Outcomes of a Delirium Prevention Program in Older Persons After Elective Surgery: A Stepped-Wedge Cluster Randomized Clinical Trial.

Importance: Delirium significantly worsens elective surgery outcomes and costs. Delirium risk is highest in elderly populations, whose surgical health care resource consumption (50%) exceeds their demographic proportion (15% to 18%) in high-resource countries. Effective nonpharmacologic delirium prevention could safely improve care in these vulnerable patients, but data from procedure-specific studies are insufficiently compelling to drive changes in practice. Delirium prevention approaches applicable to different surgical settings remain unexplored. Objective: To examine whether a multifaceted prevention intervention is effective in reducing postoperative delirium incidence and prevalence after various major surgical procedures. Design, Setting, and Participants: This stepped-wedge cluster randomized trial recruited 1470 patients 70 years and older undergoing elective orthopedic, general, or cardiac surgery from November 2017 to April 2019 from 5 German tertiary medical centers. Data were analyzed from December 2019 to July 2021. Interventions: First, structured delirium education was provided to clinical caregivers at each site. Then, the study delirium prevention team assessed patient delirium risk factors and symptoms daily. Prevention was tailored to individual patient needs and could include: cognitive, motor, and sensory stimulation; meal companionship; accompaniment during diagnostic procedures; stress relaxation; and sleep promotion. Main Outcomes and Measures: Postoperative delirium incidence and duration. Results: Of 1470 included patients, 763 (51.9%) were male, and the median (IQR) age was 77 (74-81) years. Overall, the intervention reduced postoperative delirium incidence (odds ratio, 0.87; 95% CI, 0.77-0.98; P = .02) and percentage of days with delirium (intervention, 5.3%; control, 6.9%; P = .03). The effect was significant in patients undergoing orthopedic or abdominal surgery (odds ratio, 0.59; 95% CI, 0.35-0.99; P = .047) but not cardiac surgery (odds ratio, 1.18; 95% CI, 0.70-1.99; P = .54). Conclusions and Relevance: This multifaceted multidisciplinary prevention intervention reduced postoperative delirium occurrence and days with delirium in older patients undergoing different elective surgical procedures but not cardiac procedures. These results suggest implementing this delirium prevention program will improve care and outcomes in older patients undergoing elective general and orthopedic procedures.

Presurgical Screening Improves Risk Prediction for Delirium in Elective Surgery of Older Patients: The PAWEL RISK Study.

Introduction: The number of elective surgeries for patients who are over 70 years of age is continuously growing. At the same time, postoperative delirium (POD) is common in older patients (5-60%) depending on predisposing risk factors, such as multimorbidity, cognitive impairment, neurodegenerative disorders and other dementing disorders, and precipitating factors, such as duration of surgery. Knowledge of individual risk profiles prior to elective surgery may help to identify patients at increased risk for development of POD. In this study, clinical and cognitive risk factors for POD were investigated in patients undergoing various elective cardiac and non-cardiac surgeries. Methods: The PAWEL study is a prospective, interventional trial on delirium prevention. At baseline, 880 inpatients at five surgical centers were recruited for sub-sample PAWEL-R. Multimodal assessments included clinical renal function, medication, American Society of Anesthesiologists (ASA) Physical Status Classification System, geriatric and cognitive assessments, which comprised the Montreal Cognitive Assessment Scale (MoCA), Trail-making Test, and Digit Span backward. Delirium incidence was monitored postoperatively by the Confusion Assessment Method (CAM) and a chart review for up to a week or until discharge. Multivariate regression models and Chi-square Automatic Interaction Detectors (CHAID) analyses were performed using delirium incidence as the primary outcome. Results: Eighteen risk factors were investigated in elective cardiovascular and orthopedic or general surgery. A total of 208 out of 880 patients (24%) developed POD. A global regression model that included all risk variables predicted delirium incidence with high accuracy (AUC = 0.81; 95% CI 0.77, 0.85). A simpler model (clinical and cognitive variables; model CLIN-COG) of 10 factors that only included surgery type, multimorbidity, renal failure, polypharmacy, ASA, cut-to-suture time, and cognition (MoCA, Digit Span backward, and preexisting dementia), however, exhibited similar predictive accuracy (AUC = 0.80; 95% CI 0.76, 0.84). Conclusion: The risk of developing POD can be estimated by preoperative assessments, such as ASA classification, expected cut-to-suture time, and short cognitive screenings. This rather efficient approach predicted POD risk over all types of surgery. Thus, a basic risk assessment including a cognitive screen can help to stratify patients at low, medium, or high POD risk to provide targeted prevention and/or management strategies for patients at risk.

