Interaction of Alzheimer Disease and Traumatic Brain Injury on Cortical Thickness.

INTRODUCTION: Traumatic brain injury (TBI) is associated with an accelerated course of dementia, although biological relationships are incompletely understood. METHODS: The study examined 1124 participants, including 343 with Alzheimer disease (AD), 127 with AD with TBI, 266 cognitively normal adults with TBI, and 388 cognitively normal adults without TBI. Cortical thickness was quantified from T1-weighted magnetic resonance imaging data. Multiple linear regression was used to determine the interaction between AD and TBI on cortical thickness. RESULTS: Among those with AD, TBI was associated with an earlier age of AD onset but, counterintuitively, less cortical thinning in frontotemporal regions relative to non-AD controls. DISCUSSION: AD with TBI represents a distinct group from AD, likely with distinct pathologic contributions beyond gray matter loss. This finding has important implications for the diagnosis and treatment of AD in the presence of TBI and indicates that models of AD, aging, and neural loss should account for TBI history.

Neuropsychiatric symptoms and brain morphology in patients with mild cognitive impairment, cerebrovascular disease and Parkinson disease: A cross sectional and longitudinal study.

OBJECTIVES: Neuropsychiatric symptoms (NPS) increase risk of developing dementia and are linked to various neurodegenerative conditions, including mild cognitive impairment (MCI due to Alzheimer's disease [AD]), cerebrovascular disease (CVD), and Parkinson's disease (PD). We explored the structural neural correlates of NPS cross-sectionally and longitudinally across various neurodegenerative diagnoses. METHODS: The study included individuals with MCI due to AD, (n = 74), CVD (n = 143), and PD (n = 137) at baseline, and at 2-years follow-up (MCI due to AD, n = 37, CVD n = 103, and PD n = 84). We assessed the severity of NPS using the Neuropsychiatric Inventory Questionnaire. For brain structure we included cortical thickness and subcortical volume of predefined regions of interest associated with corticolimbic and frontal-executive circuits. RESULTS: Cross-sectional analysis revealed significant negative correlations between appetite with both circuits in the MCI and CVD groups, while apathy was associated with these circuits in both the MCI and PD groups. Longitudinally, changes in apathy scores in the MCI group were negatively linked to the changes of the frontal-executive circuit. In the CVD group, changes in agitation and nighttime behavior were negatively associated with the corticolimbic and frontal-executive circuits, respectively. In the PD group, changes in disinhibition and apathy were positively associated with the corticolimbic and frontal-executive circuits, respectively. CONCLUSIONS: The observed correlations suggest that underlying pathological changes in the brain may contribute to alterations in neural activity associated with MBI. Notably, the difference between cross-sectional and longitudinal results indicates the necessity of conducting longitudinal studies for reproducible findings and drawing robust inferences.

Cerebello-cerebral Functional Connectivity Networks in Major Depressive Disorder: a CAN-BIND-1 Study Report.

Neuroimaging studies have demonstrated aberrant structure and function of the "cognitive-affective cerebellum" in major depressive disorder (MDD), although the specific role of the cerebello-cerebral circuitry in this population remains largely uninvestigated. The objective of this study was to delineate the role of cerebellar functional networks in depression. A total of 308 unmedicated participants completed resting-state functional magnetic resonance imaging scans, of which 247 (148 MDD; 99 healthy controls, HC) were suitable for this study. Seed-based resting-state functional connectivity (RsFc) analysis was performed using three cerebellar regions of interest (ROIs): ROI1 corresponded to default mode network (DMN)/inattentive processing; ROI2 corresponded to attentional networks, including frontoparietal, dorsal attention, and ventral attention; ROI3 corresponded to motor processing. These ROIs were delineated based on prior functional gradient analyses of the cerebellum. A general linear model was used to perform within-group and between-group comparisons. In comparison to HC, participants with MDD displayed increased RsFc within the cerebello-cerebral DMN (ROI1) and significantly elevated RsFc between the cerebellar ROI1 and bilateral angular gyrus at a voxel threshold (p < 0.001, two-tailed) and at a cluster level (p < 0.05, FDR-corrected). Group differences were non-significant for ROI2 and ROI3. These results contribute to the development of a systems neuroscience approach to the diagnosis and treatment of MDD. Specifically, our findings confirm previously reported associations between MDD, DMN, and cerebellum, and highlight the promising role of these functional and anatomical locations for the development of novel imaging-based biomarkers and targets for neuromodulation therapies. ClinicalTrials.gov TRN: NCT01655706; Date of Registration: August 2nd, 2012.

