI, we measured lesion size. We investigated differences in participation and its relationship with hemiparesis severity using non-parametric partial correlations (controlling for lesion size, manual ability, and socioeconomic status), interpreted as absent (r < 0.25), weak (r = 0.25-0.50), moderate (r = 0.50-0.75) or strong (r > 0.75). Analyses were performed in jamovi 1.6.3. RESULTS: Children with AIS (with or without hemiparesis) showed reduced participation frequency at school (p < 0.001), whilst participation at home and in the community resembled that of their peers. Severity of hemiparesis was moderately related to frequency and involvement at home and to involvement and desire for change in the community, although unrelated to school participation. CONCLUSION: Reduced participation in school life requires close attention in the follow-up of children with AIS - regardless of the severity of hemiparesis. Participation at home and in the community is related to hemiparesis severity and may be improved with participation-focused motor intervention strategies.

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.

The Working Memory Network and Its Association with Working Memory Performance in Survivors of non-CNS Childhood Cancer.

Childhood cancer and its treatment puts survivors at risk of low working memory capacity. Working memory represents a core cognitive function, which is crucial in daily life and academic tasks. The aim of this functional MRI (fMRI) study was to examine the working memory network of survivors of childhood cancer without central nervous system (CNS) involvement and its relation to cognitive performance. Thirty survivors (aged 7-16 years, ≥ 1 year after cancer treatment) and 30 healthy controls performed a visuospatial working memory task during MRI, including a low- and a high-demand condition. Working memory performance was assessed using standardized tests outside the scanner. When cognitive demands increased, survivors performed worse than controls and showed evidence for slightly atypical working memory-related activation. The survivor group exhibited hyperactivation in the right-hemispheric superior parietal lobe (SPL) in the high- compared to the low-demand working memory condition, while maintaining their performance levels. Hyperactivation in the right SPL coincided with poorer working memory performance outside the scanner in survivors. Even in survivors of childhood cancer without CNS involvement, we find neural markers pointing toward late effects in the cerebral working memory network.AbbreviationsfMRI: Functional magnetic resonance imaging; CNS: Central nervous system; MNI: Montreal Neurological Institute; SES: Socioeconomic status; SPL: Superior parietal lobe.

Functional connectivity and upper limb function in patients after pediatric arterial ischemic stroke with contralateral corticospinal tract wiring.

To develop individualized motor rehabilitation, knowledge of the relationship between neuroplastic reorganization and motor recovery after pediatric arterial ischemic stroke (AIS) is crucial. Thus, we investigated functional connectivity in patients after AIS with good motor outcome and in patients with hemiparesis compared with typically developing peers. We included 18 patients (n = 9 with hemiparesis, n = 9 with good motor outcome) with pediatric AIS in the chronic phase (≥ 2 years after diagnosis, diagnosed > 16 years) and 18 peers matched by age and gender. Participants underwent a standardized motor assessment, single-pulse transcranial magnetic stimulation to determine the type of corticospinal tract wiring, and resting-state functional magnetic resonance imaging to examine motor network connectivity. Corticospinal tract wiring was contralateral in all participants. Patients with hemiparesis had lower interhemispheric connectivity strength compared with patients with good clinical outcome and peers. Patients with good clinical outcome had higher intrahemispheric connectivity strength compared with peers. Further, higher intrahemispheric connectivity was related to better motor outcome in patients. Our findings suggest that better motor outcome after pediatric AIS is related to higher motor network connectivity strength. Thus, resting-state functional connectivity might be predictive for motor recovery after pediatric AIS.