Effect of Physical Exercise on MRI-Assessed Brain Perfusion in Chemotherapy-Treated Breast Cancer Patients: A Randomized Controlled Trial.

BACKGROUND: Exercise is a promising intervention to alleviate cognitive problems in breast cancer patients, but studies on mechanisms underlying these effects are lacking. PURPOSE: Investigating whether an exercise intervention can affect cerebral blood flow (CBF) in cognitively impaired breast cancer patients and to determine if CBF changes relate to memory function. STUDY TYPE: Prospective. POPULATION: A total of 181 chemotherapy-treated stage I-III breast cancer patients with cognitive problems and relatively low physical activity levels (≤150 minutes moderate to vigorous physical activity per week), divided into an exercise (N = 91) or control group (N = 90). FIELD STRENGTH/SEQUENCE: Two-dimensional echo planar pseudo-continuous arterial spin labeling CBF sequence at 3 T. ASSESSMENT: The 6-month long intervention consisted of (supervised) aerobic and strength training, 4 × 1 hour/week. Measurements at baseline (2-4 years post-diagnosis) and after 6 months included gray matter CBF in the whole brain, hippocampus, anterior cingulate cortex, and posterior cingulate cortex. Physical fitness and memory function were also assessed. Subgroup analyses were performed in patients with high fatigue levels at baseline. STATISTICAL TESTS: Multiple regression analyses with a two-sided alpha of 0.05 for all analyses. RESULTS: There was a significant improvement in physical fitness (VO2peak in mL/minute/kg) in the intervention group (N = 53) compared to controls (N = 51, ß = 1.47 mL/minute/kg, 95% CI: 0.44-2.50). However, no intervention effects on CBF were found (eg, whole brain: P = 0.565). Highly fatigued patients showed larger but insignificant treatment effects on CBF (eg, whole brain: P = 0.098). Additionally, irrespective of group, a change in physical fitness was positively associated with changes in CBF (eg, whole brain: ß = 0.75, 95% CI: 0.07-1.43). There was no significant relation between CBF changes and changes in memory performance. DATA CONCLUSION: The exercise intervention did not affect CBF of cognitively affected breast cancer patients. A change in physical fitness was associated with changes in CBF, but changes in CBF were not associated with memory functioning. LEVEL OF EVIDENCE: 1 TECHNICAL EFFICACY STAGE: 5.

Health-related quality of life after stereotactic radiosurgery in patients with brain metastases.

PURPOSE: This study aimed to assess health-related quality of life (HRQoL) in patients with brain metastases treated with stereotactic radiosurgery (SRS) and to identify factors associated with this. METHODS: HRQoL was measured pre-SRS, at 3- and 6-month follow-up. Physical functioning, cognitive functioning, role functioning, and fatigue were analyzed with the EORTC QLQ-C30 questionnaire. Motor dysfunction, future uncertainty, visual disorder, communication deficit, and headaches were analyzed with the EORTC QLQ-BN20. Clinically important symptom or functional impairment was assessed following set thresholds. Factors associated with impairment were identified through multivariable logistic regression analyses. RESULTS: At baseline, 178 patients were included; 54% (n=96) completed questionnaires at 3 months and 39% (n=70) at 6 months. Before SRS, 29% of linear accelerator (LINAC) patients reported physical and cognitive impairment, while 25% reported impairment for fatigue. At 6 months, 39%, 43%, and 57% of LINAC patients reported impairment respectively. Forty-five percent of Gamma Knife (GK) patients reported impairment pre-SRS for physical, cognitive functioning, and fatigue. At 6 months, 48%, 43%, and 33% of GK patients reported impairment respectively. Except for role functioning, pre-SRS symptom and functioning scores were associated with impairment at 3 months, whereas scores at 3 months were associated with impairment at 6 months. Age, gender, systemic therapy, and intracranial progression were not associated with clinically important impairment. CONCLUSION: As 33-57% of patients with brain metastases reported symptom burden and functional impairments that were of clinical importance, it is recommended to pay attention to the HRQoL outcomes of these patients during clinical encounters.

Brain gray matter reduction and premature brain aging after breast cancer chemotherapy: a longitudinal multicenter data pooling analysis.

