Concurrent brain structural and functional alterations in the thalamus of adult survivors of childhood brain tumors: a multimodal MRI study.

Adult survivors of childhood brain tumors often present with cognitive deficits that affect their quality of life. Studying brain structure and function in brain tumor survivors can help understand the underlying mechanisms of their cognitive deficits to improve long-term prognosis of these patients. This study analyzed voxel-based morphometry (VBM) derived from T1-weighted MRI and the amplitude of low-frequency fluctuation (ALFF) from resting-state functional magnetic resonance imaging (rs-fMRI) to examine the structural and functional alterations in 35 brain tumor survivors using 35 matching healthy individuals as controls. Compared with healthy controls, brain tumor survivors had decreased gray matter volumes (GMV) in the thalamus and increased GMV in the superior frontal gyrus. Functionally, brain tumor survivors had lower ALFF values in the inferior temporal gyrus and medial prefrontal area and higher ALFF values in the thalamus. Importantly, we found concurrent but negatively correlated structural and functional alterations in the thalamus based on observed significant differences in GMV and ALFF values. These findings on concurrent brain structural and functional alterations provide new insights towards a better understanding of the cognitive deficits in brain tumor survivors.

Concordance of informant and self-reported ratings on the Frontal Systems Behavior Scale in adult survivors of pediatric brain tumor.

OBJECTIVE: It has been theorized that pediatric brain tumor survivors may have reduced insight into their executive functioning. Agreement between informants and survivors has been used to probe this theory, but findings have been inconsistent. This study sought to expand on prior work by examining the relationship between participant role and ratings on the Frontal Systems Behavior Scale (FrSBe) among 73 adult survivors and their informants. This study also sought to test whether agreement on scores varied as a function of tumor treatment. METHOD: Dyadic mixed effects models examined the relationship between participant ratings on FrSBe subscales and the role of a participant (survivor or informant). Intraclass correlations (ICC) were used to calculate reliable change indices to evaluate significant divergence in self and informant agreement. RESULTS: Dyadic mixed effects models showed an insignificant relationship between participant role and ratings on the FrSBe apathy and executive dysfunction subscales. Participant role was related to ratings on the disinhibition subscale of the FrSBe. The ICC for apathy was ICC = .583, for disinhibition ICC = .420, and for executive dysfunction ICC = .373. Significant divergence in scores did not vary by history of chemoradiation. CONCLUSIONS: Results demonstrate an effect of role on one FrSBe subscale and weak to moderate agreement between survivor and informant scores, which suggests that agreement between informants and survivors varies by FrSBe domain. The strongest relationship between survivors and informants was seen on apathy, which suggests that apathy is a shared concern for survivors and their families.

A systematic review of pediatric neuropsychological outcomes with proton versus photon radiation therapy: A call for equity in access to treatment.

OBJECTIVE: There is increasing interest in the utilization of proton beam radiation therapy (PRT) to treat pediatric brain tumors based upon presumed advantages over traditional photon radiation therapy (XRT). PRT provides more conformal radiation to the tumor with reduced dose to healthy brain parenchyma. Less radiation exposure to brain tissue beyond the tumor is thought to reduce neuropsychological sequelae. This systematic review aimed to provide an overview of published studies comparing neuropsychological outcomes between PRT and XRT. METHOD: PubMed, PsychINFO, Embase, Web of Science, Scopus, and Cochrane were systematically searched for peer-reviewed published studies that compared neuropsychological outcomes between PRT and XRT in pediatric brain tumor patients. RESULTS: Eight studies were included. Six of the studies utilized retrospective neuropsychological data; the majority were longitudinal studies (n = 5). XRT was found to result in lower neuropsychological functioning across time. PRT was associated with generally stable neuropsychological functioning across time, with the exception of working memory and processing speed, which showed variable outcomes across studies. However, studies inconsistently included or considered medical and sociodemographic differences between treatment groups, which may have impacted neuropsychological outcomes. CONCLUSIONS: Despite methodological limitations, including limited baseline neuropsychological evaluations, temporal variability between radiation treatment and first evaluation or initial and follow-up evaluations, and heterogenous samples, there is emerging evidence of sociodemographic inequities in access to PRT. With more institutions dedicating funding towards PRT, there may be the opportunity to objectively evaluate the neuropsychological benefits of patients matched on medical and sociodemographic variables.

