Identifying New Factors Associated With Cognitive Decline and Delirium After Transcatheter Aortic Valve Implantation: A Study Protocol

Background: Transcatheter aortic valve implantation (TAVI) has become the standard-of-care for treatment of severe symptomatic aortic stenosis and is also being increasingly recommended for low-risk patients. While TAVI boasts positive post-procedural outcomes, it is also associated with cognitive complications, namely delirium and cognitive decline. There is a pressing need for accurate risk tools which can identify TAVI patients at risk of delirium and cognitive decline, as risk scores designed for general cardiovascular surgery fall short. The present effect-finding exploratory study will assess the utility of various measures in the context of aging and frailty in predicting who will and who will not develop delirium or cognitive impairment following TAVI. The measures we propose include gait, visual symptoms, voice, swallowing, mood and sleep. Methods: This is an observational prospective cohort study focused on identifying pre-procedural risk factors for the development of delirium and cognitive decline following TAVI. Potential risk factors will be measured prior to TAVI. Primary outcomes will be post-procedure cognitive decline and delirium. Secondary outcomes include activities of daily living, quality of life, and mortality. Delirium presence will be measured on each of the first 2 days following TAVI. All other outcomes will be assessed at 3-, 6-, and 12-months post-operatively. A series of logistic regressions will be run to investigate the relationship between potential predictors and outcomes (presence vs. absence of either delirium or cognitive decline). Discussion: This study will assess the strengths of associations between a range of measures drawn from frailty and aging literature in terms of association with cognitive decline and delirium following TAVI. Identified measures can be used in future development of TAVI risk prediction models, which are essential for the accurate identification of cognitive at-risk patients and successful application of pre-procedural interventions. Clinical Trial Registration: This trial is registered with the Australian New Zealand Clinical Trials Registry. [https://bit.ly/2PAotP5], [ACTRN12618001114235]

Event-related potentials in relation to risk-taking: a systematic review

Event-related potentials (ERPs) have been used to investigate neural mechanisms underlying risk-related decisions over the last 16 years. We aimed to systematically evaluate associations between risk-taking and ERP components elicited during decisions and following feedback. A total of 79 articles identified from PsychINFO and PubMed databases met the inclusion criteria. Selected articles assessed early ERP components (feedback-related negativity/FRN, error-related negativity/ERN, and medial frontal negativity/MFN) and the mid-latency P3 component, all using gambling paradigms that involved selecting between choices of varying risk (e.g., Iowa Gambling Task, Balloon Analogue Risk Task, and two-choice gambling tasks). The P3 component was consistently enhanced to the selection of risky options and when positive feedback (as compared to negative feedback) was provided. Also consistently, the early negative components were found to be larger following feedback indicating monetary losses as compared to gains. In the majority of studies reviewed here, risk was conceptualized in the context of simple economical decisions in gambling tasks. As such, this narrow concept of risk might not capture the diversity of risky decisions made in other areas of everyday experience, for example, social, health, and recreational risk-related decisions. It therefore remains to be seen whether the risk-sensitivity of the ERP components reviewed here generalizes to other domains of life.Dilushi Chandrakumar, Daniel Feuerriegel, Stefan Bode, Megan Grech and Hannah A. D. Keag

A mediterranean diet to improve cardiovascular and cognitive health: Protocol for a randomised controlled intervention study

The Mediterranean diet has demonstrated efficacy for improving cardiovascular and cognitive health. However, a traditional Mediterranean diet delivers fewer serves of dairy and less dietary calcium than is currently recommended in Australia, which may limit long-term sustainability. The present study aims to evaluate whether a Mediterranean diet with adequate dairy and calcium can improve cardiovascular and cognitive function in an at-risk population, and thereby reduce risk of cardiovascular disease (CVD) and cognitive decline. A randomised, controlled, parallel, crossover design trial will compare a Mediterranean diet supplemented with dairy foods against a low-fat control diet. Forty participants with systolic blood pressure above 120 mmHg and at least two other risk factors of CVD will undertake each dietary intervention for eight weeks, with an eight-week washout period between interventions. Systolic blood pressure will be the primary measure of interest. Secondary outcomes will include measures of cardiometabolic health, dietary compliance, cognitive function, assessed using the Cambridge Neuropsychological Test Automated Battery (CANTAB), psychological well-being and dementia risk. This research will provide empirical evidence as to whether the Mediterranean diet can be modified to provide recommended dairy and calcium intakes while continuing to deliver positive effects for cardiovascular and cognitive health. The findings will hold relevance for the field of preventative healthcare and may contribute to revisions of national dietary guidelines

