The APOE ε4 allele in relation to pre- and postsurgical cognitive functioning of patients with primary brain tumors.

BACKGROUND: Recent studies suggest a relationship between the APOE ε4 allele and cognitive outcome in patients treated for malignant brain tumors. Still, longitudinal investigations that include a pretreatment cognitive assessment are lacking and APOE's effects in patients with benign tumors are understudied. This study investigated presurgical cognitive performance and postsurgical change in ε4-carrying and non-carrying patients with glioma and meningioma. METHODS: Neuropsychological test scores (CNS Vital Signs battery [seven measures], Digit Span Forward/Backward, Letter Fluency test) were obtained as part of a prospective study in which patients with meningioma and glioma underwent cognitive assessment 1 day before (T0, n = 505) and 3 (T3, n = 418) and 12 months after (T12, n = 167) surgery. APOE isoforms were identified retrospectively. ε4 carriers and non-carriers were compared with regard to pretreatment cognitive performance on the group and individual level. Changes in performances over time were compared with longitudinal mixed model analysis in the total sample and the subgroup receiving adjuvant treatment. RESULTS: Carriers and non-carriers did not differ with regard to pretreatment performance. No significant main effect of ε4 carrier status or interaction between time (T0-T12) and carrier status was found on any of the tests in the whole sample nor in the sample receiving adjuvant treatment. CONCLUSIONS: This study found no evidence of increased vulnerability for pretreatment cognitive dysfunction or cognitive decline within 1 year after surgery in APOE ε4-carrying meningioma and glioma patients. Investigations that include larger samples at longer-term follow-up are recommended to investigate potential late treatment effects.

Cognitive impairment three months after surgery is an independent predictor of survival time in glioblastoma patients.

PURPOSE: Cognitive functioning is increasingly investigated for its prognostic value in glioblastoma (GBM) patients, but the association of cognitive status during early adjuvant treatment with survival time is unclear. The aim of this study was to determine whether cognitive performance three months after surgical resection predicted survival time, while using a clinically intuitive time ratio (TR) statistic. METHODS: Newly diagnosed patients with GBM undergoing resection between November 2010 and February 2018 completed computerized cognitive assessment 3 months after surgery with the CNS Vital Signs battery (8 measures). The association of cognitive performance (continuous Z scores and dichotomous impairment status; impaired vs. unimpaired) with survival time was assessed with multivariate Accelerated Failure Time (AFT) models that also included clinical prognostic factors and covariates related to cognitive performances. RESULTS: 114 patients were included in the analyses (median survival time 16.4 months). Of the clinical factors, postoperative Karnofsky Performance Status (TR 1.51), surgical (TR 2.20) and non-surgical (TR 1.94) salvage treatment, and pre-surgical tumor volume (cm3, TR 1.003) were significant independent predictors of survival time. Independently of the base model factors and covariates, impairment on Stroop test I and Stroop test III estimated 23% and 26% reduction of survival time (TR 0.77, TR 0.74) respectively, as compared to unimpaired performance. CONCLUSION: These findings suggest that impaired performances on tests of executive control and processing speed in the early phase of adjuvant treatment can reflect a worse prognostic outlook rather than an early treatment effect, and their assessment might allow for early refinement of current prognostic stratification.

Predicting disease progression in high-grade glioma with neuropsychological parameters: the value of personalized longitudinal assessment.

PURPOSE: Progressive disease in patients with high-grade glioma may be reflected in cognitive decline. However, the cognitive functions most sensitive to progression may differ between patients. We investigated whether decline on a personalized selection of tests predicted progressive disease according to RANO criteria in high-grade glioma patients. METHODS: Starting one day before surgery, patients underwent neuropsychological assessment every three months during standard treatment and clinical follow-up. We first made a personalized selection of three tests that showed the highest Reliable Change Index (RCI) values, i.e., most positive change, at the first post-surgical assessment for each patient. In subsequent follow up, a decline of RCI ≤ - 1 on at least two of the three tests in the selection was considered cognitive decline. We performed a discrete Cox proportional hazards model including a time-dependent coefficient cognitive decline (vs. stability) and covariate age to predict progressive disease. RESULTS: Twenty five patients were included. Cognitive decline on the personalized test selection preceded or had occurred by the time progression was established in 9/15 patients with RANO confirmed progressive disease (60%). Decline was absent in 8/10 patients (80%) with stable disease during participation. The independent hazard ratio for progression in case of cognitive decline was 5.05 (p < 0.01) compared to stable performance. CONCLUSIONS: Using only three patient-specific neuropsychological tests, we found a fivefold increased chance of disease progression in case of cognitive decline as compared to stable performance. Brief, patient-tailored cognitive assessment may be a noninvasive addition to disease monitoring without overburdening patients and clinical care.