Brain gray matter (GM) reductions have been reported after breast cancer chemotherapy, typically in small and/or cross-sectional cohorts, most commonly using voxel-based morphometry (VBM). There has been little examination of approaches such as deformation-based morphometry (DBM), machine-learning-based brain aging metrics, or the relationship of clinical and demographic risk factors to GM reduction. This international data pooling study begins to address these questions. Participants included breast cancer patients treated with (CT+, n = 183) and without (CT-, n = 155) chemotherapy and noncancer controls (NC, n = 145), scanned pre- and post-chemotherapy or comparable intervals. VBM and DBM examined GM volume. Estimated brain aging was compared to chronological aging. Correlation analyses examined associations between VBM, DBM, and brain age, and between neuroimaging outcomes, baseline age, and time since chemotherapy completion. CT+ showed longitudinal GM volume reductions, primarily in frontal regions, with a broader spatial extent on DBM than VBM. CT- showed smaller clusters of GM reduction using both methods. Predicted brain aging was significantly greater in CT+ than NC, and older baseline age correlated with greater brain aging. Time since chemotherapy negatively correlated with brain aging and annual GM loss. This large-scale data pooling analysis confirmed findings of frontal lobe GM reduction after breast cancer chemotherapy. Milder changes were evident in patients not receiving chemotherapy. CT+ also demonstrated premature brain aging relative to NC, particularly at older age, but showed evidence for at least partial GM recovery over time. When validated in future studies, such knowledge could assist in weighing the risks and benefits of treatment strategies.

Hippocampal avoidance prophylactic cranial irradiation (HA-PCI) for small cell lung cancer reduces hippocampal atrophy compared to conventional PCI.

BACKGROUND: Reducing radiation dose to the hippocampus with hippocampal avoidance prophylactic cranial irradiation (HA-PCI) is proposed to prevent cognitive decline. It has, however, not been investigated whether hippocampal atrophy is actually mitigated by this approach. Here, we determined whether HA-PCI reduces hippocampal atrophy. Additionally, we evaluated neurotoxicity of (HA-)PCI to other brain regions. Finally, we evaluated associations of hippocampal atrophy and brain neurotoxicity with memory decline. METHODS: High-quality research MRI scans were acquired in the multicenter, randomized phase 3 trial NCT01780675. Hippocampal atrophy was evaluated for 4 months (57 HA-PCI patients and 46 PCI patients) and 12 months (28 HA-PCI patients and 27 PCI patients) after (HA-)PCI. We additionally studied multimodal indices of brain injury. Memory was assessed with the Hopkins Verbal Learning Test-Revised (HVLT-R). RESULTS: HA-PCI reduced hippocampal atrophy at 4 months (1.8% for HA-PCI and 3.0% for PCI) and at 12 months (3.0% for HA-PCI and 5.8% for PCI). Both HA-PCI and PCI were associated with considerable reductions in gray matter and normal-appearing white matter, increases in white matter hyperintensities, and brain aging. There were no significant associations between hippocampal atrophy and memory. CONCLUSIONS: HA-PCI reduces hippocampal atrophy at 4 and 12 months compared to regular PCI. Both types of radiotherapy are associated with considerable brain injury. We did not find evidence for excessive brain injury after HA-PCI relative to PCI. Hippocampal atrophy was not associated with memory decline in this population as measured with HVLT-R. The usefulness of HA-PCI is still subject to debate.

[How long are medical oncology patients in The Netherlands willing to travel for their cancer care?] / Hoe lang zijn patiënten bereid te reizen voor medisch-oncologische zorg?

BACKGROUND: The number of people with cancer will increase in the Netherlands. Further concentration and network care is pursued. The aim of this study was to explore how long medical oncology patients are willing to travel for their cancer care. METHOD: A flashmob study into patients' willingness to travel for cancer care was conducted in 65 Dutch hospitals. Patients completed a questionnaire about willingness to travel and any experienced issues with traveling. RESULTS: A total of 4337 medical oncology patients completed the questionnaire. Of the patients, 20% were willing to travel more than 1 hour (one-way) for their current treatment, and more willing to travel for treatment in a hospital more experienced in their specific type of cancer (44% more than 1 hour). Willingness to travel longer was higher among patientsagedv40 years or younger, those with higher education, with better physical functioning and with a rare cancer. Willingness to travel longer was lowest among patients aged 75 or older. Approximately 30% of all patients experienced issues with traveling, especially those with comorbidities or with decreased physical functioning. CONCLUSION: In this flashmob study, 15% of patients were willing to travel up to 30 minutes (one-way) and 44% more than 1 hour for treatment and follow-up in a hospital more experienced in their specific type of cancer. Patients aged 75 years or older were less willing to travel longer. Thirty percent of patients experienced issues with travelling. It is important to take this into account in the future organization of cancer care.

