Long-term leukoencephalopathy and neurocognitive functioning in childhood sarcoma patients treated with high-dose intravenous chemotherapy.

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 Apoε 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.

Structural and functional underconnectivity as a negative predictor for language in autism.

The development of language, social interaction, and communicative skills are remarkably different in the child with autism spectrum disorder (ASD). Atypical brain connectivity has frequently been reported in this patient population. However, the interplay between their brain connectivity and language performance remains largely understudied. Using diffusion tensor imaging tractography and resting-state fMRI, the authors explored the structural and functional connectivity of the language network and its relation to the language profile in a group of healthy control subjects (N = 25) and a group of children with ASD (N = 17). The authors hypothesized that in children with ASD, a neural connectivity deficit of the language network can be related to the observed abnormal language function. They found an absence of the right-hemispheric arcuate fascicle (AF) in 28% (7/25) of the healthy control children and in 59% (10/17) of the children with ASD. In contrast to healthy control children, the absence of the right-hemispheric AF in children with autism was related to a lower language performance as indicated by a lower verbal IQ, lower scores on the Peabody Picture Vocabulary Test, and lower language scores on the Dutch version of the Clinical Evaluation of Language Fundamentals (CELF-4NL). In addition, through iterative fMRI data analyses, the language impairment of children with ASD could be linked to a marked loss of intrahemispheric functional connectivity between inferior frontal and superior temporal regions, known as the cortical language network. Both structural and functional underconnectivity patterns coincide and are related to an abnormal language function in children with ASD.

Cortical thinning and altered functional brain coherence in survivors of childhood sarcoma.

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.

Change in Right Inferior Longitudinal Fasciculus Integrity Is Associated With Naming Recovery in Subacute Poststroke Aphasia.

Background. Despite progress made in understanding functional reorganization patterns underlying recovery in subacute aphasia, the relation between recovery and changes in white matter structure remains unclear. Objective. To investigate changes in dorsal and ventral language white matter tract integrity in relation to naming recovery in subacute poststroke aphasia. Methods. Ten participants with aphasia after left-hemisphere stroke underwent language testing and diffusion tensor imaging twice within 3 months post onset, with a 1-month interval between sessions. Deterministic tractography was used to bilaterally reconstruct the superior longitudinal fasciculus (SLF), inferior fronto-occipital fasciculus (IFOF), inferior longitudinal fasciculus (ILF), middle longitudinal fasciculus (MdLF), and uncinate fasciculus (UF). Per tract, the mean fractional anisotropy (FA) was extracted as a measure of microstructural integrity. Naming accuracy was assessed with the Boston Naming Test (BNT). Correlational analyses were performed to investigate the relationship between changes in FA values and change in BNT score. Results. A strong positive correlation was found between FA change in the right ILF within the ventral stream and change on the BNT (r = 0.91, P < .001). An increase in FA in the right ILF was associated with considerable improvement of naming accuracy (range BNT change score: 12-14), a reduction with limited improvement or slight deterioration. No significant correlations were found between change in naming accuracy and FA change in any of the other right or left ventral and dorsal language tracts. Conclusions. Naming recovery in subacute aphasia is associated with change in the integrity of the right ILF.

The mis-wired language network in children with developmental language disorder: insights from DTI tractography.

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.

Altered functional connectivity of the language network in ASD: role of classical language areas and cerebellum.

The development of language, social interaction and communicative skills is remarkably different in the child with autism spectrum disorder (ASD). Atypical brain connectivity has frequently been reported in this patient population. However, the neural correlates underlying their disrupted language development and functioning are still poorly understood. Using resting state fMRI, we investigated the functional connectivity properties of the language network in a group of ASD patients with clear comorbid language impairment (ASD-LI; N = 19) and compared them to the language related connectivity properties of 23 age-matched typically developing children. A verb generation task was used to determine language components commonly active in both groups. Eight joint language components were identified and subsequently used as seeds in a resting state analysis. Interestingly, both the interregional and the seed-based whole brain connectivity analysis showed preserved connectivity between the classical intrahemispheric language centers, Wernicke's and Broca's areas. In contrast however, a marked loss of functional connectivity was found between the right cerebellar region and the supratentorial regulatory language areas. Also, the connectivity between the interhemispheric Broca regions and modulatory control dorsolateral prefrontal region was found to be decreased. This disruption of normal modulatory control and automation function by the cerebellum may underlie the abnormal language function in children with ASD-LI.