Including pork in the Mediterranean diet for an Australian population: Protocol for arandomised controlled trial assessing cardiovascular risk and cognitive function

Background. The Mediterranean diet is characterised by the high consumption of extra virgin olive oil, fruits, vegetables, grains, legumes and nuts; moderate consumption of fish, poultry, eggs and dairy; and low consumption of red meat and sweets. Cross sectional, longitudinal and intervention studies indicate that a Mediterranean diet may be effective for the prevention of cardiovascular disease and dementia. However, previous research suggests that an Australian population may find red meat restrictions difficult, which could affect long term sustainability of the diet. Methods. This paper outlines the protocol for a randomised controlled trial that will assess the cardiovascular and cognitive benefits of a Mediterranean diet modified to include 2-3 weekly serves of fresh, lean pork. A 24-week cross-over design trial will compare a modified Mediterranean diet with a low-fat control diet in at-risk men and women. Participants will follow each of the two diets for 8 weeks, with an 8-week washout period separating interventions. Home measured systolic blood pressure will be the primary outcome measure. Secondary outcomes will include body mass index, body composition, fasting blood lipids, C-reactive protein, fasting plasma glucose, fasting serum insulin, erythrocyte fatty acids, cognitive function, psychological health and well-being, and dementia risk. Discussion. To our knowledge this research is the first to investigate whether an alternate source of protein can be included in the Mediterranean diet to increase sustainability and feasibility for a non-Mediterranean population. Findings will be significant for the prevention of cardiovascular disease and age-related decline, and may inform individuals, clinicians and public health policy

A Mediterranean diet with fresh, lean pork improves processing speed and mood: Cognitive findings from the MedPork randomised controlled trial

Background: The Mediterranean diet may be capable of improving cognitive function. However, the red meat restrictions of the diet could impact long-term adherence in Western populations. The current study therefore examined the cognitive effects of a Mediterranean diet with additional red meat. Methods: A 24-week parallel crossover design compared a Mediterranean diet with 2–3 weekly servings of fresh, lean pork (MedPork) and a low-fat (LF) control diet. Thirty-five participants aged between 45 and 80 years and at risk of cardiovascular disease followed each intervention for 8 weeks, separated by an 8-week washout period. Cognitive function was assessed using the Cambridge Neuropsychological Test Automated Battery. Psychological well-being was measured through the SF-36 Health Survey and mood was measured using the Profile of Mood States (POMS). Results: During the MedPork intervention, participants consumed an average of 3 weekly servings of fresh pork. Compared to LF, the MedPork intervention led to higher processing speed performance (p = 0.01) and emotional role functioning (p = 0.03). No other significant differences were observed between diets. Conclusion: Our findings indicate that a Mediterranean diet inclusive of fresh, lean pork can be adhered to by an older non-Mediterranean population while leading to positive cognitive outcomes

How do predisposing factors differ between delirium motor subtypes? A systematic review and meta-analysis

BACKGROUND: Delirium is a common neurocognitive disorder in hospitalised older adults with vast negative consequences. The predominant method of subtyping delirium is by motor activity profile into hypoactive, hyperactive and mixed groups. OBJECTIVE: This systematic review and meta-analysis investigated how predisposing factors differ between delirium motor subtypes. METHODS: Databases (Medline, PsycINFO, Embase) were systematically searched for studies reporting predisposing factors (prior to delirium) for delirium motor subtypes. A total of 61 studies met inclusion criteria (N = 14,407, mean age 73.63 years). Random-effects meta-analyses synthesised differences between delirium motor subtypes relative to 22 factors. RESULTS: Hypoactive cases were older, had poorer cognition and higher physical risk scores than hyperactive cases and were more likely to be women, living in care homes, taking more medications, with worse functional performance and history of cerebrovascular disease than all remaining subtypes. Hyperactive cases were younger than hypoactive and mixed subtypes and were more likely to be men, with better cognition and lower physical risk scores than all other subtypes. Those with no motor subtype (unable to be classified) were more likely to be women and have better functional performance. Effect sizes were small. CONCLUSIONS: Important differences in those who develop motor subtypes of delirium were shown prior to delirium occurrence. We provide robust quantitative evidence for a common clinical assumption that indices of frailty (institutional living, cognitive and functional impairment) are seen more in hypoactive patients. Motor subtypes should be measured across delirium research. Motor subtyping has great potential to improve the clinical risk assessment and management of delirium

