Late effects of adjuvant chemotherapy on brain function and structure

Breast cancer is the most frequent malignancy in women in Western Europe and the United States. In 2009, 13,177 new cases of breast cancer were diagnosed within the Netherlands alone The lifetime risk of breast cancer in Dutch women reached 1 in 8.3 between 2005 and 2009, which is comparable to the lifetime risk of 1 in 8.2 in United States women that was observed between 2005 and 2007. The European Standardized Rates of breast cancer in the Netherlands significantly increased from 97.4 per 100,000 in 1989 to 129.6 per 100,000 in 2007. This increase has been ascribed to lifestyle changes such as delayed childbearing, lower parity, reduced breast-feeding and increased body-mass index. At the same time, mortality rates have decreased slightly as a result of improved treatment and possibly as a result of population screening. Because of the increased incidence and slightly decreased mortality, the number of survivors has increased

Focal Gray Matter Plasticity as a Function of Long Duration Head-down Tilt Bed Rest

Long duration spaceflight (i.e., > or = 22 days) has been associated with changes in sensorimotor systems, resulting in difficulties that astronauts experience with posture control, locomotion, and manual control. The microgravity environment is an important causal factor for spaceflight induced sensorimotor changes. Whether these sensorimotor changes may be related to structural and functional brain changes is yet unknown. However, experimental studies revealed changes in the gray matter (GM) of the brain after simulated microgravity. Thus, it is possible that spaceflight may affect brain structure and thereby cognitive functioning and motor behavior. Long duration head-down tilt bed rest has been suggested as an exclusionary analog to study microgravity effects on the sensorimotor system. Bed rest mimics microgravity in body unloading and bodily fluid shifts. In consideration of the health and performance of crewmembers both in- and post-flight, we are conducting a prospective longitudinal 70-day bed rest study as an analog to investigate the effects of microgravity on the brain. VBM analysis revealed a progressive decrease from pre- to in- bed rest in GM volume in bilateral areas including the frontal medial cortex, the insular cortex and the caudate. Over the same time period, there was a progressive increase in GM volume in the cerebellum, occipital-, and parietal cortex, including the precuneus. The majority of these changes did not fully recover during the post-bed rest period. Analysis of lobular GM volumes obtained with BRAINS showed significantly increased volume from pre-bed rest to in-bed rest in GM of the parietal lobe and the third ventricle. Temporal GM volume at 70 days in bed rest was smaller than that at the first pre-bed rest measurement. Trend analysis showed significant positive linear and negative quadratic relationships between parietal GM and time, a positive linear relationship between third ventricle volume and time, and a negative linear relationship between cerebellar GM volume and time. FM performance improved from pre-bed rest session 1 to session 2. From the second pre-bed rest measure to the last-day-in-bed rest, there was a significant decrease in performance that only partially recovered post-bed rest. No significant association was observed between changes in brain volume and changes in functional mobility. Extended bed rest, which is an analog for microgravity, can result in local volumetric GM increase and decrease and adversely affect functional mobility. These changes in brain structure and performance were not related in this sample. Whether the effects of bed rest dissipate at longer times post-bed rest, and if they are associated with behavior are important questions that warrant further research including more subjects and longer follow-up times

Neuropsychological performance in survivors of breast cancer more than 20 years after adjuvant chemotherapy

Purpose: Adjuvant chemotherapy for breast cancer can have adverse effects on cognition shortly after administration. Whether chemotherapy has any long-term effects on cognition is largely unknown, yet it becomes increasingly relevant because of the widespread use of chemotherapy for early-stage breast cancer and the improved survival. We investigated whether cyclophosphamide, methotrexate, and fluorouracil (CMF) chemotherapy for breast cancer is associated with worse cognitive performance more than 20 years after treatment. Patients and Methods: This case-cohort study compared the cognitive performance of patients with breast cancer who had a history of adjuvant CMF chemotherapy treatment (six cycles; average time since treatment, 21 years; n = 196) to that of a population-based sample of women never diagnosed with cancer (n = 1,509). Participants were between 50 and 80 years of age. Exclusion criteria were ever use of adjuvant endocrine therapy, secondary malignancy, recurrence, and/or metastasis. Results: The women exposed to chemotherapy performed significantly worse than the reference group on cognitive tests of immediate (P = .015) and delayed verbal memory (P = .002), processing speed (P < .001), executive functioning (P = .013), and psychomotor speed (P = .001). They experienced fewer symptoms of depression (P < .001), yet had significantly more memory complaints on two of three measures that could not be explained by cognitive test performance. Conclusion: Survivors of breast cancer treated with adjuvant CMF chemotherapy more than 20 years ago perform worse, on average, than random population controls on neuropsychological tests. The pattern of cognitive problems is largely similar to that observed in patients shortly after cessation of chemotherapy. This study suggests that cognitive deficits following breast cancer diagnosis and subsequent CMF chemotherapy can be long lasting

