Contributed by Zachary Kunicki, PhD, Assistant Professor of Psychiatry and Human Behavior, Warren Alpert Medical School of Brown University, Providence, RI, USA; Richard Jones, PhD, Professor of Psychiatry and Human Behavior and Neurology, Warren Alpert Medical School of Brown University, Providence, RI, USA; and Sharon Inouye, MD MPH, Milton and Shirley F. Levy Family Chair and Professor of Medicine, Harvard Medical School and Beth Israel Deaconess Medical Center, Boston, MA, USA
Research question: Is postoperative delirium associated with rates of cognitive aging?
Delirium is a serious condition that frequently affects older adults after surgery.1 There is growing evidence linking delirium to long-term cognitive decline2,3 and dementia,4-7 indicating the need for a better understanding of the relationship between these conditions.
Previous research using the Successful Aging after Elective Surgery (SAGES) cohort,14 found that patients with postoperative delirium had lower preoperative cognitive performance, greater immediate impairment, and greater long-term cognitive decline up to 36 months.15 In this study, we further examine SAGES to evaluate the long-term cognitive trajectory up to 72 months (6 years) following postoperative delirium. Our hypothesis was that delirium would be associated with a faster pace of cognitive decline up to 72 months.
Participants in this study were N = 560 older adults having major elective surgery with an anticipated length of stay of 3 or more days. We assessed participants for delirium preoperatively and daily postoperatively. Prior to surgery, and at 1, 2, 6, 12, 18, 24, 30, 36, 48, 60, and 72 months after surgery, participants were given a neurocognitive battery of 11 neuropsychological tests. These tests were combined into a single composite score for analysis called the GCP (general cognitive performance), with a population mean of 50 and standard deviation of 10 among community dwelling older adults aged 70 and older.16,17 Over 72 months, the study completed over 13,000 interviews with either patients or a proxy for the patient.
One of the challenges we faced was that change in cognition differed qualitatively during different time periods in relation to surgery. Therefore, our model decomposed change over time into distinct components that reflected different (and sometimes overlapping) periods: (1) acute period (baseline to 1-month); (2) a post-acute period (1- to 2-months); (3) an intermediate period (from 2-months to 24- to 30-months); and (4) a long-term period (from baseline to 72-months). The long-term period effect happened “in the background” during the acute, post-acute, and intermediate periods and became the only aspect of change being modeled after 30-months of follow-up.
This model showed the best fit to the data after comparing eight different models, including the previous cognitive change model to 36 months in the SAGES cohort.15 Delirium was included as an intermediate outcome, dependent upon baseline covariables and the pre-operative GCP. We controlled for baseline covariables of age, gender, non-White race, education, Charlson score, depressive symptoms, proxy-based cognitive performance, impairment in instrumental activities of daily living, and surgery type (orthopedic, vascular, or gastrointestinal).
We found that the baseline GCP was lower in the delirium group (M = 55.7) compared to the non-delirium group (M = 58.3), and this difference was significant (Estimate [Est.] = 2.46, Standard Error [SE]) = 0.59, p < .001). In the acute period, delirium was associated with greater decline in GCP (Est. = -1.6) compared to the decline in the non-delirium group (Est. = 0.5). This acute period difference was also significant, Est. = -1.2, SE = 0.3, p < .001.
In the post-acute period, delirium was associated with greater recovery of GCP (Est. = 2.2) compared to the non-delirium group (Est. = 1.1), which was also significant (Est. = 1.1, SE = 0.3, p < .001). The intermediate period was a period of little change in both groups, and no difference was found between the groups (p = .82). In the long-term cognitive decline period, extending from baseline to 72 months, the pace of decline was -1.0 GCP units per year in the non-delirium group, and -1.4 GCP units per in year in the delirium group. This difference was significant, Est. = -0.40, SE = 0.2, p = .01.
In this 72-month prospective study using the SAGES cohort, we found postoperative delirium is associated with faster cognitive decline. The group that developed delirium showed a 40% faster rate of cognitive decline, which is similar to the rate of decline seen in persons with at least one ApoE-ε4 allele – a known major risk factor for Alzheimer’s disease.18
These results support one of two major hypotheses. Either delirium is itself a risk factor for rapid cognitive decline, or delirium is a marker of those at risk of faster cognitive decline, possibly reflecting greater brain vulnerability. Future studies will be needed to clarify whether either or both of these hypotheses holds true. Our results highlight the importance of continuing to study delirium as an important and potentially preventable target for interventions to preserve brain health in older adults.
