Cognitive Impairment In Survivors Research Articles

White matter injury in infants with intraventricular haemorrhage: mechanisms and therapies.

Intraventricular haemorrhage (IVH) continues to be a major complication of prematurity that can result in cerebral palsy and cognitive impairment in survivors. No optimal therapy exists to prevent IVH or to treat its consequences. IVH varies in severity and can present as a bleed confined to the germinal matrix, small-to-large IVH or periventricular haemorrhagic infarction. Moderate-to-severe haemorrhage dilates the ventricle and damages the periventricular white matter. This white matter injury results from a constellation of blood-induced pathological reactions, including oxidative stress, glutamate excitotoxicity, inflammation, perturbed signalling pathways and remodelling of the extracellular matrix. Potential therapies for IVH are currently undergoing investigation in preclinical models and evidence from clinical trials suggests that stem cell treatment and/or endoscopic removal of clots from the cerebral ventricles could transform the outcome of infants with IVH. This Review presents an integrated view of new insights into the mechanisms underlying white matter injury in premature infants with IVH and highlights the importance of early detection of disability and immediate intervention in optimizing the outcomes of IVH survivors.

Cancer-related cognitive impairment in survivors of acute lymphoblastic leukemia

Cancer-related cognitive impairment in survivors of acute lymphoblastic leukemia

Abstract 275: Cardiac Arrest Etiology and Associated Cognitive Impairment in Survivors

Background: Cardiac arrest is a significant public health problem, impacting over 500,000 people in the United States annually. The four major etiologies of arrest are cardiac, respiratory, traumatic, and other. The objective was to determine the impact of etiology on cognition in cardiac arrest survivors using the Montreal Cognitive Assessment (MOCA). Hypothesis: Cardiac arrest etiology impacts cognitive exam score, and patient demographics and characteristics modify that relationship. Methods: A retrospective cohort analysis was performed on all Pittsburgh Post Cardiac Arrest Service (PCAS) patients from 2012-18. Data were acquired through medical record review. T-tests, linear and logistic regression were used to assess the relationships between exam score and modifying factors. MOCA score was analyzed as a binomial variable using a pass/fail threshold of 26/30 points (86.7%) and above for normal cognition. For statistical significance, an alpha level of 0.05 was used. Results: In total, 192 patients completed the MOCA: 104 with cardiac etiology, 35 with respiratory, 4 with trauma, and 49 with other. Median age for all patients was 59.3 years, and 58% were male. Mean (SE) MOCA score for all patients was 72.8 (1.1) percent. When MOCA score was converted to a binomial indicator of normal cognition, respiratory, traumatic, and other etiologies were more likely to exhibit impairment than cardiac etiology arrest when age, sex, witnessed status, length of ICU stay and coma were controlled for (OR: 2.52, 3.43, 2.18 respectively). These findings were nullified when time from arrest to MOCA administration was included. Of the MOCA subcategories, delayed recall was the most severely impacted, with patients recalling an average of 1.67 of 5 words after 5 minutes. Additionally, respiratory arrests performed significantly worse than cardiac etiology arrests in attention (4.1 vs 4.9 points, p=0.004) and language domains (1.9 vs. 2.3, p=0.04). Conclusions: Respiratory, traumatic, and other etiologies were more likely to exhibit abnormal cognition on the MOCA than those with a cardiac etiology. The etiological findings were nullified when time to cognitive examination was controlled for. Timing appears to influence cognitive assessments more than etiology.

Depression predicts long-term cognitive impairment in survivors of critical illness.