Neurocognitive functioning after Gamma Knife and LINAC stereotactic radiosurgery in patients with brain metastases.

PURPOSE: Brain metastases (BM) themselves and treatment with stereotactic radiosurgery (SRS) can influence neurocognitive functioning. This prospective study aimed to assess neurocognitive decline in patients with BM after SRS. METHODS: A neuropsychological test battery was assessed yielding ten test outcomes. Neurocognitive decline at 3 and 6 months post SRS was compared to measurement prior to Gamma Knife (GK) or linear accelerator (LINAC) SRS. Reliable change indices with correction for practice effects were calculated to determine the percentage of neurocognitive decline (defined as decline on ≥ 2 test outcomes). Risk factors of neurocognitive decline were analyzed with binary logistic regression. RESULTS: Of 194 patients pre-SRS, 40 GK and 29 LINAC patients had data accessible at 6 months. Compared to baseline, 38% of GK patients declined at 3 months, and 23% declined at 6 months. GK patients declined on attention, executive functioning, verbal memory, and fine motor skill. Of LINAC patients, 10% declined at 3 months, and 24% at 6 months. LINAC patients declined on executive functioning, verbal memory, and fine motor skills. Risk factors of neurocognitive decline at 3 months were high age, low education level and type of SRS (GK or LINAC). At 6 months, high age was a risk factor. Karnofsky Performance Scale, BM volume, number of BM, tumor progression and neurocognitive impairment pre-SRS were no risk factors. CONCLUSION: Neurocognitive decline occurs in a considerable proportion of patients with BM treated with GK or LINAC SRS. Overall, high age appears to be a risk factor for neurocognitive decline after SRS.

Temporal Dynamics of Resting-state Functional Networks and Cognitive Functioning following Systemic Treatment for Breast Cancer.

Many women with breast cancer suffer from a decline in memory and executive function, particularly after treatment with chemotherapy. Recent neuroimaging studies suggest that changes in network dynamics are fundamental in decline in these cognitive functions. This has, however, not yet been investigated in breast cancer patients. Using resting state functional magnetic resonance imaging, we prospectively investigated whether changes in dynamic functional connectivity were associated with changes in memory and executive function. We examined 34 breast cancer patients that received chemotherapy, 32 patients that did not receive chemotherapy, and 35 no-cancer controls. All participants were assessed prior to treatment and six months after completion of chemotherapy, or at similar intervals for the other groups. To assess memory and executive function, we used the Hopkins Verbal Learning Test - Immediate Recall and the Trail Making Test B, respectively. Using a sliding window approach, we then evaluated dynamic functional connectivity of resting state networks supporting memory and executive function, i.e. the default mode network and frontoparietal network, respectively. Next, we directly investigated the association between cognitive performance and dynamic functional connectivity. We found no group differences in cognitive performance or connectivity measures. The association between dynamic functional connectivity of the default mode network and memory differed significantly across groups. This was not the case for the frontoparietal network and executive function. This suggests that cancer and chemotherapy alter the role of dynamic functional connectivity in memory function. Further implications of these findings are discussed.

Cancer-related cognitive impairment in patients with newly diagnosed aggressive lymphoma undergoing standard chemotherapy: a longitudinal feasibility study.

PURPOSE: Cancer-related cognitive impairment (CRCI) is a recognised adverse consequence of cancer and its treatment. This study assessed the feasibility of collecting longitudinal data on cognition in patients with newly diagnosed, aggressive lymphoma undergoing standard therapy with curative intent via self-report, neuropsychological assessment, peripheral markers of inflammation, and neuroimaging. An exploration and description of patterns of cancer-related cognitive impairment over the course of treatment and recovery was also undertaken and will be reported separately. METHODS: Eligible participants completed repeated measures of cognition including self-report and neuropsychological assessment, and correlates of cognition including blood cell-based inflammatory markers, and neuroimaging at three pre-specified timepoints, time 1 (T1) - pre-treatment (treatment naïve), time 2 (T2) - mid-treatment, and time 3 (T3) - 6 to 8 weeks post-completion of treatment. RESULTS: 30/33 eligible patients (91%, 95% CI: 76%, 97%) were recruited over 10 months. The recruitment rate was 3 patients/month (95% CI: 2.0, 4.3 patients/month). Reasons for declining included feeling overwhelmed and rapid treatment commencement. Mean age was 57 years (SD = 17 years) and 16/30 (53%) were male. Most patients (20/30, 67%) had diffuse large B cell lymphoma or Hodgkin lymphoma (4/30, 13%). The neuroimaging sub-study was optional, 11/30 participants (37%) were eligible to take part, and all agreed. The remaining 19 participants were ineligible as their diagnostic PET/CT scan was completed prior. Retention and compliance with all assessments were 89 to 100% at all timepoints. Only one participant was withdrawn due to disease progression. CONCLUSIONS: Findings from this study including excellent recruitment, retention, and compliance rates demonstrate it is feasible to longitudinally assess cognition in people with newly diagnosed aggressive lymphoma during their initial treatment and recovery to inform the development of future research to improve patient experiences and cognitive outcomes. TRIAL REGISTRATION: Australian New Zealand Clinical Trials Registry ACTRN12619001649101.