A Systematic Review of Host Genomic Variation and Neuropsychological Outcomes for Pediatric Cancer Survivors.

Pediatric survivors of brain tumors and acute lymphoblastic leukemia (ALL) are at risk for long-term deficits in their neuropsychological functioning. Researchers have begun examining associations between germline single nucleotide polymorphisms (SNPs), which interact with cancer treatment, and neuropsychological outcomes. This review synthesizes the impact of treatment-related toxicity from germline SNPs by neuropsychological domain (i.e., working memory, processing speed, psychological functioning) in pediatric survivors. By focusing on specific neuropsychological domains, this review will examine outcome measurement and critique methodology. Fourteen studies were identified and included in this review using the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA). All studies were published in peer-reviewed journals in English by November 24th, 2021. Reviewed studies were not of sufficient quality for a meta-analysis due to varying measurement strategies, gaps in reported descriptive variables, and low power. All neuropsychological domains evaluated in this review had associations with SNPs, except fine motor and visual integration abilities. Only five SNPs had consistent neuropsychological findings in more than one study or cohort. Future research and replication studies should use validated measures of discrete skills that are central to empirically validated models of survivors' long-term outcomes (i.e., attention, working memory, processing speed). Researchers should examine SNPs across pathophysiological pathways to investigate additive genetic risk in pediatric cancer survivors. Two SNPs were identified that confer resiliency in neuropsychological functioning, and future work should investigate resiliency genotypes and their underlying biological mechanisms.

Inhibition explains the relationship between the efficiency of brain networks and adaptive outcomes in pediatric brain tumor survivors.

OBJECTIVE: Research has found altered brain network connectivity in pediatric brain tumor survivors. Efficient brain networks are critical for performing complex behaviors involved in adaptive functioning (AF). The present study explored relationships between structural brain network characteristics and AF in survivors. We examined whether this relationship is mediated by inhibition and cognitive flexibility, important cognitive abilities for AF. METHOD: Thirty-seven young adult survivors and 37 matched healthy controls (HC; overall Mage = 23.1, SD = 4.9) underwent neuropsychological assessment. Informants completed the Scales of Independent Behavior-Revised (SIB-R) interview. Color-Word Interference Inhibition and Inhibition-Switching from the Delis-Kaplan Executive Functioning System measured inhibition and cognitive flexibility performance. Deterministic tractography was performed on diffusion-weighted imaging, the Automated Anatomical Labeling (AAL) atlas defined nodes, and edges were the average fractional anisotropy between nodes. Global efficiency (GE), average clustering coefficient (CC), and density were computed. Partial correlations and analysis of indirect effects were conducted. RESULTS: There were significant relationships between GE and all SIB-R scales, but findings with CC were limited to two subscales. Inhibition was moderately related to GE, but this was no longer significant after Holm's correction. Cognitive flexibility was not found to be related to graph metrics. Finally, significant indirect effects were found such that inhibition explained the relationship between GE and SIB-R Motor and Social/Communication. CONCLUSIONS: Based on these findings, higher levels of brain network integration, as measured by GE, is related to inhibition in survivors, which facilitates proficient adaptive motor and social/communication skills. Future work should investigate tumor location and treatment factors as potential moderators of the relationships found in this study to better understand specific risk factors in this group. (PsycInfo Database Record (c) 2022 APA, all rights reserved).

Considerations for Reliable Digit Span as a performance validity test for long-term survivors of childhood brain tumors.

The Reliable Digit Span (RDS) is a performance validity test (PVT) used widely within non-clinical samples, but its utility is in question in clinical groups with cognitive impairment. To investigate, RDS scores were calculated and correlated with the Neurological Predictor Scale, an informant-reported Activities of Daily Living score, and a proxy measure of intelligence (Vocabulary) for 83 adult survivors of childhood brain tumors and 105 healthy controls. Analyses were covaried for age at examination. Participants were divided into passing and failing groups at each RDS cutoff, and ANCOVAs for each of the three variables of interest covaried for age at the examination were run. RDS was correlated with all three variables of interest in survivors but only Vocabulary in controls. At the ≤7 cutoff, passing and failing survivors demonstrated significant differences across all variables of interest, while passing and failing controls differed only on Vocabulary. Differences were also found between passing and failing survivors at lower cutoffs. RDS is related to and likely impacted by various neurological and cognitive challenges faced by brain tumor survivors. Using the standard RDS cutoff of ≤7 may result in inaccurate interpretation of valid performance in this population; therefore, the use of other PVTs is recommended.

