Postoperative delirium is associated with grey matter brain volume loss.

Delirium is associated with long-term cognitive dysfunction and with increased brain atrophy. However, it is unclear whether these problems result from or predisposes to delirium. We aimed to investigate preoperative to postoperative brain changes, as well as the role of delirium in these changes over time. We investigated the effects of surgery and postoperative delirium with brain MRIs made before and 3 months after major elective surgery in 299 elderly patients, and an MRI with a 3 months follow-up MRI in 48 non-surgical control participants. To study the effects of surgery and delirium, we compared brain volumes, white matter hyperintensities and brain infarcts between baseline and follow-up MRIs, using multiple regression analyses adjusting for possible confounders. Within the patients group, 37 persons (12%) developed postoperative delirium. Surgical patients showed a greater decrease in grey matter volume than non-surgical control participants [linear regression: B (95% confidence interval) = -0.65% of intracranial volume (-1.01 to -0.29, P < 0.005)]. Within the surgery group, delirium was associated with a greater decrease in grey matter volume [B (95% confidence interval): -0.44% of intracranial volume (-0.82 to -0.06, P = 0.02)]. Furthermore, within the patients, delirium was associated with a non-significantly increased risk of a new postoperative brain infarct [logistic regression: odds ratio (95% confidence interval): 2.8 (0.7-11.1), P = 0.14]. Our study was the first to investigate the association between delirium and preoperative to postoperative brain volume changes, suggesting that delirium is associated with increased progression of grey matter volume loss.

Functional brain network and trail making test changes following major surgery and postoperative delirium: a prospective, multicentre, observational cohort study.

BACKGROUND: Delirium is a frequent complication after surgery in older adults and is associated with an increased risk of long-term cognitive impairment and dementia. Disturbances in functional brain networks were previously reported during delirium. We hypothesised that alterations in functional brain networks persist after remission of postoperative delirium and that functional brain network alterations are associated with long-term cognitive impairment. METHODS: In this prospective, multicentre, observational cohort study, we included older patients who underwent clinical assessments (including the Trail Making Test B [TMT-B]) and resting-state functional MRI (rs-fMRI) before and 3 months after elective surgery. Delirium was assessed on the first seven postoperative days. RESULTS: Of the 554 enrolled patients, 246 remained after strict motion correction, of whom 38 (16%) developed postoperative delirium. The rs-fMRI functional connectivity strength increased 3 months after surgery in the total study population (ß=0.006; 95% confidence interval [CI]: 0.001-0.011; P=0.013), but it decreased after postoperative delirium (ß=-0.015; 95% CI: -0.028 to 0.002; P=0.023). No difference in TMT-B scores was found at follow-up between patients with and without postoperative delirium. Patients with decreased functional connectivity strength declined in TMT-B scores compared with those who did not (ß=11.04; 95% CI: 0.85-21.2; P=0.034). CONCLUSIONS: Postoperative delirium was associated with decreased brain functional connectivity strength after 3 months, suggesting that delirium has a long-lasting impact on brain networks. The decreased connectivity strength was associated with significant cognitive deterioration after major surgery. CLINICAL TRIAL REGISTRATION: NCT02265263.

Cognitive reserve and the risk of postoperative neurocognitive disorders in older age.

Background: Postoperative delirium (POD) and postoperative cognitive dysfunction (POCD) are postoperative neurocognitive disorders (PNDs) that frequently occur in the aftermath of a surgical intervention. Cognitive reserve (CR) is a concept posited to explain why cognitive health varies between individuals. On this qualitative understanding of cognitive health, factors like IQ, education level, and occupational complexity can affect the impact of neuropathological processes on cognitive outcomes. Methods: We investigated the association between CR and POD and CR and POCD on data from 713 patients aged≥65 years with elective surgery. Peak pre-morbid IQ was estimated from vocabulary. Occupational complexity was coded according to the Dictionary of Occupational Titles (DOT). Education level was classed according to the International Standard Classification of Education (ISCED). These three factors were used as proxies of CR. In a series of regression models, age, sex, depression, site of surgery, and several lifestyle and vascular factors were controlled for. Results: Patients with a higher IQ had lower odds of developing POD. We found no significant association between the other two CR markers with POD. None of the CR markers was associated with POCD. Conclusion: The significant association of a higher IQ with lower POD risk allows for the stratification of elderly surgical patients by risk. This knowledge can aid the prevention and/or early detection of POD. Further research should attempt to determine the lack of associations of CR markers with POCD in our study.

