The prevalence, correlation, and co-occurrence of neuropathology in old age: harmonisation of 12 measures across six community-based autopsy studies of dementia.

BACKGROUND: Population-based autopsy studies provide valuable insights into the causes of dementia but are limited by sample size and restriction to specific populations. Harmonisation across studies increases statistical power and allows meaningful comparisons between studies. We aimed to harmonise neuropathology measures across studies and assess the prevalence, correlation, and co-occurrence of neuropathologies in the ageing population. METHODS: We combined data from six community-based autopsy cohorts in the US and the UK in a coordinated cross-sectional analysis. Among all decedents aged 80 years or older, we assessed 12 neuropathologies known to be associated with dementia: arteriolosclerosis, atherosclerosis, macroinfarcts, microinfarcts, lacunes, cerebral amyloid angiopathy, Braak neurofibrillary tangle stage, Consortium to Establish a Registry for Alzheimer's disease (CERAD) diffuse plaque score, CERAD neuritic plaque score, hippocampal sclerosis, limbic-predominant age-related TDP-43 encephalopathy neuropathologic change (LATE-NC), and Lewy body pathology. We divided measures into three groups describing level of confidence (low, moderate, and high) in harmonisation. We described the prevalence, correlations, and co-occurrence of neuropathologies. FINDINGS: The cohorts included 4354 decedents aged 80 years or older with autopsy data. All cohorts included more women than men, with the exception of one study that only included men, and all cohorts included decedents at older ages (range of mean age at death across cohorts 88·0-91·6 years). Measures of Alzheimer's disease neuropathological change, Braak stage and CERAD scores, were in the high confidence category, whereas measures of vascular neuropathologies were in the low (arterioloscerosis, atherosclerosis, cerebral amyloid angiopathy, and lacunes) or moderate (macroinfarcts and microinfarcts) categories. Neuropathology prevalence and co-occurrence was high (2443 [91%] of 2695 participants had more than one of six key neuropathologies and 1106 [41%] of 2695 had three or more). Co-occurrence was strongly but not deterministically associated with dementia status. Vascular and Alzheimer's disease features clustered separately in correlation analyses, and LATE-NC had moderate associations with Alzheimer's disease measures (eg, Braak stage ρ=0·31 [95% CI 0·20-0·42]). INTERPRETATION: Higher variability and more inconsistency in the measurement of vascular neuropathologies compared with the measurement of Alzheimer's disease neuropathological change suggests the development of new frameworks for the measurement of vascular neuropathologies might be helpful. Results highlight the complexity and multi-morbidity of the brain pathologies that underlie dementia in older adults and suggest that prevention efforts and treatments should be multifaceted. FUNDING: Gates Ventures.

What do young Australian adults know about modifiable risk factors for dementia?

BACKGROUND: There are well established modifiable risk factors for late-life dementia. These risk factors account for over 30% of population attributable dementia risk and accrue over the lifespan. Young adults have the greatest potential to reduce their own risk for dementia. This study aimed to investigate what young Australian adults know about dementia and its risk factors, and further, how they estimated these risks. METHODS: An online survey promoted through various social media platforms was completed by 604 young Australian adults aged 18-44 years of age. RESULTS: Seventy percent of participants had a limited understanding of dementia (identifying cognitive or functional impairment), 25% had a good understanding, with 5% having no understanding. Twenty percent of respondents thought there were no modifiable risk factors for dementia. Less the half of participants agreed with two of the nine established dementia risk factors (hearing loss in midlife and education in early life), with over half of participants agreeing to the remaining seven risk factors. Females consistently judged the risks conferred by the nine established dementia risk factors to be higher than males. Those who were lonely judged the dementia risk conferred by loneliness to be higher than those who were not lonely; and smokers judged the dementia risk conferred by smoking to be less than non-smokers. CONCLUSION: Young adults have the greatest potential to change their dementia risk, and these findings show that there are important gaps in knowledge of dementia and its risk factors in this group.

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].

The effects of anticholinergic medications on cognition in children: a systematic review and meta-analysis.