Decreased Cognitive Functioning After Electroconvulsive Therapy Is Related to Increased Hippocampal Volume: Exploring the Role of Brain Plasticity.

OBJECTIVE: Electroconvulsive therapy (ECT) is still the most effective treatment of severe and therapy-refractory major depressive disorder. Cognitive side effects are the major disadvantage of ECT. Cognitive deficits are generally temporary in nature and may be mediated by the hippocampus. Recent studies have shown a temporary increase in hippocampal volume and a temporary decrease in cognitive functioning post-ECT compared with pre-ECT. This study investigates whether these volumetric changes are related to changes in cognitive functioning after ECT. METHODS: Nineteen medication-free patients with treatment-resistant major depressive disorder underwent a whole-brain magnetic resonance imaging scan and a neuropsychological examination (including the Rey auditory verbal learning task, Wechsler Memory Scale Visual Reproduction, fluency, Trail Making Task) within 1 week before and within 1 week after the course of ECT. Electroconvulsive therapy was administered twice a week bitemporally with a brief pulse. A matched healthy control group (n = 18) received the same neuropsychological examination and at a similar interval to that of the patients. RESULTS: Hippocampal volumes increased significantly from pretreatment to posttreatment in patients. Mean performance on cognitive tasks declined, or remained stable, whereas performance in controls generally improved because of retesting effects. The increase in hippocampal volume was related to changes in cognitive performance, indicating that this increase co-occurred with a decrease in cognitive functioning. CONCLUSIONS: Our findings tentatively suggest that the temporal increase in hippocampal volume after treatment, which may result from neurotrophic processes and is thought to be crucial for the antidepressive effect, is also related to the temporary cognitive side effects of ECT.

Executive functioning following surgery near the frontal aslant tract in low-grade glioma patients: A patient-specific tractography study.

BACKGROUND: The Frontal Aslant Tract (FAT) has been associated with executive functions (EF), but it remains unclear what role the FAT plays in EF, and whether preoperative dysfunction of the FAT is associated to long-lasting postsurgical executive impairments. METHODS: In this study, we examined the course of EF from pre-surgery (n = 75) to 3 (n = 61) and 12 (n = 25) months after surgery in patients with frontal and parietal low-grade gliomas (LGGs), to establish the degree to which long-term EF deficits exist. Secondly, we used patient-specific tractography to investigate the extent to which overlap of the tumor with the FAT, as well as integrity of the FAT, presurgery were related to EF on the short and longer term after surgery. RESULTS: LGG patients performed worse than healthy controls on all EF tests before and 3 months postsurgery. Whereas performances on three out of the four tests had normalized 1 year postsurgery (n = 26), performance on the cognitive flexibility test remained significantly worse than in healthy controls. Patients in whom the tumor overlapped with the core of the right FAT performed worse presurgery on three of the EF tests compared to those in whom the tumor did not overlap with the right FAT. Presurgical right FAT integrity was not related to presurgical EF, but only to postsurgical EF (from pre-to 3 months postsurgery). Longitudinal analyses demonstrated that patients with right (but not left) FAT core overlap performed on average worse over the pre- and postsurgical timepoints on the cognitive flexibility test. CONCLUSIONS: We emphasized that LGG patients perform worse than healthy controls on the EF tests, which normalizes 1-year postsurgery except for cognitive flexibility. Importantly, in patients with right hemispheric tumors, tumor involvement of the FAT was associated with worse pre- and 3- months postsurgical performance, specifically concerning cognitive flexibility.

The long-term course and relationship with survival of multidimensional fatigue in patients with brain metastases after Gamma Knife radiosurgery.