Different cardiovascular risk factors are related to distinct white matter hyperintensity MRI phenotypes in older adults.

The underlying mechanisms of the association between cardiovascular risk factors and a higher white matter hyperintensity (WMH) burden are unknown. We investigated the association between cardiovascular risk factors and advanced WMH markers in 155 non-demented older adults (mean age: 71 ± 5 years). The association between cardiovascular risk factors and quantitative MRI-based WMH shape and volume markers were examined using linear regression analysis. Presence of hypertension was associated with a more irregular shape of periventricular/confluent WMH (convexity (B (95 % CI)): -0.12 (-0.22--0.03); concavity index: 0.06 (0.02-0.11)), but not with total WMH volume (0.22 (-0.15-0.59)). Presence of diabetes was associated with deep WMH volume (0.89 (0.15-1.63)). Body mass index or hyperlipidemia showed no association with WMH markers. In conclusion, different cardiovascular risk factors seem to be related to a distinct pattern of WMH shape markers in non-demented older adults. These findings may suggest that different underlying cardiovascular pathological mechanisms lead to different WMH MRI phenotypes, which may be valuable for early detection of individuals at risk for stroke and dementia.

Delirium and long-term psychopathology following surgery in older adults.

OBJECTIVE: To describe the risk of postoperative delirium and long-term psychopathology (depression, anxiety or post-traumatic stress syndrome (PTSS)) in older adults. METHODS: 255 elderly patients (≥ 65 years) undergoing major surgery (planned surgical time > 60 min) in a tertiary hospital were compared to 76 non-surgical controls from general practice. Patients were assessed twice daily for postoperative delirium using the Confusion Assessment Method (CAM(-ICU)), nursing delirium screening scale (NuDESC) and validated chart review. Before surgery and 3 and 12 months thereafter, the participants filled in the Hospital Anxiety and Depression Scale (HADS), the Geriatric Depression Scale (GDS-15) and the Post-Traumatic Stress Syndrome-14-Questions Inventory (PTSS-14). Non-surgical controls filled in the same questionnaires with similar follow-up. RESULTS: Patients were more often male, had higher American Society of Anesthesiologists scores and more often had a spouse compared to controls (p < 0.005). Forty-three patients (18%) developed postoperative delirium, who were significantly older, had higher ASA scores and lower estimated IQ scores compared to the patients who did not develop delirium (p < 0.05). There were no differences in psychopathology at baseline and 3-month follow-up between patients and controls. At 12-months, surgical patients less frequently scored positive for depression (7% versus 16%) and anxiety (2% versus 10%) compared to nonsurgical controls (p < 0.05). We did not observe differences in occurrence of psychopathology between patients who had and had not developed postoperative delirium. CONCLUSION: Our results suggest that the older surgical population, with or without postoperative delirium, does not appear to be at greater risk of developing psychopathology. WHY DOES THIS PAPER MATTER?: The older surgical population does not appear to be at greater risk of developing psychopathology, neither seems this risk influenced by the occurrence of postoperative delirium.

Contribution of IQ in young adulthood to the associations of education and occupation with cognitive ability in older age.

