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Background and AimsA chronic feeling of fatigue occurs in up to 85% of childhood cancer survivors (CCS). This phenomenon has a detrimental effect on quality of life, reintegration in daily life activities and psychosocial functioning of the patient. Therefore, it is important to elucidate potential individual risk and protective factors. MethodsCCS who were treated in the University Hospital of Leuven, completed two annual questionnaires on cancer-related distress (fear of cancer recurrence and post-traumatic stress, resilience and fatigue). Associations between distress and fatigue levels were examined by performing cross-lagged panel analyses. Resilience was included as a potential moderator. These models included all within-time associations, stability paths, and cross-lagged paths. Gender and time since diagnosis were included as covariates. ResultsIn total, 110 CCS participated in this study, aged 14-25 years (average time since diagnosis 12.2 years; 41.8% boys; diagnosed with leukemia/lymphoma [49%], solid tumor [15%], brain tumor [16%] or other [20%]). Fear of cancer recurrence and post-traumatic stress at baseline positively predicted fatigue 1 year later. Cross-lagged panel analyses showed that resilience did not buffer the effect of fear of cancer recurrence on fatigue, in contrary to our expectations. Stability coefficients were high for all study variables. ConclusionThis study indicates associations between cancer-related distress (fear of cancer recurrence and post-traumatic stress), resilience and cancer-related fatigue over time in CCS. Interventions to improve fatigue levels could be focusing on both tackling cancer-related distress, while improving resilience levels as well.

Objective As preservation of cognitive functioning increasingly becomes important in the light of ameliorated survival after intracranial tumor treatments, identification of eloquent brain areas would enable optimization of these treatments. Methods This cohort study enrolled adult intracranial tumor patients who received neuropsychological assessments pre-irradiation, estimating processing speed, verbal fluency and memory. Anatomical magnetic resonance imaging scans were used for multivariate voxel-wise lesion-symptom predictions of the test scores (corrected for age, gender, educational level, histological subtype, surgery, and tumor volume). Potential effects of histological and molecular subtype and corresponding WHO grades on the risk of cognitive impairment were investigated using Chi square tests. P-values were adjusted for multiple comparisons (p Results A cohort of 179 intracranial tumor patients was included [aged 19–85 years, median age (SD) = 58.46 (14.62), 50% females]. In this cohort, test-specific impairment was detected in 20–30% of patients. Higher WHO grade was associated with lower processing speed, cognitive flexibility and delayed memory in gliomas, while no acute surgery-effects were found. No grading, nor surgery effects were found in meningiomas. The voxel-wise analyses showed that tumor locations in left temporal areas and right temporo-parietal areas were related to verbal memory and processing speed, respectively. Interpretation Patients with intracranial tumors affecting the left temporal areas and right temporo-parietal areas might specifically be vulnerable for lower verbal memory and processing speed. These specific patients at-risk might benefit from early-stage interventions. Furthermore, based on future validation studies, imaging-informed surgical and radiotherapy planning could further be improved.

BACKGROUND: The connectome, constituting a unique fingerprint of a person's brain, may be influenced by its prenatal environment, potentially affecting later-life resilience and mental health. METHODS: We conducted a prospective resting-state functional Magnetic Resonance Imaging study in 28-year-old offspring (N = 49) of mothers whose anxiety was monitored during pregnancy. Two offspring anxiety subgroups were defined: "High anxiety" (n = 13) group versus "low-to-medium anxiety" (n = 36) group, based on maternal self-reported state anxiety at 12-22 weeks of gestation. To predict resting-state functional connectivity of 32 by 32 ROIs, maternal state anxiety during pregnancy was included as a predictor in general linear models for both ROI-to-ROI and graph theoretical metrics. Sex, birth weight and postnatal anxiety were included as covariates. RESULTS: Higher maternal anxiety was associated with weaker functional connectivity of medial prefrontal cortex with left inferior frontal gyrus (t = 3.45, pFDR < 0.05). Moreover, network-based statistics (NBS) confirmed our finding and revealed an additional association of weaker connectivity between left lateral prefontal cortex with left somatosensory motor gyrus in the offspring. While our results showed a general pattern of lower functional connectivity in adults prenatally exposed to maternal anxiety, we did not observe significant differences in global brain networks between groups. CONCLUSIONS: Weaker (medial) prefrontal cortex functional connectivity in the high anxiety adult offspring group suggests a long-term negative impact of prenatal exposure to high maternal anxiety, extending into adulthood. To prevent mental health problems at population level, universal primary prevention strategies should aim at lowering maternal anxiety during pregnancy. ispartof: Brain Imaging And Behavior pages:1-13 ispartof: location:United States status: Published online

Background Cognitive functioning is increasingly assessed as a secondary outcome in neuro-oncological trials. However, which cognitive domains or tests to assess, remains debatable. In this meta-analysis, we aimed to elucidate the longer-term test-specific cognitive outcomes in adult glioma patients. Methods A systematic search yielded 7098 articles for screening. To investigate cognitive changes in glioma patients and differences between patients and controls 1-year follow-up, random-effects meta-analyses were conducted per cognitive test, separately for studies with a longitudinal and cross-sectional design. A meta-regression analysis with a moderator for interval testing (additional cognitive testing between baseline and 1-year posttreatment) was performed to investigate the impact of practice in longitudinal designs. Results Eighty-three studies were reviewed, of which 37 were analyzed in the meta-analysis, involving 4078 patients. In longitudinal designs, semantic fluency was the most sensitive test to detect cognitive decline over time. Cognitive performance on mini-mental state exam (MMSE), digit span forward, phonemic and semantic fluency declined over time in patients who had no interval testing. In cross-sectional studies, patients performed worse than controls on the MMSE, digit span backward, semantic fluency, Stroop speed interference task, trail-making test B, and finger tapping. Conclusions Cognitive performance of glioma patients 1 year after treatment is significantly lower compared to the norm, with specific tests potentially being more sensitive. Cognitive decline over time occurs as well, but can easily be overlooked in longitudinal designs due to practice effects (as a result of interval testing). It is warranted to sufficiently correct for practice effects in future longitudinal trials.