MTHFR single nucleotide polymorphism associated with working memory in pediatric medulloblastoma survivors.

Background: Associations have been found between single nucleotide polymorphisms (SNPs) in the MTHFR gene and cognitive outcomes in cancer survivors. Prior research has demonstrated that the presence of MTHFR SNPs (rs1801131 and rs1801133) in survivors of acute lymphoblastic leukemia (ALL) corresponds to impairments in attention and executive functioning. The current study examines the associations between rs1801131 and/or rs1801133 SNPs and cognitive performance in long-term survivors of medulloblastoma. Procedure: Eighteen pediatric medulloblastoma survivors, on average 12.42 years post-diagnosis, completed the Digit Span Forward, Digit Span Backward, California Verbal Learning Test Trial 1, and Auditory Consonant Trigrams tests. MTHFR SNPs were detected using whole genome sequencing data and custom scripts within R software. Results: Survivors with a rs1801131 SNP performed significantly worse on Digit Span Backward than survivors without this SNP exhibiting a large effect (p = 0.049; d = 0.95). Survivors with a rs1801131 SNP performed worse on Digit Span Forward (d = 0.478) and the CVLT Trial 1 (d = 0.417) with medium effect sizes. In contrast to rs1801131, relationships were not identified between a rs1801133 SNP and these performance measures. Conclusions: Our findings demonstrate the potential links between MTHFR SNPs and cognitive outcomes following treatment in brain tumor survivors. The current findings establish a novel relationship between rs1801131 and working memory in medulloblastoma. Increases in homocysteine levels and oxidative damage from radiation may lead to adverse long-term outcomes. This establishes the need to look beyond leukemia and methotrexate treatment to consider the risk of MTHFR SNPs for medulloblastoma survivors.

Graph Theoretical Analysis of Brain Network Characteristics in Brain Tumor Patients: A Systematic Review.

Graph theory is a branch of mathematics that allows for the characterization of complex networks, and has rapidly grown in popularity in network neuroscience in recent years. Researchers have begun to use graph theory to describe the brain networks of individuals with brain tumors to shed light on disrupted networks. This systematic review summarizes the current literature on graph theoretical analysis of magnetic resonance imaging data in the brain tumor population with particular attention paid to treatment effects and other clinical factors. Included papers were published through June 24th, 2020. Searches were conducted on Pubmed, PsycInfo, and Web of Science using the search terms (graph theory OR graph analysis) AND (brain tumor OR brain tumour OR brain neoplasm) AND (MRI OR EEG OR MEG). Studies were eligible for inclusion if they: evaluated participants with a primary brain tumor, used graph theoretical analyses on structural or functional MRI data, MEG, or EEG, were in English, and were an empirical research study. Seventeen papers met criteria for inclusion. Results suggest alterations in network properties are often found in people with brain tumors, although the directions of differences are inconsistent and few studies reported effect sizes. The most consistent finding suggests increased network segregation. Changes are most prominent with more intense treatment, in hub regions, and with factors such as faster tumor growth. The use of graph theory to study brain tumor patients is in its infancy, though some conclusions can be drawn. Future studies should focus on treatment factors, changes over time, and correlations with functional outcomes to better identify those in need of early intervention.

White matter hyperintensities relate to executive dysfunction, apathy, but not disinhibition in long-term adult survivors of pediatric cerebellar tumor.