Altered connectivity of default mode and executive control networks among female patients with persistent post-concussion symptoms.

OBJECTIVE: To examine the roles of the default mode network (DMN) and executive control network (ECN) in prolonged recovery after mild traumatic brain injury (mTBI), and relationships with indices of white matter microstructural injury. METHODS: Seventeen mTBI patients with persistent symptoms were imaged an average of 21.5 months post-injury, along with 23 healthy controls. Resting-state functional magnetic resonance imaging (rs-fMRI) was used to evaluate functional connectivity (FC) of the DMN and ECN. Diffusion tensor imaging (DTI) quantified fractional anisotropy, along with mean, axial and radial diffusivity of white matter tracts. RESULTS: Compared to controls, patients with mTBI had increased functional connectivity of the DMN and ECN to brain regions implicated in salience and frontoparietal networks, and increased white matter diffusivity within the cerebrum and brainstem. Among the patients, FC was correlated with better neurocognitive test scores, while diffusivity was correlated with more severe self-reported symptoms. The FC and diffusivity values within abnormal brain regions were not significantly correlated. CONCLUSION: For female mTBI patients with prolonged symptoms, hyper-connectivity may represent a compensatory response that helps to mitigate the effects of mTBI on cognition. These effects are unrelated to indices of microstructural injury, which are correlated with symptom severity, suggesting that rs-fMRI and DTI may capture distinct aspects of pathophysiology.

Comparing cardiovascular risk factors in older persons with mild cognitive impairment and lifetime history of major depressive disorder.

OBJECTIVES: To compare the prevalence of select cardiovascular risk factors (CVRFs) in patients with mild cognitive impairment (MCI) versus lifetime history of major depression disorder (MDD) and a normal comparison group using baseline data from the Prevention of Alzheimer's Dementia with Cognitive Remediation plus Transcranial Direct Current Stimulation (PACt-MD) study. DESIGN: Baseline data from a multi-centered intervention study of older adults with MCI, history of MDD, or combined MCI and history of MDD (PACt-MD) were analyzed. SETTING: Community-based multi-centered study based in Toronto across 5 academic sites. PARTICIPANTS: Older adults with MCI, history of MDD, or combined MCI and history of MDD and healthy controls. MEASUREMENTS: We examined the baseline distribution of smoking, hypertension and diabetes in three groups of participants aged 60+ years in the PACt-MD cohort study: MCI (n = 278), MDD (n = 95), and healthy older controls (n = 81). Generalized linear models were fitted to study the effect of CVRFs on MCI and MDD as well as neuropsychological composite scores. RESULTS: A higher odds of hypertension among the MCI cohort compared to healthy controls (p < .05) was noted in unadjusted analysis. Statistical significance level was lost on adjusting for age, sex and education (p > .05). A history of hypertension was associated with lower performance in composite executive function (p < .05) and overall composite neuropsychological test score (p < .05) among a pooled cohort with MCI or MDD. CONCLUSIONS: This study reinforces the importance of treating modifiable CVRFs, specifically hypertension, as a means of mitigating cognitive decline in patients with at-risk cognitive conditions.

Sex differences in acute and long-term brain recovery after concussion.

Concussion is associated with acute disturbances in brain function and behavior, with potential long-term effects on brain health. However, it is presently unclear whether there are sex differences in acute and long-term brain recovery. In this study, magnetic resonance imaging (MRI) was used to scan 61 participants with sport-related concussion (30 male, 31 female) longitudinally at acute injury, medical clearance to return to play (RTP), and 1-year post-RTP. A large cohort of 167 controls (80 male, 87 female) was also imaged. Each MRI session assessed cerebral blood flow (CBF), along with white matter fractional anisotropy (FA) and mean diffusivity (MD). For concussed athletes, the parameters were converted to difference scores relative to matched control subgroups, and partial least squares modeled the main and sex-specific effects of concussion. Although male and female athletes did not differ in acute symptoms or time to RTP , all MRI measures showed significant sex differences during recovery. Males had greater reductions in occipital-parietal CBF (mean difference and 95%CI: 9.97 ml/100 g/min, [4.84, 15.12] ml/100 g/min, z = 3.73) and increases in callosal MD (9.07 × 10-5 , [-14.14, -3.60] × 10-5 , z = -3.46), with greatest effects at 1-year post-RTP. In contrast, females had greater reductions in FA of the corona radiata (16.50 × 10-3 , [-22.38, -11.08] × 10-3 , z = -5.60), with greatest effects at RTP. These findings provide new insights into how the brain recovers after a concussion, showing sex differences in both the acute and chronic phases of injury.