Intensive care unit (ICU) survivorship is associated with long-term cognitive impairment (LTCI). Our work has found post-ICU depression in up to 30% and posttraumatic stress disorder (PTSD) in up to 10% of ICU survivors. We hypothesized that post-ICU depression and PTSD are independently associated with LTCI in ICU survivors. This is a five-center nested prospective cohort of critically ill patients admitted to medical and surgical ICUs who underwent neuropsychological assessments at 3 and 12 months posthospital discharge. Our primary outcome was global cognition using the Repeatable Battery for the Assessment of Neuropsychological Status (RBANS) and Trail Making Test, Part B, a test of executive functioning, at 3- and 12-month follow-up. Our independent variables were Beck Depression Inventory II and the PTSD Checklist-Specific Version measured at 3 and 12 months. We performed multivariable linear regression models controlling for covariates such as age, years of education, preexisting cognitive impairment, comorbidities, ventilator days, hypoxemia episodes, and days of delirium or coma. Of 1,047 patients in the combined cohort, 679 were alive and available for follow-up at 3 months. A total of 590 (87%) ICU survivors completed at least one 3-month assessment, and of the 554 who survived to 12 months, 519 (94%) completed both a 3- and 12-month assessment with a median age of 61 years (52-70 years) and mean daily Sequential Organ Failure Assessment score of 6 (4-8), 520 (88%) were mechanically ventilated, and 420 (71%) were with delirium. Of these, 113 (19%) had PTSD and 187 (32%) had depression at 3 months with similar rates at 12 months. Depression at 3 months was associated with lower 3-month RBANS (coefficient, -2.25; -3.10 to -1.39) and lower Trails B scores at both 3 months (odds ratio, 0.69; 0.56-0.85) and 12 months (odds ratio, 0.66; 0.52-0.84). Posttraumatic stress disorder at 3 months had no association with RBANS or Trails B scores at 3 or 12 months. Early post-ICU depression, but not PTSD, is independently associated with coexisting LTCI, even when controlling for past ICU delirium. Treatment for early depression represents a novel intervention area for LTCI prevention in ICU survivors. Prognostic/epidemiological, level III.

Prevalence and Course of Frailty in Survivors of Critical Illness.

Little is known about frailty that develops following critical illness. We sought to describe the prevalence of newly acquired frailty, its clinical course, and the co-occurrence of frailty with disability and cognitive impairment in survivors of critical illness. Longitudinal prospective cohort study. Medical and surgical ICUs at five U.S. centers. Adult patients treated for respiratory failure and/or shock. We measured frailty with the Clinical Frailty Scale at baseline (i.e., study enrollment) and at 3 and 12 months postdischarge. We constructed alluvial diagrams to describe the course of frailty and Venn diagrams to describe the overlap of frailty with disability in activities of daily living and cognitive impairment. We included 567 participants a median (interquartile range) of 61 years old (51-70 yr old) with a high severity of illness (Acute Physiology and Chronic Health Evaluation II of 23). Frailty (Clinical Frailty Scale scores ≥ 5) was present in 135 of 567 (24%) at baseline, 239 of 530 (45%) at 3 months, and 163 of 445 (37%) at 12 months. Of those with frailty at 3- or 12-month follow-up, 61% were not frail at baseline. Transition to a worse frailty state occurred in 242 of 530 of patients (46%) between baseline and 3 months and in 179 of 445 of patients (40%) between baseline and 12 months. There were 376 patients with frailty, disability, or cognitive impairment at 3-month follow-up. Of these, 53 (14%) had frailty alone. At 12 months, 276 patients had frailty, disability, or cognitive impairment, 37 (13%) of whom had frailty alone. Frailty is common among survivors of critical illness. In the majority, frailty is newly acquired. Roughly one in seven had frailty without co-occurring disability or cognitive impairment. Studies to understand outcomes of frailty that develops as the result of a critical illness and to identify modifiable risk factors for this potentially reversible syndrome are needed.

Associations of plasma brain-derived neurotrophic factor (BDNF) and Val66Met polymorphism (rs6265) with long-term cancer-related cognitive impairment in survivors of breast cancer.

