Oncology: Brain asymmetries in language-relevant brain tumors

Brain tumors are classified as rare diseases, with an annual occurrence of 300,000 cases and account for an annual loss of 241,000 lives, highlighting their devastating nature. Recent advancements in diagnosis and treatment have significantly improved the management and care of brain tumors. This chapter provides an overview of the common types of primary brain tumors affecting language functions—gliomas and meningiomas. Techniques for identifying and mapping critical language areas, including the white matter language system, such as awake brain tumor surgery and diffusion-weighted tractography, are pivotal for understanding language localization and informing personalized treatment approaches. Numerous studies have demonstrated that gliomas in the dominant hemisphere can lead to (often subtle) impairments across various cognitive domains, with a particular emphasis on language. Recently, increased attention has been directed toward (nonverbal) cognitive deficits in patients with gliomas in the nondominant hemisphere, as well as cognitive outcomes in patients with meningiomas, a group historically overlooked. A patient-tailored approach to language and cognitive functions across the pre-, intra-, and postoperative phases is mandatory for brain tumor patients to preserve quality of life. Continued follow-up studies, in conjunction with advanced imaging techniques, are crucial for understanding the brain's potential for neuroplasticity and optimizing patient outcomes

Spontaneous speech:a robust measurement before, during and after awake brain surgery in patients with glioma

BackgroundPatients with glioma often report language complaints with devastating effect on daily life. Analysing spontaneous speech can help to understand underlying language problems. Spontaneous speech monitoring is also of importance during awake brain surgery: it can guide tumour resection and contributes to maintaining language function. We aimed to investigate the spontaneous speech of patients with glioma in the perioperative period and the additional value of spontaneous speech analyses compared to standardised language testing.MethodsWe elicited and transcribed spontaneous speech of eight patients with glioma elected for awake brain surgery preoperatively, intraoperatively and 2.0-3.5 months postoperatively. Linguistic errors were coded. Type Token Ratio, Mean Length of Utterance of words, minimal utterances, and errors were extracted from the transcriptions. Patients were categorised based on total error patterns: stable, decrease or increase during surgery. Reliable Change Index scores were calculated for all spontaneous speech variables to objectify changes between time points. Language performance on language tests was compared to spontaneous speech variables.ResultsMost errors occurred in lexico-syntax, followed by phonology/articulation, syntax, and semantics. The predominant errors were Repetitions, Self-corrections, and Incomplete sentences. Most patients remained stable over time in almost all spontaneous speech variables, except in Incomplete sentences, which deteriorated in most patients postoperatively compared to intraoperatively. Some spontaneous speech variables (total errors, MLUw, TTR) gave more information on language change than a standard language test.ConclusionsWhile the course of spontaneous speech over time remained relatively stable in most patients, Incomplete sentences seems to be a robust marker of language difficulties patients with glioma. These errors can be prioritised in spontaneous speech analysis to save time, especially to determine intra- to postoperative deterioration. Importantly, spontaneous speech analyses can give more information on language change than standardised language testing and should therefore be used in addition to standardised language tests

Longitudinal analysis of cognitive function in patients treated with postoperative radiotherapy for grade 2 and 3 IDH mutant diffuse glioma

BACKGROUND: Postoperative radiotherapy and chemotherapy improve survival in IDH mutated diffuse glioma. We investigated whether neurocognitive function declines over time, and whether mean dose to the brain outside of CTV (mean brain dose) is related to neurocognitive function.PATIENTS AND METHODS: Patients that underwent resection and postoperative radiotherapy for grade 2 or 3 IDH mutated diffuse glioma were tested using the Hopkins Verbal Learning Test, Letter Fluency and Trail Making Test before surgery and afterwards up until disease progression. Mixed effects models were fitted for each of three cognitive test scores, using time from surgery, mean brain dose, CTV volume, and tumor grade as fixed effects.RESULTS: Between 1-10-2013 and 31-12-2022, 49 patients underwent longitudinal neurocognitive testing. Average mean dose to brain minus CTV was 17.8 Gy (95 % CI 16.1 - 19.4). At the time of analysis, median follow-up in patients free from disease progression was 5.8 years (range 1.1 - 20.8). Attrition rate during the first five years of follow up was 14.1 %. There was no decline of test performance over time (p ≥ 0.526). However, there was a negative effect of increasing mean brain dose on TMT score A (-0.11, p = 0.008) and TMT score B (-0.13, p = 0.004).CONCLUSIONS: In this study, no effect of time after resection on test scores was found. Multivariable modelling indicates an negative relationship between mean brain dose and specific neurocognitive test scores, accounting for effects of tumor grade and CTV volume.</p

Cognition and health-related quality of life in long-term survivors of high-grade glioma:an interactive perspective from patient and caregiver