BACKGROUND: Studies suggest that a higher education and occupation are each associated with a higher late-life cognitive ability, but their inter-relationships in their association with cognitive ability and the contribution of peak IQ in young adulthood ('pre-morbid IQ') often remain unclear. METHODS: Cross-sectional analysis of 623 participants aged ≥65 years of the BioCog study. Education was coded according to the International Standard Classification of Education (ISCED; range 1 to 6). Occupation was coded as 'semi/unskilled', 'skilled manual', 'skilled non-manual', 'managerial', 'professional'. A summary score of global ability ('g') was constructed from six cognitive tests. Pre-morbid IQ was estimated from vocabulary. The Geriatric Depression Scale assessed symptoms of depression. Age- and sex-adjusted analyses of covariance were performed. RESULTS: Education (partial eta2 0.076; p < 0.001) and occupation (partial eta2 = 0.037; p < 0.001) were each significantly associated with g. For education, the association was attenuated but remained statistically significant when pre-morbid IQ was controlled for (partial eta2 0.036; p < 0.001) and was unchanged with additional adjustment for depression (partial eta2 0.037; p < 0.001). For occupation, the association with g was no longer significant when pre-morbid IQ (partial eta2 = 0.015; p = 0.06) and depression (partial eta2 = 0.011; p = 0.18) were entered as covariates in separate steps. When education and occupation were entered concurrently into the fully adjusted model, only education was independently associated with g (partial eta2 0.030; p < 0.001; occupation, p = 0.93). CONCLUSION: While a higher education and a higher occupation were each associated with a higher late-life cognitive ability, only for education some unique contribution to cognitive ability remained over and above its relationship with pre-morbid IQ, depression, and occupation. Further research is needed to address whether a longer time spent in education may promote late-life cognitive ability.

Preoperative MRI brain phenotypes are related to postoperative delirium in older individuals.

The underlying structural correlates of predisposition to postoperative delirium remain largely unknown. A combined analysis of preoperative brain magnetic resonance imaging (MRI) markers could improve our understanding of the pathophysiology of delirium. Therefore, we aimed to identify different MRI brain phenotypes in older patients scheduled for major elective surgery, and to assess the relation between these phenotypes and postoperative delirium. Markers of neurodegenerative and neurovascular brain changes were determined from MRI brain scans in older patients (n = 161, mean age 71, standard deviation 5 years), of whom 24 (15%) developed delirium. A hierarchical cluster analysis was performed. We found six distinct groups of patients with different MRI brain phenotypes. Logistic regression analysis showed a higher odds of developing postoperative delirium in individuals with multi-burden pathology (n = 15 (9%), odds ratio (95% confidence interval): 3.8 (1.1-13.0)). In conclusion, these results indicate that different MRI brain phenotypes are related to a different risk of developing delirium after major elective surgery. MRI brain phenotypes could assist in an improved understanding of the structural correlates of predisposition to postoperative delirium.

Preoperative brain MRI features and occurrence of postoperative delirium.

OBJECTIVE: Delirium is a frequent complication after surgery with important negative outcomes for affected patients and society. However, it is still largely unknown why some patients have a predisposition for delirium and others not. To increase our understanding of the neural substrate of postoperative delirium, we studied the association between preoperative brain MRI features and the occurrence of delirium after major surgery. METHODS: A group of 413 patients without dementia (Mean 72 years, SD: 5) was included in a prospective observational two-center study design. The study was conducted at Charité Universitätsmedizin (Berlin, Germany) and the University Medical Center Utrecht (Utrecht, The Netherlands). We measured preoperative brain volumes (total brain, gray matter, white matter), white matter hyperintensity volume and shape, brain infarcts and cerebral perfusion, and used logistic regression analysis adjusted for age, sex, intracranial volume, study center and type of surgery. RESULTS: Postoperative delirium was present in a total of 70 patients (17%). Preoperative cortical brain infarcts increased the risk of postoperative delirium, although this did not reach statistical significance (OR (95%CI): 1.63 (0.84-3.18). Furthermore, we found a trend for an association of a more complex shape of white matter hyperintensities with occurrence of postoperative delirium (OR (95%CI): 0.97 (0.95-1.00)). Preoperative brain volumes, white matter hyperintensity volume, and cerebral perfusion were not associated with occurrence of postoperative delirium. CONCLUSION: Our study suggests that patients with preoperative cortical brain infarcts and those with a more complex white matter hyperintensity shape may have a predisposition for developing delirium after major surgery.