Exercise Effects on the Course of Gray Matter Changes Over 70 Days of Bed Rest

Long duration spaceflight affects posture control, locomotion, and manual control. The microgravity environment is an important causal factor for spaceflight induced sensorimotor changes through direct effects on peripheral changes that result from reduced vestibular stimulation and body unloading. Effects of microgravity on sensorimotor function have been investigated on earth using bed rest studies. Long duration bed rest serves as a space-flight analogue because it mimics microgravity in body unloading and bodily fluid shifts. It has been hypothesized that the cephalad fluid shift that has been observed in microgravity could potentially affect central nervous system function and structure, and thereby indirectly affect sensorimotor or cognitive functioning. Preliminary results of one of our ongoing studies indeed showed that 70 days of long duration head down-tilt bed rest results in focal changes in gray matter volume from pre-bed rest to various time points during bed rest. These gray matter changes that could reflect fluid shifts as well as neuroplasticity were related to decrements in motor skills such as maintenance of equilibrium. In consideration of the health and performance of crewmembers both inand post-flight we are currently conducting a study that investigates the potential preventive effects of exercise on gray matter and motor performance changes that we observed over the course of bed rest. Numerous studies have shown beneficial effects of aerobic exercise on brain structure and cognitive performance in healthy and demented subjects over a large age range. We therefore hypothesized that an exercise intervention in bed rest could potentially mitigate or prevent the effects of bed rest on the central nervous system. Here we present preliminary outcomes of our study

Focal Gray Matter Plasticity as a Function of Long Duration Bedrest: Preliminary Results

Long duration spaceflight (i.e., 22 days or longer) has been associated with changes in sensorimotor systems, resulting in difficulties that astronauts experience with posture control, locomotion, and manual control. It is unknown whether and how spaceflight impacts sensorimotor brain structure and function, and whether such changes may potentially underlie behavioral effects. Long duration head down tilt bed rest has been used repeatedly as an exclusionary analog to study microgravity effects on the sensorimotor system [1]. Bed rest mimics microgravity in body unloading and bodily fluid shifts. We are currently testing sensorimotor function, brain structure, and brain function pre and post a 70day bed rest period. We will acquire the same measures on NASA crewmembers starting in 2014. Here we present the results of the first eight bed rest subjects. Subjects were assessed at 12 and 7 days before, at 7, 30, and ~70 days in, and at 8 and 12 days post 70 days of bed rest at the NASA bed rest facility, UTMB, Galveston, TX, USA. At each time point structural MRI scans (i.e., high resolution T1weighted imaging and Diffusion Tensor Imaging (DTI)) were obtained using a 3T Siemens scanner. Focal changes over time in gray matter density were assessed using the voxel based morphometry 8 (VBM8) toolbox under SPM. Focal changes in white matter microstructural integrity were assessed using tract based spatial statistics (TBSS) as part of the FMRIB software library (FSL). TBSS registers all DTI scans to standard space. It subsequently creates a study specific white matter skeleton of the major white matter tracts. Nonparametric permutation based ttests and ANOVA's were used for voxelwise comparison of the skeletons. For both VBM and TBSS, comparison of the two pre bed rest measurements did not show significant differences. VBM analysis revealed decreased gray matter density in bilateral areas including the frontal medial cortex, the insular cortex and the caudate nucleus from pre to in bed rest. Over the same time period, there was an increase in gray matter density in the cerebellum, occipital, and parietal cortices. The majority of these changes did not recover from during to post bed rest. TBSS analyses will also be presented. Extended bed rest, which is an analog for microgravity, can result in gray matter changes and potentially in microstructural white matter changes in areas that are important for neuromotor behavior and cognition. These changes did not recover at two weeks post bed rest. These results have significant public health implications, and will also aid in interpretation of our future data obtained pre and post spaceflight. Whether the effects of bed rest wear off at longer times post bed rest, and if they are associated with behavior are important questions that warrant further research