Background: The health-related quality of life (HRQoL) and cognition are important indicators for the quality of survival in patients with high-grade glioma (HGG). However, data on long-term survivors and their caregivers are scarce. We aim to investigate the interaction between cognition and HRQoL in long-term survivors, their caregivers’ evaluations, and the effect on caregiver strain and burden.Methods: 21 long-term HGG (8 WHO grade III and 13 WHO grade IV) survivors (survival ≥ 5 years) and 15 caregivers were included. Cognition (verbal memory, attention, executive functioning, and language), HRQoL, anxiety and depression, caregiver strain, and caregiver burden were assessed with standardized measures. Questionnaires were completed by patients and/or their caregivers. Results: Mean survival was 12 years (grade III) and 8 years (grade IV). Cognition was significantly impaired with a large individual variety. Patients’ general HRQoL was not impaired but all functioning scales were deviant. Patient-proxy agreement was found in most HRQoL subscales. Three patients (14%) showed indications of anxiety or depression. One-third of the caregivers reported a high caregiver strain or a high burden. Test scores for attention, executive functioning, language, and/or verbal memory were correlated with perceived global health status, cognitive functioning, and/or communication deficits. Caregiver burden was not related to cognitive deficits.Conclusions: In long-term HGG survivors maintained HRQoL seems possible even when cognition is impaired in a large variety at the individual level. A tailored approach is therefore recommended to investigate the cognitive impairments and HRQoL in patients and the need for patient and caregiver support.</p

Longitudinal changes in qualitative aspects of semantic fluency in presymptomatic and prodromal genetic frontotemporal dementia

Background: The semantic fluency test is one of the most widely used neuropsychological tests in dementia diagnosis. Research utilizing the qualitative, psycholinguistic information embedded in its output is currently underexplored in presymptomatic and prodromal genetic FTD. Methods: Presymptomatic MAPT (n = 20) and GRN (n = 43) mutation carriers, and controls (n = 55) underwent up to 6 years of neuropsychological assessment, including the semantic fluency test. Ten mutation carriers became symptomatic (phenoconverters). Total score and five qualitative fluency measures (lexical frequency, age of acquisition, number of clusters, cluster size, number of switches) were calculated. We used multilevel linear regression modeling to investigate longitudinal decline. We assessed the co-correlation of the qualitative measures at each time point with principal component analysis. We explored associations with cognitive decline and grey matter atrophy using partial correlations, and investigated classification abilities using binary logistic regression. Results: The interrater reliability of the qualitative measures was good (ICC = 0.75–0.90). There was strong co-correlation between lexical frequency and age of acquisition, and between clustering and switching. At least 4 years pre-phenoconversion, GRN phenoconverters had fewer but larger clusters (p &lt; 0.001), and fewer switches (p = 0.004), correlating with lower executive function (r = 0.87–0.98). Fewer switches was predictive of phenoconversion, correctly classifying 90.3%. Starting at least 4 years pre-phenoconversion, MAPT phenoconverters demonstrated an increase in lexical frequency (p = 0.009) and a decline in age of acquisition (p = 0.034), correlating with lower semantic processing (r = 0.90). Smaller cluster size was predictive of phenoconversion, correctly classifying 89.3%. Increase in lexical frequency and decline in age of acquisition were associated with grey matter volume loss of predominantly temporal areas, while decline in the number of clusters, cluster size, and switches correlated with grey matter volume loss of predominantly frontal areas. Conclusions: Qualitative aspects of semantic fluency could give insight into the underlying mechanisms as to why the “traditional” total score declines in the different FTD mutations. However, the qualitative measures currently demonstrate more fluctuation than the total score, the measure that seems to most reliably deteriorate with time. Replication in a larger sample of FTD phenoconverters is warranted to identify if qualitative measures could be sensitive cognitive biomarkers to identify and track mutation carriers converting to the symptomatic stage of FTD.</p

Neuropsychiatric Adverse Effects of Synthetic Glucocorticoids:A Systematic Review and Meta-Analysis

CONTEXT: Synthetic glucocorticoids are widely used to treat patients with a broad range of diseases. While efficacious, glucocorticoids can be accompanied by neuropsychiatric adverse effects. OBJECTIVE: This systematic review and meta-analysis assesses and quantifies the proportion of different neuropsychiatric adverse effects in patients using synthetic glucocorticoids. METHODS: Six electronic databases were searched to identify potentially relevant studies. Randomized controlled trials, cohort studies, and cross-sectional studies assessing psychiatric side effects of glucocorticoids measured with validated questionnaires were eligible. Risk of bias was assessed with RoB 2, ROBINS-I, and AXIS appraisal tool. For proportions of neuropsychiatric outcomes, we pooled proportions, and when possible, differences in questionnaire scores between glucocorticoid users and nonusers were expressed as standardized mean differences (SMD). Data were pooled in a random-effects logistic regression model. RESULTS: We included 49 studies with heterogeneity in study populations, type, dose, and duration of glucocorticoids. For glucocorticoid users, meta-analysis showed a proportion of 22% for depression (95% CI, 14%-33%), 11% for mania (2%-46%), 8% for anxiety (2%-25%), 16% for delirium (6%-36%), and 52% for behavioral changes (42%-61%). Questionnaire scores for depression (SMD of 0.80 [95% CI 0.35-1.26]), and mania (0.78 [0.14-1.42]) were higher than in controls, indicating more depressive and manic symptoms following glucocorticoid use. CONCLUSION: The heterogeneity of glucocorticoid use is reflected in the available studies. Despite this heterogeneity, the proportion of neuropsychiatric adverse effects in glucocorticoid users is high. The most substantial associations with glucocorticoid use were found for depression and mania. Upon starting glucocorticoid treatment, awareness of possible psychiatric side effects is essential. More structured studies on incidence and potential pathways of neuropsychiatric side effects of prescribed glucocorticoids are clearly needed.</p

