Person:

Alsop, David

OBJECTIVES: To identify barriers and motivators to participation in long-term clinical research by high-risk elderly people and to develop procedures to maximize recruitment and retention. DESIGN: Quantitative and qualitative survey. SETTING: Academic primary care medicine and pre-anesthesia testing clinics. PARTICIPANTS: Fifty patients aged 70 and older, including 25 medical patients at high risk of hospitalization and 25 patients with planned major surgery. MEASUREMENTS: Fifteen- to 20-minute interviews involved open- and closed-ended questions guided by an in-depth script. Two planned study protocols were presented to each participant. Both involved serial neuropsychological assessments, blood testing, and magnetic resonance brain imaging (MRI); one added lumbar puncture (LP). Participants were asked whether they would be willing to participate in these protocols, rated barriers and incentives to participation, and were probed with open-ended questions. RESULTS: Of 50 participants (average age 78, 44% male, 40% nonwhite), 32 (64%) expressed willingness to participate in the LP-containing protocol, with LP cited as the strongest disincentive. Thirty-eight (76%) expressed willingness to participate in the protocol without LP, with phlebotomy and long interviews cited as the strongest disincentives. Altruism was a strong motivator for participation, whereas transportation was a major barrier. Study visits at home, flexible appointment times, assessments shorter than 75 minutes, and providing transportation and free parking were strategies developed to maximize study participation. CONCLUSION: Vulnerable elderly people expressed a high rate of willingness to participate in an 18-month prospective study. Participants identified incentives and barriers that enabled investigators to develop procedures to maximize recruitment and retention.

Cognitive and brain reserve are well studied in the context of age-associated cognitive impairment and dementia. However, there is a paucity of research that examines the role of cognitive or brain reserve in delirium. Indicators (or proxy measures) of cognitive or brain reserve (such as brain size, education, and activities) pose challenges in the context of the long prodromal phase of Alzheimer disease but are diminished in the context of delirium, which is of acute onset. This article provides a review of original articles on cognitive and brain reserve across many conditions affecting the central nervous system, with a focus on delirium. The authors review current definitions of reserve. The authors identify indicators for reserve used in earlier studies and discuss these indicators in the context of delirium. The authors highlight future research directions to move the field ahead. Reserve may be a potentially modifiable characteristic. Studying the role of reserve in delirium can advance prevention strategies for delirium and may advance knowledge of reserve and its role in aging and neuropsychiatric disease generally.

Dementia with Lewy bodies (DLB) is often associated with occipital hypometabolism or hypoperfusion, as well as deficits in cholinergic neurotransmission. In this study, 11 mild DLB, 16 mild AD and 16 age-matched controls underwent arterial spin-labeled perfusion MRI (ASL-pMRI) and neuropsychological testing. Patterns of cerebral blood flow (CBF) and cognitive performance were compared. In addition, combined ASL-pMRI and ChEI drug challenge (pharmacologic MRI) was tested as a probe of cholinergic function in 4 of the DLB participants. Frontal and parieto-occipital hypoperfusion was observed in both DLB and AD but was more pronounced in DLB. Following ChEI treatment, perfusion increased in temporal and parieto-occipital cortex, and cognitive performance improved on a verbal fluency task. If confirmed in a larger study, these results provide further evidence for brain cholinergic dysfunction in DLB pathophysiology, and use of pharmacologic MRI as an in vivo measure of cholinergic function.

Objectives: Delirium, a costly, life-threatening, and potentially preventable condition, is a common complication for older adults following major surgery. Although the basic epidemiology of delirium after surgery has been defined, the contribution of delirium to long term outcomes remains uncertain, and novel biomarkers from plasma and neuroimaging have yet to be examined. This program project was designed to contribute to our understanding of the complex multifactorial syndrome of delirium. Design: Long term prospective cohort study. Setting: Three academic medical centers (2 hospitals and 1 coordinating center). Participants: Patients without recognized dementia (targeted cohort = 550 patients) age 70 and older scheduled to undergo elective major surgery are assessed at baseline before surgery, daily during their hospital stay, and for 18 to 36 months after discharge. Measurements: The Successful Aging after Elective Surgery (SAGES) study is an innovative, interdisciplinary study that includes biomarkers, neuroimaging, cognitive reserve markers, and serial neuropsychological testing to examine the contribution of delirium to long term cognitive and functional decline. The primary goal is to examine the contribution of delirium to long term cognitive and functional decline. In addition, novel risk markers for delirium are being examined, including plasma biomarkers (eg, cytokines, proteomics), advanced neuroimaging markers (eg, volumetric, white matter hyperintensity, noncontrast blood flow, and diffusion tensor measures), and cognitive reserve markers (eg, education, occupation, lifetime activities). Conclusion: Results from this study will contribute to a fuller understanding of the etiology and prognosis of delirium. Ultimately, we hope this project will provide the groundwork for future development of prevention and treatment strategies for delirium, designed to minimize the long term negative impact of delirium in older adults.