Brain White Matter Microstructure as a Risk Factor for Cognitive Decline After Chemotherapy for Breast Cancer.

PURPOSE: Cognitive decline is frequently observed after chemotherapy. As chemotherapy is associated with changes in brain white matter microstructure, we investigated whether white matter microstructure before chemotherapy is a risk factor for cognitive decline after chemotherapy. METHODS: Neuropsychologic tests were administered before and 6 months (n = 49), 2 years (n = 32), and 3 years (n = 32) after chemotherapy in patients with breast cancer receiving anthracycline-based chemotherapy (BC + CT group), at matched intervals to patients with BC who did not receive systemic therapy (BC - CT group: n = 39, 23, and 19, respectively) and to no-cancer controls (NC group: n = 37, 29, and 28, respectively). Using multivariate normative comparison, we evaluated to what extent the cognitive profiles of patients deviated from those of controls. Fractional anisotropy (FA), derived from magnetic resonance diffusion tensor imaging, was used to measure white matter microstructure before treatment. FA was evaluated as a risk factor for cognitive decline, in addition to baseline age, fatigue, cognitive complaints, and premorbid intelligence quotient. We subsequently ran voxel-wise diffusion tensor imaging analyses to investigate white matter microstructure in specific nerve tracts. RESULTS: Low FA independently predicted cognitive decline early (6 months, P = .013) and late (3 years, P < .001) after chemotherapy. FA did not predict cognitive decline in the BC - CT and NC groups. Voxel-wise analysis indicated involvement of white matter tracts essential for cognitive functioning. CONCLUSION: Low FA may reflect low white matter reserve. This may be a risk factor for cognitive decline after chemotherapy for BC. If validated in future trials, identification of patients with low white matter reserve could improve patient care, for example, by facilitating targeted, early interventions or even by influencing choices of patients and doctors for receiving chemotherapy.

Phase 3 Randomized Trial of Prophylactic Cranial Irradiation With or Without Hippocampus Avoidance in SCLC (NCT01780675).

INTRODUCTION: To compare neurocognitive functioning in patients with SCLC who received prophylactic cranial irradiation (PCI) with or without hippocampus avoidance (HA). METHODS: In a multicenter, randomized phase 3 trial (NCT01780675), patients with SCLC were randomized to standard PCI or HA-PCI of 25 Gy in 10 fractions. Neuropsychological tests were performed at baseline and 4, 8, 12, 18, and 24 months after PCI. The primary end point was total recall on the Hopkins Verbal Learning Test-Revised at 4 months; a decline of at least five points from baseline was considered a failure. Secondary end points included other cognitive outcomes, evaluation of the incidence, location of brain metastases, and overall survival. RESULTS: From April 2013 to March 2018, a total of 168 patients were randomized. The median follow-up time was 26.6 months. In both treatment arms, 70% of the patients had limited disease and baseline characteristics were well balanced. Decline on the Hopkins Verbal Learning Test-Revised total recall score at 4 months was not significantly different between the arms: 29% of patients on PCI and 28% of patients on HA-PCI dropped greater than or equal to five points (p = 1.000). Performance on other cognitive tests measuring memory, executive function, attention, motor function, and processing speed did not change significantly different over time between the groups. The overall survival was not significantly different (p = 0.43). The cumulative incidence of brain metastases at 2 years was 20% (95% confidence interval: 12%-29%) for the PCI arm and 16% (95% confidence interval: 7%-24%) for the HA-PCI arm. CONCLUSIONS: This randomized phase 3 trial did not find a lower probability of cognitive decline in patients with SCLC receiving HA-PCI compared with conventional PCI. No increase in brain metastases at 2 years was observed in the HA-PCI arm.