Brain-derived neurotrophic factor (BDNF) and the BDNF Val66Met polymorphism (rs6265) have been implicated in neurodegenerative conditions. This study aimed to investigate the associations of plasma BDNF and rs6265 with cancer-related cognitive impairment (CRCI) at the end of chemotherapy, and with persistent and delayed CRCI up to 24months post chemotherapy, among survivors of early-stage breast cancer. A multicenter, longitudinal study involving 174 breast cancer patients was conducted. CRCI was assessed using the FACT-Cog (V3) questionnaire and the CANTAB software. Plasma BDNF levels were quantified using an enzyme-linked immunosorbent assay at serial time points and genotyping was achieved using Sanger sequencing. The associations of BDNF and rs6265 with CRCI were analyzed using logistic regressions. A smaller magnitude of reduction in plasma BDNF between baseline and the end of chemotherapy was correlated with protection from overall subjective CRCI (OR 0.88; 95% CI 0.79-0.99). Furthermore, patients with higher plasma BDNF levels at the end of chemotherapy had lower odds of developing persistent overall subjective CRCI (OR 0.74; 95% CI 0.57-0.97) and persistent CRCI in the functional interference domain (OR 0.62; 95% CI 0.39-0.98). BDNF Met allele carriers were protected against subjective CRCI at the end of chemotherapy in the multitasking and memory domains, and against persistent subjective CRCI in the mental acuity and multitasking domains. BDNF plasma level or rs6265 genotype information may facilitate the identification of patients at higher risk of long-term CRCI during survivorship and enable the implementation of early intervention strategies that increase BDNF levels.

Self‐endorsed cognitive problems versus objectively assessed cognitive impairment in blood or bone marrow transplantation recipients: A longitudinal study

Cognitive impairment in survivors of blood or bone marrow transplantation (BMT) is well documented. However, to the authors' knowledge, the clinical relevance of self-endorsed cognitive problems and their relation to objectively assessed cognitive impairment is not known. The authors assessed cognitive impairment in 378 BMT recipients (median age, 52.2years, 40% of whom were female and 68% of whom were non-Hispanic white) and 98 healthy controls at 5 predetermined time points: at baseline (before BMT) and at 6months, 1year, 2years, and 3years after BMT. Self-endorsed cognitive problems were evaluated using the Neuropsychological Impairment Scale (NIS) and correlated with a standardized 2-hour battery of objective cognitive testing at each time point. The authors examined the magnitude of difference in self-endorsed cognitive problems between BMT recipients and healthy controls, and the rate of change in scores over time. Multivariable analyses were used to identify clinical and/or demographic variables associated with self-endorsed cognitive problems. The authors also examined the association between cognitive impairment and returning to work after BMT. Compared with healthy controls, BMT recipients endorsed more cognitive problems (P<.001) at all time points, and the rate of change in NIS scores was found to be significantly greater in BMT recipients. Fatigue was associated with greater endorsement of cognitive problems at 1year after BMT (odds ratio, 4.23; 95% CI, 2.1-8.3 [P<.001]). Overall, there was a statistically significant, modest correlation noted between self-endorsed cognitive problems and objective cognitive impairment (range, 0.401-0.445 [P≤.01]). Higher self-endorsed cognitive problems were associated with a 3.7-fold (P=.02) higher odds of not returning to work at 3years after BMT. The results of the current study demonstrated that self-endorsed cognitive problems can help to identify vulnerable patient subpopulations for detailed cognitive assessment and possible cognitive remediation.

The Role of Secretase Pathway in Long-term Brain Inflammation and Cognitive Impairment in an Animal Model of Severe Sepsis.

Inflammatory cytokines are related to impaired learning and memory processes in the central nervous system, contributing to the cognitive dysfunction present in sepsis survivors. In sepsis, brain of survivors presented increased deposition of amyloid-beta (Aβ) peptide and this was associated with cognitive impairment. However, it is not known if the upregulation of secretase pathway is involved the deposition of Aβ peptide and consequent development of cognitive impairment in survivors. The aim of the study is to evaluate the effects of secretase inhibitors on behavioral, Aβ accumulation, and neuroinflammatory parameters in rats submitted to sepsis. Sepsis was induced by cecal ligation and perforation in Wistar rats, and the activity of alpha-, beta-, and gamma-secretases was determined in the hippocampus and prefrontal at different times. Additionally, in a different cohort of animal's epigallocatechin gallate, a beta-secretase inhibitor or a gamma-secretase inhibitor was administrated once a day for three consecutive days. Fifteen or 30 days after sepsis induction, Aβ content, TNF-α, IL-1β, and IL-6 and cognitive performance were determined. There was no increase in alpha-secretase activity. Both beta- and gamma-secretase activities increased, mainly late after sepsis. The inhibition of beta- or gamma-secretases improved cognitive performance 10 days after sepsis induction, and beta-secretase inhibition improved cognitive performance up to 30 days after sepsis induction. Furthermore, beta-secretase inhibition decreased IL-1β and Aβ brain levels. It was demonstrated that during sepsis development there was an increase in the amyloidogenic route, and the inhibition of this pathway promoted attenuation of neuroinflammation, Aβ peptide content, and improvement of cognitive impairment.