Focal Gray Matter Plasticity as a Function of Long Duration Head Down Tilted Bed Rest: Preliminary Results

Long duration spaceflight (i.e., 22 days or longer) has been associated with changes in sensorimotor systems, resulting in difficulties that astronauts experience with posture control, locomotion, and manual control. The microgravity environment is an important causal factor for spaceflight induced sensorimotor changes. Whether these sensorimotor changes are solely related to peripheral changes from reduced vestibular stimulation, body unloading, body fluid shifts or that they may be related to structural and functional brain changes is yet unknown. However, a recent study reported associations between microgravity and flattening of the posterior eye globe and protrusion of the optic nerve [1] possibly as the result of increased intracranial pressure due to microgravity induced bodily fluid shifts [3]. Moreover, elevated intracranial pressure has been related to white matter microstructural damage [2]. Thus, it is possible that spaceflight may affect brain structure and thereby cognitive functioning. Long duration head down tilt bed rest has been suggested as an exclusionary analog to study microgravity effects on the sensorimotor system [4]. Bed rest mimics microgravity in body unloading and bodily fluid shifts. In consideration of the health and performance of crewmembers both in- and post-flight, we are conducting a prospective longitudinal 70-day bed rest study as an analog to investigate the effects of microgravity on brain structure [5]. Here we present results of the first six subjects. Six subjects were assessed at 12 and 7 days before-, at 7, 30, and ~70 days in-, and at 8 and 12 days post 70 days of bed rest at the NASA bed rest facility in UTMB, Galveston, TX, USA. At each time point structural MRI scans (i.e., high resolution T1-weighted imaging and Diffusion Tensor Imaging (DTI)) were obtained using a 3T Siemens scanner. Focal changes over time in gray matter density were assessed using the voxel based morphometry 8 (VBM8) toolbox under SPM. Longitudinal processing in VBM8 includes linear registration of each scan to the mean of the subject and subsequently transforming all scans in to MNI space by applying the warp from the mean subject to MNI to the individual gray matter segmentations. Modulation was applied so that all images represented the volume of the original structure in native space. Voxel wise analysis was carried out on the gray matter images after smoothing, using a flexible factorial design with family wise error correction. Focal changes in white matter microstructural integrity were assessed using tract based spatial statistics (TBSS) as part of FMRIB software library (FSL). TBSS registers all DTI scans to standard space. It subsequently creates a study specific white matter skeleton of the major white matter tracts. For each subject, for each DTI metric (i.e. fractional anisotropy (FA), mean diffusivity (MD), axial diffusivity (AD), and radial diffusivity (RD)), the maximum value in a line perpendicular to the skeleton tract is projected to the skeleton. Non-parametric permutation based t-tests and ANOVA's were used for voxel-wise comparison of the skeletons. For both VBM and TBSS, comparison of pre bed rest measurements did not show significant differences. VBM analysis revealed decreased gray matter density in bilateral areas including the frontal medial cortex, the insular cortex and the caudate (see Figure) from 'pre to in bed rest'. Over the same time period, there was an increase in gray matter density in the cerebellum, occipital-, and parietal cortex, including the precuneus (see Figure). The majority of these changes did not recover from 'during to post bed rest'. TBSS analysis did not reveal significant changes in white matter microstructural integrity after correction for multiple comparisons. Uncorrected analyses (p<.015) revealed an increase in RD in the cerebellum and brainstem from pre bed rest to the first week in bed rest that did not recover post bed rest. Extended bed rest, which is an analog for microgravity, can result in gray matter changes and potentially in microstructural white matter changes in areas that are important for neuro motor behavior and cognition. These changes did not recover at two weeks post bed rest. Whether the effects of bed rest wear off at longer times post bed rest, and if they are associated with behavior are important questions that warrant further research

The Effects of Long Duration Bed Rest on Functional Mobility and Balance: Relationship to Resting State Motor Cortex Connectivity