Cognitive side effects of anticholinergic medications in older adults are well documented. Whether these poor cognitive outcomes are observed in children has not been systematically investigated. We aimed to conduct a systematic review and meta-analysis on the associations between anticholinergic medication use and cognitive performance in children. Systematic review was conducted using Medline, PsychInfo, and Embase, identifying studies testing cognitive performance relative to the presence versus absence of anticholinergic medication(s) in children. We assessed effects overall, as well as relative to drug class, potency (low and high), cognitive domain, and duration of administration. The systematic search identified 46 articles suitable for meta-analysis. For the most part, random effects meta-analyses did not identify statistically significant associations between anticholinergic exposure and cognitive performance in children; the one exception was a small effect of anticholinergic anti-depressants being associated with better cognitive function (Hedges' g = 0.24, 95% CI 0.06-0.42, p = 0.01). Anticholinergic medications do not appear to be associated with poor cognitive outcomes in children, as they do in older adults. The discrepancy in findings with older adults may be due to shorter durations of exposure in children, differences in study design (predominantly experimental studies in children rather than predominantly epidemiological in older adults), biological ageing (e.g. blood brain barrier integrity), along with less residual confounding due to minimal polypharmacy and comorbidity in children.

Risk Factors for Delirium and Cognitive Decline Following Coronary Artery Bypass Grafting Surgery: A Systematic Review and Meta-Analysis.

Background Coronary artery bypass grafting (CABG) is known to improve heart function and quality of life, while rates of surgery-related mortality are low. However, delirium and cognitive decline are common complications. We sought to identify preoperative, intraoperative, and postoperative risk or protective factors associated with delirium and cognitive decline (across time) in patients undergoing CABG. Methods and Results We conducted a systematic search of Medline, PsycINFO, EMBASE, and Cochrane (March 26, 2019) for peer-reviewed, English publications reporting post-CABG delirium or cognitive decline data, for at least one risk factor. Random-effects meta-analyses estimated pooled odds ratio for categorical data and mean difference or standardized mean difference for continuous data. Ninety-seven studies, comprising data from 60 479 patients who underwent CABG, were included. Moderate to large and statistically significant risk factors for delirium were as follows: (1) preoperative cognitive impairment, depression, stroke history, and higher European System for Cardiac Operative Risk Evaluation (EuroSCORE) score, (2) intraoperative increase in intubation time, and (3) postoperative presence of arrythmia and increased days in the intensive care unit; higher preoperative cognitive performance was protective for delirium. Moderate to large and statistically significant risk factors for acute cognitive decline were as follows: (1) preoperative depression and older age, (2) intraoperative increase in intubation time, and (3) postoperative presence of delirium and increased days in the intensive care unit. Presence of depression preoperatively was a moderate risk factor for midterm (1-6 months) post-CABG cognitive decline. Conclusions This meta-analysis identified several key risk factors for delirium and cognitive decline following CABG, most of which are nonmodifiable. Future research should target preoperative risk factors, such as depression or cognitive impairment, which are potentially modifiable. Registration URL: https://www.crd.york.ac.uk/prosp​ero/; Unique identifier: CRD42020149276.

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.

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.

Cognitive Outcomes of Cardiovascular Surgical Procedures in the Old: An Important but Neglected Area.

Older individuals can now undergo invasive cardiovascular procedures without serious concern about mortality, and the numbers and proportions of the over 65s and 85s doing so in Australia has been increasing over the last 20 years. There is overwhelming evidence linking cardiovascular conditions to late-life (65 years and over) cognitive impairment and dementia including Alzheimer's Disease, primarily due to impaired cerebrovascularisation and cascading neuropathological processes. Somewhat paradoxically, these cardiovascular interventions, carried out with the primary aim of revascularisation, are not usually associated with short- or long-term improvements in cognitive function in older adults. We discuss factors associated with cognitive outcomes post-cardiovascular surgeries in patients over 65 years of age. There are many opportunities for future research: we know almost nothing about cognitive outcomes following invasive cardiac procedures in the oldest old (85 years and over) nor how to predict the cognitive/delirium outcome using pre-surgical data, and lastly, intervention opportunities exist both pre and postoperatively that have not been tested. As our population ages with increased cardiovascular burden and rates of cardiovascular interventions and surgeries, it is critical that we understand the cognitive consequences of these procedures, who is at greatest risk, and ways to optimise cognition.

The N170 and face perception in psychiatric and neurological disorders: A systematic review.