Measuring decline in white matter integrity after systemic treatment for breast cancer: omitting skeletonization enhances sensitivity.

Chemotherapy for non-central nervous system cancers is associated with abnormalities in brain structure and function. Diffusion tensor imaging (DTI) allows for studying in vivo microstructural changes in brain white matter. Tract-based spatial statistics (TBSS) is a widely used processing pipeline in which DTI data are typically normalized to a generic DTI template and then 'skeletonized' to compensate for misregistration effects. However, this approach greatly reduces the overall white matter volume that is subjected to statistical analysis, leading to information loss. Here, we present a re-analysis of longitudinal data previously analyzed with standard TBSS (Menning et al., BIB 2018, 324-334). For our current approach, we constructed a pipeline with an optimized registration method in Advanced Normalization Tools (ANTs) where DTI data are registered to a study-specific, high-resolution T1 template and the skeletonization step is omitted. In a head to head comparison, we show that with our novel approach breast cancer survivors who had received chemotherapy plus or minus endocrine therapy (BC + SYST, n = 26) showed a global decline in overall FA that was not present in breast cancer survivors who did not receive systemic therapy (BC-SYST, n = 23) or women without a cancer diagnosis (no cancer controls, NC, n = 30). With the standard TBSS approach we did not find any group differences. Moreover, voxel-based analysis for our novel pipeline showed a widespread decline in FA in the BC + SYST compared to the NC group. Interestingly, the BC-SYST group also showed a decline in FA compared to the NC group, although in much less voxels. These results were not found with the standard TBSS approach. We demonstrate that a modified processing pipeline makes DTI data more sensitive to detecting changes in white matter integrity in non-CNS cancer patients after treatment, particularly chemotherapy.

Effects of prolonged methylphenidate treatment on amygdala reactivity and connectivity: a randomized controlled trial in stimulant treatment-naive, male participants with ADHD.

Background: Problems with emotional processing are widely reported in individuals with attention-deficit/hyperactivity disorder (ADHD). Although methylphenidate (MPH) effectively alleviates inattention and hyperactivity symptoms in ADHD, its effects on emotional processing and internalizing symptoms have remained elusive. While we previously found that acute MPH administration modulated neural mechanisms underlying emotional processing in an age-dependent manner, the effects of prolonged administration remained unknown. Objectives: Therefore, we investigated: (i) whether prolonged MPH treatment influences neural substrates (amygdala reactivity and connectivity) of emotional processing, and (ii) whether these effects are modulated by age. Methods: The "effects of Psychotropic drugs On Developing brain-MPH" ("ePOD-MPH") randomized controlled trial was a 16-week double-blind, placebo-controlled, multi-center trial with MPH in 50 boys (10-12 years of age) and 49 men (23-40 years of age), all stimulant treatment-naive and diagnosed with ADHD. Participants performed an emotional face-matching task during functional magnetic resonance imaging. We assessed their symptoms of ADHD and internalizing symptoms at baseline, during the trial (8 weeks), and 1 week after the trial end (17 weeks). Results and Conclusions: We did not find effects of prolonged MPH treatment on emotional processing, as measured by amygdala reactivity and connectivity and internalizing symptoms in this trial with stimulant treatment-naive participants. This differs from our findings on emotional processing following acute MPH administration and the effects of prolonged MPH treatment on the dopamine system, which were both modulated by age. Interestingly, prolonged MPH treatment did improve ADHD symptoms, although depressive and anxiety symptoms showed a medication-independent decrease. Furthermore, our data indicate that baseline internalizing symptoms may be used to predict MPH treatment effects on ADHD symptoms, particularly in (male) adults with ADHD.

Brain structure prior to non-central nervous system cancer diagnosis: A population-based cohort study.