No Evidence That Cognitive and Physical Activities Are Related to Changes in EEG Markers of Cognition in Older Adults at Risk of Dementia.

An active lifestyle as well as cognitive and physical training (PT) may benefit cognition by increasing cognitive reserve, but the underlying neurobiological mechanisms of this reserve capacity are not well understood. To investigate these mechanisms of cognitive reserve, we focused on electrophysiological correlates of cognitive performance, namely on an event-related measure of auditory memory and on a measure of global coherence. Both measures have shown to be sensitive markers for cognition and might therefore be suitable to investigate potential training- and lifestyle-related changes. Here, we report on the results of an electrophysiological sub-study that correspond to previously published behavioral findings. Altogether, 65 older adults with subjective or objective cognitive impairment and aged 60-88 years were assigned to a 10-week cognitive (n = 19) or a 10-week PT (n = 21) or to a passive control group (n = 25). In addition, self-reported lifestyle was assessed at baseline. We did not find an effect of both training groups on electroencephalography (EEG) measures of auditory memory decay or global coherence (ps ≥ 0.29) and a more active lifestyle was not associated with improved global coherence (p = 0.38). Results suggest that a 10-week unimodal cognitive or PT and an active lifestyle in older adults at risk for dementia are not strongly related to improvements in electrophysiological correlates of cognition.

Global EEG coherence as a marker for cognition in older adults at risk for dementia.

Quantitative electroencephalography (EEG) provides useful information about neurophysiological health of the aging brain. Current studies investigating EEG coherence and power for specific brain areas and frequency bands have yielded inconsistent results. This study assessed EEG coherence and power indices at rest measured over the whole skull and for a wide frequency range as global EEG markers for cognition in a sample at risk for dementia. Since global markers are more reliable and less error-prone than region- and frequency-specific indices they might help to overcome previous inconsistencies. Global EEG coherence (1-30 Hz) and an EEG slowing score were assessed. The EEG slowing score was calculated by low-frequency power (1-8 Hz) divided by high-frequency power (9-30 Hz). In addition, the prognostic value of the two EEG indices for cognition and cognitive decline was assessed in a 5-year follow-up pilot study. Baseline global coherence correlated positively with cognition at baseline, but not with cognitive decline or with cognition at the 5-year follow-up. The EEG slowing ratio showed no significant association, neither with cognition at baseline or follow-up, nor with cognitive decline over a period of 5 years. The results indicate that the resting state global EEG coherence might be a useful and easy to assess electrophysiological correlate for neurocognitive health in older adults at risk for dementia. Because of the small statistical power for the follow-up analyses, the prognostic value of global coherence could not be determined in the present study. Future studies should assess its prognostic value with larger sample sizes.

Jigsaw Puzzling Taps Multiple Cognitive Abilities and Is a Potential Protective Factor for Cognitive Aging.

Prevention of neurocognitive disorders is currently one of the greatest unmet medical challenges. The cognitive effects of solving jigsaw puzzles (JPs) have not been studied so far, despite its frequent use as a leisure activity in all age cohorts worldwide. This study aimed at closing this gap between a lack of science and a frequent real-world use by investigating the cognitive abilities recruited by JP as well as the cognitive benefits of lifetime and 30-day JP experience. A total of 100 cognitively healthy adults (≥50 years of age) were randomized to either a 30-day home-based JP intervention (≥1 h/day) plus four sessions of cognitive health counseling (JP group) or four sessions of cognitive health counseling only (counseling group). We measured global visuospatial cognition by averaging the scores of eight z-standardized visuospatial cognitive abilities (perception, constructional praxis, mental rotation, speed, flexibility, working memory, reasoning, and episodic memory). JP skill was assessed with an untrained 40 piece JP and lifetime JP experience with retrospective self-report. JP skill was associated with all assessed cognitive abilities (rs ≥ 0.45, ps < 0.001), and global visuospatial cognition (r = 0.80 [95% CI: 0.72-0.86], p < 0.001). Lifetime JP experience was associated with global visuospatial cognition, even after accounting for other risk and protective factors (ß = 0.34 [95% CI: 0.18-0.50], p < 0.001). The JP group connected on average 3589 pieces in 49 h. Compared to the counseling group, they improved in JP skill (Cohen's d = 0.38 [95% CI: 0.21-0.54], p < 0.001), but not in global visuospatial cognition (Cohen's d = -0.08, [CI: -0.27 to 0.10], p = 0.39). The amount of jigsaw puzzling was related to changes in global visuospatial cognition within the JP group, only after accounting for baseline performance (ß = 0.33 [95% CI: 0.02-0.63], p = 0.03). In sum, our results indicate that jigsaw puzzling strongly engages multiple cognitive abilities and long-term, but not short-term JP experiences could relevantly benefit cognition. Trial Registration: ClinicalTrials.gov Identifier: NCT02667314.