OBJECTIVE: To systematically evaluate evidence for configural and affective face processing abnormalities as measured by the N170 and Vertex Positive Potential (VPP) event-related potential components, and analogous M170 magnetoencephalography (MEG) component, in neurological and psychiatric disorders. METHODS: 1251 unique articles were identified using PsychINFO and PubMed databases. Sixty-seven studies were selected for review, which employed various tasks to measure the N170, M170 or VPP; the 13 neurological/psychiatric conditions were Attention-Deficit Hyperactivity Disorder (ADHD), Alcohol Dependence, Alzheimer's Disease, Autism Spectrum Disorders (ASDs), Bipolar Disorder, Bulimia Nervosa, Fibromyalgia, Huntington's Disease, Major Depressive Disorder, Parkinson's Disease, Prosopagnosia, Schizophrenia and Social Phobia. RESULTS: Smaller N170 and VPP amplitudes to faces compared to healthy controls were consistently reported in Schizophrenia but not in ASDs. In Schizophrenia N170 and VPP measures were not correlated with clinical symptoms. Findings from other disorders were highly inconsistent; however, reported group differences were almost always smaller amplitudes or slower latencies to emotional faces in disordered groups regardless of diagnosis. CONCLUSIONS: Results suggest that N170/VPP abnormalities index non-specific facial affect processing dysfunction in these neurological and psychiatric conditions, reflecting social impairments being broadly characteristic of these groups. SIGNIFICANCE: The N170 and analogous components hold promise as diagnostic and treatment monitoring biomarkers for social dysfunction.

Event-related wave activity in the EEG provides new marker of ADHD.

OBJECTIVE: This study examines the utility of new measures of event-related spatio-temporal waves in the EEG as a marker of ADHD, previously shown to be closely related to the P3 ERP in an adult sample. METHODS: Wave activity in the EEG was assessed during both an auditory Oddball and a visual continuous performance task (CPT) for an ADHD group ranging in age from 6 to 18 years and comprising mostly Combined and Inattentive subtypes, and for an age and gender matched control group. RESULTS: The ADHD subjects had less wave activity at low frequencies ( approximately 1 Hz) during both tasks. For auditory Oddball targets, this effect was shown to be related to smaller P3 ERP amplitudes. During CPT, the approximately 1 Hz wave activity in the ADHD subjects was inversely related to clinical and behavioral measures of hyperactivity and impulsivity. CPT wave activity at approximately 1 Hz was seen to "normalise" following treatment with stimulant medication. CONCLUSIONS: The results identify a deficit in low frequency wave activity as a new marker for ADHD associated with levels of hyperactivity and impulsivity. SIGNIFICANCE: The marker is evident across a range of tasks and may be specific to ADHD. While lower approximately 1 Hz activity partly accounts for reduced P3 ERPs in ADHD, the effect also arises for tasks that do not elicit a P3. Deficits in behavioral inhibition are hypothesized to arise from underlying dysregulation of cortical inhibition.

Distractibility in AD/HD predominantly inattentive and combined subtypes: the P3a ERP component, heart rate and performance.

The current study aimed to investigate whether children and adolescents diagnosed with Attention Deficit/Hyperactivity Disorder Predominantly Inattentive (AD/HD-in; Child n = 24, Adolescent n = 33) and Combined (AD/HD-com; Child n = 30, Adolescent n = 42) subtypes were more distractible than controls (Child n = 54; Adolescents n = 75), by assessing event-related potential (ERP), performance and peripheral arousal measures. All AD/HD groups displayed smaller amplitudes and/or shorter latencies of the P3a ERP component - thought to reflect involuntary attention switching - following task-deviant novel stimuli (checkerboard patterns) embedded in a Working Memory (WM) task. The P3a results suggested that both AD/HD-in and AD/HD-com subtypes ineffectively evaluate deviant stimuli and are hence more "distractible". These abnormalities were most pronounced over the central areas. AD/HD groups did not display any abnormalities in averaged heart rate over the WM task, a measure of peripheral arousal. They did display abnormalities in performance measures from the task, but these were unrelated to P3a abnormalities. AD/HD groups also displayed a number of deficits on Switching of Attention and Verbal Memory tasks, however, the pattern of abnormality mostly reflected general cognitive deficits rather than resulting from distraction.