A cross sectional analytical study of cognitive impairment in survivors of spontaneous intracranial hemorrhage (ICH). (P5.3-034)

A cross sectional analytical study of cognitive impairment in survivors of spontaneous intracranial hemorrhage (ICH). (P5.3-034)

Lung injury does not aggravate mechanical ventilation-induced early cerebral inflammation or apoptosis in an animal model.

IntroductionThe acute respiratory distress syndrome is not only associated with a high mortality, but also goes along with cognitive impairment in survivors. The cause for this cognitive impairment is still not clear. One possible mechanism could be cerebral inflammation as result of a “lung-brain-crosstalk”. Even mechanical ventilation itself can induce cerebral inflammation. We hypothesized, that an acute lung injury aggravates the cerebral inflammation induced by mechanical ventilation itself and leads to neuronal damage.MethodsAfter approval of the institutional and state animal care committee 20 pigs were randomized to one of three groups: lung injury by central venous injection of oleic acid (n = 8), lung injury by bronchoalveolar lavage in combination with one hour of injurious ventilation (n = 8) or control (n = 6). Brain tissue of four native animals from a different study served as native group. For six hours all animals were ventilated with a tidal volume of 7 ml kg-1 and a scheme for positive end-expiratory pressure and inspired oxygen fraction, which was adapted from the ARDS network tables. Afterwards the animals were killed and the brains were harvested for histological (number of neurons and microglia) and molecular biologic (TNFalpha, IL-1beta, and IL-6) examinations.ResultsThere was no difference in the number of neurons or microglia cells between the groups. TNFalpha was significantly higher in all groups compared to native (p < 0.05), IL-6 was only increased in the lavage group compared to native (p < 0.05), IL-1beta showed no difference between the groups.DiscussionWith our data we can confirm earlier results, that mechanical ventilation itself seems to trigger cerebral inflammation. This is not aggravated by acute lung injury, at least not within the first 6 hours after onset. Nevertheless, it seems too early to dismiss the idea of lung-injury induced cerebral inflammation, as 6 hours might be just not enough time to see any profound effect.

Brain Network Connectivity and Executive Function in Long-Term Survivors of Childhood Acute Lymphoblastic Leukemia.

Chemotherapeutic agents used to treat acute lymphoblastic leukemia (ALL), the most common cancer affecting young children, have been associated with long-term cognitive impairments that reduce quality of life. Executive dysfunction is one of the most consistently observed deficits and can have substantial and pervasive effects on academic success, occupational achievement, psychosocial function, and psychiatric status. We examined the neural mechanisms of executive dysfunction by measuring structural and functional connectomes in 161 long-term survivors of pediatric ALL, age 8-21 years, who were treated on a single contemporary chemotherapy-only protocol for standard/high- or low-risk disease. Lower global efficiency, a measure of information exchange and network integration, of both structural and functional connectomes was found in survivors with executive dysfunction compared with those without dysfunction (p < 0.046). Patients with standard/high- versus low-risk disease and those who received greater number of intrathecal treatments containing methotrexate had the lowest network efficiencies. Patients with executive dysfunction also showed hyperconnectivity in sensorimotor, visual, and auditory-processing regions (p = 0.037) and poor separation between sensorimotor, executive/attention, salience, and default mode networks (p < 0.0001). Connectome disruption was consistent with a pattern of delayed neurodevelopment that may be associated with reduced resilience, adaptability, and flexibility of the brain network. These findings highlight the need for interventions that will prevent or manage cognitive impairment in survivors of pediatric acute lymphoblastic leukemia.