White matter hyperintensities (WMHs) have been related to executive dysfunction, apathy and disinhibition in a wide range of neurological populations. However, this relationship has not been examined in survivors of pediatric brain tumor. The goal of this study was to investigate how executive dysfunction, apathy, and disinhibition relate to WMHs in 31 long-term survivors of pediatric cerebellar brain tumor and 58 controls, using informant-report data from the Frontal Systems Behavior Scale. Total WMH volume was quantified using the Lesion Growth Algorithm. Further, periventricular, and subcortical volumes were identified based on proximity to custom ventricle masks generated in FSL. A ratio of WMH volume to whole brain volume was used to obtain normalized WMH volumes. Additionally, a multivariate regression analysis was performed. On average, informant-report scores were within normal limits and only executive dysfunction was significantly higher in survivors compared to controls (t(47.9) = -2.4, p=.023). Informants reported clinically significant levels of apathy in 32.3% of survivors. Informants also reported clinically significant executive dysfunction in 19.4 % of survivors and clinically significant disinhibition in, again, 19.4 % of survivors. Increased volume of WMHs was positively correlated with executive dysfunction (r = 0.33, p = 0.02) and apathy (r = 0.23, p = .04). Similarly, multivariate regression demonstrated correlations with executive dysfunction (p=.05, FDR corrected) and apathy (p=.05, FDR corrected). Exploratory analysis demonstrated an interaction wherein the relationship between total WMHs and executive dysfunction and apathy depends on whether the participant was a survivor. The current findings indicate that increased WMH volumes are associated with higher ratings of apathy and executive dysfunction, and that these results are likely unique to cerebellar brain tumor survivors. WMH burden may serve as a useful marker to identify survivors at risk of executive dysfunction or increased apathy.

White matter hyperintensity volumes are related to processing speed in long-term survivors of childhood cerebellar tumors.

PURPOSE: Across several clinical populations, higher white matter hyperintensity (WMH) burden is consistently associated with decreases in cognitive performance, especially processing speed. Research of childhood cancer survivors has not utilized WMH quantification methodology to better understand the impact of WMH burden and its relationship with core cognitive skills. The present study aimed to quantify WMH volumes in a sample of long-term survivors of childhood cerebellar tumor and investigate the relationships with performance on a measure of oral processing speed. To further explore brain-behavior relationships, multivariate sparse canonical correlations was employed to identify WMH areas that predict processing speed performance. METHODS: Thirty-five survivors and 56 healthy controls underwent neuroimaging and completed a measure of oral processing speed. The survivor group was further divided based on treatment (i.e., chemoradiation therapy (n = 20) vs. surgery only (n = 15)) to better understand the impact of treatment. RESULTS: Survivors, and especially those treated with chemoradiation therapy, showed higher total WMH volumes and slower processing speed. Higher total WMH volumes were significantly associated with poorer processing speed (r = - 0.492, p = 0.003). Multivariate brain-behavior relationships revealed that periventricular WMHs were significantly associated with slower processing speed performance (p < 0.05). CONCLUSION: Results exemplify that long-term survivors treated with and without chemoradiation therapy are at increased risk of developing higher WMH volumes compared to healthy peers. In addition, processing speed was robustly shown to be related to periventricular WMHs using an automated neuroimaging pipeline. This methodology to monitor WMH burden has the potential to be implemented efficiently with routine clinical neuroimaging of cancer survivors.

Functional Connectivity Networks and Their Recruitment During Working Memory Tasks in Adult Survivors of Childhood Brain Tumors.

Background: Assessments of functional connectivity of default mode network (DMN) and positive task-related networks (TRNs) using independent component analysis (ICA) may help describe long-term effects of childhood brain tumors and adjuvant treatments. Methods: Aiming to identify potential neuronal markers that may aid in prognosis and inform interventions to optimize outcomes, this study used ICA to evaluate the presence of functional connectivity networks and their recruitment during a letter n-back task in 23 adult survivors of childhood posterior fossa tumors (9 low grade, 14 high grade) at least 5 years past diagnosis compared with 40 age- and sex-matched healthy peers. Results: DMN components generally demonstrated increasing disengagement as task difficulty increased, and relationships between effective DMN disengagement and improved performance were observed in healthy controls (HCs). Low-grade brain tumor survivors (LGS) demonstrated unique patterns in DMN recruitment that suggested increased involvement of the medial prefrontal cortex in LGS during tasks. TRN components generally demonstrated increasing engagement, which was related to improved task performance in HCs for one executive control network (ECN) component. High-grade brain tumor survivors (HGS) demonstrated distinct challenges recruiting an ECN component at more difficult task levels and showed a relationship between recruitment of another ECN component and task performance, indicating a potential compensatory mechanism for some HGS. Conclusions: Findings suggest the importance of cognitive intervention in both survivor groups and the necessity to track LGS despite their cognitive abilities often resembling those of their healthy peers. Impact statement Distinct functional connectivity patterns were identified between both adult survivor of childhood brain tumor groups and peers during attention and working memory tasks, reflecting different damage and recovery from treatment. Survivors of low-grade tumors demonstrated unique patterns of recruitment of default mode network components in the context of similar cognitive abilities, whereas survivors of high-grade tumors demonstrated poorer cognitive abilities and may be utilizing compensatory executive control network components in the face of challenging tasks. Long-term clinical follow-up and cognitive remediation is warranted for both groups, including low grade cerebellar tumor patients who have traditionally not been monitored as closely.