Improved treatment landscape has led to better outcomes for paediatric acute lymphoblastic leukemia (ALL) survivors. As the number of survivors increase, we need to elucidate the long-term quality of life (QoL) and domains of complaints in these patients. Furthermore, the main priorities of these patients need to be clarified. We assessed long-term QoL outcomes of survivors of childhood ALL compared to matched population controls.QoL data were collected from survivors recruited in France and Belgium between 2012 and 2017, including the Short Form Health Survey (SF-12) and the Quality of Life Systemic Inventory (QLSI). The Wilcoxon test was used to compare SF-12 scale scores between survivors and matched population controls. For the QLSI, comparisons were mainly descriptive.One hundred and eighty-six survivors (mean age: 27.6 years; range: 18.1-52.8) at follow-up completed QoL measures, amongst whom 180 were matched to controls. Overall, survivors had higher QoL on all SF12 scale scores, indicating that they had better functioning compared to controls. Statistically significant differences on the SF12 were observed for Vitality, Social Functioning, Role Limitations due to Emotional Problems and Mental Health scales. QLSI outcomes suggested that survivors were happier than controls with Couple and Social Relations. Controls were unhappiest compared to survivors with Money, Love life, Self-esteem, Nutrition and Paid Work.Our findings suggest that survivors of childhood ALL have better QoL outcomes on some domains compared to the general population, specifically around social and emotional functioning, and that they tend to prioritize their relationships more. Interventions for improving QoL outcomes, might build on existing positive experiences with family, friends and partners.

Medulloblastoma is a malign posterior fossa brain tumor, mostly occurring in childhood. The CNS-directed chemoradiotherapy treatment can be very harmful to the developing brain and functional outcomes of these patients. However, what the underlying neurotoxic mechanisms are remain inconclusive. Hence, this review summarizes the existing literature on the association between advanced neuroimaging and neurocognitive changes in patients that were treated for pediatric medulloblastoma. The PubMed/Medline database was extensively screened for studies investigating the link between cognitive outcomes and multimodal magnetic resonance (MR) imaging in childhood medulloblastoma survivors. A behavioral meta-analysis was performed on the available IQ scores. A total of 649 studies were screened, of which 22 studies were included. Based on this literature review, we conclude medulloblastoma patients to be at risk for white matter volume loss, more frequent white matter lesions, and changes in white matter microstructure. Such microstructural alterations were associated with lower IQ, which reached the clinical cut-off in survivors across studies. Using functional MR scans, changes in activity were observed in cerebellar areas, associated with working memory and processing speed. Finally, cerebral microbleeds were encountered more often, but these were not associated with cognitive outcomes. Regarding intervention studies, computerized cognitive training was associated with changes in prefrontal and cerebellar activation and physical training might result in microstructural and cortical alterations. Hence, to better define the neural targets for interventions in pediatric medulloblastoma patients, this review suggests working towards neuroimaging-based predictions of cognitive outcomes. To reach this goal, large multimodal prospective imaging studies are highly recommended.

Background Many breast cancer survivors suffer from cognitive complaints after cancer treatment, affecting their quality of life. The objective of this pilot study was to investigate the effect of a blended‐care mindfulness‐based intervention (MBI) on chemotherapy‐related cognitive impairment and functional brain changes. Furthermore, correlations between changes in cognitive functioning and self‐reported behavioral factors were investigated. Methods Breast cancer survivors (n = 33) who reported cognitive impairment were randomly allocated to a mindfulness condition (n = 18) or a waitlist control condition (n = 15). Patients completed questionnaires on cognitive impairment, emotional distress, and fatigue; neuropsychological tests; and resting‐state functional magnetic resonance imaging before the start of MBI (time 1 [T1]), immediately after the completion of an 8‐week MBI program (T2), and 3 months postintervention (T3). Resting‐state functional connectivity was estimated in the default mode network, the dorsal and salience attention networks, and the frontoparietal network. Mixed model repeated‐measures analysis was performed to test the intervention effect. Results Patients in the mindfulness condition exhibited significantly higher connectivity between the dorsal and salience attention networks after the mindfulness intervention compared with those in the control condition. MBI participants also had reduced subjective cognitive impairment, emotional distress, and fatigue. No intervention effect was observed on neurocognitive tests. Conclusions MBI may induce functional brain changes in networks related to attention and may have a positive effect on subjective measures of cognitive impairment in breast cancer survivors. Therefore, MBI could be a suitable intervention to improve quality of life in this population and deserves further study in this context. ispartof: Cancer vol:126 issue:18 pages:4246-4255 ispartof: location:United States status: published

Long-term sequelae are well-known in childhood brain tumor survivors, but motor functioning remains poorly described. This cross-sectional study aimed to assess objective motor functioning, patient-specific risk factors, and parental perceptions. Fifty-two childhood brain tumor patients (pilocytic astrocytoma, medulloblastoma, and other types) who were at least 6 months out of treatment were evaluated. Mean age at testing was 11.7 years. Objective motor functioning was assessed with the Movement Assessment Battery for Children (MABC-2-NL) and/or Bruininks-Oseretsky test of motor proficiency (BOT-2). Functional walking capacity was assessed with the 6-min walk test (6MWT). Parent-reported motor functioning was addressed using the ABILHAND-Kids, ABILOCO-Kids questionnaires, and a standardized anamnesis. Patients showed impaired motor functioning in all domains (p p = 0.006). Adjuvant treatment resulted in lower scores for fine manual control of the BOT-2 (p = 0.024) and balance of MABC-2-NL (p = 0.036). Finally, questionnaires revealed an underestimation of motor problems as perceived by the parents. In conclusion, many children who are in follow-up for a brain tumor show impaired motor functioning on multiple aspects, with younger age at diagnosis and adjuvant treatment as specific risk factors. Based on the questionnaires and anamnesis, motor problems appear to be underestimated by the parents. Conclusion: These findings point to the need for timely prospective screening of motor functioning. Based on a screening assessment, adequate rehabilitation programs can be applied in childhood brain tumor survivors, aiming to reduce the adverse impact on their daily lives, both for functional activities and cardiovascular fitness. What is Known:• A pediatric brain tumor and its treatment are associated with potential long-term motor sequelae.• Test assessments could enable us to objectify motor functioning of these patients. What is New:• Pediatric brain tumors survivors show lower motor performance compared to the norm, which is often underestimated by parents.• Younger age at diagnosis and adjuvant treatment could be specific risk factors.

UNLABELLED: Acute lymphoblastic leukaemia/lymphoma (ALL/LBL) and its treatment interfere with normal physical functioning. However, it remains unclear how physical fitness (PF) is affected throughout treatment for ALL/LBL. Sixty-two patients (2.1 to 18.3 years) treated for ALL/LBL underwent four physical tests at nine timepoints from baseline up to 6 months post-treatment. We assessed muscle strength of the quadriceps and tibialis anterior, standing broad jump test (SBJ) for functional mobility and six-minute walk test (6MWT) for endurance. One-sample t-tests were used to compare our results to the norm at each timepoint. Norm-referenced Z-scores were predicted based on time, risk group and age at diagnosis, using linear mixed models. Quadriceps strength, SBJ and 6MWT scores were significantly lower than norm values at all timepoints from diagnosis up to 6 months after maintenance therapy. Significant decreases over time were encountered for quadriceps strength and SBJ, mainly occurring after induction therapy (F = 3.568, p