PURPOSE: Many studies have shown that patients with non-central nervous system (CNS) cancer can have brain abnormalities, such as reduced gray matter volume and cerebral microbleeds. These abnormalities can sometimes be present even before start of treatment, suggesting a potential detrimental effect of non-CNS cancer itself on the brain. In these previous studies, psychological factors associated with a cancer diagnosis and selection bias may have influenced results. To overcome these limitations, we investigated brain structure with magnetic resonance imaging (MRI) prior to cancer diagnosis. PATIENTS AND METHODS: Between 2005 and 2014, 4,622 participants from the prospective population-based Rotterdam Study who were free of cancer, dementia, and stroke, underwent brain MRI and were subsequently followed for incident cancer until January 1st, 2015. We investigated the association between brain MRI measurements, including cerebral small vessel disease, volumes of global brain tissue, lobes, and subcortical structures, and global white matter microstructure, and the risk of non-CNS cancer using Cox proportional hazards models. Age was used as time scale. Models were corrected for e.g. sex, intracranial volume, educational level, body mass index, hypertension, diabetes mellitus, smoking status, alcohol use, and depression sum-score. RESULTS: During a median (interquartile range) follow-up of 7.0 years (4.9-8.1), 353 participants were diagnosed with non-CNS cancer. Results indicated that persons who develop cancer do not have more brain abnormalities before clinical manifestation of the disease than persons who remain free of cancer. The largest effect estimates were found for the relation between presence of lacunar infarcts and the risk of cancer (hazard ratio [HR] 95% confidence interval [CI] = 1.39 [0.97-1.98]) and for total brain volume (HR [95%CI] per standard deviation increase in total brain volume = 0.76 [0.55-1.04]). CONCLUSION: We did not observe associations between small vessel disease, brain tissue volumes, and global white matter microstructure, and subsequent cancer risk in an unselected population. These findings deviate from previous studies indicating brain abnormalities among patients shortly after cancer diagnosis.

Is (poly-) substance use associated with impaired inhibitory control? A mega-analysis controlling for confounders.

Many studies have reported that heavy substance use is associated with impaired response inhibition. Studies typically focused on associations with a single substance, while polysubstance use is common. Further, most studies compared heavy users with light/non-users, though substance use occurs along a continuum. The current mega-analysis accounted for these issues by aggregating individual data from 43 studies (3610 adult participants) that used the Go/No-Go (GNG) or Stop-signal task (SST) to assess inhibition among mostly "recreational" substance users (i.e., the rate of substance use disorders was low). Main and interaction effects of substance use, demographics, and task-characteristics were entered in a linear mixed model. Contrary to many studies and reviews in the field, we found that only lifetime cannabis use was associated with impaired response inhibition in the SST. An interaction effect was also observed: the relationship between tobacco use and response inhibition (in the SST) differed between cannabis users and non-users, with a negative association between tobacco use and inhibition in the cannabis non-users. In addition, participants' age, education level, and some task characteristics influenced inhibition outcomes. Overall, we found limited support for impaired inhibition among substance users when controlling for demographics and task-characteristics.

Effect of physical exercise on cognitive function and brain measures after chemotherapy in patients with breast cancer (PAM study): protocol of a randomised controlled trial.

INTRODUCTION: After treatment with chemotherapy, many patients with breast cancer experience cognitive problems. While limited interventions are available to improve cognitive functioning, physical exercise showed positive effects in healthy older adults and people with mild cognitive impairment. The Physical Activity and Memory study aims to investigate the effect of physical exercise on cognitive functioning and brain measures in chemotherapy-exposed patients with breast cancer with cognitive problems. METHODS AND ANALYTICS: One hundred and eighty patients with breast cancer with cognitive problems 2-4 years after diagnosis are randomised (1:1) into an exercise intervention or a control group. The 6-month exercise intervention consists of twice a week 1-hour aerobic and strength exercises supervised by a physiotherapist and twice a week 1-hour Nordic or power walking. The control group is asked to maintain their habitual activity pattern during 6 months. The primary outcome (verbal learning) is measured at baseline and 6 months. Further measurements include online neuropsychological tests, self-reported cognitive complaints, a 3-tesla brain MRI, patient-reported outcomes (quality of life, fatigue, depression, anxiety, work performance), blood sampling and physical fitness. The MRI scans and blood sampling will be used to gain insight into underlying mechanisms. At 18 months online neuropsychological tests, self-reported cognitive complaints and patient-reported outcomes will be repeated. ETHICS AND DISSEMINATION: Study results may impact usual care if physical exercise improves cognitive functioning for breast cancer survivors. TRIAL REGISTRATION NUMBER: NTR6104.

Brain Hyperconnectivity >10 Years After Cisplatin-Based Chemotherapy for Testicular Cancer.