- Inouye SK, Westendorp RGJ, Saczynski JS. Delirium in elderly people. The Lancet. 2014;383(9920):911-922. doi: 10.1016/S0140-6736(13)60688-1
- Fong TG, Davis D, Growdon ME, Albuquerque A, Inouye SK. The interface between delirium and dementia in elderly adults. The Lancet Neurology. 2015;14(8):823-832. doi: 10.1016/S1474-4422(15)00101-5
- Richardson SJ, Davis DHJ, Stephan BCM, et al. Recurrent delirium over 12 months predicts dementia: results of the Delirium and Cognitive Impact in Dementia (DECIDE) study. Age and Ageing. 2020;50(3):914-920. doi: 10.1093/ageing/afaa244
- Witlox J, Eurelings LS, de Jonghe JF, Kalisvaart KJ, Eikelenboom P, Van Gool WA. Delirium in elderly patients and the risk of postdischarge mortality, institutionalization, and dementia: a meta-analysis. JAMA. 2010;304(4):443-451. doi: 10.1001/jama.2010.1013
- Goldberg TE, Chen C, Wang Y, et al. Association of Delirium With Long-term Cognitive Decline: A Meta-analysis. JAMA Neurology. 2020;77(11):1373-1381. doi: 10.1001/jamaneurol.2020.2273
- Khachaturian AS, Hayden KM, Devlin JW, et al. International drive to illuminate delirium: A developing public health blueprint for action. Alzheimer’s Dement. 2020;16(5):711-725. doi: 10.1002/alz.12075
- Davis DH, Muniz Terrera G, Keage H, et al. Delirium is a strong risk factor for dementia in the oldest-old: a population-based cohort study. Brain. 2012;135(Pt 9):2809-2816. doi: 10.1093/brain/aws190
- Fong TG, Vasunilashorn SM, Libermann T, Marcantonio ER, Inouye SK. Delirium and Alzheimer disease: A proposed model for shared pathophysiology. Int J Geriatr Psychiatry. 2019;34(6):781-789. doi: 10.1002/gps.5088
- Casey CP, Lindroth H, Mohanty R, et al. Postoperative delirium is associated with increased plasma neurofilament light. Brain. 2020;143(1):47-54. doi: 10.1093/brain/awz354
- Fong TG, Vasunilashorn SM, Ngo L, et al. Association of Plasma Neurofilament Light with Postoperative Delirium. Annals of Neurology. 2020;88(5):984-994. doi: 10.1002/ana.25889
- Halaas NB, Blennow K, Idland AV, et al. Neurofilament Light in Serum and Cerebrospinal Fluid of Hip Fracture Patients with Delirium. Dementia and geriatric cognitive disorders. 2018;46(5-6):346-357. doi: 10.1159/000494754
- Vasunilashorn SM, Dillon ST, Chan NY, et al. Proteome-Wide Analysis Using SOMAscan Identifies and Validates Chitinase-3-Like Protein 1 as a Risk and Disease Marker of Delirium Among Older Adults Undergoing Major Elective Surgery. The Journals of Gerontology: Series A. 2021;77(3):484-493. doi: 10.1093/gerona/glaa326
- Vasunilashorn SM, Ngo LH, Dillon ST, et al. Plasma and cerebrospinal fluid inflammation and the blood-brain barrier in older surgical patients: the Role of Inflammation after Surgery for Elders (RISE) study. Journal of Neuroinflammation. 2021;18(1):103. doi: 10.1186/s12974-021-02145-8
- Schmitt EM, Marcantonio ER, Alsop DC, et al. Novel Risk Markers and Long-Term Outcomes of Delirium: The Successful Aging after Elective Surgery (SAGES) Study Design and Methods. Journal of the American Medical Directors Association. 2012;13(9):818.e811-818.e810. doi: 10.1016/j.jamda.2012.08.004
- Inouye SK, Marcantonio ER, Kosar CM, et al. The short-term and long-term relationship between delirium and cognitive trajectory in older surgical patients. Alzheimer’s & Dementia. 2016;12(7):766-775. doi: 10.1016/j.jalz.2016.03.005
- Jones RN, Rudolph JL, Inouye SK, et al. Development of a unidimensional composite measure of neuropsychological functioning in older cardiac surgery patients with good measurement precision. Journal of Clinical and Experimental Neuropsychology. 2010;32(10):1041-1049. doi: 10.1080/13803391003662728
- Gross AL, Jones RN, Fong TG, Tommet D, Inouye SK. Calibration and Validation of an Innovative Approach for Estimating General Cognitive Performance. Neuroepidemiology. 2014;42(3):144-153. doi: 10.1159/000357647
- Hofer SM, Christensen H, Mackinnon AJ, et al. Change in cognitive functioning associated with ApoE genotype in a community sample of older adults. Psychol Aging. 2002;17:194-208. doi: 10.1037/0882-79126.96.36.199
Kunicki, Zachary; Jones, Richard; and Inouye, Sharon. The Trajectory of Cognitive Aging after Experiencing Postoperative Delirium, Network for Investigation of Delirium: Unifying Scientists (NIDUS); June, 2023, Available at: https://deliriumnetwork.org/trajectory-of-cognitive-aging-after-postoperative-delirium/ (accessed today’s date)