Long-term neurocognitive difficulties in children treated for a brain tumor are well documented and known to be affected by treatment. However, longitudinal studies of these neurocognitive difficulties are scarce. In the present study, we investigated the impact of radiotherapy (RT) on the evolution of neurocognition between different consecutive time points after diagnosis, and throughout treatment and survivorship. This study included 69 children diagnosed with a brain tumor at the University Hospitals Leuven who completed a comprehensive neuropsychological test battery (intelligence, memory, visuomotor functioning, and QoL) on at least three consecutive time points (2-year interval). Of all patients, 40 completed the test battery at 4 time points. The first assessment was conducted at the earliest possible moment after diagnosis and before the start of any adjuvant therapy. Mean age at diagnosis and first assessment were 7.75 and 7.92 years, respectively. The most common diagnoses were pilocytic astrocytoma (n=33) and medulloblastoma (n=11). 29.0% of the children received local RT and 15.9% received craniospinal RT. A repeated measures analysis with cranial irradiation (no, focal, craniospinal) as between-subjects factor and age at diagnosis as covariate demonstrated a significant interaction effect between time and type of irradiation for both overall intelligence (p=0.007) and QoL (p=0.006) for children with three and four assessments. Children who received craniospinal irradiation demonstrated a significant decline in overall intelligence and a significant worsening of QoL. For the non-irradiated group, an improvement of QoL was observed. For processing speed, a significant time effect was found for children with three and four assessments (p

A brain tumor treatment has previously been associated with long-term neurocognitive sequelae. However, clinical profiles differ between certain patient subgroups. We investigated the impact of tumor location, radiotherapy (RT), and age at diagnosis in childhood brain tumor survivors on long-term cognitive outcomes. Adult survivors (n=32) of pediatric brain tumors (n=11 infratentorial, n=21 supratentorial; 14 astrocytomas, 3 craniopharyngiomas, 2 ependymomas, 2 germinomas, 1 hemangioblastomas, 4 medulloblastomas, 6 nervus opticus gliomas) participated in this neuropsychological study (n=11 RT) (16.8-35.1 years old, >2years after treatment, mean age at diagnosis = 9.2 years, 50% male). An extensive neurocognitive test battery was used to assess intelligence scales (n=5), verbal and visual memory (n=2), and language (n=3). In order to investigate the effects of tumor location (infra- versus supratentorial), RT (yes vs. no), and age at diagnosis on the cognitive scores, a multivariate ANCOVA model was tested including the main effects and interaction between age and RT. Of all included scales, only visual memory was significantly associated with the risk factors. More specifically, patients who received RT (F=10.3, p=.004) and were younger at diagnosis (F=6.9, p=.014) scored worse on this task. Furthermore, the interaction effect between these factors was also significant (F=8.8, p=.006). These findings suggest that younger patients could be more vulnerable to the radiotoxic effects to visual memory outcomes. Tumor location (supra- vs. infratentorial) was not significantly associated with any outcome. In this study, only visual memory appeared to be associated with the risk factors of interest. Both radiotherapy and age at radiotherapy, as well as their interaction, could be risk factors for altered neurodevelopmental patterns of brain areas associated with visual memory.

Simple Summary Up to 70% of chemotherapy-treated patients experience problems with memory and concentration, potentially caused by direct and indirect neurotoxicity, such as (neuro-)inflammatory processes. Can neuroinflammation changes be detected in chemotherapy-treated patients with breast cancer using translocator protein [18F]DPA714 simultaneous positron emission tomographic- and magnetic resonance imaging? Moreover, what is the association with clinical biomarkers? In a study including 19 chemotherapy-treated breast cancer patients, 18 chemotherapy-naïve and 37 healthy controls, we found significant relative glial overexpression in parietal and occipital brain regions in chemotherapy-treated patients compared to controls, which were associated with cognitive abnormalities and markers of neuronal survival. Shortly after ending chemotherapy, changes in brain neuroinflammation seem to occur, possibly contributing to the cognitive decline seen in breast cancer patients. Additionally, blood levels of an axonal damage marker were 20-fold higher in chemotherapy-treated patients, providing evidence for its use as a biomarker to assess neurotoxic effects of anticancer chemotherapies. Abstract To uncover mechanisms underlying chemotherapy-induced cognitive impairment in breast cancer, we studied new biomarkers of neuroinflammation and neuronal survival. This cohort study included 74 women (47 ± 10 years) from 22 October 2017 until 20 August 2020. Nineteen chemotherapy-treated and 18 chemotherapy-naïve patients with breast cancer were assessed one month after the completion of surgery and/or chemotherapy, and 37 healthy controls were included. Assessments included neuropsychological testing, questionnaires, blood sampling for 17 inflammatory and two neuronal survival markers (neurofilament light-chain (NfL), and brain-derived neurotrophic factor (BDNF) and PET-MR neuroimaging. To investigate neuroinflammation, translocator protein (TSPO) [18F]DPA714-PET-MR was acquired for 15 participants per group, and evaluated by volume of distribution normalized to the cerebellum. Chemotherapy-treated patients showed higher TSPO expression, indicative for neuroinflammation, in the occipital and parietal lobe when compared to healthy controls or chemotherapy-naïve patients. After partial-volume correction, differences with healthy controls persisted (pFWE < 0.05). Additionally, compared to healthy- or chemotherapy-naïve controls, cognitive impairment (17–22%) and altered levels in blood markers (F ≥ 3.7, p ≤ 0.031) were found in chemotherapy-treated patients. NfL, an axonal damage marker, was particularly sensitive in differentiating groups (F = 105, p = 4.2 × 10 −21), with levels 20-fold higher in chemotherapy-treated patients. Lastly, in chemotherapy-treated patients alone, higher local TSPO expression was associated with worse cognitive performance, higher blood levels of BDNF/NfL, and decreased fiber cross-section in the corpus callosum (pFWE < 0.05). These findings suggest that increased neuroinflammation is associated with chemotherapy-related cognitive impairment in breast cancer. Additionally, NfL could be a useful biomarker to assess neurotoxic effects of anticancer chemotherapies.

Repetition suppression (RS) reflects a neural attenuation during repeated stimulation. We used fMRI and the subsequent memory paradigm to test the predictive coding hypothesis for RS during visual memory processing by investigating the interaction between RS and differences due to memory in category-selective cortex (FFA, pSTS, PPA, and RSC). Fifty-six participants encoded face and house stimuli twice, followed by an immediate and delayed (48 h) recognition memory assessment. Linear Mixed Model analyses with repetition, subsequent recognition performance, and their interaction as fixed effects revealed that absolute RS during encoding interacts with probability of future remembrance in face-selective cortex. This effect was not observed for relative RS, i.e. when controlled for adapter-response. The findings also reveal an association between adapter response and RS, both for short and long term (48h) intervals, after controlling for the mathematical dependence between both measures. These combined findings are challenging for predictive coding models of visual memory and are more compatible with adapter-related and familiarity accounts., In order to examine underlying mechanisms of repetition suppression, Stam et al conducted an fMRI study in which participants were presented with face and house stimuli followed by an immediate and 48 h-delayed memory task. Their data demonstrated that adapter-related and familiarity account modelling are more likely to be more accurate for visual memory than previous predictive coding models.