Auditory Memory Decay as Reflected by a New Mismatch Negativity Score Is Associated with Episodic Memory in Older Adults at Risk of Dementia.

The auditory mismatch negativity (MMN) is an event-related potential (ERP) peaking about 100-250 ms after the onset of a deviant tone in a sequence of identical (standard) tones. Depending on the interstimulus interval (ISI) between standard and deviant tones, the MMN is suitable to investigate the pre-attentive auditory discrimination ability (short ISIs, ≤ 2 s) as well as the pre-attentive auditory memory trace (long ISIs, >2 s). However, current results regarding the MMN as an index for mild cognitive impairment (MCI) and dementia are mixed, especially after short ISIs: while the majority of studies report positive associations between the MMN and cognition, others fail to find such relationships. To elucidate these so far inconsistent results, we investigated the validity of the MMN as an index for cognitive impairment exploring the associations between different MMN indices and cognitive performance, more specifically with episodic memory performance which is among the most affected cognitive domains in the course of Alzheimer's dementia (AD), at baseline and at a 5-year-follow-up. We assessed the amplitude of the MMN for short ISI (stimulus onset asynchrony, SOA = 0.05 s) and for long ISI (3 s) in a neuropsychologically well-characterized cohort of older adults at risk of dementia (subjective memory impairment, amnestic and non-amnestic MCI; n = 57). Furthermore, we created a novel difference score (ΔMMN), defined as the difference between MMNs to short and to long ISI, as a measure to assess the decay of the auditory memory trace, higher values indicating less decay. ΔMMN and MMN amplitude after long ISI, but not the MMN amplitude after short ISI, was associated with episodic memory at baseline (ß = 0.38, p = 0.003; ß = -0.27, p = 0.047, respectively). ΔMMN, but not the MMN for long ISIs, was positively associated with episodic memory performance at the 5-year-follow-up (ß = 0.57, p = 0.013). The results suggest that the MMN after long ISI might be suitable as an indicator for the decline in episodic memory and indicate ΔMMN as a potential biomarker for memory impairment in older adults at risk of dementia.

Jigsaw Puzzles As Cognitive Enrichment (PACE) - the effect of solving jigsaw puzzles on global visuospatial cognition in adults 50 years of age and older: study protocol for a randomized controlled trial.

BACKGROUND: Neurocognitive disorders are an important societal challenge and the need for early prevention is increasingly recognized. Meta-analyses show beneficial effects of cognitive activities on cognition. However, high financial costs, low intrinsic motivation, logistic challenges of group-based activities, or the need to operate digital devices prevent their widespread application in clinical practice. Solving jigsaw puzzles is a cognitive activity without these hindering characteristics, but cognitive effects have not been investigated yet. With this study, we aim to evaluate the effect of solving jigsaw puzzles on visuospatial cognition, daily functioning, and psychological outcomes. METHODS: The pre-posttest, assessor-blinded study will include 100 cognitively healthy adults 50 years of age or older, who will be randomly assigned to a jigsaw puzzle group or a cognitive health counseling group. Within the 5-week intervention period, participants in the jigsaw puzzle group will engage in 30 days of solving jigsaw puzzles for at least 1 h per day and additionally receive cognitive health counseling. The cognitive health counseling group will receive the same counseling intervention but no jigsaw puzzles. The primary outcome, global visuospatial cognition, will depict the average of the z-standardized performance scores in visuospatial tests of perception, constructional praxis, mental rotation, processing speed, flexibility, working memory, reasoning, and episodic memory. As secondary outcomes, we will assess the eight cognitive abilities, objective and subjective visuospatial daily functioning, psychological well-being, general self-efficacy, and perceived stress. The primary data analysis will be based on mixed-effects models in an intention-to-treat approach. DISCUSSION: Solving jigsaw puzzles is a low-cost, intrinsically motivating, cognitive leisure activity, which can be executed alone or with others and without the need to operate a digital device. In the case of positive results, these characteristics allow an easy implementation of solving jigsaw puzzles in clinical practice as a way to improve visuospatial functioning. Whether cognitive impairment and loss of independence in everyday functioning might be prevented or delayed in the long run has to be examined in future studies. TRIAL REGISTRATION: ClinicalTrials.gov, NCT02667314 . Registered on 27 January 2016.

Novel Blood-Based Biomarkers of Cognition, Stress, and Physical or Cognitive Training in Older Adults at Risk of Dementia: Preliminary Evidence for a Role of BDNF, Irisin, and the Kynurenine Pathway.