Stability of neuropsychological test performance in older adults serving as normative controls for a study on postoperative cognitive dysfunction.

OBJECTIVE: Studies of postoperative cognitive dysfunction (POCD) rely on repeat neuropsychological testing. The stability of the applied instruments, which are affected by natural variability in performance and measurement imprecision, is often unclear. We determined the stability of a neuropsychological test battery using a sample of older adults from the general population. Forty-five participants aged 65 to 89 years performed six computerized and non-computerized neuropsychological tests at baseline and again at 7 day and 3 months follow-up sessions. Mean scores on each test were compared across time points using repeated measures analyses of variance (ANOVA) with pairwise comparison. Two-way mixed effects, absolute agreement analyses of variance intra-class correlation coefficients (ICC) determined test-retest reliability. RESULTS: All tests had moderate to excellent test-retest reliability during 7-day (ICC range 0.63 to 0.94; all p < 0.01) and 3-month intervals (ICC range 0.60 to 0.92; all p < 0.01) though confidence intervals of ICC estimates were large throughout. Practice effects apparent at 7 days eased off by 3 months. No substantial differences between computerized and non-computerized tests were observed. We conclude that the present six-test neuropsychological test battery is appropriate for use in POCD research though small sample size of our study needs to be recognized as a limitation. Trial registration ClinicalTrials.gov Identifier NCT02265263 (15th October 2014).

The association between frailty and MRI features of cerebral small vessel disease.

Frailty is a common syndrome in older individuals that is associated with poor cognitive outcome. The underlying brain correlates of frailty are unclear. The aim of this study was to investigate the association between frailty and MRI features of cerebral small vessel disease in a group of non-demented older individuals. We included 170 participants who were classified as frail (n = 30), pre-frail (n = 85) or non-frail (n = 55). The association of frailty and white matter hyperintensity volume and shape features, lacunar infarcts and cerebral perfusion was investigated by regression analyses adjusted for age and sex. Frail and pre-frail participants were older, more often female and showed higher white matter hyperintensity volume (0.69 [95%-CI 0.08 to 1.31], p = 0.03 respectively 0.43 [95%-CI: 0.04 to 0.82], p = 0.03) compared to non-frail participants. Frail participants showed a non-significant trend, and pre-frail participants showed a more complex shape of white matter hyperintensities (concavity index: 0.04 [95%-CI: 0.03 to 0.08], p = 0.03; fractal dimensions: 0.07 [95%-CI: 0.00 to 0.15], p = 0.05) compared to non-frail participants. No between group differences were found in gray matter perfusion or in the presence of lacunar infarcts. In conclusion, increased white matter hyperintensity volume and a more complex white matter hyperintensity shape may be structural brain correlates of the frailty phenotype.

Basal forebrain cholinergic system volume is associated with general cognitive ability in the elderly.