Chemotherapy for testicular cancer (TC) has been associated with neurotoxic effects shortly post-treatment. Late effects of chemotherapy on brain function in this patient group are still unknown. In this study, we investigated differences between patients with and without chemotherapy in functional brain networks at rest and during an affective processing functional magnetic resonance imaging (fMRI) task on average >14 years post-treatment. In addition, we report on changes in cognitive functioning during survivorship by comparing present and previous performance on a neuropsychological test battery on average 11 years earlier (3 years post-treatment). Twenty-eight chemotherapy (43.1 ± 7.5 years) and 23 surgery-only (48.2 ± 9.5 years) TC survivors were examined using neurocognitive tests and 3T-fMRI >10 years after treatment end. Brain functional networks were identified using dual regression independent component analysis. Task fMRI was analyzed using a block design. Standardized domain change scores were calculated for each individual to assess cognitive change. TC patients in the chemotherapy group showed functional hyperconnectivity at rest in the precuneus network, sensory and motor function network, executive control network, and the ventral stream network when compared with surgery-only patients. Furthermore, hypoactivation was found when performing the affective processing task. Cognitive data revealed that both groups showed comparable patterns of change from 3 to 14 years after initial treatment. This study provides novel insights on the possible underlying neurobiological mechanisms of late neurotoxic effects of cisplatin-based chemotherapy. Present findings reveal that functional hyperconnectivity is widespread, possibly to compensate for the pathophysiological disturbances. This concurs with our previous findings of structural hyperconnectivity in white matter. Longitudinal multimodal imaging studies are warranted to further investigate the association between long-term structural and functional network connectivity data, as well as its relationship with cognitive changes.

Multi-center reproducibility of structural, diffusion tensor, and resting state functional magnetic resonance imaging measures.

PURPOSE: The aim of this study is to assess multi-center reproducibility and longitudinal consistency of MRI imaging measurements, as part of a phase III longitudinal multi-center study comparing the neurotoxic effect following prophylactic cranial irradiation with hippocampal avoidance (HA-PCI), in comparison with conventional PCI in patients with small-cell lung cancer. METHODS: Harmonized MRI acquisition protocols from six participating sites and two different vendors were compared using both physical and human phantoms. We assessed variability across sites and time points by evaluating various phantoms and data including hippocampal volume, diffusion metrics, and resting-state fMRI, from two healthy volunteers. RESULTS: We report average coefficients of variation (CV) below 5% for intrascanner, intravendor, and intervendor reproducibility for both structural and diffusion imaging metrics, except for diffusion metrics obtained from tractography with average CVs ranging up to 7.8%. Additionally, resting-state fMRI showed stable temporal SNR and reliable generation of subjects DMN across vendors and time points. CONCLUSION: These findings indicate that the presented multi-site MRI acquisition protocol can be used in a longitudinal study design and that pooling of the acquired data as part of the phase III longitudinal HA-PCI project is possible with careful monitoring of the results of the half-yearly QA assessment to follow-up on potential scanner-related longitudinal changes in image quality.

ADHD and maturation of brain white matter: A DTI study in medication naive children and adults.

Several diffusion tensor imaging (DTI) studies in attention deficit hyperactivity disorder (ADHD) have shown a delay in brain white matter (WM) development. Because these studies were mainly conducted in children and adolescents, these WM abnormalities have been assumed, but not proven to progress into adulthood. To provide further insight in the natural history of WM maturation delay in ADHD, we here investigated the modulating effect of age on WM in children and adults. 120 stimulant-treatment naive male ADHD children (10-12 years of age) and adults (23-40 years of age) with ADHD (according to DSM-IV; all subtypes) were included, along with 23 age and gender matched controls. Fractional anisotropy (FA) values were compared throughout the WM by means of tract-based spatial statistics (TBSS) and in specific regions of interest (ROIs). On both TBSS and ROI analyses, we found that stimulant-treatment naive ADHD children did not differ in FA values from control children, whereas adult ADHD subjects had reduced FA values when compared to adult controls in several regions. Significant age × group interactions for whole brain FA (p = 0.015), as well as the anterior thalamic radiation (p = 0.015) suggest that ADHD affects the brain WM age-dependently. In contrast to prior studies conducted in medicated ADHD children, we did not find WM alterations in stimulant treatment naïve children, only treatment-naïve adults. Thus, our findings suggest that the reported developmental delay in WM might appear after childhood, and that previously reported differences between ADHD children and normal developing peers could have been attributed to prior ADHD medications, and/or other factors that affect WM development, such as age and gender.