Methotrexate (MTX), an important chemotherapeutic agent, is often accompanied with mucositis. The occurrence and severity are unpredictable and show large interindividual variability. In this study, we review and meta-analyze previously studied genetic variants in relation to MTX-induced mucositis. We conducted a systematic search in Medline and Embase. We included genetic association studies of MTX-induced mucositis in cancer patients. A meta-analysis was conducted for single nucleotide polymorphisms (SNPs) for which at least two studies found a statistically significant association. A total of 34 SNPs were associated with mucositis in at least one study of the 57 included studies. Two of the seven SNPs included in our meta-analysis were statistically significantly associated with mucositis: MTHFR c.677C > T (recessive, grade ≥3 vs grade 0–2, OR 2.53, 95 %CI [1.48–4.32], False Discovery Rate[FDR]-corrected p-value 0.011) and MTRR c.66A > G (overdominant, grade ≥1 vs grade 0, OR 2.08, 95 %CI [1.16–3.73], FDR-corrected p-value 0.042).

The rise in cancer survival rates has raised concerns about the long-term adverse effects of cancer treatment, including neurocognitive impairment. Neurocognitive deficits such as attention and processing speed are frequently observed and can have a profound, lifelong impact in daily life of cancer patients. Interestingly, large interpatient variability exists in cognitive outcomes. Emerging evidence indicates that such differences may be related to genetic variation. The aim of our review was to systematically summarize the current literature on the modulatory effects of germline genetic polymorphisms on cancer treatment-induced cognitive changes and the potential age-dependent impact in cancer survivors. The PubMed/Medline database was screened using an extensive search string focusing on four components: "cancer", "cancer treatment", "neurocognitive outcome" and "germline genetic variation". Seventeen studies meeting predefined eligibility criteria were analyzed, including sixteen candidate gene studies and one genome-wide association study. 38 polymorphisms in 15 genes across proposed pathophysiological pathways, including (1) neural plasticity and repair, (2) neuroinflammation and defenses against oxidative stress, (3) neurotransmission, and (4) folate metabolism pathway, were reported to be significantly associated with treatment-related neurocognitive dysfunction or neuroimaging abnormalities. Still, some study results remained discordant, partly due to the methodological heterogeneity (i.e. in test assessments, age, cancer-type populations). Future large-scale, (epi-)genome studies integrating neurocognitive assessments and advanced neuroimaging techniques, are recommended in order to investigate neurotoxicity throughout the lifespan. Hence, adverse neurodevelopmental problems during childhood and neurodegenerative processes later in life could be minimized based on genetic risk classifications.

This retrospective correlation study investigated the putative link between methylene tetrahydrofolate reductase (MTHFR) A1298C mutations and chemotherapy-related brain function changes in adult childhood-leukemia survivors. To this end, we determined the relationship between the particular MTHFR1298 genotype (AA, AC or CC) of 31 adult childhood-leukemia survivors, and (1) their CSF Tau and phosphorylated Tau (pTau) levels at the time of treatment, (2) their adult performance intelligence quotient (PIQ), and (3) their regional brain connectivity using diffusion magnetic resonance imaging (dMRI) and resting-state functional MRI (rsfMRI). We confirmed that neuropathology markers Tau and pTau significantly increased in CSF of children after intrathecal methotrexate administration. Highest concentrations of these toxicity markers were found during the induction phase of the therapy. Moreover, CSF concentrations of Tau and pTau during treatment were influenced by the children's particular MTHFR1298 genotype. CSF Tau (but not pTau) levels significantly dropped after folinic acid supplementation. At adult age (on average 13.1 years since the end of their treatment), their particular MTHFR1298 genotype (AA, AC or CC) influenced the changes in PIQ and cortical connectivity that we found to be related to their childhood exposure to chemotherapeutics. In summary, we suggest that homozygous MTHFR1298CC individuals are more vulnerable to the adult sequelae of antifolate chemotherapy. ispartof: Plos One vol:16 issue:4 pages:1-13 ispartof: location:United States status: published

Simple Summary In this study, we investigated standardized post-chemotherapy magnetic resonance (MR) scans for leukoencephalopathy and patient- and treatment-related risk factors in childhood leukemia patients. As prevalence numbers are limited, our study provides the required estimations for this population. Furthermore, we demonstrate that younger patients might be more at-risk for development of leukoencephalopathy (LE), and that a higher intravenous methotrexate (IV-MTX) dose has a cumulative toxic effect, while the number of intrathecal administrations was not significantly associated with the extent of LE. This can suggest we should modify chemotherapeutic treatment regimens by decreasing the number of IV-MTX applications, with special attention for younger patients. Abstract Methotrexate (MTX) is associated with leukoencephalopathy (LE) in children treated for lymphoblastic leukemia/lymphoma (ALL/LBL). However, large-scale studies with systematic MR acquisition and quantitative volumetric lesion information remain limited. Hence, the prevalence of lesion burdens and the potential risk factors of LE in this population are still inconclusive. FLAIR-MRI scans were acquired at the end of treatment in children who were treated for ALL/LBL, which were quantitatively analyzed for LE. Voxels were assigned to the lesion segmentation if indicated by two raters. Logistic and linear regression models were used to test whether lesion presence and size were predicted by risk factors such as age at diagnosis, gender, intrathecal (IT-) or intravenous (IV-)MTX dose, CNS invasion, and acute neurological events. Patients with a pre-existing neurological condition or low-quality MR scan were excluded from the analyses. Of the 129 patients, ten (8%) suffered from CNS invasion. Chemotherapy-associated neurological events were observed in 13 patients (10%) during therapy, and 68 patients (53%) showed LE post-treatment. LE was more frequent in cases of lower age and higher cumulative IV-MTX doses, while the extent of LE and neurological symptoms were associated only with IV-MTX doses. Neurological events were not significantly associated with LE, even though symptomatic patients demonstrated a higher ratio of LE (n = 9/13) than asymptomatic patients (n = 59/116). This study suggests leukoencephalopathy frequently occurs in both symptomatic and asymptomatic leukemia patients. Younger children and patients treated with higher cumulative IV-MTX doses might need more regular screening for early detection and follow-up of associated sequelae.