 Psychosocial stress and physical, cognitive, and social activity predict the risk of cognitive decline and dementia. The aim of this study was to elucidate brain-derived neurotrophic factor (BDNF), irisin, and the kynurenine pathway (KP) as potential underlying biological correlates. We evaluated associations of irisin and the KP with BDNF in serum and with cognition, stress, and activities. Furthermore, changes in serum concentrations of BDNF, irisin, and KP metabolites were investigated after physical or cognitive training. Forty-seven older adults at risk of dementia were assigned to 10 weeks of physical training, cognitive training, or a wait-list control condition. Previous physical, cognitive, and social activities and stressful life events were recorded; global cognition, episodic memory, and executive functions were assessed. Serum levels of L-kynurenine, kynurenic acid, 3-hydroxykynurenine (3-HK), and quinolinic acid (QUIN) were determined by validated assays based on liquid chromatography coupled to tandem mass spectrometry. BDNF and irisin serum levels were determined with enzyme-linked immunosorbent assays. BDNF and irisin correlated positively with global cognition and episodic memory, while the neurotoxic metabolite QUIN correlated negatively with executive functions. Stressful life events were associated with reduced BDNF and increased 3-HK. 3-HK decreased after cognitive training, while BDNF tended to increase after physical training. This suggests that psychosocial stress as well as cognitive and physical training may impact BDNF serum levels and the KP. Irisin and QUIN may constitute novel serum biomarkers of cognitive impairment, in addition to BDNF. Larger scale trials are needed to replicate and extend these novel findings.

No Evidence That Short-Term Cognitive or Physical Training Programs or Lifestyles Are Related to Changes in White Matter Integrity in Older Adults at Risk of Dementia.

Cognitive and physical activities can benefit cognition. However, knowledge about the neurobiological mechanisms underlying these activity-induced cognitive benefits is still limited, especially with regard to the role of white matter integrity (WMI), which is affected in cognitive aging and Alzheimer's disease. To address this knowledge gap, we investigated the immediate and long-term effects of cognitive or physical training on WMI, as well as the association between cognitive and physical lifestyles and changes in WMI over a 6-month period. Additionally, we explored whether changes in WMI underlie activity-related cognitive changes, and estimated the potential of both trainings to improve WMI by correlating training outcomes with WMI. In an observational and interventional pretest, posttest, 3-month follow-up design, we assigned 47 community-dwelling older adults at risk of dementia to 50 sessions of auditory processing and working memory training (n = 13), 50 sessions of cardiovascular, strength, coordination, balance and flexibility exercises (n = 14), or a control group (n = 20). We measured lifestyles trough self-reports, cognitive training skills through training performance, functional physical fitness through the Senior Fitness Test, and global cognition through a cognitive test battery. WMI was assessed via a composite score of diffusion tensor imaging-based fractional anisotropy (FA) of three regions of interest shown to be affected in aging and Alzheimer's disease: the genu of corpus callosum, the fornix, and the hippocampal cingulum. Effects for training interventions on FA outcomes, as well as associations between lifestyles and changes in FA outcomes were not significant. Additional analyses did show associations between cognitive lifestyle and global cognitive changes at the posttest and the 3-month follow-up (ß ≥ 0.40, p ≤ 0.02) and accounting for changes in WMI did not affect these relationships. The targeted training outcomes were related to FA scores at baseline (cognitive training skills and FA composite score, rs = 0.68, p = 0.05; functional physical fitness and fornix FA, r = 0.35, p = 0.03). Overall, we found no evidence of a link between short-term physical or cognitive activities and WMI changes, despite activity-related cognitive changes in older adults at risk of dementia. However, we found positive associations between the two targeted training outcomes and WMI, hinting at a potential of long-term activities to affect WMI.

Cognitive change is more positively associated with an active lifestyle than with training interventions in older adults at risk of dementia: a controlled interventional clinical trial.

