Cohort Study of Risk Factors for Postoperative Cognitive Decline

Summary

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Adults 65 years and older represent the fastest-growing age group in the United States, and account for one third of all surgical patients. These older adults are at the highest risk for deleterious postoperative neurocognitive outcomes. Postoperative cognitive dysfunction (POCD) occurs in up to 40%...

Adults 65 years and older represent the fastest-growing age group in the United States, and account for one third of all surgical patients. These older adults are at the highest risk for deleterious postoperative neurocognitive outcomes. Postoperative cognitive dysfunction (POCD) occurs in up to 40% of older adults after major non-cardiac surgery. POCD is a syndrome characterized by a decrease in performance on neuropsychological test battery from before to after surgery. Neuropsychological testing for POCD typically spans cognitive domains including memory, attention, concentration, and/or executive function. There is an increasing body of literature suggesting that exposure to surgery and anesthesia increases the risk of Alzheimer's disease (AD). Surgery and anesthesia enhance neuropathologic changes known to underlie AD including amyloid beta accumulation and aggregation, neuroinflammation, increased levels of tau and tau phosphorylation, and memory decline. However, not everyone with a history of surgery and anesthesia develops POCD, suggesting biological risk factors are involved. It is well established that the gene most strongly associated with AD is apolipoprotein E (APOE), with the APOE4 allele conferring an increased risk of AD in a sex-dependent manner. Our recent retrospective longitudinal cohort study found that an APOE4 allele was associated with an accelerated rate of cognitive and functional status decline following surgery. Another gene polymorphism of interest is the PLA2-allele of the gene encoding platelet glycoprotein IIIa. A recent investigation of cardiac surgery patients found that PLA2-allele was present in a significantly higher percentage among subjects that had POCD when compared to those without cognitive decline. Although the mechanisms of POCD remain unclear, our preliminary data suggest that the PLA2 and APOE4 alleles contribute to POCD in older adults in a sex-dependent manner. Presently, the role of either genetic factors or biological sex in the development of POCD is unknown. There is, therefore, a critical need to determine which individuals are at high-risk for developing POCD by virtue of biological sex or genetic predisposition. The knowledge gained in the proposed research has the potential to shed light on mechanistic pathways, a necessary next step in order to ultimately identify therapeutic strategies. Innovation Sex Differences: Though half of the US surgical population is comprised of women, basic and clinical perioperative research studies have either excluded women or have matched cases-controls by sex to avoid confounding. We will be the first to determine effects of sex in POCD in a prospective, clinical cohort. Multi-disciplinary Approach: One barrier to progress in this field is the lack of a multi-disciplinary, collaborative approach. Few perioperative physicians are well versed in aging/dementia research or neuropsychological testing. This proposal describes collaboration among experts in neurology, anesthesiology, geriatrics, dementia, and perioperative medicine. Study population: Because age and pre-existing cognitive impairment are the most well known risk factors for POCD, we will enrich our study population by including only subjects ?65 years. Unlike prior studies, we will not exclude participants with mild cognitive impairment. Study Outcomes: We will include functional status outcomes (i.e. IADLs), which are absent from most POCD studies. Genetic variables: This will be the first study to investigate the role of PLA2 in POCD following non-cardiac surgery. Preliminary Studies APOE4 increases the risk of postoperative cognitive dysfunction: We performed a retrospective cohort analysis of several Oregon Alzheimer's disease Center (OADC) longitudinal cohort studies: the Oregon Brain Aging Study (OBAS), the Intelligent Systems for Assessing Aging Changes (ISAAC),14 the Klamath Exceptional Aging project (KEAP), and the African American Dementia and Aging Project (AADAPt). We compared the rate of change over time in various cognitive and functional status measures. Out of a total of 1,052 subjects, 247 subjects had surgery/anesthesia after study enrollment. Subjects underwent cognitive and functional test batteries once/year. The mean follow-up after study enrollment was 7 years (SD=4.6). After controlling for age, level of education, and Cumulative Illness Rating Scale (CIRS) score, we found that the surgical group experienced a more rapid rate of deterioration compared with the nonsurgical group in multiple cognitive and functional measures. Furthermore, when compared with APOE- subjects, subjects with an APOE4 allele had an accelerated rate of cognitive and functional decline after surgical exposure. Older men with APOE4 are at higher risk of postoperative cognitive dysfunction: Next, we divided the above cohort by sex and repeated the analyses comparing men and women who were exposed to surgery/anesthesia. When controlling for the presence of an APOE4 allele, we did not find any sex differences in cognitive outcomes after surgery. (Data not shown) However, when we compared men vs. women APOE4 carriers, we found that men with at least one copy of the APOE4 allele who were exposed to surgery/anesthesia had a more rapid rate of decline in several measures of cognition.

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