Due to the rising use of chemotherapy treatment in cancer patients and growing survival rates, therapy-induced neurotoxic side effects are increasingly reported. Given the ambiguity about the prevalence and severity of leukoencephalopathy, one of such toxic side effects, in non-central nervous system (CNS) cancer patients, we performed a systematic literature search using the PubMed/Medline database to summarize existing literature regarding leukoencephalopathy epidemiology in non-CNS cancer patients and its potential cognitive sequelae. The search was based on the following terms: ('MRI' OR 'T2-weighted MRI' OR 'FLAIR') AND ('cancer' OR 'tumour' OR 'leukaemia' OR 'neoplasms') AND ('chemotherapy' OR 'radiotherapy') AND ('posterior reversible encephalopathy' OR 'leukoencephalopathy' OR 'cerebral ischaemia' OR 'stroke'). Thirty-two studies discussing the occurrence of leukoencephalopathy in cancer patients were included, of which the majority investigated Acute Lymphoblastic Leukaemia (ALL) patients (n = 22).Regularly scanned ALL patients showed a prevalence of leukoencephalopathy between 17 - 87%, and 15 - 83% of patients presented with leukoencephalopathy when only scanned after a CNS event. When diagnosed with posterior reversible encephalopathy syndrome, 100% of patients showed leukoencephalopathy because its diagnosis is based in part on observable lesions. An increased prevalence was observed in ALL patients treated with higher doses of methotrexate (5 g/m2 MTX, 42 - 87%) when compared to lower doses (< 5 g/m2, 32 - 67%). By contrast, in breast cancer patients, white matter lesions were mainly detected in case of neurological symptoms, but not (yet) clearly associated with chemotherapy administration. However, chemotherapy treatment was associated with more infratentorial microbleeds in breast cancer patients . Up to 50% of other (neurologically asymptomatic) solid tumour patients presented white matter lesions, even years after treatment. When cognitive data were investigated, lesioned patients showed lower scores on neurocognitive tests in 50% of studies, years after ending therapy.In conclusion, leukoencephalopathy is well-documented for ALL patients (with a focus on methotrexate), but there is a lack of knowledge for other intravenous chemotherapeutics, other oncological populations, wider age ranges and possible risk factors (e.g. history of CNS event). Furthermore, the long-term neuropsychological impact and potential risk for neurodegenerative processes due to leukoencephalopathy remains inconclusive. Hence, large international databanks, epidemiological and prospective case-control studies are necessary to stratify risk groups for CNS-related side effects. ispartof: Journal Of Chemotherapy vol:32 issue:7 ispartof: location:England status: Published online

Background Childhood infratentorial tumor patients frequently suffer from long-term cognitive deficits. As each constituent of their treatment can lead to neurotoxicity, cascade effects can lead to profound reorganization of the underlying brain network, the so-called ‘connectome’. However, to date, few studies have assessed the relationship between brain network topology, the functional role of network hubs (i.e. highly connected regions), and neurocognitive outcomes in adult survivors of childhood infratentorial tumors. Methods In this cross-sectional study, childhood infratentorial tumor survivors (n = 21: pilocytic astrocytoma (n = 8), ependymoma (n = 1) and medulloblastoma (n = 12)) and healthy controls (n = 21) were recruited. Using multishell diffusion-weighted MRI, microstructural organization and topology of supratentorial white matter was investigated; using a voxel-based approach, a fixel-based analysis, and a graph theoretical approach. In addition, neurocognitive subscales of the WAIS-IV intelligence test, and their relationship with nodal strength and network efficiency metrics were assessed. Results Similar to earlier studies, we observed widespread decreases in fractional anisotropy (FA) in patients compared to controls, based on voxel-based analyses. In addition, the fixel-based analyses dissociated macro- from microstructural changes, which were encountered in in infratentorial versus supratentorial brain areas, respectively. Finally, regional reorganization (i.e. differences in local efficiency) occurred mainly in hubs, which suggests a specific vulnerability of these areas. These hubs were not only mostly affected, but also most strongly correlated with the intelligence subscales. Conclusion This study suggests that network hubs are functionally important for intellectual outcomes in infratentorial tumor survivors. Furthermore, these regions could be the primary targets of treatment toxicity. Validation of this specific hypothesis in larger samples is required.

High-dose chemotherapy is increasingly evidenced to be neurotoxic and result in long-term neurocognitive sequelae. However, research investigating grey matter alterations in childhood cancer patients remains limited. As childhood sarcoma patients receive high-dose chemotherapy, we aimed to investigate cortical brain alterations in adult survivors. We analyzed high-resolution structural (T1-weighted) MRI and resting-state functional MRI (rsfMRI), to derive structural and functional cortical information in survivors of childhood sarcoma, treated with high-dose intravenous chemotherapy (n = 33). These scans were compared to age- and gender- matched controls (n = 34). Cortical volume and thickness were investigated using voxel-based morphometry and vertex-wise surface-based morphometry. Brain regions showing significant group differences in volume or thickness were implemented as seeds of interest to estimate their resting state co-activity with other areas (i.e. functional coherence). We explored whether structural measures were associated with potential risk factors, such as age at diagnosis, and cumulative doses of chemotherapeutic agents (methotrexate, ifosfamide). Finally, we investigated the link between functional regional strength, neurocognitive assessments and daily life complaints. In patients relative to controls we observed lower grey matter volumes in cerebellar and frontal areas, as well as frontal cortical thinning. Cerebellar volume and orbitofrontal thickness appeared dose- and age-related, respectively. Cortical thickness of the parahippocampal area appeared lower, only if the group comparison was not adjusted for depression. This region specifically showed lower functional coherence, which was associated with lower processing speed. This study suggests cortical thinning as well as decreased functional coherence in survivors of childhood sarcoma, which could be important for both long-term attentional functioning and emotional distress in daily life. Frontal areas might be specifically vulnerable during adolescence. ispartof: BRAIN IMAGING AND BEHAVIOR vol:15 issue:2 pages:677-688 ispartof: location:United States status: published