Delirium is a strong risk factor for dementia in the oldest-old: a population-based cohort study

Recent studies suggest that delirium is associated with risk of dementia and also acceleration of decline in existing dementia. However, previous studies may have been confounded by incomplete ascertainment of cognitive status at baseline. Herein, we used a true population sample to determine if delirium is a risk factor for incident dementia and cognitive decline. We also examined the effect of delirium at the pathological level by determining associations between dementia and neuropathological markers of dementia in patients with and without a history of delirium. The Vantaa 85+ study examined 553 individuals (92% of those eligible) aged ≥85 years at baseline, 3, 5, 8 and 10 years. Brain autopsy was performed in 52%. Fixed and random-effects regression models were used to assess associations between (i) delirium and incident dementia and (ii) decline in Mini-Mental State Examination scores in the whole group. The relationship between dementia and common neuropathological markers (Alzheimer-type, infarcts and Lewy-body) was modelled, stratified by history of delirium. Delirium increased the risk of incident dementia (odds ratio 8.7, 95% confidence interval 2.1-35). Delirium was also associated with worsening dementia severity (odds ratio 3.1, 95% confidence interval 1.5-6.3) as well as deterioration in global function score (odds ratio 2.8, 95% confidence interval 1.4-5.5). In the whole study population, delirium was associated with loss of 1.0 more Mini-Mental State Examination points per year (95% confidence interval 0.11-1.89) than those with no history of delirium. In individuals with dementia and no history of delirium (n = 232), all pathologies were significantly associated with dementia. However, in individuals with delirium and dementia (n = 58), no relationship between dementia and these markers was found. For example, higher Braak stage was associated with dementia when no history of delirium (odds ratio 2.0, 95% confidence interval 1.1-3.5, P = 0.02), but in those with a history of delirium, there was no significant relationship (odds ratio 1.2, 95% confidence interval 0.2-6.7, P = 0.85). This trend for odds ratios to be closer to unity in the delirium and dementia group was observed for neuritic amyloid, apolipoprotein ε status, presence of infarcts, α-synucleinopathy and neuronal loss in substantia nigra. These findings are the first to demonstrate in a true population study that delirium is a strong risk factor for incident dementia and cognitive decline in the oldest-old. However, in this study, the relationship did not appear to be mediated by classical neuropathologies associated with dementia.Daniel H. J. Davis, Graciela Muniz Terrera, Hannah Keage, Terhi Rahkonen, Minna Oinas, Fiona E. Matthews ... et al

Cognitive outcomes following coronary artery bypass grafting: a systematic review and meta-analysis of 91,829 patients

BACKGROUND:Cognitive impairments, including delirium, are common after coronary artery bypass grafting (CABG) surgery, as described in over three decades of research. Our aim was to pool estimates across the literature for the first-time, relative to time (from pre- to post-CABG) and diagnosis (cognitive impairment, delirium and dementia). METHODS:A systematic search of four databases was undertaken. 215 studies incorporating data from 91,829 patients were used to estimate the prevalence of cognitive impairments pre- and post-CABG, including delirium and dementia post-CABG, using random effects meta-analyses. RESULTS:Pre-surgical cognitive impairment was seen in 19% of patients. Post-operatively, cognitive impairment was seen in around 43% of patients acutely; this resolved to 19% at 4-6 months and then increased to 25% of patients between 6-months to 1-year post-operatively. In the long term, between 1 and 5-years post-operatively, cognitive impairment increased and was seen in nearly 40% of patients. Post-operative delirium was apparent in 18% of CABG patients which increased to 24% when a diagnostic instrument was utilized alongside clinical criteria. Dementia was present in 7% of patients 5-7 years post-surgery. CONCLUSION:The results of this meta-analysis demonstrate that cognitive impairment and delirium are major issues in CABG patients which require specific attention. It is imperative that appropriate methods for investigating cognitive impairment, and screening for delirium using a diagnostic instrument, occur in both pre-and post-CABG settings.Danielle Greaves, Peter J.Psaltis, Tyler J.Ross, Daniel Davis, Ashleigh E.Smith, Monique S.Boord, Hannah A.D.Keag