Tablet Technology for Writing and Drawing during Functional Magnetic Resonance Imaging: A Review.

Functional magnetic resonance imaging (fMRI) is a powerful modality to study brain activity. To approximate naturalistic writing and drawing behaviours inside the scanner, many fMRI-compatible tablet technologies have been developed. The digitizing feature of the tablets also allows examination of behavioural kinematics with greater detail than using paper. With enhanced ecological validity, tablet devices have advanced the fields of neuropsychological tests, neurosurgery, and neurolinguistics. Specifically, tablet devices have been used to adopt many traditional paper-based writing and drawing neuropsychological tests for fMRI. In functional neurosurgery, tablet technologies have enabled intra-operative brain mapping during awake craniotomy in brain tumour patients, as well as quantitative tremor assessment for treatment outcome monitoring. Tablet devices also play an important role in identifying the neural correlates of writing in the healthy and diseased brain. The fMRI-compatible tablets provide an excellent platform to support naturalistic motor responses and examine detailed behavioural kinematics.

Scale-free functional brain dynamics during recovery from sport-related concussion.

Studies using blood-oxygenation-level-dependent functional magnetic resonance imaging (BOLD fMRI) have characterized how the resting brain is affected by concussion. The literature to date, however, has largely focused on measuring changes in the spatial organization of functional brain networks. In the present study, changes in the temporal dynamics of BOLD signals are examined throughout concussion recovery using scaling (or fractal) analysis. Imaging data were collected for 228 university-level athletes, 61 with concussion and 167 athletic controls. Concussed athletes were scanned at the acute phase of injury (1-7 days postinjury), the subacute phase (8-14 days postinjury), medical clearance to return to sport (RTS), 1 month post-RTS and 1 year post-RTS. The wavelet leader multifractal approach was used to assess scaling ( c1 ) and multifractal ( c2 ) behavior. Significant longitudinal changes were identified for c1 , which was lowest at acute injury, became significantly elevated at RTS, and returned near control levels by 1 year post-RTS. No longitudinal changes were identified for c2 . Secondary analyses showed that clinical measures of acute symptom severity and time to RTP were related to longitudinal changes in c1 . Athletes with both higher symptoms and prolonged recovery had elevated c1 values at RTS, while athletes with higher symptoms but rapid recovery had reduced c1 at acute injury. This study provides the first evidence for long-term recovery of BOLD scale-free brain dynamics after a concussion.

Neural Basis of Long-term Musical Memory in Cognitively Impaired Older Persons.

OBJECTIVE: The objective of this study was to determine whether exposure to long-known music would evoke more extensive activation of brain regions minimally affected by Alzheimer disease (AD) pathology and outside traditional memory networks using a functional magnetic resonance imaging paradigm involving listening to long-known and recently-learned music in older adults with cognitive impairment to provide insight into mechanisms of long-term musical memory preservation in cognitively impaired older persons. METHODS: Seventeen subjects with a diagnosis of mild AD or mild cognitive impairment were recruited for this study. Subjects were scanned using functional magnetic resonance imaging while they performed a music listening task, which included short clips of personally selected music from the patient's past and newly-composed music heard for the first time 60 minutes before scanning. From this task, we obtained group-level maps comparing brain areas associated with long-known and recently-heard music in all subjects. RESULTS: Exposure to long-known music preferentially activated brain regions including the medial prefrontal cortex, precuneus, anterior insula, basal ganglia, hippocampus, amygdala, and cerebellum relative to recently-heard music. These areas are involved in autobiographical memory and associated emotional responses. In addition, they are minimally affected by early stage AD pathology, thus providing a neural basis for long-known musical memory survival. CONCLUSIONS: Long-known music activates a bilateral network of prefrontal, emotional, motor, auditory, and subcortical regions (cerebellum, putamen, limbic structures). This extensive activation, relative to recently-heard music, may offer structural and functional clues as to why long-term musical memory appears to be relatively preserved among cognitively impaired older persons.