Background: This study applies multimodal MRI to investigate neurodevelopment in nine-year-old children born to cancer-complicated pregnancies. Methods: In this cohort study, children born after cancer-complicated pregnancies were recruited alongside 1:1 matched controls regarding age, sex and gestational age at birth (GA). Multimodal MRI was used to investigate whole-brain and subcortical volume, cortical structure (using surface-based morphometry), white matter microstructure (using fixel-based analysis) and functional connectivity (using resting-state bloodoxygen-level-dependant signal correlations). Graph theory probed whole-brain structural and functional organization. For each imaging outcome we conducted two group comparisons: 1) children born after cancer-complicated pregnancies versus matched controls, and 2) the subgroup of children with prenatal chemotherapy exposure versus matched controls. In both models, we used the covariate of GA and the group-byGA interaction, using false-discovery-rate (FDR) or family-wise-error (FWE) correction for multiple comparisons. Exploratory post-hoc analyses investigated the relation between brain structure/function, neuropsychological outcome and maternal oncological/obstetrical history. Findings: Forty-two children born after cancer-complicated pregnancies were included in this study, with 30 prenatally exposed to chemotherapy. Brain organization and functional connectivity were not significantly different between groups. Both cancer and chemotherapy in pregnancy, as compared to matched controls, were associated with a lower travel depth, indicating less pronounced gyrification, in the left superior temporal gyrus (pFDR 006), with post-hoc analysis indicating platinum derivatives during pregnancy as a potential risk factor (p = .028). Both cancer and chemotherapy in pregnancy were related to a lower fibre cross-section (FCS) and lower fibre density and cross-section (FDC) in the posterior corpus callosum and its tapetal fibres, compared to controls. Higher FDC in the chemotherapy subgroup and higher FCS in the whole study group were observed in the anterior thalamic radiations. None of the psycho-behavioural parameters correlated significantly with any of the brain differences in the study group or chemotherapy subgroup. Interpretation: Prenatal exposure to maternal cancer and its treatment might affect local grey and white matter structure, but not functional connectivity or global organization. While platinum-based therapy was identified as a potential risk factor, this was not the case for chemotherapy in general. Funding: This project has received funding from the European Union’s Horizon 2020 research and innovation program (European Research council, grant no 647,047), the Foundation against cancer (Stichting tegen kanker, grant no. 2014 152) and the Research Foundation Flanders (FWO, grants no. 11B9919N, 12ZV420N) ispartof: EClinicalMedicine vol:28 ispartof: location:England status: Published online

Correction to: European Journal of Pediatrics (2022) 181:2731–2740 https://doi.org/10.1007/s00431-022-04472-1In the original published version of the above article, the authors’ names were incorrectly presented. The names are now corrected and cited correctly as, “Gielis, M., Dirix, V., Vanderhenst, E., Uyttebroeck, A., Feys, H., Sleurs, C., Jacobs, S.”

Background: This study aimed to assess functional and structural brain connectivity in adult childhood leukemia survivors and the link with cognitive functioning and previously identified risk factors such as intrathecal methotrexate dose and age at start of therapy. Methods: Thirty-one nonirradiated adult childhood leukemia survivors and 35 controls underwent cognitive testing and multimodal magnetic resonance imaging (resting state functional MRI, T1-weighted, diffusion-weighted, and myelin water imaging [MWI]). Analyses included dual regression, voxel-based morphometry, advanced diffusion, and MWI modeling techniques besides stepwise discriminant function analysis to identify the most affected executive cognitive domain. Correlations with discrete intrathecal MTX doses and (semi)continuous variables were calculated using Spearman’s rank and Pearson’s correlation, respectively. All correlation tests were two-sided. Positive and negative T-contrasts in functional and structural MRI analysis were one-sided. Results: Survivors demonstrated lower functional connectivity between the default mode network (DMN) and inferior temporal gyrus (ITG; P < .008). Additionally, we observed higher fractional anisotropy (FA; P ¼ .04) and lower orientation dispersion index (ODI; P ¼ .008) at the left centrum semiovale, which could—given that several fiber bundles cross this region—suggest selective reduced integrity of the respective white matter tracts. Set shifting reaction time, a measure of cognitive flexibility, was mostly impaired and correlated with lower FA (r ¼ –0.53, P ¼ .003) and higher ODI (r ¼ 0.40, P ¼ .04) in survivors but not with DMN-ITG connectivity. There were no statistically significant differences between survivors and controls in WM or GM volume, nor was there a statistically significant correlation between imaging measurements and age at start of therapy or intrathecal methotrexate dose. Conclusions: Adult, nonirradiated childhood leukemia survivors show altered brain connectivity, which is linked with cognitive flexibility.

Aim: Osteosarcoma patients receive high doses of methotrexate (MTX). However, pharmacogenetic information remains limited and has mainly been investigated in leukemia so far. Patients & methods: We investigated the link between the MTHFR C677T genotype, toxicity levels (mucositis, MTX plasma level, hematological toxicity and hepatotoxicity) and survival of 48 pediatric osteosarcoma patients. Results: The TT genotype did not show more toxicity compared with the CC/CT genotype. However, plasma MTX levels were related with mucositis, but not with hematological toxicity, nor hepatotoxicity. Survival rates did not differ between homozygous and non-homozygous patients. Yet, homozygous patients had higher relapse risk. Conclusion: The MTHFR C667T polymorphism is not predictive for toxicity or overall survival, but could be used for relapse risk stratification.

OBJECTIVE This study examines the long-term impact of prenatal exposure to chemotherapy on executive functioning and the contribution of late-prematurity to this effect, using event- related potentials. METHODS Mothers of the prenatal-exposed children (n=20) were diagnosed with cancer and received chemotherapeutic treatment during pregnancy. We recruited healthy controls (n=20) who were matched on a 1:1 ratio regarding prematurity, age and sex. We assessed executive functioning at the age of nine, using two event-related potential paradigms: a Go/Nogo paradigm to investigate processes of response inhibition and conflict monitoring, as well as a Posner paradigm to investigate spatial attention. RESULTS Lower potentials were found in prenatal-exposed children compared to controls in the Go/Nogo P3 and Posner positive slow wave. Moreover, prenatal-exposed children responded slower on the Posner paradigm compared to controls (p

This study aims to detect the neural substrate underlying the language impairment in children with developmental language disorder (DLD) using diffusion tensor imaging (DTI) tractography. Deterministic DTI tractography was performed in a group of right-handed children with DLD (N = 17; mean age 10;07 ± 2;01 years) and a typically developing control group matched for age, gender and handedness (N = 22; mean age 11;00 ± 1;11 years) to bilaterally identify the superior longitudinal fascicle, arcuate fascicle, anterior lateral segment and posterior lateral segment (also called dorsal language network) and the middle and inferior longitudinal fascicle, extreme capsule fiber system and uncinate fascicle (also called ventral language network). Language skills were assessed using an extensive, standardized test battery. Differences in language performance, white matter organization and structural lateralization of the language network were statistically analyzed. Children with DLD showed a higher overall volume and higher ADC values for the left-hemispheric language related WM tracts. In addition, in children with DLD, the majority (88%; 7/8) of the studied language related WM tracts did not show a significant left or right lateralization pattern. These structural alterations might underlie the language impairment in children with DLD. ispartof: Brain Imaging And Behavior vol:13 issue:4 pages:937-984 ispartof: location:United States status: published