BACKGROUND: While observational studies show that an active lifestyle including cognitive, physical, and social activities is associated with a reduced risk of cognitive decline and dementia, experimental evidence from corresponding training interventions is more inconsistent with less pronounced effects. The aim of this study was to evaluate and compare training- and lifestyle-related changes in cognition. This is the first study investigating these associations within the same time period and sample. METHODS: Fifty-four older adults at risk of dementia were assigned to 10 weeks of physical training, cognitive training, or a matched wait-list control condition. Lifestyle was operationalized as the variety of self-reported cognitive, physical, and social activities before study participation. Cognitive performance was assessed with an extensive test battery prior to and after the intervention period as well as at a 3-month follow-up. Composite cognition measures were obtained by means of a principal component analysis. Training- and lifestyle-related changes in cognition were analyzed using linear mixed effects models. The strength of their association was compared with paired t-tests. RESULTS: Neither training intervention improved global cognition in comparison to the control group (p = .08). In contrast, self-reported lifestyle was positively associated with benefits in global cognition (p < .001) and specifically in memory (p < .001). Moreover, the association of an active lifestyle with cognitive change was significantly stronger than the benefits of the training interventions with respect to global cognition (ps < .001) and memory (ps < .001). CONCLUSIONS: The associations of an active lifestyle with cognitive change over time in a dementia risk group were stronger than the effects of short-term, specific training interventions. An active lifestyle may differ from training interventions in dosage and variety of activities as well as intrinsic motivation and enjoyment. These factors might be crucial for designing novel interventions, which are more efficient than currently available training interventions. TRIAL REGISTRATION: ClinicalTrials.gov Identifier NCT01061489 . Registered February 2, 2010.

Cognitive Reserve in Alzheimer's Dementia: Diagnostic Accuracy of a Testing-the-Limits Paradigm.

Individuals with higher cognitive reserve are more able to cope with pathological brain alterations, potentially due to the application of more efficient cognitive strategies. The extent to which an individual's cognitive performance can be increased by advantageous conditions differs substantially between patients with Alzheimer's dementia (AD) and healthy older adults and can be assessed with the Testing-the-Limits (TtL) approach. Thus, TtL has been proposed as a tool for the early diagnosis of AD. Here, we report the diagnostic accuracy of a memory TtL paradigm to discriminate between AD patients and controls. The TtL paradigm was administered to 57 patients with clinically diagnosed AD and 94 controls. It consisted of a pre-test condition, representing baseline cognitive performance, the presentation of an encoding strategy, and two subsequent post-test conditions, representing learning potential. Receiver operating characteristic (ROC) curves were analyzed for each condition in order to receive optimal cutoff points along with their sensitivity and specificity and to compare the diagnostic accuracy of the conditions. Differentiation between AD patients and controls, indicated by the area under the ROC curve, increased significantly for the TtL post-test and total error scores compared to the pre-test score. The combined error score in the two post-tests could differentiate between AD patients and controls with a sensitivity of 0.93 and a specificity of 0.80. The presented approach can be carried out in 25 minutes and thus constitutes a time- and cost-effective way to diagnose AD with high accuracy.

Novelty interventions to enhance broad cognitive abilities and prevent dementia: synergistic approaches for the facilitation of positive plastic change.

Process-based cognitive trainings (PCTs) and novelty interventions are two traditional approaches aiming to prevent cognitive decline and dementia. However, both have their limitations. PCTs improve performance only in cognitive tests similar to the training tasks with inconsistent transfer effects on dissimilar tests. We argue that this learning specificity is due to a low training task variability. Novelty interventions are characterized by a high task variability but do not target specific processing demands affected in aging and dementia. To overcome the limitations of both approaches, we developed a process-based novelty intervention using a card and board game-based training approach. Here, we use highly variable tasks, which overlap in targeted processing demands ("overlapping variability" framework). Another nontraditional training approach combines cognitively with physically challenging tasks to induce multimechanistic effects, which might even interact positively. Initial results of both synergistic approaches indicate their potential to enhance broad cognitive abilities and prevent dementia.

Taking perspective into account in a communicative task.

Previous neuroimaging studies of spatial perspective taking have tended not to activate the brain's mentalising network. We predicted that a task that requires the use of perspective taking in a communicative context would lead to the activation of mentalising regions. In the current task, participants followed auditory instructions to move objects in a set of shelves. A 2x2 factorial design was employed. In the Director factor, two directors (one female and one male) either stood behind or next to the shelves, or were replaced by symbolic cues. In the Object factor, participants needed to use the cues (position of the directors or symbolic cues) to select one of three possible objects, or only one object could be selected. Mere presence of the Directors was associated with activity in the superior dorsal medial prefrontal cortex (MPFC) and the superior/middle temporal sulci, extending into the extrastriate body area and the posterior superior temporal sulcus (pSTS), regions previously found to be responsive to human bodies and faces respectively. The interaction between the Director and Object factors, which requires participants to take into account the perspective of the director, led to additional recruitment of the superior dorsal MPFC, a region activated when thinking about dissimilar others' mental states, and the middle temporal gyri, extending into the left temporal pole. Our results show that using perspective taking in a communicative context, which requires participants to think not only about what the other person sees but also about his/her intentions, leads to the recruitment of superior dorsal MPFC and parts of the social brain network.