Association Between Neuropsychiatric Symptom Trajectory and Conversion to Alzheimer Disease.

INTRODUCTION: Neuropsychiatric symptoms (NPS) are both common in mild cognitive impairment and Alzheimer disease (AD). Studies have shown that some NPS such as apathy and depression are a key indicator for progression to AD. METHODS: We compared Neuropsychiatric Inventory (NPI) total score and NPI subdomain score between mild cognitive impairment-converters (MCI-C) and mild cognitive impairment-nonconverters (MCI-NC) longitudinally for 6 years using the Alzheimer's Disease Neuroimaging Initiative (ADNI) database. In addition to the NPI, Mini-Mental State Examination (MMSE) scores were also compared to find out if MMSE scores would differ between different NPI groups. Lastly, a linear regression model was done on MMSE and NPI total score to establish a relationship between MMSE and NPI total score. RESULTS: The results in this study showed that NPI total scores between MCI-C and MCI-NC differed significantly throughout 6 years. MCI-C subjects had a higher mean NPI total score and lower MMSE score compared with MCI-NC subjects. In addition, MMSE scores were significantly different between the 3 groups of NPI total score. Subjects who have a high NPI score have the lowest mean MMSE score, thus demonstrating that NPI scores do indeed affect MMSE scores. Further analyses using a regression model revealed that a unit change in NPI total score lead to 0.1 to 0.3 decrease in MMSE. DISCUSSION: On the basis of the findings, this study showed evidence that increase in NPS burden (reflected by increase in NPI) over time predicts conversion to AD, whereas stability of symptoms (reflected by stable NPI score) favors nonconversion. Further study should investigate the underlying mechanisms that drive both NPS burden and cognitive decline.

Brain activation during laparoscopic tasks in high- and low-performing medical students: a pilot fMRI study.

BACKGROUND: Up to 20% of medical students are unable to reach competency in laparoscopic surgery. It is unknown whether these difficulties arise from heterogeneity in neurological functioning across individuals. We sought to examine the differences in neurological functioning during laparoscopic tasks between high- and low-performing medical students using functional magnetic resonance imaging (fMRI). METHODS: This prospective cohort study enrolled North American medical students who were within the top 20% and bottom 20% of laparoscopic performers from a previous study. Brain activation was recorded using fMRI while participants performed peg-pointing, intracorporeal knot tying (IKT), and the Pictorial Surface Orientation (PicSOr) test. Brain activation maps were created and areas of activation were compared between groups. RESULTS: In total, 9/12 high and 9/13 low performers completed the study. High performers completed IKT faster and made more successful knot ties than low performers [standing: 23.5 (5.0) sec vs. 37.6 (18.4) sec, p = 0.03; supine: 23.2 (2.5) sec vs. 72.7 (62.8) sec, p = 0.02; number of successful ties supine, 3 ties vs. 1 tie, p = 0.01]. Low performers showed more brain activation than high performers in the peg-pointing task (q < 0.01), with no activation differences in the IKT task. There were no behavioral differences in the PiCSOr task. CONCLUSIONS: This study is the first to show differences between low and high performers of laparoscopic tasks at the brain level. This pilot study has shown the feasibility of using fMRI to examine laparoscopic surgical skills. Future studies are needed for further exploration of our initial findings.

Gender role in sleep disturbances among older adults with traumatic brain injury.

Older adults are particularly vulnerable to poor long-term outcomes, and the rate of TBI in this group is increasing. Studies have shown females experience worse outcomes from TBI than males, however this research has been limited. The aim of this study is to examine gender effects on the frequency of sleep disturbances in older adults post-TBI. An analysis was conducted on data obtained from the National Alzheimer's Coordinating Center (NACC) Uniform Data Set. A total of 405 patients greater than 60 years of age were examined. Sleep disturbances were measured using the Nighttime Behavioural Disturbances domain of the Neuropsychiatric Inventory-Questionnaire (NPI-Q). A significant difference (p = 0.025) in reported sleep disturbance was identified in the female TBI population relative to the female non-TBI population. In the male non-TBI group, 14.8% (n = 12) experienced nighttime disturbances while 19.8% (n = 17) of those with TBI experienced nighttime disturbances. This difference was not significant (p = 0.305). These results suggest there is a greater impact from traumatic brain injury on sleep disturbances in older females than males. Further research examining gender differences in older adults related to neuropsychiatric outcomes of TBI should be considered given the implications for treatment.

