Publications

BACKGROUND: There is strong association of Alzheimer's disease (AD) pathology with gait disorder and falls in older adults without dementia. The goal of the study was to examine the prevalence and severity of AD pathology in older adults without dementia who fall and sustain hip fracture.

METHODS: Cerebrospinal fluid (CSF) was obtained from 168 hip fracture patients. CSF Aβ42/40 ratio, p-tau, and t-tau measures were dichotomized into normal vs. abnormal, and categorized according to the A/T/N classification.

RESULTS: Among the hip fracture patients, 88.6% of the cognitively normal (Clinical Dementia Rating-CDR 0; n = 70) and 98.8% with mild cognitive impairment (CDR 0.5; n = 81) fell in the abnormal biomarker categories by the A/T/N classification.

CONCLUSIONS: A large proportion of older hip fracture patients have CSF evidence of AD pathology. Preoperative determination of AD biomarkers may play a crucial role in identifying persons without dementia who have underlying AD pathology in perioperative settings.

Cognitive change affecting patients after anaesthesia and surgery has been recognised for more than 100 yr. Research into cognitive change after anaesthesia and surgery accelerated in the 1980s when multiple studies utilised detailed neuropsychological testing for assessment of cognitive change after cardiac surgery. This body of work consistently documented decline in cognitive function in elderly patients after anaesthesia and surgery, and cognitive changes have been identified up to 7.5 yr afterwards. Importantly, other studies have identified that the incidence of cognitive change is similar after non-cardiac surgery. Other than the inclusion of non-surgical control groups to calculate postoperative cognitive dysfunction, research into these cognitive changes in the perioperative period has been undertaken in isolation from cognitive studies in the general population. The aim of this work is to develop similar terminology to that used in cognitive classifications of the general population for use in investigations of cognitive changes after anaesthesia and surgery. A multispecialty working group followed a modified Delphi procedure with no prespecified number of rounds comprised of three face-to-face meetings followed by online editing of draft versions. Two major classification guidelines [Diagnostic and Statistical Manual for Mental Disorders, fifth edition (DSM-5) and National Institute for Aging and the Alzheimer Association (NIA-AA)] are used outside of anaesthesia and surgery, and may be useful for inclusion of biomarkers in research. For clinical purposes, it is recommended to use the DSM-5 nomenclature. The working group recommends that 'perioperative neurocognitive disorders' be used as an overarching term for cognitive impairment identified in the preoperative or postoperative period. This includes cognitive decline diagnosed before operation (described as neurocognitive disorder); any form of acute event (postoperative delirium) and cognitive decline diagnosed up to 30 days after the procedure (delayed neurocognitive recovery) and up to 12 months (postoperative neurocognitive disorder).

BACKGROUND: Delirium is associated with a significantly increased risk of postoperative morbidity and mortality. Furthermore, delirium has been associated with an increased risk of prolonged cognitive deficits and accelerated long-term cognitive decline. To date, experimental interventions for delirium have mainly focused on alternative pharmacologic and behavioral strategies in the postoperative period. Few studies have examined whether proactive strategies started before surgery can prevent delirium or reduce its sequelae. Neurocognitive training programs such as Lumosity have been shown to be effective in increasing cognitive performance in both elderly healthy volunteers and patients suffering from a myriad of acute and chronic medical conditions. When initiated in the preoperative period, such training programs may serve as interesting and novel patient-led interventions for the prevention of delirium and postoperative cognitive decline (POCD). We hypothesize that perioperative neurocognitive training is feasible in the older cardiac surgical population and are testing this hypothesis using a randomized controlled design.

METHODS: The Prevention of Early Postoperative Decline (PEaPoD) study is a randomized, controlled trial with a target enrollment of 45 elderly cardiac surgical patients. Subjects will be randomized in a 1:1 ratio to undergo either at least 10 days of preoperative neurocognitive training, continued for 4 weeks postoperatively, or usual care control. The primary outcome, feasibility, will be assessed by study recruitment and adherence to protocol. Secondary outcomes will include potential differences in the incidence of postoperative in-hospital delirium and POCD up to 6 months, as determined by the Confusion Assessment Method and the Montreal Cognitive Assessment.

DISCUSSION: PEaPoD will be the first trial investigating the use of perioperative cognitive training to potentially reduce delirium and POCD in the cardiac surgical population. Information gleaned from this feasibility study will prove valuable in designing future efficacy studies aimed at determining whether this low-risk, patient-led intervention can reduce serious postoperative morbidity.

TRIAL REGISTRATION: ClinicalTrials.gov, NCT02908464 . Registered on 21 September 2016.