Associations of depression, anxiety and PTSD with neurological disability and cognitive impairment in survivors of moyamoya disease

Depression, anxiety and posttraumatic stress disorder (PTSD) are common complications of cerebrovascular diseases. However, they were seldom explored in Moyamoya Disease (MMD) survivors. In this study, we measured the prevalence of depression, anxiety and PTSD in MMD survivors. We evaluated the association of mental disorders with neurological disability and cognitive impairment, and further find out the independent protective and risk factors of neurological disability and cognitive impairment. In MMD survivors, the prevalence of these three mental disorders is high, 46.7% for depression, 50% for anxiety and 47.5% for PTSD. Anxiety and PTSD were significantly associated with more severe neurological disability (p = 0.039 and < 0.001); depression and anxiety were significantly associated with greater cognitive deficiency (p = 0.004 and 0.002). We further found PTSD was the only risk factor associated with neurological disability, and the corresponding odds ratio (OR) and 95% confidence interval (CI) was 81.74 (9.91–674.17); depression and anxiety were risk factors associated with cognitive impairment, and the corresponding OR and 95%CI were 2.73 (1.10–6.81) and 3.37 (1.29–8.78). Therefore, these three mental disorders were associated with more severe neurological disability and greater cognitive deficiency in MMD survivors.

Abstract P4-19-03: A meta-analysis of cognitive impairment in breast cancer survivors treated with chemotherapy

Abstract Background: Cognitive impairment in women with breast cancer has long been attributed to chemotherapy, but the evidence for this has been inconsistent, and more recent research suggests that additional cancer- and treatment-related factors also impact cognition. To systematically evaluate and describe “chemobrain,” a multilevel meta-analysis of objective cognitive function in breast cancer survivors treated with chemotherapy was conducted to estimate the magnitude of impairment across 9 cognitive domains and explore moderating variables. Method: PubMed, Embase, CINAHL, Cochrane CENTRAL, Scopus, and PsycINFO were searched from their inception to May 2016 to identify studies that compared the cognitive performance of survivors treated with chemotherapy to a control group or to their own prechemotherapy testing. Multilevel modelling was used to account for the interdependence among effect sizes obtained within the same study. Results: Seventy-seven studies involving 3417 cancer patients treated with chemotherapy yielded 1548 effect sizes. Cross-sectional comparisons revealed worse overall cognitive performance in survivors treated with chemotherapy relative to healthy controls (d = -0.27, 95% CI [-0.32, -0.21]) but not disease-specific controls (d = -0.07, 95% CI [-0.14, 0.00]). Relative to all controls, cognitive impairment in survivors treated with chemotherapy was observed in tests assessing language (d = -0.25), executive function (d = -0.21), processing speed (d = -0.15), delayed recall (d = -0.15), and attention/concentration (d = -0.14), but not in visual/spatial perception, immediate recall, recognition memory, or psychomotor domains. Because patients and controls were not well matched in many studies on age, education, and IQ, which are known to impact cognitive test performance, group differences in these variables were explored as moderators of observed cognitive deficits in post hoc analyses. Results showed that chemotherapy patients and controls performed equivalently when the controls were 6 years older or had 1 less year of education. Longitudinal comparisons showed improved postchemotherapy performance relative to prechemotherapy baseline, but practice effects were not accounted for in these comparisons. Conclusion: Breast cancer survivors treated with chemotherapy show subtle yet diffuse cognitive impairment. Their cognitive performance was equivalent to that of women in comparison groups who were 6 years older, which suggests that chemotherapy accelerates cognitive aging. Results from breast cancer patients who were not treated with chemotherapy, however, indicate that chemotherapy is not the only determinant of cognitive dysfunction. Group differences in age and education moderated the magnitude of cognitive impairment. The cognitive reserve framework, which posits that individuals differ in the degree of neural disruption they can withstand before exhibiting cognitive deficits, should be considered in future studies in order to better understand moderating effects on cancer-related cognitive dysfunction. In particular, both cross-sectional and longitudinal studies should ensure that comparison cohorts are closely matched on age, education, and other relevant cognitive reserve variables. Citation Format: Bernstein LJ, McCreath GA, Rich JB. A meta-analysis of cognitive impairment in breast cancer survivors treated with chemotherapy [abstract]. In: Proceedings of the 2016 San Antonio Breast Cancer Symposium; 2016 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2017;77(4 Suppl):Abstract nr P4-19-03.