Cerebellar-Subcortical-Cortical Systems as Modulators of Cognitive Functions.

Over the past few decades, research has established that the cerebellum is involved in executive functions; however, its specific role remains unclear. There are numerous theories of cerebellar function and numerous cognitive processes falling under the umbrella of executive function, making investigations of the cerebellum's role in executive functioning challenging. In this review, we explored the role of the cerebellum in executive functioning through clinical and cognitive neuroscience frameworks. We reviewed the neuroanatomical systems and theoretical models of cerebellar functions and the multifaceted nature of executive functions. Using attention deficit hyperactivity disorder and cerebellar tumor as clinical developmental models of cerebellar dysfunction, and the functional magnetic resonance imaging literature, we reviewed evidence for cerebellar involvement in specific components of executive function in childhood, adolescence, and adulthood. There is evidence for posterior cerebellar contributions to working memory, planning, inhibition, and flexibility, but the heterogeneous literature that largely was not designed to study the cerebellum makes it difficult to determine specific functions of the cerebellum or cerebellar regions. In addition, while it is clear that cerebellar insult in childhood affects executive function performance later in life, more work is needed to elucidate the mechanisms by which executive dysfunction occurs and its developmental course. The limitations of the current literature are discussed and potential directions for future research are provided.

The Neurological Predictor Scale Predicts Adaptive Functioning via Executive Dysfunction in Young Adult Survivors of Childhood Brain Tumor.

OBJECTIVES: Survivors of childhood brain tumors experience neurological sequelae that disrupt everyday adaptive functioning (AF) skills. The Neurological Predictor Scale (NPS), a cumulative measure of tumor treatments and sequelae, predicts cognitive outcomes, but findings on its relation to informant-reported executive dysfunction (ED) and AF are mixed. Given known effects of frontal-subcortical system disruptions on AF, this study assessed the NPS' relationship with AF as mediated by frontal systems dysfunction, measured by the Frontal Systems Behavior Scale (FrSBe). METHODS: 75 participants (Mage = 23.5, SDage = 4.5) were young adult survivors of childhood brain tumors at least 5 years past diagnosis. FrSBe and Scales of Independent Behavior-Revised (SIB-R), a measure of AF, were administered to informants. Parallel multiple mediator models included Apathy and ED as mediators, and age at diagnosis and time between diagnosis and assessment as covariates. RESULTS: More complex treatment and sequelae were correlated with poorer functioning. Mediation models were significant for all subscales: Motor Skills (MS), p = .0001; Social Communication (SC), p = .002; Personal Living (PL), p = .004; Community Living (CL), p = .007. The indirect effect of ED on SC and CL was significant; the indirect effect of Apathy was not significant for any subscales. CONCLUSIONS: More complex tumor treatment and sequelae were associated with poorer long-term AF via increased ED. Cognitive rehabilitation programs may focus on the role of executive function and initiation that contribute to AF, particularly SC and CL skills, to help survivors achieve comparable levels of independence in everyday function as their peers.

Oral processing speed as a key mechanism in the relationship between neurological risk and adaptive functioning in survivors of pediatric brain tumors.