Postoperative delirium (POD) is an acute change in the mental state with consciousness and attention deficits. It is a common complication after surgical procedures and can have serious consequences. Thus, the evidence- and consensus-based guidelines for POD appeals with the highest recommendation level that patients be regularly screened for delirium in the postoperative phase, from the recovery room to the fifth postoperative day and at least once per shift, using a validated test instrument for the detection of POD. In 2014, Marcantonio et al. published the 3D-CAM (3-Minute Diagnostic Interview for CAM-defined Delirium). In the 3D-CAM, the algorithm of the Confusion Assessment Method (CAM) is maintained by using individual elements that operationalize the evaluation of the criteria. Therefore, it requires less training, be faster to use, and, due to a standardized approach, has less interrater variability than the CAM, whereas the high sensitivity and specificity are maintained. Our goal was to translate the 3D-CAM from English to German, so as to make this instrument available to German-speaking countries. The translation of the 3D-CAM was based on the 2005 published guideline on Translation and Cultural Adaptation of Patient Reported Outcome Measures of the International Society for Pharmacoeconomics and Outcome Research. Three independent forward translations were harmonized to a preliminary translation, which then was translated back into the original language. Original authors reviewed the back translation. According to a cognitive debriefing, the translation was revised and in addition was adapted for use in the recovery room. Due to close contact with the original authors during the translation process, it was possible to ensure that the contents of the test instrument were remained intact during the translation process.

BACKGROUND: Delirium is a common, morbid, and costly postoperative complication. We aimed to identify blood-based postoperative delirium markers in a nested case-control study of older surgical patients using a proteomics approach followed by enzyme-linked immunosorbent assay (ELISA) validation.

METHODS: The Successful Aging after Elective Surgery study enrolled dementia-free adults ≥70 years old undergoing major scheduled noncardiac surgery (N = 566; 24% delirium). Plasma was collected at four time points: preoperative, postanesthesia care unit, postoperative day 2, and 1 month postoperative. Matched pairs were selected for the independent discovery (39 pairs) and replication cohorts (36 pairs), which were subsequently combined into the pooled cohort (75 pairs). Isobaric tags for relative and absolute quantitation-based relative quantitation mass spectrometry proteomics were performed to identify the strongest delirium-related protein, which was selected for ELISA validation. Using the ELISA results, statistical analyses using nonparametric signed rank tests were performed in all cohorts examining the association between the identified protein and delirium.

RESULTS: C-reactive protein emerged from the proteomics analysis as the strongest delirium-related protein. Validation by ELISA confirmed that compared with controls, cases had significantly higher C-reactive protein levels in the discovery, replication, and pooled cohorts at the preoperative (median paired difference [MPD] 1.97 mg/L [p < .05], 0.29 mg/L, 1.56 mg/L [p < .01]), postanesthesia care unit (MPD 2.83 mg/L, 2.22 mg/L [p < .05], 2.53 mg/L [p < .01]) and postoperative day 2 (MPD 71.97 mg/L [p < .01], 35.18 mg/L [p < .05], 63.76 mg/L [p < .01]) time points, but not 1 month postoperative (MPD 2.72 mg/L, -0.66 mg/L, 1.10 mg/L).

CONCLUSIONS: Elevated preoperative and postoperative plasma levels of C-reactive protein were associated with delirium, suggesting that a preinflammatory state and heightened inflammatory response to surgery are potential pathophysiologic mechanisms of delirium.

PURPOSE: To investigate whether measurement of arterial transit time (ATT) can improve the accuracy of arterial spin labeling (ASL) cerebral blood flow (CBF) quantification in an elderly cohort due to the potentially prolonged ATT in the cohort.

MATERIALS AND METHODS: We employed a 1-minute, low-resolution (12 mm in-plane), sequential multidelay ATT measurement (both with and without vessel suppression) approach to characterize and correct ATT errors in CBF imaging of an elderly, clinical cohort. In all, 140 nondemented subjects greater than 70 years old were imaged at 3T with a single delay, volumetric continuous ASL sequence and also with the fast ATT measurement method. Nine healthy young subjects (28 ± 6 years old) were also imaged.

RESULTS: ATTs measured without vessel suppression (superior frontal: 1.51 ± 0.27 sec) in the elderly were significantly shorter than those with suppression (P < 0.0001). Correction of CBF for ATT significantly increased average CBF in multiple brain regions where ATT was longer than the postlabeling delay (P < 0.01) and decreased intersubject variability of CBF in frontal, parietal, and occipital regions (P < 10-8 ). Measured ATT with vessel suppression was significantly longer in the elderly subjects (eg, superior frontal: 1.76 ± 0.25 sec) compared to the younger adults (superior frontal: 1.59 ± 0.19 sec) in basal ganglia and frontal cortical regions (P < 0.05).

CONCLUSION: The ATT measurement is beneficial for imaging of elderly clinical populations. If ATT mapping is not feasible or available, postlabeling delays of 2-2.3 seconds should be used for elderly populations based on longest measured regional ATTs.

LEVEL OF EVIDENCE: 1 J. Magn. Reson. Imaging 2017;45:472-481.