White matter during concussion recovery: Comparing diffusion tensor imaging (DTI) and neurite orientation dispersion and density imaging (NODDI).

Concussion pathophysiology in humans remains incompletely understood. Diffusion tensor imaging (DTI) has identified microstructural abnormalities in otherwise normal appearing brain tissue, using measures of fractional anisotropy (FA), axial diffusivity (AD), and radial diffusivity (RD). The results of prior DTI studies suggest that acute alterations in microstructure persist beyond medical clearance to return to play (RTP), but these measures lack specificity. To better understand the observed effects, this study combined DTI with neurite orientation dispersion and density imaging (NODDI), which employs a more sophisticated description of water diffusion in the brain. A total of 66 athletes were recruited, including 33 concussed athletes, scanned within 7 days after concussion and at RTP, along with 33 matched controls. Both univariate and multivariate methods identified DTI and NODDI parameters showing effects of concussion on white matter. Spatially extensive decreases in FA and increases in AD and RD were associated with reduced intra-neurite water volume, at both the symptomatic phase of injury and RTP, indicating that effects persist beyond medical clearance. Subsequent analyses also demonstrated that concussed athletes with higher symptom burden and a longer recovery time had greater reductions in FA and increased AD, RD, along with increased neurite dispersion. This study provides the first longitudinal evaluation of concussion from acute injury to RTP using combined DTI and NODDI, significantly enhancing our understanding of the effects of concussion on white matter microstructure.

Delusions in Alzheimer Disease are Associated With Decreased Default Mode Network Functional Connectivity.

OBJECTIVE: Approximately one-third of patients with Alzheimer disease (AD) develop delusions. Delusions have been linked to numerous adverse outcomes, including worsened cognitive and functional decline, increased caregiver burden, and higher mortality rates. Previous studies have indicated that both AD and neuropsychiatric symptoms within AD are associated with abnormal functional connectivity of the resting brain, but no studies have focused on how delusions alter resting-state functional connectivity. The authors' objective was to test for differences in resting brain function between delusional and non-delusional patients with AD. The authors hypothesized that patients with AD with delusions would exhibit reduced connectivity of the default mode network (DMN) compared with patients with AD without delusions. METHODS: Resting-state functional magnetic resonance imaging was used to investigate differences in functional connectivity between 15 patients with AD with delusions and 15 comparable patients with AD without delusions. A group-level principal component analysis was used to identify functional networks accounting for greatest variability over all subjects, and the DMN was selected for between-group analysis. Dual regression was used to reconstruct individual subject component maps, and a two-sample t test was used to compare groups with and without delusion, adjusted at a false discovery rate of 0.05. RESULTS: The two cohorts were comparable demographically and cognitively. The patients with delusions showed significantly reduced connectivity of the left inferior parietal lobule (IPL) with the rest of the DMN. CONCLUSION: Delusions in AD are associated with reduced connectivity within the DMN, specifically the left IPL. The authors' findings provide insight into the underlying neuropathophysiology of delusions in AD.

Gray Matter Changes Associated With the Development of Delusions in Alzheimer Disease.

OBJECTIVE: Delusions affect approximately a third of Alzheimer disease (AD) patients and are associated with poor outcomes. Previous studies investigating the neuroanatomic correlates of delusions have yet to reach a consensus, with findings of reduced volume across all lobes, particularly in frontal regions. The current study examined the gray matter (GM) differences associated with delusions in AD. METHODS: Using voxel-based morphometry, we assessed GM in 23 AD patients who developed delusions (AD+D) and 36 comparable AD patients who did not (AD-D) at baseline and follow-up. Analysis of variance was used to identify consistent differences between AD+D and AD-D patients across time points (main effect of group), consistent changes from baseline to follow-up (main effect of time), and differential changes between AD+D and AD-D over time (interaction of group and time). All data were obtained from the National Alzheimer's Coordinating Center database. RESULTS: The AD+D group had consistently lower frontal GM volume, although both groups showed decreased GM in frontotemporal brain regions over time. An interaction was observed between delusions and longitudinal change, with AD+D patients having significantly elevated GM in predominantly temporal areas at baseline assessment, becoming significantly lower than the AD-D group at follow-up. CONCLUSION: These findings suggest that, there are specific volumetric markers that distinguish patients with delusions from those without, before, and after the onset of delusions. Specifically, the decline of GM in temporal areas that had elevated levels prior to the onset of delusions may be involved in the manifestation of delusions.