Longitudinal changes in qualitative aspects of semantic fluency in presymptomatic and prodromal genetic frontotemporal dementia

Background: The semantic fluency test is one of the most widely used neuropsychological tests in dementia diagnosis. Research utilizing the qualitative, psycholinguistic information embedded in its output is currently underexplored in presymptomatic and prodromal genetic FTD. Methods: Presymptomatic MAPT (n = 20) and GRN (n = 43) mutation carriers, and controls (n = 55) underwent up to 6 years of neuropsychological assessment, including the semantic fluency test. Ten mutation carriers became symptomatic (phenoconverters). Total score and five qualitative fluency measures (lexical frequency, age of acquisition, number of clusters, cluster size, number of switches) were calculated. We used multilevel linear regression modeling to investigate longitudinal decline. We assessed the co-correlation of the qualitative measures at each time point with principal component analysis. We explored associations with cognitive decline and grey matter atrophy using partial correlations, and investigated classification abilities using binary logistic regression. Results: The interrater reliability of the qualitative measures was good (ICC = 0.75–0.90). There was strong co-correlation between lexical frequency and age of acquisition, and between clustering and switching. At least 4 years pre-phenoconversion, GRN phenoconverters had fewer but larger clusters (p &lt; 0.001), and fewer switches (p = 0.004), correlating with lower executive function (r = 0.87–0.98). Fewer switches was predictive of phenoconversion, correctly classifying 90.3%. Starting at least 4 years pre-phenoconversion, MAPT phenoconverters demonstrated an increase in lexical frequency (p = 0.009) and a decline in age of acquisition (p = 0.034), correlating with lower semantic processing (r = 0.90). Smaller cluster size was predictive of phenoconversion, correctly classifying 89.3%. Increase in lexical frequency and decline in age of acquisition were associated with grey matter volume loss of predominantly temporal areas, while decline in the number of clusters, cluster size, and switches correlated with grey matter volume loss of predominantly frontal areas. Conclusions: Qualitative aspects of semantic fluency could give insight into the underlying mechanisms as to why the “traditional” total score declines in the different FTD mutations. However, the qualitative measures currently demonstrate more fluctuation than the total score, the measure that seems to most reliably deteriorate with time. Replication in a larger sample of FTD phenoconverters is warranted to identify if qualitative measures could be sensitive cognitive biomarkers to identify and track mutation carriers converting to the symptomatic stage of FTD.</p

Cognition and health-related quality of life in long-term survivors of high-grade glioma:an interactive perspective from patient and caregiver

Background: The health-related quality of life (HRQoL) and cognition are important indicators for the quality of survival in patients with high-grade glioma (HGG). However, data on long-term survivors and their caregivers are scarce. We aim to investigate the interaction between cognition and HRQoL in long-term survivors, their caregivers’ evaluations, and the effect on caregiver strain and burden. Methods: 21 long-term HGG (8 WHO grade III and 13 WHO grade IV) survivors (survival ≥ 5 years) and 15 caregivers were included. Cognition (verbal memory, attention, executive functioning, and language), HRQoL, anxiety and depression, caregiver strain, and caregiver burden were assessed with standardized measures. Questionnaires were completed by patients and/or their caregivers. Results: Mean survival was 12 years (grade III) and 8 years (grade IV). Cognition was significantly impaired with a large individual variety. Patients’ general HRQoL was not impaired but all functioning scales were deviant. Patient-proxy agreement was found in most HRQoL subscales. Three patients (14%) showed indications of anxiety or depression. One-third of the caregivers reported a high caregiver strain or a high burden. Test scores for attention, executive functioning, language, and/or verbal memory were correlated with perceived global health status, cognitive functioning, and/or communication deficits. Caregiver burden was not related to cognitive deficits. Conclusions: In long-term HGG survivors maintained HRQoL seems possible even when cognition is impaired in a large variety at the individual level. A tailored approach is therefore recommended to investigate the cognitive impairments and HRQoL in patients and the need for patient and caregiver support.</p