Three-dimensional Arterial Spin Labeling (ASL) MRI was performed before surgery in a cohort of 146 prospectively enrolled subjects ≥ 70 years old scheduled to undergo elective surgery. We investigated the prospective association between ASL-derived measures of cerebral blood flow (CBF) before surgery with postoperative delirium incidence and severity using whole-brain and globally normalized voxel-wise analysis. We also investigated the cross-sectional association of CBF with patients' baseline performance on specific neuropsychological tests, and with a composite general cognitive performance measure (GCP). Out of 146 subjects, 32 (22%) developed delirium. We found no significant association between global and voxel-wise CBF with delirium incidence or severity. We found the most significant positive associations between CBF of the posterior cingulate and precuneus and the Hopkins Verbal Learning Test - Revised total score, Visual Search and Attention Test (VSAT) score and the GCP composite. VSAT score was also strongly associated with right parietal lobe CBF. ASL can be employed in a large, well-characterized older cohort to examine associations between CBF and age-related cognitive performance. Although ASL CBF measures in regions previously associated with preclinical Alzheimer's Disease were correlated with cognition, they were not found to be indicators of baseline pathology that may increase risk for delirium.

OBJECTIVE: To describe functional recovery after elective surgery and to determine whether improvements differ among individuals who develop delirium.

BACKGROUND: No large studies of older adults have investigated whether delirium influences the trajectory of functional recovery after elective surgery. The prospective observational study assessed this association among 566 individuals aged 70 years and older.

METHODS: Patients undergoing major elective surgery were assessed daily while in hospital for presence and severity of delirium using the Confusion Assessment Method, and their functional recovery was followed for 18 months thereafter. The Activities of Daily Living and Instrumental Activities of Daily Living Scales and the Physical Component Summary of the Short Form-12 were obtained before surgery and at 1, 2, 6, 12, and 18 months. A composite index (standard deviation 10, minimally clinically significant difference 2) derived from these scales was then analyzed using mixed-effects regression.

RESULTS: Mean age was 77 years; 58% of participants were women and 24% developed postoperative delirium. Participants with delirium demonstrated lesser functional recovery than their counterparts without delirium; at 1 month, the covariate-adjusted mean difference on the physical function composite was -1.5 (95% confidence interval -3.3, -0.2). From 2 to 18 months, the corresponding difference was -1.8 (95% confidence interval -3.2, -0.3), an effect comparable with the minimally clinically significant difference.

CONCLUSIONS: Delirium was associated with persistent and clinically meaningful impairment of functional recovery, to 18 months. Use of multifactorial preventive interventions for patients at high risk for delirium and tailored transitional care planning may help to maximize the functional benefits of elective surgery.

OBJECTIVES: To examine the effect of hospital readmission on functional recovery after elective surgery in older adults.

DESIGN: Prospective cohort of individuals aged 70 and older undergoing elective surgery, enrolled from June 2010 to August 2013.

SETTING: Two academic medical centers.

PARTICIPANTS: Community-dwelling older adults (N = 566; mean age ± standard deviation 77 ± 5) undergoing major elective surgery and expected to be admitted for at least 3 days.

MEASUREMENTS: Readmission was assessed in multiple interviews with participants and family members over 18 months and validated against medical record review. Physical function was assessed according to ability to perform instrumental activities of daily living (IADLs) and activities of daily living (ADL), Medical Outcomes Study 12-item Short-Form Survey Physical Component Summary score, and a standardized functional composite.

RESULTS: Two hundred fifty-five (45%) participants experienced 503 readmissions. Readmissions were associated with delays in functional recovery in all measures of physical function. Having two or more readmissions over 18 months was associated with persistent and significantly greater risk of IADL dependence (relative risk (RR) = 1.8, 95% confidence interval (CI) = 1.5-2.3) and ADL dependence (RR = 3.3, 95% CI = 1.7-6.4). Degree of functional impairment increased progressively with number of readmissions. Readmissions within 2 months resulted in delayed functional recovery to baseline by 18 months, and readmissions between 12 and 18 months after surgery resulted in loss of functional recovery previously achieved.

CONCLUSION: Readmission after elective surgery may contribute to delays in functional recovery and persistent functional deficits in older adults.

Delirium is a common problem associated with substantial morbidity and increased mortality. However, the brain dysfunction that leads some individuals to develop delirium in response to stressors is unclear. In this article, we briefly review the neurophysiologic literature characterizing the changes in brain function that occur in delirium, and in other cognitive disorders such as Alzheimer's disease. Based on this literature, we propose a conceptual model for delirium. We propose that delirium results from a breakdown of brain function in individuals with impairments in brain connectivity and brain plasticity exposed to a stressor. The validity of this conceptual model can be tested using Transcranial Magnetic Stimulation in combination with Electroencephalography, and, if accurate, could lead to the development of biomarkers for delirium risk in individual patients. This model could also be used to guide interventions to decrease the risk of cerebral dysfunction in patients preoperatively, and facilitate recovery in patients during or after an episode of delirium.