Computerised cognitive training to improve cognition including delirium following coronary artery bypass grafting surgery: protocol for a blinded randomised controlled trial

INTRODUCTION:Coronary artery bypass grafting (CABG) surgery is known to improve vascular function and cardiac-related mortality rates; however, it is associated with high rates of postoperative cognitive decline and delirium. Previous attempts to prevent post-CABG cognitive decline using pharmacological and surgical approaches have been largely unsuccessful. Cognitive prehabilitation and rehabilitation are a viable yet untested option for CABG patients. We aim to investigate the effects of preoperative cognitive training on delirium incidence, and preoperative and postoperative cognitive training on cognitive decline at 4 months post-CABG. METHODS AND ANALYSIS:This study is a randomised, single-blinded, controlled trial investigating the use of computerised cognitive training (CCT) both pre-CABG and post-CABG (intervention group) compared with usual care (control group) in older adults undergoing CABG in Adelaide, South Australia. Those in the intervention group will complete 1-2 weeks of CCT preoperatively (45-60 min sessions, 3.5 sessions/week) and 12 weeks of CCT postoperatively (commencing 1 month following surgery, 45-60 min sessions, 3 sessions/week). All participants will undergo cognitive testing preoperatively, over their hospital stay including delirium, and postoperatively for up to 1 year. The primary delirium outcome variable will be delirium incidence (presence vs absence); the primary cognitive decline variable will be at 4 months (significant decline vs no significant decline/improvement from baseline). Logistic regression modelling will be used, with age and gender as covariates. Secondary outcomes include cognitive decline from baseline to discharge, and at 6 months and 1 year post-CABG. ETHICS AND DISSEMINATION:Ethics approval was obtained from the Central Adelaide Local Health Network Human Research Ethics Committee (South Australia, Australia) and the University of South Australia Human Ethics Committee, with original approval obtained on 13 December 2017. It is anticipated that approximately two to four publications and multiple conference presentations (national and international) will result from this research. TRIAL REGISTRATION NUMBER:This clinical trial is registered with the Australian New Zealand Clinical Trials Registry and relates to the pre-results stage. Registration number: ACTRN12618000799257.Danielle Greaves, Peter J Psaltis, Amit Lampit, Daniel H J Davis, Ashleigh E Smith ... Hannah A D Keage ... et al

Putative risk alleles for LATE-NC with hippocampal sclerosis in population-representative autopsy cohorts

Limbic-predominant age-related TAR-DNA-binding protein-43 (TDP-43) encephalopathy with hippocampal sclerosis pathology (LATE-NC + HS) is a neurodegenerative disorder characterized by severe hippocampal CA1 neuron loss and TDP-43-pathology, leading to cognitive dysfunction and dementia. Polymorphisms in GRN, TMEM106B and ABCC9 are proposed as LATE-NC + HS risk factors in brain bank collections. To replicate these results in independent population-representative cohorts, hippocampal sections from brains donated to three such studies (Cambridge City over 75-Cohort [CC75C], Cognitive Function and Ageing Study [CFAS], and Vantaa 85+ Study) were stained with hematoxylin-eosin (n = 744) and anti-pTDP-43 (n = 713), and evaluated for LATE-NC + HS and TDP-43 pathology. Single nucleotide polymorphism genotypes in GRN rs5848, TMEM106B rs1990622 and ABCC9 rs704178 were determined. LATE-NC + HS (n = 58) was significantly associated with the GRN rs5848 genotype (chi(2)(2) = 20.61, P <0.001) and T-allele (chi(2)(1) = 21.04, P <0.001), and TMEM106B rs1990622 genotype (Fisher's exact test, P <0.001) and A-allele (chi(2)(1) = 25.75, P <0.001). No differences in ABCC9 rs704178 genotype or allele frequency were found between LATE-NC + HS and non-LATE-NC + HS neuropathology cases. Dentate gyrus TDP-43 pathology associated with GRN and TMEM106B variations, but the association with TMEM106B nullified when LATE-NC + HS cases were excluded. Our results indicate that GRN and TMEM106B are associated with severe loss of CA1 neurons in the aging brain, while ABCC9 was not confirmed as a genetic risk factor for LATE-NC + HS. The association between TMEM106B and LATE-NC + HS may be independent of dentate TDP-43 pathology.Peer reviewe