Cognitive Impairment in Survivors of Adolescent and Early Young Adult Onset Non-CNS Cancers: Does Chemotherapy Play a Role?

The development of complex cognitive functions including executive functions occurs during adolescence and early young adulthood. Survivors of cancers diagnosed during adolescence and young adulthood (AYA) may be at specific risk for chemotherapy-associated cognitive impairment; however, little data are available that specifically examine long-term cognitive outcomes in the AYA-onset cancer survivor population. A literature search was conducted between January 1991 to December 2015 using a variety of search terms pertaining to the AYA-onset cancer population and cognitive outcomes. Articles that described cognitive outcomes in AYA-onset cancer survivors without primary or secondary central nervous system lesions diagnosed at ages 14-25 years old were examined and reported. Three articles fulfilled the inclusion criteria. All three evaluated cognitive outcomes in AYA-onset cancer survivors at varying time points after receipt of systemic chemotherapy. Target groups and neuropsychological evaluation techniques differ across studies. All studies reported increased rates of objective or self-reported cognitive impairment in AYA-onset cancer survivors. AYA-onset cancer survivors experience cognitive impairment. Despite the nature of normal adolescent neurodevelopment, chemotherapy exposure during the AYA years may not significantly contribute to cognitive impairment. Chronic cognitive impairment may be associated with chronic complications of cancer therapy. Large-scale standardized, prospective, and longitudinal evaluations of cognitive outcomes specific to AYA-onset cancer survivor population are needed to better understand associated risk factors.

Functional consequence of cognitive impairment in survivors of childhood acute lymphoblastic leukemia (ALL): The role of cancer symptoms as mediators.

235 Background: Although cognitive impairment of childhood cancer survivors affects daily functional status, the mechanisms are less understood. This study aimed to examine the role of cancer symptoms on the association of cognitive impairment with functional status in childhood ALL survivors treated on a chemotherapy only protocol. Methods: 213 survivors (mean age = 14.8 years) were assessed at &gt; 5 years post-diagnosis. Testing included measures of executive function (Delis-Kaplan Executive Function System; Wechsler Intelligence Scale for Children-IV [WISC-IV]), processing speed (WISC-IV; Grooved Pegboard), visual-spatial processing (Wechsler Abbreviated Scale of Intelligence), memory span (WISC-IV), and attention (Conners CPT-II). Symptoms (e.g., pain, worry, cognitive, communication) and daily functional status (physical, emotional, social, school) were reported by parents using the PedsQL. Association of cognitive impairment with symptoms and functional status was tested using regression analyses. The extent to which cognitive impairment influences functional status through symptoms was tested using mediation analyses. Results: Cognitive impairment ( &gt; 1SD below age-adjusted norm) was identified in 18-41% of the survivors. Impaired executive function, processing speed, and memory span were associated with high cancer symptoms (all p’s &lt; 0.05), typically driven by perceived cognitive and communication problems. Impaired executive function, processing speed, visual-spatial processing, and memory span were associated with poor functional status (all p’s &lt; 0.05). In each cognitive domain, impairment was related to poor school function (all p’s &lt; 0.05). Impact of cognitive function (except attention) on overall functional status was mediated by overall cancer symptoms (all p’s &lt; 0.05). Conclusions: Although the frequency of impairment in survivors treated with chemotherapy was less than that seen with cranial irradiation, cognitive impairment is related to elevated cancer symptoms and decreased functional status. Mediation analyses suggest that cognitive function works through cancer symptoms to impact functional status.