OBJECTIVE: At the present, it is unclear whether association of basal forebrain cholinergic system (BFCS) volume with cognitive performance exists in healthy as well as in cognitively impaired elderly subjects. Whereas one small study reported an association of BFCS volume with general cognitive ability 'g' in healthy ageing, effects on specific cognitive domains have only been found in subjects with cognitive decline. Here we aim to clarify whether an association of BFCS volume and 'g' is present in a larger sample of elderly subjects without obvious symptoms of dementia and whether similar associations can also be observed in specific cognitive domains. METHODS: 282 pre-surgical patients from the BioCog study (aged 72.7 ±â€¯4.9 years with a range of 65-87 years, 110 women) with a median MMSE score of 29 points (range 24-30) were investigated. BFCS and brain volume as well as brain parenchymal fraction were assessed in T1-weighted MR images using SPM12 and a probabilistic map of the BFCS. Neuropsychological assessment comprised the CANTAB cognitive battery and paper-and-pencil based tests. For data analysis, generalised linear models and quantile regression were applied. RESULTS: Significant associations of BFCS volume with 'g' and several cognitive domains were found, with the strongest association found for 'g'. BFCS volume explained less variance in cognitive performance than brain volume. The association was not confounded by brain parenchymal fraction. Furthermore, the association of BFCS volume and 'g' was similar in high- and low-performers. CONCLUSION: Our results extend previous study findings on BFCS volume associations with cognition in elderly subjects. Despite the observed associations of BFCS volume and cognitive performance, this association seems to reflect a more general association of brain volume and cognition. Accordingly, a specific association of BFCS volume and cognition in non-demented elderly subjects is questionable.

Resting-state fMRI reveals network disintegration during delirium.

Delirium is characterized by inattention and other cognitive deficits, symptoms that have been associated with disturbed interactions between remote brain regions. Recent EEG studies confirm that disturbed global network topology may underlie the syndrome, but lack an anatomical basis. The aim of this study was to increase our understanding of the global organization of functional connectivity during delirium and to localize possible alterations. Resting-state fMRI data from 44 subjects were analyzed, and motion-free data were available in nine delirious patients, seven post delirium patients and thirteen non-delirious clinical controls. We focused on the functional network backbones using the minimum spanning tree, which allows unbiased network comparisons. During delirium a longer diameter (mean (M) = 0.30, standard deviation (SD) = 0.05, P = .024) and a lower leaf fraction (M = 0.32, SD = 0.03, P = .027) was found compared to the control group (M = 0.28, SD = 0.04 respectively M = 0.35, SD = 0.03), suggesting reduced functional network integration and efficiency. Delirium duration was strongly related to loss of network hierarchy (rho = -0.92, P = .001). Connectivity strength was decreased in the post delirium group (M = 0.16, SD = 0.01) compared to the delirium group (M = 0.17, SD = 0.03, P = .024) and the control group (M = 0.19, SD = 0.02, P = .001). Permutation tests revealed a decreased degree of the right posterior cingulate cortex during delirium and complex regional alterations after delirium. These findings indicate that delirium reflects disintegration of functional interactions between remote brain areas and suggest long-term impact after the syndrome resolves.

The association between brain volume, cortical brain infarcts, and physical frailty.

Physical frailty is an age-associated syndrome of decreased reserve leading to vulnerability to physiological stressors and associated with negative outcomes. The underlying structural brain abnormalities of physical frailty are unclear. We investigated the association between brain volume, cortical brain infarcts, and physical frailty. In this multicenter study, 214 nondemented participants were classified as frail (n = 32), prefrail (n = 107), or nonfrail (n = 75) based on the Fried frailty phenotype. The associations between frailty and brain volumes and cortical brain infarcts were investigated by linear or logistic regression analyses. Participants in the frail group showed a lower total brain volume (-19.67 mL [95% confidence interval -37.84 to -1.50]) and lower gray matter volume (-12.19 mL [95% confidence interval -23.84 to -0.54]) compared to nonfrail participants. Frailty was associated with cortical brain infarcts [frail 16% [n = 5], prefrail 11% [n = 12], and nonfrail 3% [n = 2]). Reduced total brain volume and gray matter volume and increased cortical brain infarcts seem therefore to be part of the structural substrate of the physical frailty phenotype.

MRI Markers of Neurodegenerative and Neurovascular Changes in Relation to Postoperative Delirium and Postoperative Cognitive Decline.