A Systematic Review and Meta-Analysis on the Association Between Driving Ability and Neuropsychological Test Performances after Moderate to Severe Traumatic Brain Injury.

OBJECTIVES: Guidelines on return-to-driving after traumatic brain injury (TBI) are scarce. Since driving requires the coordination of multiple cognitive, perceptual, and psychomotor functions, neuropsychological testing may offer an estimate of driving ability. To examine this, a meta-analysis of the relationship between neuropsychological testing and driving ability after TBI was performed. METHODS: Hedge's g and 95% confidence intervals were calculated using a random effects model. Analyses were performed on cognitive domains and individual tests. Meta-regressions examined the influence of study design, demographic, and clinical factors on effect sizes. RESULTS: Eleven studies were included in the meta-analysis. Executive functions had the largest effect size (g = 0.60 [0.39-0.80]), followed by verbal memory (g = 0.49 [0.27-0.71]), processing speed/attention (g = 0.48 [0.29-0.67]), and visual memory (g = 0.43 [0.14-0.71]). Of the individual tests, Useful Field of Vision (UFOV) divided attention (g = 1.12 [0.52-1.72]), Trail Making Test B (g = 0.75 [0.42-1.08]), and UFOV selective attention (g = 0.67 [0.22-1.12]) had the largest effects. The effect sizes for Choice Reaction Time test and Trail Making Test A were g = 0.63 (0.09-1.16) and g = 0.58 (0.10-1.06), respectively. Years post injury (ß = 0.11 [0.02-0.21] and age (ß = 0.05 [0.009-0.09]) emerged as significant predictors of effect sizes (both p < .05). CONCLUSIONS: These results provide preliminary evidence of associations between neuropsychological test performance and driving ability after moderate to severe TBI and highlight moderating effects of demographic and clinical factors.

Efficacy and safety of erythropoietin and iron therapy to reduce red blood cell transfusion in surgical patients: a systematic review and meta-analysis.

PURPOSE: Iron restricted anemia is prevalent in surgical patients and is associated with an increased risk of allogeneic red blood cell (RBC) transfusion and adverse events. Treatment of anemia includes oral and intravenous iron and erythropoiesis stimulating agents (ESAs). More recent studies have focused on the use of intravenous iron as the primary approach to treating anemia. Nevertheless, the optimal treatment strategy for anemia remains to be established. Our primary objective was to evaluate the efficacy and safety of ESA and iron therapy relative to iron therapy alone in reducing RBC transfusion in surgical patients. SOURCE: We searched the Cochrane Library, MEDLINE, EMBASE, and ClinicalTrials.gov from inception to May 2018. We included randomized-controlled trials in which adult surgical patients received an ESA and iron, vs iron alone, prior to cardiac and non-cardiac surgery. Our primary outcome was RBC transfusion rate. Secondary outcomes included hemoglobin concentration (post-treatment and postoperatively), number of RBC units transfused, mortality, stroke, myocardial infarction (MI), renal dysfunction, pulmonary embolism (PE), and deep vein thrombosis (DVT). PRINCIPAL FINDINGS: In total, 25 studies (4,719 participants) were included. Erythropoiesis stimulating agents and iron therapy reduced RBC transfusion relative to iron therapy (relative risk [RR] 0.57; 95% confidence interval [CI], 0.46 to 0.71) without any change in mortality (RR 1.31; 95% CI, 0.80 to 2.16), stroke (RR 1.91; 95% CI, 0.63 to 5.76), MI (RR 1.12; 95% CI, 0.50 to 2.50), renal dysfunction (RR 0.96; 95% CI, 0.72 to 1.26), PE (RR 0.92; 95% CI, 0.15 to 5.83), or DVT (RR 1.48; 95% CI, 0.95 to 2.31). CONCLUSION: Administration of ESA and iron therapy reduced the risk for RBC transfusion compared with iron therapy alone in patients undergoing cardiac and non-cardiac surgery. Nevertheless, publication bias and heterogeneity reduces the confidence of the finding. Although the analysis was probably under-powered for some outcomes, no difference in the incidence of serious adverse events was observed with ESA and iron compared with iron alone. Further large prospective trials are required to confirm these findings.

Prioritization and Timing of Outcomes and Endpoints After Aneurysmal Subarachnoid Hemorrhage in Clinical Trials and Observational Studies: Proposal of a Multidisciplinary Research Group.