PURPOSE: Brain tumor (BT) survivors are at risk for difficulties with adaptive functioning (AF). Recent work has associated neurological risk with poorer AF outcomes using the Neurological Predictor Scale (NPS), a quantification of neurological risk factors. Survivors also have poorer attention, processing speed, and working memory, which are all important for AF. The current study examined whether these cognitive constructs explain the relationship between the NPS and AF in survivors. METHODS: Ninety-five adult BT survivors and 135 healthy controls were recruited from the Atlanta area. The Oral Symbol Digits Modalities test was used to measure processing speed, Digit Span Backward assessed working memory, and Digit Span Forward measured attention. Informants completed the Scales of Independent Behavior (SIB-R) to measure AF. Group differences and correlations were assessed, and the PROCESS macro for SPSS tested indirect effects. RESULTS: Survivors were significantly lower on AF and cognitive measures compared with controls. Attention span and processing speed had significant indirect effects in relationship between NPS and AF individually, but processing speed was the only variable with a significant indirect effect when all cognitive variables were included in the model. The NPS and processing speed together account for approximately 39% of variance in AF outcomes. CONCLUSIONS: BT survivors in our sample have lower AF than controls, and processing speed appears to be particularly important in explaining the relationship between neurological risk and AF. In the future, the development of interventions aimed at increasing young adult independence should target both cognitive processing speed and AF skills.

Double Dissociation of Auditory Attention Span and Visual Attention in Long-Term Survivors of Childhood Cerebellar Tumor: A Deterministic Tractography Study of the Cerebellar-Frontal and the Superior Longitudinal Fasciculus Pathways.

OBJECTIVE: Right cerebellar-left frontal (RC-LF) white matter integrity (WMI) has been associated with working memory. However, prior studies have employed measures of working memory that include processing speed and attention. We examined the relationships between the RC-LF WMI and processing speed, attention, and working memory to clarify the relationship of RC-LF WMI with a specific cognitive function. Right superior longitudinal fasciculus II (SLF II) WMI and visual attention were included as a negative control tract and task to demonstrate a double dissociation. METHODS: Adult survivors of childhood brain tumors [n = 29, age: M = 22 years (SD = 5), 45% female] and demographically matched controls were recruited (n = 29). Tests of auditory attention span, working memory, and visual attention served as cognitive measures. Participants completed a 3-T MRI diffusion-weighted imaging scan. Fractional anisotropy (FA) and radial diffusivity (RD) served as WMI measures. Partial correlations between WMI and cognitive scores included controlling for type of treatment. RESULTS: A correlational double dissociation was found. RC-LF WMI was associated with auditory attention (FA: r = .42, p = .03; RD: r = -.50, p = .01) and was not associated with visual attention (FA: r = -.11, p = .59; RD: r = -.11, p = .57). SLF II FA WMI was associated with visual attention (FA: r = .44, p = .02; RD: r = -.17, p = .40) and was not associated with auditory attention (FA: r = .24, p = .22; RD: r = -.10, p = .62). CONCLUSIONS: The results show that RC-LF WMI is associated with auditory attention span rather than working memory per se and provides evidence for a specificity based on the correlational double dissociation.

GSTP1 polymorphisms sex-specific association with verbal intelligence in survivors of pediatric medulloblastoma tumors.

Glutathione S-transferase (GST) single nucleotide polymorphisms (SNPs) have been associated with a lower intellectual quotient (IQ) in medulloblastoma survivors. We investigated the association of GSTP1 polymorphisms with intellectual, neurocognitive skills (e.g., attention span, working memory, and processing speed), and adaptive outcomes for long-term pediatric medulloblastoma survivors. We hypothesized that genetic risk and sex-specific risk would contribute to significantly lower performances across all measures. Eighteen long-term pediatric medulloblastoma survivors completed the Wechsler Abbreviated Scale Intelligence, California Verbal Learning Test-II, Auditory Consonant Trigrams, and Oral Symbol Digit Modality Test. Informants were interviewed with the Scales of Independent Behavior-Revised (SIB-R). After controlling for the false discovery rate, females with a polymorphism performed significantly worse than females without a polymorphism on verbal IQ (p = .005) and SIB-R (p = .012). There was a significant interaction between sex and polymorphism status for verbal IQ (b = -1.8, SE = 0.827, CI: -3.58, -.036). The main effect of this interaction was significant for females (p = .004) and not for males (p = .557). We found large effect sizes between males with the polymorphism and females with the polymorphism across measures of attention span (g = .877), working memory (g = 1.12), and processing speed (g = 1.53). Female medulloblastoma survivors with a GSTP1 polymorphism may have increased vulnerability to deficits in core cognitive skills, IQ, and everyday functional outcomes. Sex-specific genetic risk contributes to the variability in long-term verbal intelligence for medulloblastoma survivors.