P139. Cognitive impairments in survivors of severe sepsis can be measured via magnetoencephalography

Cognitive impairment is a major determinant in the context of long-term sequelae of sepsis and still insufficiently characterized. In a magnetoencephalography (MEG) study, we measured visually evoked brain signals in twenty-six survivors of severe sepsis and septic shock, who were followed in a time range up to one year after sepsis onset. Twenty-three healthy age matched individuals without any history of sepsis and/or ICU stay and patients diagnosed with liver cirrhosis served as control groups. Evoked oscillatory responses to rhythmic visual stimuli were measured and analyzed to study brain synchrony via MEG. Neural oscillations are fundamental to brain function and their entrainment to external rhythms enhances (cognitive) processing. Our recent study has shown that the entrainment of the brain to the frequency of a flickering stimulation is impaired in patients with liver cirrhosis showing signs of hepatic encephalopathy. Participants also underwent neuropsychological testing (DemTect). Dynamical adaptation of cerebral neurons in terms of frequency coupling to the rhythmic flicker stimulation was significantly decreased in sepsis survivors and in liver cirrhosis patients, but in sepsis survivors, it increased with time following sepsis. Importantly, a coupling index developed from MEG data was highly sensitive to the semantic content of the visual stimuli and strongly correlated with the DemTect. We believe that the cognitive impairment results from pathologically synchronized neuronal oscillations and from an altered oscillatory coupling in the brain. Our study provides evidence that (a) long-term cognitive impairment is still present one year after severe sepsis; (b) cognitive impairment is reflected by an abnormal functional brain synchronicity. The question arises whether the modifications found in survivors of severe sepsis and liver cirrhosis patients are related to structural brain damage (e.g. an atrophy) or to a disturbance of the functional interaction between different brain regions.

Effect of cardiac arrest on cognitive impairment and hippocampal plasticity in middle-aged rats.

Cardiopulmonary arrest is a leading cause of death and disability in the United States that usually occurs in the aged population. Cardiac arrest (CA) induces global ischemia, disrupting global cerebral circulation that results in ischemic brain injury and leads to cognitive impairments in survivors. Ischemia-induced neuronal damage in the hippocampus following CA can result in the impairment of cognitive function including spatial memory. In the present study, we used a model of asphyxial CA (ACA) in nine month old male Fischer 344 rats to investigate cognitive and synaptic deficits following mild global cerebral ischemia. These experiments were performed with the goals of 1) establishing a model of CA in nine month old middle-aged rats; and 2) to test the hypothesis that learning and memory deficits develop following mild global cerebral ischemia in middle-aged rats. To test this hypothesis, spatial memory assays (Barnes circular platform maze and contextual fear conditioning) and field recordings (long-term potentiation and paired-pulse facilitation) were performed. We show that following ACA in nine month old middle-aged rats, there is significant impairment in spatial memory formation, paired-pulse facilitation n dysfunction, and a reduction in the number of non-compromised hippocampal Cornu Ammonis 1 and subiculum neurons. In conclusion, nine month old animals undergoing cardiac arrest have impaired survival, deficits in spatial memory formation, and synaptic dysfunction.

Critical illness-induced dysglycemia and the brain.

Dysglycemia is a characteristic feature of critical illness associated with adverse outcome. Whether dysglycemia contributes to brain dysfunction during critical illness and long-term neurological complications is unclear. We give an overview of glucose metabolism in the brain and review the literature on critical illness-induced dysglycemia and the brain. Medline database search using relevant search terms on dysglycemia, critical illness, acute brain injury/dysfunction, and randomized controlled trial. Hyperglycemia has been associated with deleterious effects on the nervous system. Underlying mechanisms in critical illness remain largely speculative and are often extrapolated from knowledge in diabetes mellitus. Increased hyperglycemia-induced blood-brain barrier permeability, oxidative stress, and microglia activation may play a role and compromise neuronal and glial cell integrity. Hypoglycemia is feared as critically ill patients cannot recognize or communicate hypoglycemic symptoms, which furthermore are masked by sedation and analgesia. However, observational data on the impact of brief hypoglycemia on the brain in critical illness are controversial. Secondary analysis of two large randomized studies suggested neuroprotection by strict glycemic control with insulin during intensive care, with lowered intracranial pressure, reduction of seizures, and better long-term rehabilitation in patients with isolated brain injury, and reduced incidence of critical illness polyneuromyopathy in the general critically ill patient population. Several subsequent studies failed to reproduce neurological benefit, likely explained by methodological issues, which include divergent achieved glucose levels and inaccurate glucose monitoring tools. Preventing hyperglycemia during critical illness holds promise as a neuroprotective strategy to preserve brain cell viability and prevent acute brain dysfunction and long-term cognitive impairment in survivors.