INTRODUCTION: In studies on aneurysmal subarachnoid hemorrhage (SAH), substantial variability exists in the use and timing of outcomes and endpoints, which complicates interpretation and comparison of results between studies. The aim of the National Institute of Health/National Institute of Neurological Disorders and Stroke/National Library of Medicine Unruptured Intracranial Aneurysm (UIA) and SAH common data elements (CDE) Project was to provide a common structure for future UIA and SAH research. METHODS: This article summarizes the recommendations of the UIA and SAH CDE Outcomes and Endpoints subgroup, which consisted of an international and multidisciplinary ad hoc panel of experts in clinical outcomes after SAH. Consensus recommendations were developed by review of previously published CDEs for other neurological diseases and the SAH literature. Recommendations for CDEs were classified by priority into "Core," "Supplemental-Highly Recommended," "Supplemental," and "Exploratory." RESULTS: The subgroup identified over 50 outcomes measures and template case report forms (CRFs) to be included as part of the UIA and SAH CDE recommendations. None was classified as "Core". The modified Rankin Scale score and Montreal Cognitive Assessment were considered the preferred outcomes and classified as Supplemental-Highly Recommended. Death, Glasgow Outcome Scale score, and Glasgow Outcome Scale-extended were classified as Supplemental. All other outcome measures were categorized as "Exploratory". We propose outcome assessment at 3 months and at 12 months for studies interested in long-term outcomes. We give recommendations for standardized dichotomization. CONCLUSION: The recommended outcome measures and CRFs have been distilled from a broad pool of potentially useful CDEs, scales, instruments, and endpoints. The adherence to these recommendations will facilitate the comparison of results across studies and meta-analyses of individual patient data.

Spontaneous subarachnoid haemorrhage.

Subarachnoid haemorrhage is an uncommon and severe subtype of stroke affecting patients at a mean age of 55 years, leading to loss of many years of productive life. The rupture of an intracranial aneurysm is the underlining cause in 85% of cases. Survival from aneurysmal subarachnoid haemorrhage has increased by 17% in the past few decades, probably because of better diagnosis, early aneurysm repair, prescription of nimodipine, and advanced intensive care support. Nevertheless, survivors commonly have cognitive impairments, which in turn affect patients' daily functionality, working capacity, and quality of life. Additionally, those deficits are frequently accompanied by mood disorders, fatigue, and sleep disturbances. Management requires specialised neurological intensive care units and multidisciplinary clinical expertise, which is better provided in high-volume centres. Many clinical trials have been done, but only two interventions are shown to improve outcome. Challenges that remain relate to prevention of subarachnoid haemorrhage by improved screening and development of lower-risk methods to repair or stabilise aneurysms that have not yet ruptured. Multicentre cooperative efforts might increase the knowledge that can be gained from clinical trials, which is often limited by small studies with differing criteria and endpoints that are done in single centres. Outcome assessments that incorporate finer assessment of neurocognitive function and validated surrogate imaging or biomarkers for outcome could also help to advance the specialty.

To drive or not to drive, that is still the question: current challenges in driving recommendations for patients with brain tumours.

Driving is a complex task that requires integration of various skills that may be impaired in patients with brain tumours. Determining fitness to drive is a responsibility of all physicians in Canada; however, it is an inconsistent practice based on few objective guidelines. The primary purpose of the study is to determine the consistency of driving recommendations amongst health care professionals in Ontario. Secondary aims include evaluation of physician awareness of driving regulations and determination of whether physicians would benefit from more specific driving guidelines. An 18-item questionnaire was sent to 126 health care professionals who take care of patients with brain tumours in Ontario. Seventy-five health care professionals responded to the survey. Less than 10% said they could reliably determine fitness to drive and almost an equal percentage of respondents indicated that determining fitness to drive should be a shared responsibility. The factors deemed important in determining driving safety were highly variable; 70% indicated that cognitive and emotional deficits were important. Over a third of respondents never heard of the CMA guidelines and of those who were familiar with it, 12.5% felt they were sufficient to inform clinical decisions. 90% of respondents wanted more specific and detailed driving guidelines for patients with brain tumours. The current guidelines for physicians are not specific enough for physicians to confidently determine fitness to drive in this population. These findings suggest the need for more detailed guidelines for driving safety that are based on empirical studies on driving habits and performance in patients with a variety of brain tumours.