PURPOSE Knowledge is limited regarding the prevalence and persistence of chemotherapy-induced leukoencephalopathy in childhood sarcoma patients. This study explored the presence, clinical relevance, and potential risk factors of leukoencephalopathy in childhood bone and soft tissue sarcoma survivors, treated with intravenous chemotherapy. METHODS We acquired cross-sectional neurocognitive data in adult survivors (n = 34) (median age at diagnosis [AaD] = 13.32 years, age range = 16-35 years) and healthy age-matched controls (n = 34). Additionally, magnetic resonance imaging included T2-weighted FLAIR (leukoencephalopathy Fazekas rating), multiexponential T2 relaxation (MET2), and multishell diffusion MRI to estimate myelin integrity-related metrics and fluid movement restrictions. Finally, chemotherapy subgroups (methotrexate, alkylating agents, or combination), AaD, and Apoe and MTHFRC677T polymorphisms were explored as potential risk factors for leukoencephalopathy. RESULTS At the group level, quality of life, working memory, processing speed, and visual memory were significantly lower in patients compared to controls. Furthermore, long-term leukoencephalopathy was observed in 27.2% of the childhood sarcoma survivors, which was related to attentional processing speed. Lesions were related to diffusion-derived, but not to myelin-sensitive metrics. A significant interaction effect between AaD and chemotherapy group demonstrated more lesions in case of high-dose methotrexate (HD-MTX) (F = 3.434, P = .047). However, patients treated with alkylating agents (without HD-MTX) also showed lesions in younger patients. Genetic predictors were nonsignificant. CONCLUSION AND IMPLICATION This study suggests long-term leukoencephalopathy with possibly underlying changes in vasculature, inflammation, or axonal injury, but not necessarily long-term demyelination. Such lesions could affect processing speed, and as such long-term daily life functioning of these patients.

In children with unilateral cerebral palsy (uCP), the corticospinal tract (CST) wiring patterns may differ (contralateral, ipsilateral or bilateral), partially determining motor deficits. However, the impact of such CST wiring on functional connectivity remains unknown. Here, we explored differences in functional connectivity of the resting-state sensorimotor network in 26 uCP with periventricular white matter lesions (mean age (SD): 12.87m (±4.5), CST wiring: 9 contralateral, 9 ipsilateral, 6 bilateral) compared to 60 healthy controls (mean age (SD): 14.54 (±4.8)), and between CST wiring patterns. Functional connectivity from each M1 to three bilateral sensorimotor regions of interest (primary sensory cortex, dorsal and ventral premotor cortex) and the supplementary motor area was compared between groups (healthy controls vs. uCP; and healthy controls vs. each CST wiring group). Results from the seed-to-voxel analyses from bilateral M1 were compared between groups. Additionally, relations with upper limb motor deficits were explored. Aberrant sensorimotor functional connectivity seemed to be CST-dependent rather than specific from all the uCP population: in the dominant hemisphere, the contralateral CST group showed increased connectivity between M1 and premotor cortices, whereas the bilateral CST group showed higher connectivity between M1 and somatosensory association areas. These results suggest that functional connectivity of the sensorimotor network is CST wiring-dependent, although the impact on upper limb function remains unclear.

In children with unilateral cerebral palsy (uCP), the corticospinal tract (CST)-wiring patterns may differ (contralateral, ipsilateral or bilateral), partially determining motor deficits. However, the impact of such CST-wiring on functional connectivity remains unknown. Here, we explored resting-state sensorimotor functional connectivity in 26 uCP with periventricular white matter lesions (mean age (standard deviation): 12.87 m (±4.5), CST wiring: 9 contralateral, 9 ipsilateral, 6 bilateral) compared to 60 healthy controls (mean age (standard deviation): 14.54 (±4.8)), and between CST-wiring patterns. Functional connectivity from each M1 to three bilateral sensorimotor regions of interest (primary sensory cortex, dorsal and ventral premotor cortex) and the supplementary motor area was compared between groups (controls vs. uCP; and controls vs. each CST-wiring group). Seed-to-voxel analyses from bilateral M1 were compared between groups. Additionally, relations with upper limb motor deficits were explored. Aberrant sensorimotor functional connectivity seemed to be CST-dependent rather than specific from all the uCP population: in the dominant hemisphere, the contralateral CST group showed increased connectivity between M1 and premotor cortices, whereas the bilateral CST group showed higher connectivity between M1 and somatosensory association areas. These results suggest that functional connectivity of the sensorimotor network is CST-wiring-dependent, although the impact on upper limb function remains unclear., Scientific Reports, 9 (1), ISSN:2045-2322

It is well known that neurocognition in children treated for a brain tumor can be affected. However, studies on the trajectory of these neurocognitive problems are scarce. In the present study we investigated the evolution of neurocognition between timepoints of diagnosis, 2, 4 and 6 years later. A total of 53 children diagnosed with a brain tumor were recruited in this study, of which all completed a comprehensive neuropsychological test battery at three successive timepoints and 30 at 4 timepoints. The first assessment was conducted as soon as possible after diagnosis and before initiation of chemo- and/or radiotherapy. Mean age at diagnosis was 8.06 years. The most common diagnoses were pilocytic astrocytoma (n=28) and medulloblastoma (n=10). 24.5% and 18.9% of these patient groups received focal or craniospinal irradiation, respectively. A repeated measures analysis with cranial irradiation (no, focal, craniospinal) as between-subjects factor demonstrated a significant interaction effect between time and type of irradiation for overall intelligence (p=0.02) for children with three assessments. The same interaction effect was found for overall intelligence and processing speed for children with four assessments (p=.005 and p=.002, respectively). The group who received craniospinal irradiation demonstrated the most pronounced decline. Interestingly, no main time effect or interaction effect was found for general memory functioning. Our results demonstrate that not all neurocognitive functions in children treated for a brain tumor decline after treatment. Overall IQ and processing speed are the most vulnerable outcomes in our cohort, especially for the children treated with craniospinal irradiation.

PURPOSE A brain tumor treatment including cranial radiotherapy has previously been associated with long-term neurocognitive sequelae. Since underlying neurological mechanisms remain inconclusive, we investigated cortical features in childhood posterior fossa tumor survivors. METHODS T1-weighted MRI (MPRAGE, resolution=.98x.98x1.2mm) was acquired to investigate the cortical structure in adult survivors of childhood infratentorial tumors (n=19, 15males) (16.4–34.8 years old, >2years after treatment). These scans were compared to age- and gender- matched controls. Supratentorial cortical volume and thickness were investigated using voxel-based morphometry (VBM) and surface-based morphometry (SBM), respectively. We compared patients and controls, irradiated (n=13) versus non-irradiated patients, and investigated the age at radiotherapy (peak level: p RESULTS Lower GM volumes were encountered in multiple brain areas of patients compared to controls, with the largest clusters in the right and left occipital fusiform gyri. Irradiated patients showed lower GM volumes then non-irradiated patients in the superior and middle frontal gyri, the right supramarginal gyrus and precuneus. Age at radiotherapy was associated with GM volume in the inferior frontal gyrus. SBM yielded larger cortical thickness in patients in the left precuneus, inferior temporal and fusiform gyrus. The opposite effect was only marginally significant, in the left temporal lingual gyrus. Age at radiotherapy was not associated with cortical thickness, but radiotherapy was associated with lower thickness of the left pars opercularis. CONCLUSION Widespread differences in cortical volumes and thickness were observed in posterior fossa tumor survivors. Both radiotherapy and age at radiotherapy could be suggested as risk factors for long-term cortical development.