Abstract 220: Comparison of 3 Cognitive Exams in Cardiac Arrest Survivors

Background: Cognitive deficits may detract from quality of life after cardiac arrest (CA). The pattern and prevalence of these deficits are not well documented. We used the Computer Assessment of Mild Cognitive Impairment (CAMCI), the Montreal Cognitive Assessment (MOCA) and the 41 Cent Test to assess cognitive impairment in survivors of CA. We hypothesized that CAMCI subscales and other scores that were highly correlated could identify specific domains of impairment in CA survivors. Methods: Four researchers administered the CAMCI, MOCA, and/or the 41 Cent Test to CA survivors after discharge from the intensive care unit between 2010 and 2014. Physicians screened patients with the Mini-Mental State Exam to determine when this cognitive testing was feasible. We compared the distribution of scores between patients who presented with coma and those who awoke immediately after CA. Pairwise correlations between the different subscales and tests were considered significant with alpha error of 0.05. Results: Ninety-two participants completed the CAMCI, of which 18 participants completed the CAMCI, MOCA and 41 Cent Test. The mean (SD) percentile score for CAMCI was 32.2 (20.3) out of possible 100, for the MOCA was 20.3 (5.2) out of a possible 30 points and the 41 Cent Test was 5.4 (1.1) out of a possible 7 points. MOCA correlated strongly with the overall CAMCI score (r = 0.82) and with the executive accuracy subscale of the CAMCI (r = 0.75). The executive accuracy subscale and overall CAMCI score correlated with one another (r = 0.81) when all 92 CAMCI exams were considered. The MOCA and 41 Cent Test were correlated with each other (r = 0.63). Conclusion: The CAMCI detects cognitive impairment after CA; the MOCA correlates strongly with the overall CAMCI and the executive function subscale of the CAMCI. The 41 Cent Test may not be as effective as the MOCA in detecting cognitive deficits.

A novel automated test battery reveals enduring behavioural alterations and cognitive impairments in survivors of murine pneumococcal meningitis

Pneumococcal meningitis, caused by Streptococcus pneumoniae infection, is a major form of lethal bacterial meningitis. Survivors are predisposed to developing lifelong disabling sequelae, including cognitive impairment, psychological problems and motor deficits. In our experimental model, ventricular inoculation of 10(5) colony-forming units of S. pneumoniae type 3 caused 90% of mice to develop life-threatening meningitis within 48 h. Antibiotic treatment with ceftriaxone 20 h post infection reduced the incidence of severe meningitis to <10%. At the time of treatment, upregulation of pro-inflammatory cytokines was detected, including interleukin-1β, interleukin-6 and tumour necrosis factor. We evaluated the long-term behavioural and cognitive sequelae in control mice and those surviving meningitis using an automated system (the IntelliCage) in which mice perform a range of behavioural and spatial tasks to obtain water rewards from conditioning units in their home cage. Surviving mice showed a number of altered behaviours relative to controls, including (i) hypoexploration when first exposed to the IntelliCage, (ii) altered activity patterns (fewer visits to conditioning stations during the light phase and more in the dark phase), (iii) avoidance of light (a constant or flashing LED stimulus), (iv) impaired spatial learning (a complex patrolling task), and (v) impaired discrimination reversal learning. Overall these results suggest photophobia and weakened learning ability in post-meningitic mice, particularly on tasks engaging hippocampal and prefrontal neural substrates. This study also demonstrates a standardised and comprehensive battery of tests that can be readily used to investigate neurological sequelae in undisturbed mice residing in a complex home cage environment.