NASA offers researchers from a variety of backgrounds the opportunity to study bed rest as an experimental analog for space flight. Extended exposure to a head-down tilt position during long duration bed rest can resemble many of the effects of a low-gravity environment such as reduced sensory inputs, body unloading and increased cephalic fluid distribution. The aim of our study is to a) identify changes in brain function that occur with prolonged bed rest and characterize their recovery time course; b) assess whether and how these changes impact behavioral and neurocognitive performance. Thus far, we completed data collection from six participants that include task based and resting state fMRI. The data have been acquired through the bed rest facility located at the University of Texas Medical Branch (Galveston, TX). Subjects remained in bed with their heads tilted down 6 degrees below their feet for 70 consecutive days. Behavioral measures and neuroimaging assessments were obtained at seven time points: a) 7 and 12 days before bed rest; b) 7, 30, and 65 days during bed rest; and c) 7 and 12 days after bed rest. Functional connectivity magnetic resonance imaging (FcMRI) analysis was performed to assess the connectivity of motor cortex in and out of bed rest. We found a decrease in motor cortex connectivity with vestibular cortex and the cerebellum from pre bed rest to in bed rest. We also used a battery of behavioral measures including the functional mobility test and computerized dynamic posturography collected before and after bed rest. We will report the preliminary results of analyses relating brain and behavior changes. Furthermore, we will also report the preliminary results of a spatial working memory task and vestibular stimulation during in and out of bed rest

The Amsterdam studies of acute psychiatry I (ASAP-I); A prospective cohort study of determinants and outcome of coercive versus voluntary treatment interventions in a metropolitan area

Background: The overall number of involuntary admissions is increasing in many European countries. Patients with severe mental illnesses more often progress to stages in which acute, coercive treatment is warranted. The number of studies that have examined this development and possible consequences in terms of optimizing health care delivery in emergency psychiatry is small and have a number of methodological shortcomings. The current study seeks to examine factors associated with compulsory admissions in the Amsterdam region, taking into account a comprehensive model with four groups of predictors: patient vulnerability, social support, responsiveness of the health care system and treatment adherence. Methods/Design: This paper describes the design of the Amsterdam Study of Acute Psychiatry-I (ASAP-I). The study is a prospective cohort study, with one and two-year follow-up, comparing patients with and without forced admission by means of a selected nested case-control design. An estimated total number of 4,600 patients, aged 18 years and over, consecutively coming into contact with the Psychiatric Emergency Service Amsterdam (PESA) are included in the study. From this cohort, a randomly selected group of 125 involuntary admitted subjects and 125 subjects receiving non-coercive treatment are selected for further evaluation and comparison. First, socio-demographic, psychopathological and network characteristics, and prior use of health services will be described for all patients who come into contact with PESA. Second, the in-depth study of compulsory versus voluntary patients will examine which patient characteristics are associated with acute compulsory admission, also taking into account social network and healthcare variables. The third focus of the study is on the associations between patient vulnerability, social support, healthcare characteristics and treatment adherence in a two-year follow-up for patients with or without involuntarily admittance at the index consultation. Discussion: The current study seeks to establish a picture of the determinants of acute compulsory admissions in the Netherlands and tries to gain a better understanding of the association with the course of illness and patient's perception of services and treatment adherence. The final aim is to find specific patient and health care factors that can be influenced by adjusting treatment programs in order to reduce the number of involuntary admissions

The Effects of Long Duration Head Down Tilt Bed Rest on Neurocognitive Performance: The Effects of Exercise Interventions

We are conducting ongoing experiments in which we are performing structural and functional magnetic resonance brain imaging to identify the relationships between changes in neurocognitive function and neural structural alterations following a six month International Space Station mission and following 70 days exposure to a spaceflight analog, head down tilt bedrest. Our central hypothesis is that measures of brain structure, function, and network integrity will change from pre to post intervention (spaceflight, bedrest). Moreover, we predict that these changes will correlate with indices of cognitive, sensory, and motor function in a neuroanatomically selective fashion. Our interdisciplinary approach utilizes cutting edge neuroimaging techniques and a broad ranging battery of sensory, motor, and cognitive assessments that will be conducted pre flight, during flight, and post flight to investigate potential neuroplastic and maladaptive brain changes in crewmembers following long-duration spaceflight. Success in this endeavor would 1) result in identification of the underlying neural mechanisms and operational risks of spaceflight-induced changes in behavior, and 2) identify whether a return to normative behavioral function following re-adaptation to Earth's gravitational environment is associated with a restitution of brain structure and function or instead is supported by substitution with compensatory brain processes. Our ongoing bed rest participants are also engaging in exercise studies directed by Dr. Lori Ploutz Snyder. In this presentation, I will briefly highlight the existing literature linking exercise and fitness to brain and behavioral functions. I will also overview the metrics from my study that could be investigated in relation to the exercise and control subgroups