PURPOSE: The aims of this study were to evaluate long-term multidimensional fatigue in patients with brain metastases (BM) up to 21 months after Gamma Knife radiosurgery (GKRS) and (change in) fatigue as predictor of survival. METHODS: Patients with 1 to 10 BM, expected survival > 3 months, and Karnofsky Performance Status ≥ 70, and Dutch non-cancer controls were included. Fatigue was measured with the Multidimensional Fatigue Inventory. Levels of fatigue between patients and controls were compared using independent-samples t-tests. Linear mixed models were used to evaluate fatigue within the patient group up to 21 months after GKRS. Pre-GKRS fatigue and minimal clinically important (MCI) changes in fatigue in the first three months (defined as a 2-point difference) after GKRS were evaluated as predictors of survival time. RESULTS: Prior to GKRS, patients with BM (n = 92) experienced significantly higher fatigue on all subscales than controls (n = 104). Over 21 months, physical fatigue increased, and mental fatigue decreased significantly. More specifically, general, and physical fatigue increased significantly between pre-GKRS and 3 months, followed by stable scores between 3 (n = 67) and 6 (n = 53), 6 and 12 (n = 34) and 12 and 21 (n = 21) months. An MCI increase in general or physical fatigue over the first 3 months after GKRS was a significant predictor of shorter survival time. CONCLUSION: Except for mental fatigue, all aspects of fatigue remained elevated or further increased up to 21 months after treatment. Furthermore, an increase in general or physical fatigue within three months after GKRS may be a prognostic indicator for poorer survival. GOV IDENTIFIER: NCT02953756, November 3, 2016.

Presurgical Identification of Patients With Glioblastoma at Risk for Cognitive Impairment at 3-Month Follow-up.

BACKGROUND: Pre- and postoperative cognitive deficits have repeatedly been demonstrated in patients with glioblastoma (GBM). OBJECTIVE: To identify presurgical risk factors that facilitate the identification of GBM patients at risk for postoperative cognitive impairment. METHODS: Patients underwent neuropsychological assessment using Central Nervous System Vital Signs 1 d before (T0) and 3 mo after surgery (T3). Patients' standardized scores on 7 cognitive domains were compared to a normative sample using one-sample z tests. Reliable change indices with correction for practice effects were calculated to assess cognitive changes in individual patients over time. Logistic regression models were performed to assess presurgical sociodemographic, clinical, psychological, and cognitive risk factors for postoperative cognitive impairments. RESULTS: At T0, 208 patients were assessed, and 136 patients were retested at T3. Patients showed significantly lower performance both prior to and 3 mo after surgery on all cognitive domains compared to healthy controls. Improvements and declines over time occurred respectively in 11% to 32% and 6% to 26% of the GBM patients over the domains. The regression models showed that low preoperative cognitive performance posits a significant risk factor for postoperative cognitive impairment on all domains, and female sex was a risk factor for postoperative impairments in Visual Memory. CONCLUSION: We demonstrated preoperative cognitive risk factors that enable the identification of GBM patients who are at risk for cognitive impairment 3 mo after surgery. This information can help to inform patients and clinicians at an early stage, and emphasizes the importance of recognizing, assessing, and actively dealing with cognitive functioning in the clinical management of GBM patients.

Cognitive functioning in patients with nonfunctioning pituitary adenoma before and after endoscopic endonasal transsphenoidal surgery.

OBJECTIVE: Patients with nonfunctioning pituitary adenomas (NFPAs) can suffer from cognitive dysfunction. However, the literature on longitudinal cognitive follow-up of patients undergoing endoscopic endonasal transsphenoidal surgery (EETS) is limited. This study was performed to investigate perioperative cognitive status and course in patients with NFPAs. METHODS: Patients underwent computerized neuropsychological assessment 1 day before (n = 45) and 3 months after (n = 36) EETS. Performance in 7 domains was measured with a computerized test battery (CNS Vital Signs) and standardized using data from a healthy control group. The authors conducted analyses of cognitive performance at both time points and changes pre- to post-ETSS on a group and an individual level. Linear multiple regression analyses were employed to investigate predictors of cognitive performance. RESULTS: On average, patients scored significantly lower in 6 of 7 cognitive domains before and after surgery than controls. Impairment proportions were significantly higher among patients (56% before surgery, 63% after surgery) than among controls. Patients showed no change over time in group-level (mean) performance, but 28% of individual patients exhibited cognitive improvement and 28% exhibited cognitive decline after surgery. Hormonal deficiency showed a positive correlation with verbal memory before surgery. Postoperative performances in all cognitive domains were predicted by preoperative performances. CONCLUSIONS: Cognitive impairment was present before and after EETS in over half of NFPA patients. Individual patients showed diverse postoperative cognitive courses. Monitoring of cognitive functioning in clinical trajectories and further identification of disease-related and psychological predictors of cognition are warranted.