Postoperative delirium (POD) and postoperative cognitive decline (POCD) are common in elderly patients. The aim of the present review was to explore the association of neurodegenerative and neurovascular changes with the occurrence of POD and POCD. Fifteen MRI studies were identified by combining multiple search terms for POD, POCD, and brain imaging. These studies described a total of 1,422 patients and were all observational in design. Neurodegenerative changes (global and regional brain volumes) did not show a consistent association with the occurrence of POD (four studies) or POCD (two studies). In contrast, neurovascular changes (white matter hyperintensities and cerebral infarcts) were more consistently associated with the occurrence of POD (seven studies) and POCD (five studies). In conclusion, neurovascular changes appear to be consistently associated with the occurrence of POD and POCD, and may identify patients at increased risk of these conditions. Larger prospective studies are needed to study the consistency of these findings and to unravel the underlying pathophysiological mechanisms.

Effects of omega-3 polyunsaturated fatty acids on human brain morphology and function: What is the evidence?

Public opinion and media coverage suggest that there are benefits of long-chain ω-3 polyunsaturated fatty acid (LC-PUFA) intake on brain functioning. However, it is an open question whether this is indeed the case. Therefore, we reviewed the evidence for effects of ω-3 LC-PUFA on human brain morphology and function. We included studies on (1) naturalistic long-term ω-3 LC-PUFA intake during life (2) the effects of short-term ω-3 LC-PUFA supplementation in healthy subjects and (3) the effects of ω-3 LC-PUFA supplementation as alternative or add-on treatment for psychiatric or neurological disorders. To date, 24 studies have been published on the effect of ω-3 LC-PUFA on brain function and structure. Findings from naturalistic studies and clinical trials in healthy individuals indicate that ω-3 LC-PUFA intake may be associated with increased functional activation of the prefrontal cortex in children, and greater gray matter volume and white matter integrity during aging. However, most naturalistic studies were cross-sectional or did not find any effect on cognition. As such, it is hard to estimate the magnitude of any beneficial effects. Furthermore, there is only limited evidence to support that ω-3 LC-PUFA supplementation is beneficial in brain disorders, such as Alzheimer's Disease, Attention Deficit/Hyperactivity Disorder, Major Depressive Disorder and schizophrenia. Overall, the literature suggests that sensitivity to supplementation may vary over development, and as a consequence of brain disorders. The biological mechanisms underlying any (beneficial) effects ω-3 LC-PUFAs on the brain are currently unknown and need to be investigated.

Emotion processing in schizophrenia is state and trait dependent.

BACKGROUND: Substantial evidence exists about emotion processing (EP) impairments in schizophrenia patients. However, whether these deficits are present primarily during psychosis (i.e., state dependent) or an integral part of the disorder (i.e., trait dependent) remains unclear. METHODS: EP was assessed with the degraded facial affect recognition task in schizophrenia patients (N=521) and healthy controls (N=312) at baseline (T1) and after a three year follow-up (T2). In schizophrenia patients symptomatic remission was assessed with the Positive and Negative Syndrome Scale (PANSS) remission tool. Patients were divided into four groups: remission T1 and remission T2 (RR); remission T1 and non-remission T2 (RN); non-remission T1 and non-remission T2 (NN) and non-remission T1 and remission T2 (NR). Factorial repeated measures ANCOVA was used to compare EP performance over time between groups. Age, gender and general cognition were included as covariates. RESULTS: Schizophrenia patients performed worse than healthy controls on EP at T1 (p=0.001). The patients that were in symptomatic remission at both time points (the RR group) performed worse than the healthy controls at T2 (p<0.001). Significant group×time interactions were found between RR and RN (p=0.001), and between NR and RN (p=0.04), indicating a differential EP performance over time. No group×time interaction was found between NN and NR. CONCLUSION: The results show relatively poor EP performance in schizophrenia patients compared to healthy controls. EP performance in schizophrenia patients was associated with symptomatic remission. The results provide support for the hypothesis that EP deficits in schizophrenia are both state and trait dependent.