Background: The nested case-control study (NCC) design within a prospective cohort study is used when outcome data are available for all subjects, but the exposure of interest has not been collected, and is difficult or prohibitively expensive to obtain for all subjects. A NCC analysis with good matching procedures yields estimates that are as efficient and unbiased as estimates from the full cohort study. We present methodological considerations in a matched NCC design and analysis, which include the choice of match algorithms, analysis methods to evaluate the association of exposures of interest with outcomes, and consideration of overmatching. Methods: Matched, NCC design within a longitudinal observational prospective cohort study in the setting of two academic hospitals. Study participants are patients aged over 70 years who underwent scheduled major non-cardiac surgery. The primary outcome was postoperative delirium from in-hospital interviews and medical record review. The main exposure was IL-6 concentration (pg/ml) from blood sampled at three time points before delirium occurred. We used nonparametric signed ranked test to test for the median of the paired differences. We used conditional logistic regression to model the risk of IL-6 on delirium incidence. Simulation was used to generate a sample of cohort data on which unconditional multivariable logistic regression was used, and the results were compared to those of the conditional logistic regression. Partial R-square was used to assess the level of overmatching. Results: We found that the optimal match algorithm yielded more matched pairs than the greedy algorithm. The choice of analytic strategy—whether to consider measured cytokine levels as the predictor or outcome-- yielded inferences that have different clinical interpretations but similar levels of statistical significance. Estimation results from NCC design using conditional logistic regression, and from simulated cohort design using unconditional logistic regression, were similar. We found minimal evidence for overmatching. Conclusions: Using a matched NCC approach introduces methodological challenges into the study design and data analysis. Nonetheless, with careful selection of the match algorithm, match factors, and analysis methods, this design is cost effective and, for our study, yields estimates that are similar to those from a prospective cohort study design.

Patients with dementia due to Alzheimer’s disease (AD) have increased risk of developing delirium. This study investigated the relationship between a magnetic resonance imaging (MRI)-derived biomarker associated with preclinical AD and postoperative delirium. Participants were older adults (≥70 years) without dementia who underwent preoperative MRI and elective surgery. Delirium incidence and severity were evaluated daily during hospitalization. Cortical thickness was averaged across a published set of a priori brain regions to derive a measure known as the “AD signature.” Logistic and linear regression was used, respectively, to test whether the AD signature was associated with delirium incidence in the entire sample (N=145) or with the severity of delirium among those who developed delirium (N=32). Thinner cortex in the AD signature did not predict incidence of delirium (odds ratio=1.15, p=.38), but was associated with greater delirium severity among those who developed delirium (b=−1.2, p=.014). These results suggest that thinner cortices, perhaps reflecting underlying neurodegeneration due to preclinical AD, may serve as a vulnerability factor that increases severity once delirium occurs.

This narrative review examines serum biomarkers for the diagnosis and monitoring of delirium. Serum biomarkers for delirium fall into three major groups: 1) those that are present or elevated prior to disease onset—risk markers, 2) those that rise with onset and fall with recovery—disease markers, and 3) those that rise in proportion to the consequences of disease—end products. As risk markers, we examine serum chemistries and genetic risk markers. As disease markers, we examine serum anticholinergic activity, amino acids, melatonin, cytokines, cortisol, and gene expression. As end products of delirium, we examine markers of neuronal injury. Finally, we discuss methodological and biostatistical considerations for future biomarker studies. Identifying accurate biomarkers for delirium may shed further light into its pathophysiology and on the interrelationship between delirium and dementia.

Understanding of delirium pathogenesis remains limited despite improved diagnosis, and elucidation of risk factors and prognosis. Major advances in neuroimaging offer the possibility of probing the mechanisms and networks involved in delirium and hence improving understanding of this often devastating syndrome. This review describes the current literature of imaging studies in delirium and related conditions, introduces some of the newer capabilities of neuroimaging with magnetic resonance imaging, positron emission tomography, and single photon emission computed tomography, and discusses how these techniques may be applied to the study of delirium. Despite considerable challenges in patient recruitment, study design, intersubject variability, and scanner and contrast agent availability, imaging offers great potential for the identification and clarification of pathogenic mechanisms of delirium and its long-term sequelae.

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.

INTRODUCTION Since the relationship between delirium and long-term cognitive decline has not been well-explored, we evaluated this association in a prospective study.

METHODS SAGES is an on-going study involving 560 adults age 70+ without dementia scheduled for major surgery. Delirium was assessed daily in the postoperative period using the Confusion Assessment Method. General Cognitive Performance (GCP) and the Informant Questionnaire for Cognitive Decline in the Elderly (IQCODE) were assessed preoperatively then repeatedly out to 36 months.

RESULTS On average, patients with post-operative delirium had significantly lower preoperative cognitive performance, greater immediate (1 month) impairment, equivalent recovery at 2 months, and significantly greater long-term cognitive decline relative to the non-delirium group. Proxy reports corroborated the clinical significance of the long-term cognitive decline in delirious patients.

DISCUSSION Cognitive decline following surgery is biphasic and accelerated among persons with delirium. The pace of long-term decline is similar to that seen with Mild Cognitive Impairment.