The Pediatric Perceived Cognitive Function (PedsPCF) item bank is a short parent and self-reported cognitive screening questionnaire developed in the context of pediatric oncology. The PedsPCF demonstrated satisfactory psychometric properties and the scores of the PedsPCF are found to be associated with clinical outcomes. Today little research is available to evaluate whether the PedsPCF is correlated with direct assessments of neurocognitive domains. The aim of the current study is to investigate whether important cognitive domains, such as different aspects of intelligence, memory, visuomotor integration can predict the PedsPCF score. We obtained 100 PedsPCF filled in by parents from children treated for a brain tumor. All these children completed a comprehensive neuropsychological battery. Mean age at diagnosis was 7.47 years and mean age at completion of PedsPCF and testing 13.84. The most common diagnoses were pilocytic astrocytoma (n=43) and medulloblastoma (n=14). A linear regression model with verbal comprehension, perceptual reasoning, processing speed, visuomotor integration as predictors for overall PedsPCF score was significant (p.005), but the overall model fit was limited (adjusted R2: 14%). Visuomotor integration and processing speed were significant predictors (beta = 0.56 and -0.29). Our results are in line with the overall finding that the correlation between questionnaires assessing quality of survival and direct assessments of cognition are low. For clinical practice these results are important as the PedsPCF can’t be used to replace direct cognitive assessments or vice versa.

Background In childhood acute lymphoblastic leukemia (ALL), radiotherapy for CNS prophylaxis is not used in frontline therapy anymore. Standard treatment for ALL nowadays consists of polychemotherapy. Therefore, assessment of potential chemotherapy-induced cognitive side effects becomes important. Although neurotoxicity was demonstrated in cross-sectional studies, longitudinal studies remain scarce. Procedure We evaluated intellectual development of 94 pediatric ALL patients between 1990 and 1997, diagnosed before the age of 12 years, treated according to the European Organisation for Research and Treatment of Cancer Children's Leukemia Group 58881 protocol. Three assessments of the Wechsler Intelligence Scale for Children Revised were performed since diagnosis, according to age. Using repeated measures regression analysis, we investigated the effect of gender (low versus increased) risk group, parents' education, age at diagnosis, intelligence quotient (IQ) subscale (verbal (VIQ) versus performance (PIQ) intelligence), and test session. Results PIQ scores were lower than VIQ at baseline (−5.3 points on average, p = 0.0032), yet PIQ increased more strongly (PIQ: +3.9 points per test session; VIQ: +0.8, p = 0.0079), so this baseline difference disappeared (p = 0.0079). There were no clear effects of gender (girls: +0.6 points; p = 0.78) or risk group (low risk: +1.5 points; p = 0.49), but IQ scores were higher when one parent had followed higher education (+9.5 points, p

INTRODUCTION: Brain tumor survivors frequently suffer from cognitive deficits. However, microstructural reorganization of white matter following treatment remains unclear. Recently, more tract-specific (fixel-based) analysis was introduced to dissociate micro- from macrostructural changes. METHOD: In this study, diffusion-weighted MR-scans were acquired in 21 childhood posterior fossa tumor tumor survivors and 21 matched controls. Mean age at diagnosis = 8.3 years; age range = [16-34] years; >2 years out of treatment, pilocytic astrocytoma (n=8), ependymoma (n=1) or medulloblastoma (n=12) at the University Hospitals of Leuven. An echo-planar, multi-shell diffusion imaging scheme (b=700,1000,2800s/mm2) was applied. P(re-)rocessing was performed using MRtrix3 and FSL. Besides typical diffusion-derived parameters (DTI-derived Fractional Anisotropy (FA) and Apparent Diffusion Coefficient (ADC)), we compared advanced parameters: fixel-based Apparent Fiber Density (AFD) and Fiber Cross-section (FC) to dissociate microstructural from macrostructural white matter properties, respectively. Non-parametric testing was performed for group comparisons. Finally, microstructural AFD values were compared between cranial irradiated and non-irradiated patients, and correlated with WAIS intelligence subscales within the patient subgroup. RESULTS: Differences in DTI-derived parameters and microstructural changes (AFD) were found in both supratentorial and infratentorial regions, whereas lower macrostructural changes (FC) were found only in cerebellar tracts. Microstructural AFD values were lowest in irradiated patients (F=11.181, p=.004), and correlated with working memory (r=.461, p=.047) and processing speed (r=.527, p=.020). DISCUSSION: Macrostructural changes were very specific for cerebellar tracts, probably due to neurosurgery and the remaining cavity. Specific lower microstructural values in supratentorial regions rather suggest systemic treatment or cascade effects, which might highly affect attentional functioning.

INTRODUCTION: Each constituent of posterior fossa tumor treatment can affect brain development tremendously. We investigated cognition in survivors of childhood posterior fossa tumor. METHOD: Neurocognitive assessments and T1-weighted MRI-images were acquired in 21 survivors (mean age at diagnosis 8.3 years; >2 years post-treatment, pilocytic astrocytoma (n=8), ependymoma (n=1) or medulloblastoma (n=12)); and 21 age- and gender-matched controls. A comprehensive neurocognitive test battery and questionnaires (WAIS-IV, RVDLT, AVLT, ANT, PPVT, COWAT, CFQ, BRIEF, STAI, BDI, PedsQL) were assessed. Based on anatomical scans, cerebellar tissue proportions were analyzed (as indication of atrophy). Scores were compared between patients and healthy controls. Interdependence of treatment-related risk factors (craniospinal radiation dose (0, 23.4, 35-36 and 40 Gy), posterior fossa boost, intraventricular MTX, (sub)total resection, postsurgical mutism, age at diagnosis and time since treatment) and cerebellar tissue was assessed, to predict cognitive scores by independent factors. RESULTS: First, IQ subscales, as well as visual memory and object naming were significantly lower in patients. Second, radiation dose, postsurgical mutism and time since treatment were found to be independent, and used for further analyses. Radiation dose was associated IQ and attentional reaction times, whereas the presence of postsurgical mutism was related to worse perceptual reasoning and emotional regulation. After corrections, only the link between RT and attentional reaction times remained significant. Finally, radiation dose and IV-MTX were associated with reduced current cerebellar tissue. DISCUSSION: Craniospinal irradiation showed the strongest effect on attentional reaction times. The association between decreased cerebellar tissue and RT doses suggests radiation-induced atrophy, which might have additional impact.