Neuroimaging of the component white matter connections and structures within the cerebellar-frontal pathway in posterior fossa tumor survivors.

INTRODUCTION: In posterior fossa tumor survivors, lower white matter integrity (WMI) in the right cerebellar-left frontal pathway has been well documented and appears to be related to proximity to the cerebellum, radiation treatment, as well as time since treatment in both cranial radiation and surgery-only treatment groups. The current study investigated theories of transneural degeneration following cerebellar tumor resection that may underlie or relate to reductions in WMI and regional brain volumes using correlations. We hypothesized a positive relationship between the volume of the right cerebellum and known white matter output pathways, as well as with the volume of structures that receive cerebellar projections along the pathway. METHODS: Adult survivors of childhood brain tumors were recruited (n = 29; age, M = 22 years, SD = 5; 45% female). Age- and gender-matched controls were also included (n = 29). Participants completed 3 T diffusion-weighted and T1 MPRAGE MRI scans. Brain structure volume relative to intracranial vault served as regional volumetric measures. Fractional anisotropy (FA) and radial diffusivity (RD) served as WMI measures. In the survivor group, partial correlations between WMI and regional volume included controlling for disease severity. RESULTS: In posterior fossa tumor survivors, the volumes of the cerebellum, thalamus, and frontal lobe were correlated with WMI of the thalamic-frontal segment of the cerebellar-frontal pathway (r = 0.41-0.49, p < .05). Cerebellar atrophy was correlated with reduced WMI in the cerebellar-rubral segment (FA, r = -0.32 p > .05; RD, r = 0.53, p < .01). In the no-radiation survivor group, the regional volume of each structure along the pathway was associated with WMI in the cerebellar-rubral segment. In the radiation survivor group, significant correlations were found between the regional brain volume of each structure and the thalamic-frontal segment of the pathway. DISCUSSION: The results of this multimodal neuroimaging study provide correlational evidence that the mechanism of injury subsequent to brain tumor treatment may be different depending on type of treatment(s). Without radiation, the primary mechanism of injury is cerebellar tumor growth, resection, and hydrocephalus. Therefore, the most proximal connection to that injury (cerebellar-rubral pathway) was correlated with reductions in volume along the pathway. In contrast, the survivor group treated with radiation may have had possible radiation-induced demyelination of the thalamic-frontal portion of the pathway, based on a strong correlation with volume loss in the cerebellum, red nucleus, thalamus, and frontal lobe.

The Effects of Radiation and Sex Differences on Adaptive Functioning in Adult Survivors of Pediatric Posterior Fossa Brain Tumors.

OBJECTIVE: Radiation therapy (RT) improves rates of survival of patients with childhood brain tumors but increases deficits in cognition and independent living skills. Previous literature has studied difficulties in basic cognitive processes, but few explore impairment in higher-order skills such as adaptive functioning. Some studies identify females as at risk for cognitive deficits due to RT, but few investigate sex differences in adaptive functioning. It was hypothesized that females would exhibit poorer long-term independent living skills and core cognitive skills relative to males following RT. METHODS: Forty-five adult survivors of posterior fossa childhood brain tumors (24 females) completed the Wechsler Abbreviated Scale of Intelligence (WASI-II), Wechsler Memory Scale, Third Edition (WMS-III) Digit Span Forward (DSF) and Backward (DSB), and Oral Symbol Digit Modalities Test (OSDMT). Informants completed the Scales of Independent Behavior-Revised (SIB-R). RESULTS: DSF and OSDMT were positively correlated with all five SIB-R domains, full-scale IQ (FSIQ) was positively correlated with four SIB-R domains, and DSB was positively correlated with three SIB-R domains. There was an interaction between sex and RT for OSDMT and community living skills with trend level interactions for personal living skills and broad independent living skills, where females without RT had higher scores than females with RT. CONCLUSIONS: Female survivors were more affected by RT than males across the community living skills domain of adaptive functioning as well as processing speed. Processing speed deficits may have a cascading impact on daily living skills. Future studies should investigate how clinical and biological factors may contribute to personalized treatment plans between sexes. (JINS, 2019, 25, 729-739).